Fcps Paediatrics

Long/Short Cases
Paediatrics
Dr Muhammad Qasim Memon
DR MUHAMMAD QASIM MEMON

SHORT/LONG CASES FCPS PAEDIATRICS
INDEX
S.No: Topics Page
1. Chronic Liver Disease 04

2. TOF 43
3. Aortic Stenosis 52
4. Rheumatic Fever/RHD/IE 55
5. VSD 84
6. PDA 85
7. Addison Disease 87
8. Ambiguous Genitalia 108
9. Diabetes Mellitus 114
10. Goitre 148
11. Short Stature 153
12. Thallessemia 156
13. Haemophilia 173
14. ITP 190
15. Aplastic Anaemia 195
16. Chronic Diarrhoa 199
17. CKD 214
18. AFP 247
19. Ataxia 279
20. Cerebral Palsy 286
21. Chorea 295
22. Degenerative Brain Disorders 298
23. DMD 317
24. Stroke/CVA 327
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25. Meningomyelocele 343
26. Obesity 348
27. Bronchiectasis 356
. | Dr Muhammad Qasim Memon

S.No: Topics Page
28. JIA 378

29. SLE 397
30. JIA Short Case 414
31. Down syndrome 418
32. Lukemia 426

FCPS-II PAEDIATRICS
SHORT/LONG CASES
CLD (LONG/SHORT CASE):
Presenting complaints of patient can be:
 Jaundice
 Abdominal distension
 Hematemesis
 Malena
 Gum bleed/ patechae
 Encephalopathy.
 Pallor
 Fever / PUO.
JAUNDICE: --(jaundice for last …days , gradual in onset progressively increasing with no
aggravating/relieving factors along with dark colour stool and yellow urine , it was not associated
with hx of pallor, fever, respiratory distress, abdominal distention, pain, vomting, hematemesis,
malena, bruise, bleed from any site , fits , altered sensorium, unconsciousness , joint pain, rash)
 Duration.
 Onset.
 Progression.
 Urine /stool colour.
 Increasing or decreasing factors.
 Associated hx of: pallor , respiratory distress, abdominal pain, distention, vomiting, hematemesis,
malena, bruise / bleed any site, fever, fits unconsciousness, joint pain, rash.
ABDOMINAL DISTENSION:
 Duration .
 Onset.
 Progression .
 Isolated/generalized body swelling.
 Increasing/ decreasing factors associated hx of: respiratory distress, urinary complaint, abdominal
pain , vomiting, hematemesis, malena, bruises, petechae, fever, joint pain, rash.
4
HEMATEMESIS:
 Duration.

 Onset.
 Frequency.
 amount , colour of blood.
 Progression.
 Precipitating factors:
 fever, cough.
 Constipation.
 NSAIDs.
 Associated hx of malena: jaundice, abdominal distension, bruise, rash, petechae, joint pain altered
sensorium.
MALENA: (bleeding per rectum for last ----days , mixed with stools, …. Times, offensive ,
…….coulur, not associated with tenesmus, constipation, fever, Any drug intake before, abdominal
distention, bruise.
 Duration.
 Onset.
 Frequency.
 Progression.
 Offensive/ not
 Tenesmus /not.
 Associated ppt factors like: constipation, fever, NSAIDs, cough.
GUM BLEED:
 Duration.
 Onset.
 Amount.
 Frequency.
 hx of trauma/spontaneous.
 Petechae, bruise, bleeding from other site.
 hematemsis, malena, pallor.
 Hx of joint pain,
 Abdominal distension.
 Lymphadenopathy.
 Vomiting.
 Abdominal pain.
 Altered sensorium.
Encephalopathy:
5
 Duration.
 Onset
 Fits.

 Severity of encephalopathy,
 Altered pattern of sleep & arousal,
 Altered conscious.
 Flapping tremors.
 Predisposing factors:
 Jaundice.
 Constipation.
 Bleeding.
 Hematemsis.
 Malena.
 Electrolyte imbalance—(hypokalemia)
 Fever.
 Use of sedative medications.
 Associated symptoms:
 Hematemsis.
 Malena.
 Bruise.
 Pallor.
 N.G bleed.
 Constipation.
QUESTIONS REGARDING DIFFERATIALS:
 POST INFECTIOUS:
 Prev. Blood trnx, IM/ IV injection.
 Family hx of hep B& C., Jaundice.
 Hx of jaundice in mother during pregnancy.
 Razor change (barber), ear piercing.
 Prolong Jaundice in newborn life.
 FOR WILSON:
 Poor school performance.
 Detoriation of mental activites, labile emotionally.
 Abnormal movements.
 Arthritis
 Polyurea/polydypsia—(fanconi association)
 FOR ALPHA 1 ANTITRYSIN & CF.
 Recurrent chest infections--/IN FAMILY HX?
 Malabsorption.
 FOR AUTOIMMUNE:
 Rash
6
 Joint pain/ swelling.
 Oral ulcer
 Hair loss.
 Thyroid swelling.
 FOR IBD HEPATITIS: (child > 5 yr , well grown)

 Blood diarrhea.
 Tenesmus.
 Joint swellin & pain
 Abdominal pain.
 Sinus / fistula.
 growth
 DRUG hx.
 Hx REGARDING TREATMENT & COMPLICATIONS OF TRX:
 What treatment has been offered.
 i.v fluids, FFP, injections.
 PCV transfusion.
 Endoscopic intervension.
 Any specific investigations.
 Liver bx.
 Paracentesis.
 24 hr urine test from outside like AKU.
 Sib screen.
 Slit Eye examination.
 Progression of disease in ward.
 Parental knowledge.
 Hepatic Transplantation knowledge.
 Details of followup.
 Monitoring
 S/E of drugs.
 Vistamine complications—(abnormal test, diarhea—(dysgenesia), rash, oral ulcer
(SLE) body swelling (NEPHROTIC)petechae bruise –(aplastic).
 Zinc acetate.
 Dietry restrictions.
 QUESTIONS REGARDING COMPLICATIONS OF DS:

 FTT.
 UGI bleed –(hematemsis, malena).
 Swelling/ edema.
 Bruise .
 Vitamin deffeciencies:
 A: Night blindness.
 D:Tetany.
 E: Ataxia, numbness, frequent falls, burning , tingling.
 K: petechae, bruise, bleed.
 Malabsorptive stools.
 Hepatorenal syndrome  oligoure, body swelling.
 Pruritis .
 Encephalopathy / unconscious / seizures.
 Pallor.
 Family hx.
 Birth hx
 Developmental hx.
 Vaccination hx.
7
 Dietry hx.
 Parents concersn
 Disease impact---schooling, sibs, parents.
 Socioeconomic status.

EXAMINATION:
Check list for examination of CLD pt.
 Nutritional status.
 Confirm jaundice in sunlight.
 Sequential and smooth approach.
 Thyroid examination.
 Joint examination.
 Asterixis.
 Ask to write something.
 Abnormal movemt/ behavior.
 Gait
Same protocol of examination ht , wt.
GPE  abdominal  chest  CVS Neurological examination Musculoskeletal.
LONG CASE PROTOTYPE:
My patient ........ 14 yr of age admitted 2 days back thru ER CH&ICH with PC of fever pain in abdomen
for last 8 days. And body swelling for last 6 days.
According to pts mother child was in usual state of health 8 days back then she had pain in abdomen
in both hypochochondrium region ,moderate in severity not radiated nor reffered to any side, with
no aggravating factors relieved by taking anelgesics associated with hx of cough and sorethroat,
while no hx of urinary complaint, glandular swelling, loose motion and vomiting.
Hx of ,fever undocumented with diurnal variation more At night time relieved by taking medication
but no associated with rigors, chills, cough flu, night sweating,Urinary complaint, sorethroat, skin
infection,ear discharge, fits.loose motions,vomiting ,headache.
progressive increasing body swelling started from feet to face with no specific timing relation,
with/without aggravating or relieving factors, no associated hx of urinary complaint in form of
oligourea, dysurea, respiratory distress.
For these compliant they went to

.............:....................................................................................................................................................
................................................................................ 8

No associated hx of:
rash, petechae, bruise,gum bleed ,ear prick , injections any blood transfusion before , fits,altered
sensorium, ,sleep disturbance, hematenesis, malena , bodys welling , palpitation, arhalgia, oral ulcer,
alopecia,photosensitivity, polyureas polydypsea, repeated chest infections (CF), pruritis, tenesmus ,
visual distrubance, tetany, gait disturbance, Or dystonia, and deterioration in school performance..
No hx suggestive of Complications of treatment in form of ………(SLE, Nephrotic syndrome, good

pasture syndrome, SJS, as she is taking vistamine).
No/ hx of liver biopsy. Paracentesis. Endoscopic intervention, slit lamp examination, 24 hour urinary
Cu level by pencillamine challenge.
DISCUSSION:
CLD DEFINATION :
Duration of liver disease ( clinically /biochemically) >3-6 month or evidence of severe liver disease or
physical stigmata of of CLD (clubbing, short stature, spider telangectasia, hepatosplenomegally)
CIRHOSIS –chronic irrversible parenchymal disease of liver resulting from necrosis of liver cells
followed by fibrosis and nodule formation , architecture is diffusely lost , and interfere with liver
blood flow lead to portal HTN.
Cirrhosis histologicaly definition:
1. Diffuse hepatocyte injury & regeneration

2. Increase in CT fibrosis
3. Disorganization of lobular and vascular architecture.
Types
Micro-nodular -- <3 mm –Wilson disease, metabolic.
Macronodular -- >3 mm –hepatitis B,C, drugs.
Post necrotic –wilson, autoimmune, hepatitis, galactosemia,
Biliary cirrhosis –biliary atresia, choledocal cyst, C.F.

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Viral hepatitis:
 This disorder is caused by at least five pathogenic hepatotropic viruses recognized to date: hepatitis A,
B, C, D, and E –new is G
 Other viruses usually as one component of a multisystem disease:
 herpes simplex virus (HSV),
 cytomegalovirus (CMV).
 Epstein-Barr virus (EBV).
 varicella-zoster virus.
 HIV, rubella, adenoviruses, enteroviruses, parvovirus B19, and arboviruses.
 Hepatitis G virus (GBV)
 transfusion transmissible virus (TTV)
Features of the Hepatotropic Viruses
HAV HBV HCV HDV HEV HGV[*] TTV[**]
Virology RNA DNA RNA RNA RNA RNA DNA
Incubation 15– 60– 14– 21– 21– ? ?

(days) 19 180 160 42 63
Transmission
Parenteral Rare Yes Yes Yes No Yes Yes
Fecal-oral Yes No No No Yes Possible Possible
Sexual No Yes Yes Yes No Yes Possible
Perinatal No Yes Rare Yes No Yes Yes
Chronic No Yes Yes Yes No Yes Yes

infection
Fulminant Rare Yes Rare Yes Yes No No

disease
COMMON BIOCHEMICAL PROFILES IN THE ACUTE INFECTIOUS PHASE.
cytopathic injury to the hepatocytesALT/AST. 10
 little prognostic value. bilirubin level normalize first , AST/ALT levels

 Rapidly falling aminotransferase levels +  PT & Bilipredict a poor outcome, this combination
of findings usually indicates that massive hepatic injury has occurred.

Cholestasis:,
 elevated serum conjugated bilirubin levels, results from abnormal biliary flow at the canalicular
and cellular level due to hepatocyte damage and inflammatory mediators.
 all following mark cholestasis:
 Elevation of serum alkaline phosphatase (ALP).
 5′-nucleotidase.
 γ-glutamyl transpeptidase (GGT).
 Urobilinogen.
altered synthetic functionThe most important marker of liver injury.
 Monitoring of synthetic function should be the main focus in clinical follow-up to define the
acuity of the disease.
 In the acute phase, the degree of liver synthetic dysfunction guides treatment and helps to
establish intervention criteria.
 Abnormal liver synthetic function is a marker of liver failure and is an indication for prompt
referral to a transplant center.
 Synthetic dysfunction is reflected by:
 Abnormal protein synthesis
 prolonged prothrombin time.
 High INR.
 Low serum albumin levels.
 Hypoglycemia.
 Lactic acidosis.
 Hyperammonemia
 clinical signs, such as poor clearance of medications dependant on liver function
and altered sensorium with increased deep tendon reflexes (hepatic
encephalopathy.
HEPATITIS A
 Hepatitis A virus (HAV) is the most prevalent of the five viruses in the United States and
worldwide.
 This virus is also respons ible for most forms of acute and benign hepatitis; although fulminant
hepatic failure can occur, it is rare and occurs more often in adults than in children.
 RNA virus, a member of the picornavirus family.
 most prevalent in the developing countries
TRANSMISSION: HAV is highly contagious. through the fecal-oral route. Parenteral
transmission occurs rarely; no other form of transmission is recognized.
INCUBATION PERIOD: mean for HAV is ≈3 wk
PERIOD OF INFECTIVITY:
Fecal excretion of the virus starts late in the incubation period, reaches its peak just
before the onset of symptoms, and resolves by 2 wk after the onset of jaundice in 11
older subjects. The duration of viral excretion is prolonged in infants. The patient is
therefore contagious before clinical symptoms are apparent, and remains so until viral
shedding stops.

CLINICAL MANIFESTATIONS.
 acute hepatitis only. Often, this is an anicteric illness-DD-acute gastroenteritis.

 more likely to be symptomatic in older adolescents or adults, in patients with underlying liver
disorders, and in those who are immunocompromised.
 It is characteristically an acute febrile illness with an abrupt onset of anorexia, nausea, malaise,
vomiting, and jaundice. The typical duration of illness is 7–14 days
 Regional lymph nodes and the spleen may be enlarged..
COMPLICATIONS:
 Hypoplastic/ aplastic anemia.

 Small intestinal ulceration.
 Acute pancreatitis and myocarditis—rarely.
nephritis, arthritis, vasculitis, and cryoglobulinemia can result from circulating immune complexes.
Acute liver failure (ALF)  rare but not infrequent complication of HAV. Those at risk for this
complication are adults, but also patients with underlying liver disorders or those who are
immunocompromised.
In endemic areas of the world, HAV constitutes up to 40% of all cases of pediatric ALF.
prolonged cholestatic syndrome that waxes and wanes over multiple months. Pruritus and fat
malabsorption are problematic and require symptomatic support with antipruritic medications and
fat-soluble vitamins. This syndrome occurs in the absence of any liver synthetic dysfunction and
resolves with no sequelae.
DIAGNOSIS.
 LFTs Rises in ALT, AST, bilirubin, ALP, 5′-nucleotidase, and GGT are almost universally found and
do not help to differentiate the cause of hepatitis
 anti-HAV - Ig M.
 Anti-HAV is detectable when the symptoms are clinically apparent, and remains
positive for 4–6 mo after the acute infection.
anti-HAV (IgG) is usually detected within 8 wk of symptoms onset, and is measured as

part of a total anti-HAV in the serumconferring long-term protection.
 Stool for HAVThe virus is excreted in stools from 2 wk before to 1 wk after the onset of illness.
TREATMENT.
 There is no specific treatment for hepatitis A.

 Supportive treatment: hydration ,antipruritic agents and fat-soluble vitamins Serial monitoring for 12
signs of acute liver failure

PREVENTION.
 Patients infected with HAV are contagious for 2 wk before and about 7 days after the onset of
jaundice and should be excluded from school, child care, or work during this period.
 Careful handwashing is necessary, particularly after changing diapers and before preparing or
serving food.
 VACCINE.
 The availability of two inactivated, highly immunogenic, and safe HAV vaccines
has had a major impact on the prevention of HAV infection.
 Both vaccines are approved for children >1 yr of age.
 They are administered intramuscularly in a two-dose schedule, with the 2nd
dose given 6–12 mo after the 1st dose.
 Seroconversion rates in children exceed 90% after an initial dose and approach
100% after the 2nd dose.
 For persons >1 yr of age, vaccine is preferable to immunoglobulin for pre-
exposure prophylaxis .
 Greater consideration is being give
(1) children >1 yr of age in defined and circumscribed communities with endemic
rates or periodic outbreaks of HAV infection.
(2) patients with chronic liver disease.
(3) individuals at occupational risk of exposure.
(4) persons with clotting factors and immune disorders.
The use of Ig >2 wk after exposure is not indicated. Ig is not routinely

recommended for sporadic nonhousehold exposure (e.g., protection of hospital
personnel or schoolmates).
POSTEXPOSURE PROPHYLAXIS
≤2 wk since exposure Ig 0.02 mL/kg and HAV vaccine if >1 yr and

future exposure likely
>2 wk since exposure No prophylaxis. Consider HAV vaccine if >1

yr and future exposure likely
HEPATITIS B
HBV has 8 genotypes (A-H).
 A is pandemic.
 B and C are prevalent in Asia.
 D is seen in Southern Europe.
 E in Africa.
 F in the United States.
Incubation period ranges from 45 to 160 days, with a mean of ~120 days. 13
 HBV is present in high concentrations in blood, serum, and serous exudates and in moderate
concentration in saliva, vaginal fluid, and semen.

Transmission:
 blood exposure.
 sexual contact.
Risk factors:
 intravenous drugs.
 blood products.
 Acupuncture/tattoos.
 sexual contact.
 institutional care.
 Intimate contact with carriers.
 No risk factors are identified in ∼40% of cases.
HBV is not thought to be transmitted via indirect exposure such as sharing toys.
 In children, the most important risk factor for acquisition of HBV remains perinatal exposure to an
HBsAg-positive mother.
 The risk of transmission is greatest if the mother is also HBeAg positive; up to 90% of these infants
become chronically infected if untreated.
 In most cases, serologic markers of infection and antigenemia appear 1-3 mo after birth, suggesting
that transmission occurred at the time of delivery.
 Virus contained in amniotic fluid or in maternal feces or blood may be the source. Immunoprophylaxis
of those infants is very effective in preventing infection and protects >95% of neonates
 HBsAg is inconsistently recovered in human milk of infected mothers.

 Breast-feeding of nonimmunized infants by infected mothers does not confer a greater risk of
hepatitis than does formula feeding
 Rate of vertical transmission is 3-5%.
 The risk of developing chronic HBV infection, defined as being positive for HBsAg for >6 mo, is
inversely related to age of acquisition.
 chronic infection is 90% in children <1 yr; the risk is 30% for those 1-5 yr and 2% for adults. Chronic
infection is associated with the development of chronic liver disease and hepatocellular carcinoma.
The carcinoma risk is independent of the presence of cirrhosis and was the most prevalent cancer-
related death in young adults in Asia where HBV was endemic.

PATHOGENESIS:
 predominantly non-cytopathogenic virus that causes injury mostly by immune-mediated processes.

 The severity of hepatocyte injury reflects the degree of the immune response, with the most complete
immune response being associated with the greatest likelihood of viral clearance but also the most
severe injury to hepatocytes.
 The first step in the process of acute hepatitis is infection of hepatocytes by HBV, resulting in 14
expression of viral antigens on the cell surface.
 The most important of these viral antigens may be the nucleocapsid antigens—( HBcAg and HBeAg).
These antigens, in combination with class I major histocompatibility (MHC) proteins, make the cell a
target for cytotoxic T-cell lysis.

 The mechanism for development of chronic hepatitis is less well understood. To permit hepatocytes
to continue to be infected, the core protein or MHC class I protein might not be recognized, the
cytotoxic lymphocytes might not be activated, or some other, yet unknown mechanism might
interfere with destruction of hepatocytes. This tolerance phenomenon predominates in the cases
acquired perinatally, resulting in a high incidence of persistent infection in children with no or little
inflammation in the liver. Although end-stage liver disease rarely develops in those patients, the
inherent hepatocellular carcinoma risk is very high, possibly related, in part, to uncontrolled viral
replication cycles.
 ALF has been seen in infants of chronic carrier mothers who have anti-HBe or are infected with a
precore-mutant strain
 Immune-mediated mechanisms are also involved in the extrahepatic conditions that can be
associated with HBV infections. Circulating immune complexes containing HBsAg can occur in patients
who develop associated polyarteritis nodosa, membranous or membranoproliferative
glomerulonephritis, polymyalgia rheumatica, leukocytoclastic vasculitis, and Guillain-Barre syndrome
CLINICAL MANIFESTATIONS:
 Many acute cases of HBV infection in children are asymptomatic.

 Enlarged tender liver + , splenomegaly may have lymphadenopathy.
 The usual acute symptomatic episode is similar to that of HAV and HCV infections but may be
more severe and is more likely to include involvement of skin and joints
 The first biochemical evidence of HBV infection is elevation of serum ALT levels, which begin to
rise just before development of fatigue, anorexia, and malaise, which occurs about 6-7 wk after
exposure.
 The illness is preceded in a few children by a serum sickness–like prodrome marked by arthralgia
or skin lesions, including urticarial, purpuric, macular, or maculopapular rashes. Papular
acrodermatitis, the Gianotti-Crosti syndrome, can also occur.
Extrahepatic conditions associated with HBV:
 Polyarteritis.
 Glomerulonephritis.
 Aplastic anemia.
 GBS
Jaundice  in ∼25% of acutely infected patients, usually begins ∼8 wk after exposure and lasts for
∼4 wk
 In the usual course of resolving HBV infection, symptoms are present for 6-8 wk.
 Most patients do recover, but the “chronic carrier state” complicates up to 10% of cases acquired in
adulthood
Chronic HBV infection has 3 identified phases: 15
1. Immune tolerant –(mosr pts, no effective therapy at this yet developed)

2. Immune active.—active inflammation ,elvetaed LFTs and progressive fibrosis—treatment targeted at
this.

3. Inactive.—(Seroconversion happenedno fibrosis, inflammation)
Immune-tolerant phase
Spontaneous HBeAg seroconversion occurs at this stage but at low rates of 4-5% per year. It is more
common in childhood-acquired HBV rather than in vertically transmitted infections. Seroconversion
can last many years, during which significant damage to the liver can happen.
Reactivation of chronic infection has been reported in immunosuppressed children (treated with
chemotherapy, biologic immunomodulators, T-cell depleting agents), leading to an increased risk of
ALF or to rapidly progressing fibrotic liver disease.
DIAGNOSIS
Routine screening for HBV infection requires assay of ≥3 serologic markers (HBsAg, anti-HBc, anti-
HBs).
 HBsAg:
o first serologic marker of infection to appear and is found in almost all infected persons.
o rise closely coincides with the onset of symptoms.
o Persistence of HBsAg beyond 6 mo defines the chronic infection state.
 anti-HBc IgM
o During recovery from acute infection, because HBsAg levels fall before symptoms wane, IgM
antibody to HBcAg (anti-HBc IgM) might be the only marker of acute infection.
o This antibody appear in window period.
o Anti-HBc IgM rises early after the infection and remains positive for many months before
being replaced by anti-HBc IgG.
 anti-HBc IgG
o persists for years Anti-HBc is therefore a valuable serologic marker of acute HBV infection.
 Anti-HBs:
o marks serologic recovery and protection.
o Only anti-HBs is present in persons immunized with hepatitis B vaccine.
o whereas both anti-HBs and anti-HBc are detected in persons with resolved infection.
 HBeAg:
o present in active acute or chronic infection and is a marker of infectivity.
 anti-HBe
o The development of anti-HBe marks improvement and is a goal of therapy in chronically
infected patients.
Note: HBV DNA can be detected in the serum of acutely infected patients and chronic carriers. High
DNA titers are seen in patients with HBeAg, and they typically fall once anti-HBe develops.
Core antigen mutation –HbeAg in negative while HBV-DNA is posetive.
COMPLICATIONS: 16
1. ALF -- occurs more commonly with HBV than with the other hepatotropic viruses.

The risk of ALF is further increased when there is co-infection or super-infection with HDV and in an
immunosuppressed host.
Mortality due to ALF is >30%, and liver transplantation is the only effective intervention.
Supportive care aimed at sustaining patients and early referral to a liver transplantation center can be
lifesaving.
2. chronic hepatitis  which can lead to cirrhosis, end-stage liver disease complications, and primary
hepatocellular carcinoma.
3. Membranous glomerulonephritis  with deposition of complement and HBeAg in glomerular
capillaries is a rare complication of HBV infection.
Treatment
 acute HBV infection is largely supportive. Close monitoring for liver failure and extrahepatic
morbidities is key.
 chronic HBV infection is in evolution.
o No one drug currently achieves reliably complete eradication of the virus.
o Reason of not availing Rx is….The natural history of HBV chronic infection in children is
complex, and there is a lack of reliable long-term outcome data on which to base treatment
recommendation.
o Goal of treatment is to reduce viral replication as defined by undetectable HBV DNA in the
serum and development of anti-HBe.
Currently, treatment is only indicated for patients in the immune-active form of the disease, with
evidence of ongoing inflammation and fibrosis putting the child at higher risk for cirrhosis during
childhood.
TREATMENT STRATEGIES
1. Interferon-α-2b (IFN-α2b) :---------24 weeks/ S/C twice-thrice/ week.

 Immunomodulatory and antiviral effects.
 It has been used in children.
 long-term viral response rates similar to the 25% rate reported in adults.
 side effects :
 marrow suppression.
 Depression.
 retinal changes.
 autoimmune disorder.
IFN is contraindicated in decompensated cirrhosis, autoimmune hepatitis neuropsyciatric disorder,

organ transplantation.
2. Lamivudine :
 oral synthetic nucleoside analog that inhibits the viral enzyme reverse
transcriptase.
 In children >2 yr >52 wk resulted in HBeAg clearance in 34% of patients
with an ALT >2 times normal; 88% remained in remission at 1 yr. 17
 It has a good safety profile.
 Lamivudine has to be used for ≥6 mo after viral clearance,
 Use it long term if emergence of mutant viral strain like pre-core mutant.
3. Combination therapy ---above 2 –less effective but also tried.

4. Adefovir (a purine analog that inhibits viral replication).
 approved for use in children >12 yr of age  in whom a prospective 1-yr study
showed 23% seroconversion.
5. Peginterferon-α2 and several new nucleotide/nucleoside analogs (Telbivudine, Tenofevir,
and Entecavir):
 are approved for use in adults.
 They seem to have an improved efficacy and less viral resistance than IFN-α2b
or Lamivudine in the adult population.
 No data are yet available on their use in children <16 yr of age.
Good prognostic factors for treatment response are:
1. low serum HBV DNA titers.

2. HBeAg positive.
3. Active hepatic inflammation (ALT greater than twice the upper limit of normal).
4. Recently acquired disease.
Immunotolerant patients are currently not considered for treatment, although the emergence of
new treatment paradigms are promising for this large, yet hard to treat.
PREVENTION
1. Hepatitis B vaccine.
2. Hepatitis B immunoglobulin (HBIG).
Hepatitis B vaccine (recombivax HEP-B, injerex –B)
 Two recombinant DNA vaccines are available in the United States; both are highly immunogenic in
children.
 The safety profile of HBV vaccine is excellent.
 The most reported side effects are pain at the injection site (up to 29% of cases) and fever (up to 6%
of cases).
Counseling for prevention:
 Household, sexual, and needle-sharing contacts should be identified and vaccinated if they are
susceptible to HBV infection.
 Patients should be advised about the perinatal and intimate contact risk of transmission of HBV.
 HBV is not spread by breast-feeding, kissing, hugging, or sharing water or utensils.
 Children with HBV should not be excluded from school, play, child care, or work, unless they are
prone to biting.
A support group might help children to cope better with their disease. All patients positive
for HBsAg should be reported to the state or local health department, and chronicity is
diagnosed if they remain positive past 6 mo.
18

Current HBV vaccination recommendations are as follows
 For all medically stable infants weighing >2,000 g at birth and born to HBsAg-negative mothers, the
first dose of HBV vaccine should be administered before hospital discharge.
 Preterm infants weighing <2,000 g at birth and born to HBsAg-negative mothers should have their
initial dose delayed until 1 mo of age or before hospital discharge.
 To prevent perinatal transmission through improved maternal screening and immunoprophylaxis of
infants born to HbsAg-positive mothers, infants born to HBsAg-positive women should receive
vaccine at birth, 1-2 mo, and 6 mo of age (see Table 350-4). The first dose should be accompanied by
administration of 0.5 mL of HBIG as soon after delivery as possible (within 12 hr) because the
effectiveness decreases rapidly with increased time after birth. Post-vaccination testing for HBsAg
and anti-HBs should be done at 9-18 mo. If the result is positive for anti-HBs, the child is immune to
HBV. If the result is positive for HBsAg only, the parent should be counseled and the child evaluated
by a pediatric gastroenterologist. If the result is negative for both HBsAg and anti-HBs, a 2nd
complete hepatitis B vaccine series should be administered, followed by testing for anti-HBs to
determine if subsequent doses are needed.
Hepatitis B Immunoglobulin
 HBIG is indicated only for specific postexposure circumstances and provides only temporary
protection (3-6 mo).
 It plays role in preventing perinatal transmission when administered within 12 h of birth.
 RX SUMMARY OF HEPATITIS-B
 HBsAg +ve LFT  ALT  Go for HBeAg
o If HBeAg + start Rx with INF + lamivudine
o If HBeAg –ve go for HBV-PCR
 If HBV-PCR +  start Rx
 If HBV-PCR –ve  look for other causes and repeat DNA.
 If ALT is normal HBeAg +ve  wait for 6 month.
o If after 6 month ALT elevated –start Rx
o If ALT remain normal  liver bx  histology activity index >3  start Rx.
HEPATITIS C
 HCV is a single-stranded RNA virusFlaviviridae family.

 It has 6 major genotypes Genotype variation might partially explain the differences in clinical
course and response to treatment.
 Genotype 1b is the most common in United States and is the least responsive to the currently
available medications—poor prognostic
 Genotype 2 –in Pakistan –good Rx response.
Epidemiology 19
 170 million people worldwide are estimated to be infected with HCV.

 In children, seroprevalence of HCV is 0.2% in children <11 yr of age and 0.4% in children ≥11 yr of age.

Risk factors for HCV transmission:
 blood transfusion as the most common route of infection, but, with the current screening practices,
the risk of HCV transmission is now about 0.001% per unit transfused.
 Perinatal transmission—most prevalent mode in children
 Illegal drug use with exposure to blood or blood products
 Sexual transmission, especially through multiple sexual partners -- is the second most common cause
of infection.
 occupational exposure;
 Perinatal transmission occurs in up to 5% of infants born to viremic mothers. HIV co-infection and
high viremia titers (HCV RNA positive) in the mother can increase the transmission rate to 20%.
The incubation period is 7-9 wk (range, 2-24 wk).
Pathogenesis
HCV appears to cause injury primarily by cytopathic mechanisms, but immune-mediated injury can
also occur.
The cytopathic component appears to be mild, because the acute illness is typically the least severe
of all hepatotropic virus infections.
CLINICAL MANIFESTATIONS
 Acute HCV infection tends to be mild and insidious in onset .

 ALF rarely occurs.
 HCV is the most likely hepatotropic virus to cause chronic infection.
 Of affected adults, <15% clear the virus; the rest develop chronic hepatitis.
 In pediatric studies, 6-19% of children achieved spontaneous sustained clearance of the virus during a
6 yr follow-up.
ACUTE HEPATITIS C-------- <1%  FULMINANT HEPATIC FAILURE.
__________
 
20-40% 60-80%
 
ERADICATION PERSISTANT INFECTION
 
NORMAL ALT LEVEL CHRONIC HEPATITIS
20%
CIRHOSIS
 4% 20
HCC

Chronic HCV:
 clinically silent until a complication develops.

 Serum aminotransferase levels fluctuate and are sometimes normal, but histologic inflammation is
universal.
 Progression of liver fibrosis is slow over several years, unless comorbid factors are present, which can
accelerate fibrosis progression.
 About 25% of infected patients ultimately progress to cirrhosis, liver failure, and, occasionally,
primary hepatocellular carcinoma (HCC) within 20-30 yr of the acute infection.
 Although progression is rare within the pediatric age range, cirrhosis and HCC from HCV have been
reported in children.
 Chronic HCV infection can be associated with small vessel vasculitis and is a common cause of
essential mixed cryoglobulinemia.
Extrahepatic manifestations:--( predominantly seen in adults)
 cutaneous vasculitis.
 peripheral neuropathy.
 Cerebritis.
 MPG.
 Nephritic syndrome.
 Antibodies to smooth muscle, antinuclear antibodies, and low thyroid hormone levels may also be
present.
DIAGNOSIS
 LFTs
 serologic testenzyme immunoassay (EIA) to detect anti-HCV—widely used.
 False-negative results also occur because antibodies remain negative for as long as 1-3 mo
after clinical onset of illness.
 Anti-HCV is not a protective antibody and does not confer immunity; it is usually present
simultaneously with the virus.
 PCR- HCV-RNA —QUANTITATIVE commonly used.
 which permits detection of small amounts of HCV RNA in serum and tissue samples within
days of infection.
 The qualitative PCR detection is especially useful in patients with recent or perinatal
infection, hypogammaglobulinemia, or immunosuppression and is very sensitive.
 The quantitative PCR aids in identifying patients who are likely to respond to therapy and in
monitoring response to therapy.
 HCV genotype
 We do when therapy is considered.
 Genotype 1 is poorly responsive; genotypes 2 and 3 are more reliably responsive to therapy.
 LIVER BIOPSY.
 only means to assess the presence and extent of hepatic fibrosis.
 A liver biopsy is indicated only before starting any treatment and to rule out other causes of
overt liver disease.
COMPLICATIONS
 ALF—rare.
21
 Chronic hepatitis—more than all
 HCC

TREATMENT
After doing councelling and liver biopsy by looking at liver status and PCR viral load--<2 million
copies /ml –favourable, and genotype, I will start 48 weeks treatment with s/c weekly INF + daily
oral RIBA continue with viral response monitoring if at 6 month of Rx viral response is poor I will
discontinue Rx.
 Peginterferon (Schering), IFN-α2b, and ribavirin are approved by the Food and Drug Administration
(FDA) for use in children >3 yr of age with HCV hepatitis.
 In adults, peginterferon (subcutaneous, weekly) combined with oral daily ribavirin is the most
effective therapy.
 Indications of INF:
 Elevated ALT
 Chronic hepatitis on liver bx
 Detectable HCV RNA
 Cirrhosis –not contraindication for therapy so give .
Most likely to respond:
 mild hepatitis.
 shorter duration of infection.
 low viral titers.
 Genotypes 2 and 3 are the most sensitive to treatment.
 GOAL is to achieve a sustained viral response (SVR), as defined by the absence of viremia 6 mo after
stopping the medications; SVR is associated with improved histology and decreased risk of
morbidities.
 The natural history of HCV infection in children is still being defined. It is believed that children have a
higher rate of spontaneous clearance than in adults (up to 45% by age 19 yr).
 Studies of IFN monotherapy in children have shown a higher SVR than in adults, with better
compliance and fewer side effects.
 Factors associated with a higher likelihood of response are
 age <12 yr.
 Genotypes 2 and 3.
 in patients with genotype 1b an RNA titer <2 million copies/mL of blood.
 viral response (PCR at weeks 4 and 12 of treatment).
 Side effects of INF:
 anemia, neutropenia, and influenza-like symptoms.
S/E OF RIBAVIRIN:
 Flu like symptoms.

 BM suppression.
 Teratogenic—advisable to do contraception 6 month after d/c Rx.
Treatment should be considered for patients with:
 Genotype 2,3 –consider Rx for all.

 Evidence of advanced fibrosis or injury on liver biopsy.
Treatment consists of 48 wk of IFN and ribavarin (therapy should be stopped if still detectable 22
on viral PCR at 24 wk of therapy).

Newer Treatments
 Peginterferon and an antiviral telaprevir (NS3 viral protease inhibitor) have shown a much
improved SVR success in adults. Studies are pending in pediatrics. Combination therapy schemes and
staggered therapy is also being explored in adults.
Prevention:
 No vaccine is available to prevent HCV.

 Current immunoglobulin preparations are not beneficial.
 neutralizing antibodies to HCV were found to be protective and might pave the road for vaccine
development.
 Once HCV infection is identified patients should be screened yearly with a liver ultrasound and
serum α-fetoprotein for HCC, as well as for any clinical evidence of liver disease. Vaccinating the
affected patient against HAV and HBV will prevent super-infection with these viruses and the
increased risk of developing severe liver failure.
Prognosis
 Viral titers should be checked yearly to document spontaneous remission.

 Most patients develop chronic hepatitis.
Bad prognostic factors:

 Older age
 Obesity
 Male gender
 Co-morbidity
 Moderate alcohol consumption –2 oz/day.
 Genotype 1
Hepatitis D
 HDV, the smallest known animal virus, is considered defective because it cannot produce infection
without concurrent HBV infection.
 incapable of making its own coat protein; its outer coat is composed of excess HBsAg from HBV.
 The inner core of the virus is single-stranded circular RNA that expresses the HDV antigen.
Can cause infection by:
Co-infection: can cause an infection at the same time as the initial HBV infection superinfection:
can infect a person who is already infected with HBV.
Transmission usually occurs by intrafamilial or intimate contact in areas of high prevalence, which
23
are primarily developing countries .
The incubation period:

 super-infection is about 2-8 wk with co-infection, the incubation period is similar to that of HBV
infection.
Pathogenesis
 Liver pathology in HDV hepatitis has no distinguishing features except that damage is usually quite
severe.
 It causes injury directly by cytopathic mechanisms.
Many of the most severe cases of HBV infection appear to be a result of co-infection of HBV and
HDV.
 Symptoms similar but severe.

 The clinical outcome for HDV infection depends on the mechanism of infection. In co-infection, acute
hepatitis, which is much more severe than for HBV alone, is common, but the risk of developing
chronic hepatitis is low.
 In super-infection, acute illness is rare and chronic hepatitis is common.
 Risk of ALF is highest in super-infection.
 Hepatitis D should be considered in any child who experiences ALF.
DIAGNOSIS
 No antigen.
 Anti-HDV-IgM: the antibodies to HDV develop ∼2-4 wk after co-infection and ∼10 wk after a super-
infection.
 PCR assays for viral RNA are available as research tools.
Complications
 ALF.
 Co-infection with HBV can also result in a more severe chronic disease.
TREATMENT
 No treatment yet for HDV.

 Treatment of HBV—Controll HDV.
PREVENTION
 No vaccine
 Immunize for hep-B/ Use of HBIG.
HEPATITIS E
 RNA-caliciviruses/
24
 Hepatitis E is the epidemic form of what was formerly called non-A, non-B hepatitis. Transmission is
fecal-oral (often waterborne.
 mean incubation period is ∼40 days (range, 15-60 days).
 HEV appears to act as a cytopathic virus.

Clinical Manifestations
 The clinical illness associated with HEV infection is similar to that of HAV but is often more severe.
 chronic illness does not occur.
 In addition to often causing a more severe episode than HAV, HEV tends to affect older patients, with
a peak age between 15 and 34 yr.
 HEV is a major pathogen in pregnant women, in whom it causes ALF with a high fatality incidence.
 also lead to decompensation of pre-existing chronic liver disease.
COMPLICATIONS
 HEV is associated with a high risk of death in pregnant women. No other complications are recognized
in association with this virus.
DIAGNOSIS:
 Anti-HEV -IgM /IgG--antibody to viral antigen becomes positive after ∼1 wk of illness.

 Viral RNA can be detected in stool and serum by PCR.
PREVENTION
 A recombinant hepatitis E vaccine is highly effective in adults.

 No evidence suggests that immunoglobulin is effective in preventing HEV infections. Immunoglobulin
pooled from patients in endemic areas might prove to be effective.
WILSON DISEASE: --(HEPATOLENTICULAR DEGENERATION)

 A.R
 DEGENERATIVE CHANGES UN BRAIN, LIVER DISEASE, AND KF RINGS IN CORNEA.
 1/50,00 to 1/100,000 births.
Pathogenesis
 Gene  long arm of chromosome 13 (13q14.3).
 The Wilson disease gene encodes a copper transporting P-type ATPase ATP7B, which is mainly but
not exclusively expressed in hepatocytes and is critical for biliary copper excretion and copper
incorporation into ceruloplasmin.
 Absence or malfunction of ATP7B results in decreased biliary copper excretion and diffuse
accumulation of copper in the cytosol of hepatocytes. With time, liver cells become overloaded and
copper is redistributed to other tissues, including the brain and kidneys, causing toxicity, primarily as a
potent inhibitor of enzymatic processes  Ionic copper inhibits pyruvate oxidase in brain and ATPase
in membranes, leading to decreased ATP-phosphocreatine and potassium content of tissue.
 More than 250 mutations in the gene have been identified.
 Most patients are compound heterozygotes.
 Mutations that completely knock out gene function are associated with an onset of disease symptoms
as early as 2-3 yr of age.
 Milder mutations –late presentation till 5-7 decade.
Recent advances  Cloning of the gene for Wilson disease raises the prospect of precise presymptomatic
detection of Wilson disease, timely initiation of therapy, and, ultimately, gene therapy.
 asymptomatic hepatomegaly (with or without splenomegaly). 25
 subacute or chronic hepatitis.—40%
 acute hepatic failure (with or without hemolytic anemia).
 Cryptogenic cirrhosis, portal hypertension, ascites, edema,variceal bleeding.
 other effects of hepatic dysfunction (delayed puberty, amenorrhea, coagulation defect).

 Disease presentations are variable, with a tendency to familial patterns.
 The younger the patient, the more likely hepatic involvement will be the predominant manifestation.
 Girls are 3 times more likely than boys to present with acute hepatic failure.
 After 20 yr of age, neurologic symptoms predominate.
Neurologic disorders : intention tremor, dysarthria, rigid dystonia, parkinsonism, choreiform movements, lack
of motor coordination, deterioration in school performance, or behavioral changes. Kayser-Fleischer rings may
be absent in young patients with liver disease but are always present in patients with neurologic symptoms.
Psychiatric manifestations include depression, personality changes, anxiety, or psychosis.
Eye findings in Wilson disease:
1. Kayser-Fleischer (K-F) ring --There is a brown discoloration at the outer margin of the cornea
because of the deposition of copper in Descemet's membrane.
 Appear first Superior –then inferior –> lateral .
 Golden yellow green brown
 90% present in neurowilson ds.
 50-60% in isolated hepatic Wilson
2. Sunflower cataract
Coombs-negative hemolytic anemia may be an initial manifestation, possibly related to the release of large
amounts of copper from damaged hepatocytes—hemolysis this form of Wilson disease is usually fatal
without transplantation.
During hemolytic episodes, urinary copper excretion and serum copper levels (not ceruloplasmin bound) are
markedly elevated.
Manifestations of renal Fanconi syndrome and progressive renal failure with alterations in tubular transport of
amino acids, glucose, and uric acid may be present.
Unusual manifestations:
 Arthritis.
 Infertility.
 or recurrent miscarriages.
 Cardiomyopathy.
 endocrinopathies (hypoparathyroidism).
PATHOLOGY
 All grades of hepatic injury occur with steatosis, heptocellular ballooning and degeneration, glycogen
granules, minimal inflammation, and enlarged Kupffer cells. The lesion may be indistinguishable from
that of autoimmune hepatitis.
 progressive parenchymal damage, fibrosis and cirrhosis develop.
 Ultrastructural changes primarily involve the mitochondria and include increased density of the matrix
material, inclusions of lipid and granular material, and increased intracristal space with dilatation of
the tips of the cristae.
DIAGNOSIS:
ENLIST INVESTIGATIONS .
 LFTS
 S.ALBUMIN
 PT/INR
 BSR
 SERUM COPPER LEVEL
 SERUM CERULOPLASMIN LEVEL
 URINARY CU EXCRETION TEST
 URINARY CU EXCRETION AFTER PENCILLAMINE CHALLENGE TEST
 SLIT LAMP EYE EXAMINATION FOR KF RINGS
 LIVER BIOPSY –cu Content+ degree of severity (cu content in liver is not available in pakistan) 26
 COOMBS TEST -- negative
 CBC –anemia, plts.
 ABDOMINAL USG.
 URINARY ELAECTROLYTE –if suspecting fanconi –don’t mention in short case

 SERUM CA+, PO4, ALP.
Clinical Dx :-Wilson disease should be considered in children and teenagers with unexplained acute or chronic
liver disease, neurologic symptoms of unknown cause, acute hemolysis, psychiatric illnesses, behavioral
changes, Fanconi syndrome, or unexplained bone (osteoporosis, fractures) or muscle disease (myopathy,
arthralgia).
LFT –(S.Billurubin with fraction , ALT/AST, GGT,ALP.)

Dispropotionate elevated to liver enzymes i.e s.billi > while ALT/AST are not.
AST:ALT  (4:1)
BILLI:ALPO4 (2:1)
SERUM CERULOPLASMIN LEVEL :- decreased ceruloplasmin levels (<20 mg/dL).

The failure of copper to be incorporated into ceruloplasmin leads to a plasma protein with a shorter half-life
and, therefore, a reduced steady-state concentration of ceruloplasmin in the circulation.
Other causes of elevated level:
 Any acute illness –coz it is aute inflammatory marker.
 Pregnancy.
 OCP.
 estrogen therapy.
Other Causes of decreased level :-
 Aceruloplasminea.
 Malnutrition.
 Nephritic.
 Protein losing enteropathy.
SERUM COPPER LEVEL --may be elevated in early Wilson disease.

URINARY COPPER EXCRETION LEVEL (usually <40 ug/day) is increased to >100 ug/day and often up to 1,000 ug
or more per day.
In equivocal cases  response of urinary copper output to chelation may be of diagnostic help.
24 HR URINARY COPPER AFTER PENCILLAMINE CHALANGE:
Give 2 Tablet Vistamine 250 mg stat ( morning) then after 12 hr (evening) start collection of urine in a
container given by lab from morning dose of vistamine till next motrning.
Half life of vistamine is 12 hr.
Children hospital protocol use total 6 tablets.
affected patients excrete >1600 ug/24 hr.
SLIT LAMP EYE EXAMINATION Kayser-Fleischer rings
LIVER BIOPSY:
Extent and severity of disease.
Hepatic copper content .
(normally <10 ug/g dry weight).
In Wilson disease > 250 ug/g dry weight.
In later stages of Wilson disease hepatic copper content can be unreliable because cirrhosis leads to variable
hepatic copper distribution and sampling error.
SCREENING OF FAMILY MEMBERS: screening for presymptomatic Wilson disease.
serum ceruloplasmin level and urinary copper excretion.
If these results are abnormal or equivocal  liver biopsy should be carried out to determine morphology and
hepatic copper content.
Genetic screening by either linkage analysis or direct DNA mutation analysis is possible, especially if the
mutation for the proband case is known or the patient is from an area where a specific mutation is known. (in 27
central and eastern Europe, the H1069Q mutation is present in 50-80% of patients).

TREATMENT
General management :
 Management of acute liver symproms / complications
 Treatment of coagulation derangements –FFP/Vitamin K
 Treatment of anemia –PCV Tx
 Correction of electrolyte imbalances
 Treatment of ascites –diuretics –potasium sparing.
 Nutritional rehabilitation –ADEK + Water soluble vitamins
 Treatment of itching –ursodeoxycholic acid/cholestyramine.
 Treatment and prevention of hepatic encephalopathy—if associated –flumazanil.
SPECIFIC MEASURES :
Dietry modification –major step ( DIETRY Cu should be <1mg/day)
1. Avoid (all dry fruits-nuts, liver, chocolates, red meat )–coz they contain > Cu+ amount.
2. Use water with < 0.1 mg/l.
3. Don’t use chlorinated water.
+
Cu chelating agents:  excretion of deposited cu.
 d. pencillamine –20 mg/kg/day 2DD before meal(tablet vistamine 250mg Rs= ).
 PYRIDOXINE (vitamin B6) 25mg/day--supplement along with pencillamine –coz it is antimetabolate
of B6.
Or
 Triethylene tetramine dihydrochloride –(TRIEN, TETA , TRIENTENE)-20mg/kg/day
 ZINC ACETATE 25mg/day TDS.
 In response to chelation, urinary copper excretion markedly increases, and with continued
administration, urinary copper levels can become normal, with marked improvement in hepatic and
neurologic function and the disappearance of Kayser-Fleischer rings.
 Pencillamine is amino acid metabolite of pencillin with no antibiotic property.

o Two forms are available L and D / L –toxic –inhibit pyridoxine / we have D form available
 Approximately 10-50% of patients initially treated with penicillamine for neurologic

symptoms have a worsening of their condition.
Toxic effects of penicillamine 10-20%:
o DYSGENESIA –Abnormal test,Anorexia, vomiting, diarrhea –most common side
effect (30%)
o SLE
o SJS
o NEPHROTIC SYNDROME –Membranous GN
o GOODPASTURE SYNDROME.
o MYOSITIS –myasthenia like
o APLASTIC ANEMIA
o ZINC DEFFECIENCY
o FOLIC ACID DEFECIENCY
TRIETHYLENE TETRAMINE DIHYDROCHLORIDE (trientine) –20mg/kg/day.

 is a preferred alternative if hypersensitive adverse effects of pencillamine.
 considered 1st-line therapy for some patients.
 Less potent than pencillamine.
 Trientine has few known side effects.
 Hypersensitivity reactions
 Loss of taste 28
 Hemorrhagic gastritis
 Rash
 Sideroblastic anemia.
 Costly available in Pakistan –karachi 400 Rs/tab

AMMONIUM TETRATHIOMOLYBDATE:
 is another alternative chelating agent under investigation for patients with neurologic disease.
 The initial dose is 120 mg/day (20 mg between meals tid and 20 mg with meals tid).
 Side effects:
 Anemia.
 Leucopenia.
 Thrombocytopenia.
 Mild elevations of transaminases.
ZINC ACETATE : impair the gastrointestinal absorption of copper
 adjuvant therapy/Maintenance therapy/Primary therapy in presymptomatic patients.
 Dose :
 adults  25-50 mg of elemental zinc 3 times a day .
 children >5 yr  25 mg 3 times a day.
 Side effects are mostly limited to gastric upset.
PROGNOSIS
Untreated patients with Wilson disease can die of hepatic, neurologic, renal, or hematologic complications.
The prognosis for patients receiving prompt and continuous penicillamine is variable and depends on the time
of initiation of and the individual response to chelation.
Liver transplantation indications in Wilson disease :

1. fulminant liver disease.
2. Not responding to medical Rx
3. decompensated cirrhosis—coagulopathy/encephalopathy.
4. progressive neurologic disease  controversial.
 Liver transplantation is curative, with a survival rate of ∼85-90%.
 Wilson disease doesn’t occur after transplantation –effective phenotypic cure it convert Cu kinetic of
homozygous child to heterozygous.
 In asymptomatic siblings of affected patients, early institution of chelation or zinc therapy can prevent
expression of the disease.
SCREENING OF FAMILY MEMBERS:

First degree relatives of Wilson pt should be screened
1. History
2. Examination
3. LFTs.
4. CBC –( Coombs negative hemolytic anemia)
5. KF rings—slit lamp examination
6. Urinary cu level.
7. Serum ceruloplasmin level.
If any one of above found + then
8. Liver biopsy
Asymptomatic carrier should be treated with zinc acetate / monitoring of B6 level/zinc level.
If a sib is < 6 yr then should be tested for all above in next 5-10 yr of age.
Genetic councelling should be done.
IF PATIENT IS ALLERGIC TO PENCILLAMINE

Preferable is to start with alternative drug but that is not so common available then we have other option:
Stop medicine for 1 week and start low dose steroid
Restart with 25 mg/day and double at weekly interval as long as tolerated then tapper steroid and continue 29
tolerable dose.
MONITORING OF THERAPY:
1. Measure 24 hr urinary copper –(initial goal is excretion of 2000 ug/day  this value fall to
<500ug/day at 4-6 month of Rx.

2. CBC
3. URINE C/E-protein/RBC.
STOP PENCILLAMINE WHEN:
 WBC < 3000
 PLT 120000
 STEADY DECLINE IN 3 LINES
 PROTEINUREA EXCEED 2+
 >10 RBC/HPF
IF WILSON PATIENT IS UNDERGOING FOR SURGERY THEN WHAT U WILL DO?

Decrease the dose of pencillamine 25-50% of presurgery dose but don’t discontinue coz it may impair wound
healing.
WILSON PREGNANT PT THEN WHAT MEASURES U WILL DO?
Just decrease dose of pencillamine 25-50% of pre pregnancy in third trimester –coz it is not teratogenic
however neonate may have some cutaneous manifestation , coz it also improve wound healing in c.sec
WHAT ADVISE U WILL GIVE TO LACTATING MOTHER ?
Continue with pencillamine / zinc acetate
Although it may lead to reduction in Cu and zinc content of breast milk.
CAUSES OF INCREASE Cu IN LIVER

 wilson
 billiary atresia
 pfic
 primary biliary cirrhosis
 hepatic tumours
 schlerosing cholangitis
WHY WE DO PENCILAMINE CHALENGE TEST?

Because there are other variety of liver conditions associated with increase Cu+ excretion in urine so we use
pencillamine which specifically increase Cu excretion in urine of Wilson pt while less specific for others
CONDITIONS ASSOCIATED WITH KF RINGS

 primary biliary cirhosis
 neonatal cholestasis
 chronic active hepatitis.
 intrahepatic cholestasis with cirhosis.
URINE SAMPLE COLLECTION FOR WILSON:

Rinse container with distilled water (not tap) and add 30 ml of HCL to container to prevent formation of Cu
hydroxide precipitates.
DIAGNSIS OF FULMINANT HEPATIC FAILURE DUE TO WILSON:

 Coombs –ve hemolytic anemia
 Coagulaopathy unresponsive to vitamin K
 Rapidly progressive renal failure
 Aminotranferase levels < 2000 IU/l AST>ALT
 Normal / subclinical ALKpo4 <40 iu/L.
MENKES DISEASE –XLR – disorder of Cu transport leading to  ceruloplasmin and Cu+ deficiency.
INDIAN CHILDHOOD CIRRHOSIS 30

Non wilsonian liver disease affect young children manu=y unknown abnormalities of cu metabolism
Increased cu content in diet usually contaminated thru utensils used to feed babies /animal milk.
Increased copper content >700 ug/g dry wt
Biopsy shows Mallory bodies , fibrosis, inflammation.
Clinical : jaundice , liver+ spleen +,

Rx –vistamine as like Wilson .
Other causes of CLD:-----( although rare but should be entertained in DD)
ALPHA –1 ANTITRYPSIN DEECIENCY

Clinical presentation : Most common cause of CLD in neonate
Recurrent chest infection in pt and family hx
Cholestasis , FTT, vitamin K RESPONSIVE COAGULOPATHY, emphysema
Diagnosis:
 Dec level of alpha -1 antitrypsin
 PiZZ mutation—( homozygous protease inhibitor mutation) –early cirrhosis in childhood.
 PiMM –Normal
Rx – no specific/ Vaccinate for B,C and danazol??
Prognosis:
rd
1/3 need liver tx
rd
1/3 recover
rd
1/3 cirrhosis.
TYROSINEMIA TYPE- 1
 A.R
 Excess tyrosine in liver , heart , kidney, brain.
 In infant –acute liver failure
 Older children –CLD
DX
S.AFP elevated >>.
Rx
 low protein diet
 Vitamin –D
 Cyclohexinidione (NTBC)
 Liver Transplantation.
CYSTIC FIBROSIS
Focal biliary cirrhosis
nd
After 2 decade usually
1-8% C.F pt develop this.
Rx with ursodeoxycholic acid+ supportive
----------------
HEREDITARY FRUCTOSE INTOLERANCE
A.R
Neonatal hypoglycemia and lactic acidosis
FTT. Cirhosis, GI bleeding, vomiting, seizures, proximal RTA+.
Rx
Avoid fructose containing diet –( avoid fasting)
Don’t require liver transplantation.
Autoimmune Hepatitis
 Autoimmune hepatitis is a chronic hepatic inflammatory process manifested by elevated serum
aminotransaminase concentrations, liver-associated serum autoantibodies, and/or
31
hypergammaglobulinemia.
 The target of the inflammatory process can include hepatocytes and to a lesser extent bile duct
epithelium.

 Chronicity is determined either by duration of liver disease (typically >3-6 mo) or by evidence of
chronic hepatic decompensation (hypoalbuminemia, thrombocytopenia) or physical stigmata of
chronic liver disease (clubbing, spider telangiectasia, hepatosplenomegaly).
.
Chronic hepatitis
 Chronic active
 Chronic persistant.
More than 90% of hepatitis B infections in the 1st yr of life become chronic, compared with 5-10% among older
children and adults.
Chronic hepatitis develops in >50% of acute hepatitis C virus infections.
Autoimmune hepatitis
ALT/AST +  Antibodies + hypergamaglobulinemia.
Targets of inflammation
 Hepatocyte –autoimmune hepatitis
 Bile duct epithelium –autoimmune cholangiopathy & sclerosing cholangitis.
De novo hepatitis is seen in a subset of liver transplant recipients whose initial disease was not autoimmune.
Etiology :
 Imbalance between CD4 & CD 8 lymphocytes.
 Genetic predispodition
 Virus/drugs –may start process.
Clinically they can present :
1. Acute hepatitis –(25%-30%)
2. Chronic hepatitis.
3. Extra-hepatic manifestations –(arthritis, vascultitis , nephritis—hematurea , thyroiditis –cold
intolerance, constipation, goiter, coombs positive anemia, rash, IBD.
Liver is often tender and enlarged –may be cirrhotic
Criteria for Dx
 Female
 ALT
 ALP= N
 Gama globulin + antibodies(ANA/LKM/SM) +histology.
 ALONG WITH ABSENCE OF OTHER CAUSES –(VIRAL MARKERS HEP-B,C,D, BLOOD PRODUCT
EXPOSURE).
INVESTIGATIONS :
 LFT
o ALT/AST –100-300 in asymptomatics
o Upto 1000 in symptomatics
o Direct Billi 2-10.
o ALP/GGT –normal
 serum gammaglobulin (IgG>16g/l).
 SERUM AUTOANTIBODIES—ANA/anti-cytosol antibodies/anti-smooth muscle antibody/anti-LKM.
 Liver-BIOPSY—typical piece meal necrosis.
CLASSIFICATION OF AUTOIMMUNE HEPATITIS

TYPE 2 AUTOIMMUNE
VARIABLE TYPE 1 AUTOIMMUNE HEPATITIS
HEPATITIS
Antibody against liver-kidney
Antinuclear antibody*
microsome 1*
32
Characteristic autoantibodies Smooth-muscle antibody*
[†]
Antiactin antibody Antibody against liver cytosol 1*
Autoantibodies against soluble liver antigen

TYPE 2 AUTOIMMUNE
VARIABLE TYPE 1 AUTOIMMUNE HEPATITIS
HEPATITIS
[‡]
and liver-pancreas antigen
Atypical perinuclear antineutrophil
cytoplasmic antibody
Worldwide; rare in North
Geographic variation Worldwide
America
Predominantly childhood and
Age at presentation Any age
young adulthood
Sex of patients Female in ~75% of cases Female in ~95% of cases
Association with other
Common Common
autoimmune diseases
Clinical severity Broad range Generally severe
Histopathologic features at
Broad range Generally advanced
presentation
Treatment failure Infrequent Frequent
Relapse after drug withdrawal Variable Common
Need for long-term
Variable ~100%
maintenance
 Type 1 are less severe and can occur at any age , good response to Rx and have less frequent
relapse.
 Type ii are more severe, childhood and young adult ,frequent Rx failure, common relapses.
TREATMENT:
goal is to suppress or eliminate hepatic inflammation with minimal side effects
 Prednisone, with or without azathioprine or 6-mercaptopurine, improves the clinical, biochemical,

and histologic features in most patients with autoimmune hepatitis and prolongs survival in most
patients with severe disease.
 choleretic agent ursodeoxycholic acid may be particularly useful in patients with biliary features of
their disease.
 Prednisone at an initial dose of 1-2 mg/kg/24 hr is continued until aminotransferase values return to
less than twice the upper limit of normal.
 The dose should then be lowered in 5 mg decrements over 2-4 mo until a maintenance dose of 0.1-0.3
mg/kg/24 hr is achieved.
 In patients who respond poorly, who experience severe side effects, or who cannot be maintained on
low-dose steroids  azathioprine (1.5-2.0 mg/kg/24 hr, up to 100 mg/24 hr) can be added, with
frequent monitoring for bone marrow suppression.
 Single-agent therapy with alternate-day corticosteroids should be used with great caution, although
addition of azathioprine to alternate-day steroids can be an effective approach that minimizes 33
corticosteroid-related toxicity.
 STEROID SPARING DRUGS : / cases refractory to standard therapy

o Budesonid.

o Cyclosporine.
o Tacrolimus.
o mycophenylate mofetil.
o sirolimus.
 Follow-up liver biopsy is therefore especially important in patients for whom consideration is given to
discontinuing corticosteroid therapy.
 In patients with disappearance of symptoms and biochemical abnormalities and resolution of the
necroinflammatory process on biopsy, an attempt at gradual discontinuation of medication is justified.
 There is a high rate of relapse after discontinuation of therapy. Relapse can require reinstitution of
high levels of immunosuppression to control disease.
 Total 2 biopsies taken one at start and other when plan to d/c steroids.
PROGNOSIS:
 Transaminase and billurubin level normalizes over 1-3 months
 Albumin and PT takes 3-9 month to normalize.
 50% relapse occur over a variable period of time.
FULMINANT HEPATIC FAILURE
The currently accepted definition in children includes:

biochemical evidence of acute liver injury (usually <8 wk duration)
+
no evidence of chronic liver disease.
prothrombin time (PT) >15 sec or international normalized ratio (INR) >1.5 not corrected by vitamin K in the
presence of clinical hepatic encephalopathy.
Or
PT >20 sec or INR >2 regardless of the presence of clinical hepatic encephalopathy.
Causes :
 Infections-all hepatotrophic viruses, herpes simplex, adeno, entero, CMV, parvo,VZV.
 Autoimmune hepatitis –5%.
 ideopathic 40-50%.
 Drugs/chemicals –CCL4, paracetamol, INH, Halothane.
 Ischemia/hypoxia –CCF,CCHD,circulatory shock.
 Metabolic disorders –wilson,galactosemia, Tyrosinema ,HFI, Mitochondrial
PATHOGENESIS
 Direct cytotoxic effect of virus
 Immune response to viral antigen
Both above lead to increase serum ammonia and falssse neurotransmitters ,GABA activity –all due to dec
clearance by damaged hepatocytes.
STAGES OF HEPATIC ENCEPHALOPATHY
STAGES
I II III IV
Drowsiness, Stupor but
Periods of lethargy, Coma
inappropriate arousable,
euphoria; reversal of IVa responds to
Symptoms behavior, agitation, confused,
day-night sleeping; may noxious stimuli
wide mood swings, incoherent
be alert IVb no response 34
disorientation speech
Asterixis, fetor Asterixis,
Trouble drawing figures, Areflexia, no asterixis,
Signs hepaticus, hyperreflexia,
performing mental tasks flaccidity
incontinence extensor

STAGES
I II III IV
reflexes, rigidity
Markedly abnormal
Markedly
Generalized slowing, bilateral slowing, d
EEG Normal abnormal,
q waves waves, electric-cortical
triphasic waves
silence
INVESTIGATIONS:
LFT—ALT/AST,BILL  (May come down as pt detoriate)
Serum ammonia 
PT /INR >>  always / no responsive to vitamin K
BSR  
S/E  Hypokalemia /hyponatremia
ABGS – metabolic acidosis / respiratory alkalosis.

MANAGEMANT
 MAINTAIN I.V LINE
 MONITOR VITALS
 Keep NPO and pass NG TUBE
 Dec Protein intake
 I.V FLUIDS-n/s+ 10% dextrose.
 FFP/PCV
 VITAMIN –K
 Sterilize GUT –NEOMYCIN/STREPTOMYCIN
 LactuloseDIARRHEA -- TRANSIT TIME of food in intestine so less time
for bacteria to act upon .
 Sodium benzoate—increase excretion of ammonia
 Flumazanil –benzodiazepam antagonist--competative inhibitor of ammonia
–don’t let ammonia to enter in cell
 Prevent /treat hypokalemia –coz increase k+ will not not let ammonia to
enter cell
 Prevent hypoglycemia/hyponatremia.
 Prevent n Rx cerebral edema
 Avoid precipitating factors of H.ENCEPH.
 TREAT CAUSE.
 LIVER TRX.
PORTAL HTN
>10-12 mmHg (N=<7)
Causes:
 Pre-hepatic-(PVT)
 Hepatic—(all CLD causes-wilson, viral etc)
 Post-hepatic—(budd chiari)
 Idiopathic
Clinical presentation:
 Bleeding from esophageal varices—most common presentation
 Signs of CLD—intrahepatic
 Only spleenomegally –Pre-hepatic 35
DIAGNOSIS
 Doppler USG –(direction of flow of blood in PV/ Reversal of blood flow-hepatofugal id associated with
variecal hemorrhage.

 USG abdomen
 Contrast CTA/MRA
 Selective angiography
 Endoscopy –varices –red spot over vrices –strong predictor of imminent hemorrhage.
 LFT+ PT/INR +BASELINE
MANAGEMENT:
Acute—(stop bleeding)Chronic—(prevent bleeding)
Acute
 Admit
 Maintain i.v line
 Keep NPO pass NG
 Monitor vitals
 Correction of:
 Hypovolumia – PCV /Crystalloids-limited—avoid overload which may leasd to high PV pressure—risk
of bleed.
 coagulation profile –Vitamin K, FFP,Plt.
 H2 Blocker –ranitidine
 Somatostatin analogue—octreotide –1-5 ug/kg/hr (it has minimum S.E)
 Vasopressin S/E-vasoconstriction of renal,GI, heart, and liver.
 Nitroglycerine patch –(covers side effects of vasopressin)

 If still no control on bleeding

 Endoscopic Sclerotherapy /band ligation –(band is better)

 Still not controlled

 Sengestaken blackmure tube –(mechanical compression—aspiration can be problem)

 No control

 Portosystemic shunts –(Portovaval /mesocaval/splenorenal/REX/ TIPS) TIPS –btw Rt hepatic vein + R/L
branch of PV

 Liver transplantation –for intrahepatic diseases.
 LONG TERM TRX

 Beta-blocker –propranolol  it decreases cardiac output  dec portal blood flow  monitored by
heart rate.
 PROGNOSIS –poor with PH sec to intrahepatic causes.
Nonalcoholic steatohepatitis:
 obesity
 insulin resistance
 responds to weight reduction and/or vitamin E therapy
danger of vistamine withdrawl 36

 not effective again
pre-requisties for cu excretion test

 normal RFT & Creatinine clearance

Causes of ascites in CLD
o Portal HTN
o Hypoalbuminemia
o Peripheral arterial vasodilation /NOxide
o Increase aldosterone and salt/water retention.
 We advise aldectone in CLD pt which is aldosterone antagonist bcz it its level increases due to dec
metabolism in liver –so it lead to diuresis and dec salt retaining.
Signs of portal HTN

 Ascites
 splenomegally
 Hypersplenism
 Varices
Compensated CLD
 Any child with hepatosplenomegally on the background of hepatitis/metabolic disease with only
elevated aminotranferases, no jaundice or ascites .
Decompensated CLD:
 Any child with CLD who develop signs of jaundice, Ascites, hepatic encephalopathy, coagulopathy.
In CLD pts jaundice implies the hepatocellular degeneration exceeds regeneration.
Causes of delayed puberty in Wilson:

 Vistamine
 Cu accumulation
 Nutritional
CHILD PUGH CLASSIFICATION FOR CLD PTS UNDERGOING HEPATIC TRANSPLANTATION

PARAMETER 1 POINT 2 POINT 3 POINT UNITS
T.BILLIURUBIN <34 (<2) 34-50 (2-3) >50 (>30) Umol/l or mg/dl
S.ALBUMIN >3.5 2.8-3.5 <2.8 g/dl
INR <1.7 1.71-2.20 >2.20 NO UNIT
ASCITES NONE suppressed with Refractory No unit
medication
Hepatic None Grade i-ii or Grade iii-iv or No unit.
encephalopathy suppressed with refractory
medication
INTERPRETATION:
CLD is classified into child pugh class A-C
POINTS CLASS 1 Yr survival rate 2 yr survival rate
5-6 A 100% 85%
7-9 B 80% 57%
10-15 C 45% 35%
Any pt fall in classification C is advised for liver transplantation –if fall in B then wait till C. 37
Metabolic derangements in CLD

 Hyponatremia –dilutional
 Hypokalemia

 Hypocalcemia
 Hypomagnesemia
 Hypophosphatemia
Respiratory acidosis –initially due to ammonia

Metabolic acidosis –terminaly due to shock.
Copper accumulation sequence in Wilson

Liver –cornea—CNS—kidney
Clinical description for management of CLD

I will councell my pt regarding disease , complication, course and treatment options, Sir as my pt is already
admitted in hospital and he is on treatment I would review his treatment chart and will look at ……….
Specific treatment …………………………. Till liver transplantation option.

I will take care of his nutrition with daily adequate supplement of calories along with MCT vitamin ADEK
supplement with water soluble vitamins.
If any feature suggestive of sholestasis during management I will start choleretic agents and see response.
I will advise him propranolol for long term to prevent from bleeding and follow up screening endoscopies.
As my pt is case of inherited Wilson disease so I will advise genetic councelling & screen his sibs with serum
ceruloplasmin and urinary cu excretion test and advise for zinc acetate if they prove to be asymptomatic
carrier.
I will ensure his proper compliance and follow up.
38

CLD –----------------------------------------------------------------------------------------------SHORT CASE/
COMMOND: DO ABDOMINAL EXAMINATION & RELEVANT
DESCRIPTION:
EXAMINED A CHILD WHO IS CONSCIOUS CO-OPERATIVE WITH OBV. JAUNDICE DURING MY EXAMINATION &
NO RESP. DISTRESS/ DYSMORPHISM .
HIS ABDOMEN IS DISTENDED WITH PROMINENT VISIBLE VEINS AT UPPER ABDOMEN & LOWER CHEST WITH
DIRECTION OF THEIR BLOOD FLOW AWAY FROM UMBLICUS , WITH CENTRAL PLACED EVERTED UMBLICUS, HE
HAS ABDOMINOTHORACIC TYPE OF MOVEMENT HOWEVER NO VISBLE SCAR .
HE HAS NONTENDER ABDOMEN WITH HEPATOMEGALLY , MEASURING 5 cm BCM WITH TOTAL SPAN OF 13
cm, WHICH IS TENDER, FIRM IN CONSISTENCY , SMOOTH SURFACE, REGULAR MARGINS & UPPER BORDER IS
TH
AT 6 IC SPACE.
HE HAS ASCITES BASED ON EVIDENCE OF FLUID THRILL.
HOWEVER NO EVIDENCE OF SPLEEN & OTHER VISCEROMEGALLY.
ALL HERNIAL ORIFICES ARE INTACT, GENITALS ARE NORMAL & ARE PREPUBERTAL
BACK OF PT IS ALSO NORMAL.
HE IS VITALLY STABLE CHILD WITH STIGMATA/NO OF CLD IN FORM OF PALLOR, JAUNDICE, PETACHAE, BRUISE,
BLEED, JOINT TENDERNESS/SWELLING, SPIDER NEVI, CAPUT MEDUSAE, XANTHOMA, FLAPPING TREMORS,
ALSO NO EVIDENCE OF CATARACT, RICKETS, SCRATCH MARK, HE IS WITH BCG SCAR & POOR ORODENTAL
HYGIENE. NO SIGNS RICKETS & MACRONUTRIENT DEFECIECY IN MY PT.
BCG SCAR SEEN & NORMAL JVP, ORODENTAL HYGIENE, & THYROID.
CVS EXAMINATION IS NORMAL.
HIS GAIT IS NORMAL ALTHOUGHT I WANT TO DO EXTENDED EXAMINATION .
IMPRESSION:
differentials of isolated hepatomegally in 5 yr child with no other findings at all.
1. Enteric fever.-------( febrile child, NON-tender liver, otherwise may have rose spots )
2. Anicteric hepatitis.—( tender liver+, no other stigmata at all may be treated case).
3. Malignancy—( petechae, bruise, bleed sick look, but may be initial satart of illness)
4. Malaria –(they are pale, febrile, very less likely to cause isolated hepatomegally without causing spleen
to enlarge )
5. Bud chiari syndrome.—( tender liver, with prominat lower chest viens,& acites no spleen but
considerled last differential because very rare/ uncommon.
39
Other conditions associated with tender hepatomegally:
 AVH
 CCF

 Budd chiari syndrome.
 Hepatoblastoma.
 Abscess.
BUDD-CHIARI SYNDROME:
Uncommon condition induced by thrombotic or nonthrombotic obstruction of hepatic venous outflow and
characterized by hepatomegaly, ascites, and abdominal pain.
 Signs and symptoms

 Jaundice
 Ascites
 Hepatomegaly
 Splenomegaly
 Ankle edema
 Stasis ulcerations
 Prominence of collateral veins
The clinical variants of Budd-Chiari syndrome:
Acute and subacute forms: Characterized by rapid development of abdominal pain, ascites (which can cause
abdominal distention), hepatomegaly, jaundice, and renal failure.
Chronic form: Most common presentation; patients present with progressive ascites; jaundice is absent;
approximately 50% of patients also have renal impairment
Fulminant form: Uncommon presentation; fulminant or subfulminant hepatic failure is present, along with
ascites, tender hepatomegaly, jaundice, and renal failure.
PATHOPHYSIOLOGY
Occlusion of a single hepatic vein is usually silent. Overt Budd-Chiari syndrome generally requires the occlusion
of at least 2 hepatic veins. Venous congestion of the liver causes hepatomegaly, which can stretch the liver
capsule and be very painful. Enlargement of the caudate lobe is common because blood is shunted through it
directly into the inferior vena cava (IVC).
Congenital membranous obstructions:
These include the following:
 Type I: Thin membrane is present at the vena cava or atrium

 Type II: A segment of the vena cava is absent
 Type III: The inferior vena cava (IVC) cannot be filled, and collaterals have developed.
OBSTRUCTION OF THE VENOUS OUTFLOW TRACT OF THE LIVER IN THE BUDD–CHIARI SYNDROME.
The Budd–Chiari syndrome results from the obstruction of the hepatic venous outflow tract due to ostial
stenosis,thrombosis, or inferior vena caval webs (Panel A). Because the caudate lobe drains directly into the 40
inferior vena cava, it hypertrophies in response to liver necrosis in other lobes and may thus compress the
inferior vena cava. Findings on physical examination include ascites and an absent hepatojugular reflux. The
abdominal veins are dilated (inset) as a result of obstruction of the inferior vena cava. A collateral circulation is
formed that connects superficial inferior epigastric veins (inferior vena cava territory) to superior epigastric

veins (superior vena cava territory). On venographic examination, the right hepatic vein is not visualized;
instead, there is a rich collateral circulation between the tributaries of the hepatic
vein and the liver capsule, which forms a “spider’s web” (Panel B). When the occlusion of the hepatic vein is
incomplete, there is a coarse collateral circulation. On histologic examination, the hepatic sinusoids
surrounding the central vein may be dilated and filled with blood . Liver cells around the central vein are
necrotic (centrilobular necrosis). In the normal liver, venographic examination of the right hepatic vein shows
no collateral circulation between the tributaries of the hepatic vein. Histologic examination shows plates of
hepatocytes
arranged around the portal tract and draining into the central vein; the sinusoids between the plates are not
dilated.
PROGNOSIS
The natural history of Budd-Chiari syndrome is not well known. The following factors, however, have been
associated with a good prognosis:
 Younger age at diagnosis

 Low Child-Pugh score
 Absence of ascites or easily controlled ascites
 Low serum creatinine level
The 5-year survival rate for patients with the syndrome is 38-87% following portosystemic shunting. The
actuarial 5-year survival rate following liver transplantation is 70%.
DIFFERENTIAL DIAGNOSIS:
 Tricuspid regurgitation,
 Constrictive pericarditis.
 Right atrial myxoma
these other conditions can be ruled out by careful cardiovascular examination. The absence of
hepatojugular reflux with the application of abdominal pressure also rules out a cardiac cause of ascites.
Diagnosis
Imaging studies
 Ultrasonography-doppler
 Computed tomography (CT) scanning
 Magnetic resonance imaging (MRI)
 Venography
41

Biopsy
Findings in liver biopsy are:
(1) high-grade venous congestion and centrilobular liver cell atrophy.
(2) thrombi within the terminal hepatic venules.
Management :
Pharmacologic therapy
 Anticoagulants
 Thrombolytics
 Diuretics
Procedures and surgery
 Balloon angioplasty
 Localized thrombolysis
 Placement of a stent or transjugular intrahepatic portacaval shunt (TIPS)
 Variceal treatment
 Paracentesis.
 Portal decompression
 Percutaneous transhepatic balloon angioplasty (PTBA)
 Liver transplantation.
----------------------------------------------
42

CYANOTIC CONGENITAL HEART DISEASE ----------------------------------------------long case.
Mostly it is TOF—long standing known case –with /without complications
 BIODATA.
 ATTANDANT TIME -- (3 min )
 Presenting complaints of pt can be:
o Cyanotic spell
o Infective endocarditis.
o CNS symptoms –(CVA/ spell related.)
o Bleeding
o CCF—( Easy fatigue, FTT, respiratory distress, body swelling)
 HOPC:
 Cyanotic spell
o Mode of onset-sponatneous / after some ppt factors—(cry, fever, loose motion, vomiting,
onfection, hypothermia, dehydration, constipation)
o Time of onset –usually morning.
o What happens during spell
o Duration of spell
o How terminated/managed
o Post spell effects.
 IF IE suspected:
o Symptoms
o Risk factors
o i.v lines
o central lines
o immunocompromised
o any surgical procedure –dental
o tooth abscess
o systemic infection.
 CVA
o Fever
o Headache
o Altered sensorium
o Fits weakness
o Facial asymmetry
 Pallor
 Headache
 Confusion
 Respiratory distress
 Sweliing
 Vertigo
 Bleeding –polycythemia
 Episode of dehydration ( vomiting , diarrhea , before episode)
 What treatment has been given so for ----investigations
 What is response ------current status.
 Which medicine ---How medicine arranged .
 Any procedure planned /done—(BT shunting , phlebotomy, abscess drainage-craniotomy) 43
 Knowledge of parents –what is treatment offered –surgery if not done yet ask the reason ..*

PAST HISTORY: ----
 Initial diagnosis:
o When , at what age, where,
o Initial symptoms
o What investigations dome
o Managnemant of symptoms.
 PROGRESSION OF DISEASE:
o No/frequency of tet spells
o Is he/she thriving well? FTT/ activity
o No. of hospitalization –cause –mangement
o Any surgical procedure done
 TREATMENT DETAIL
o Medical treatment
o Propranolol—inderal
o Iron supplement
o Anti-coagulant –aspirin/clopidogril/warfarin—their monitoring
o Effect on symptoms
o Surgical treatment –corrective/palliative –if done before ask their effect.
 SYSTEMIC INQUIRY
o Complication of disease:
 FTT
 Delayed puberty
 CVA / Abscess
 Bleeding diathesis
 Adverse psycosocial effects
 Joint swelling
 –ankle –GOUT
 --Fingers –clubbing –osteoarthropathy.
 Ask aymptoms about CCHD with increase pulmonary flow
o Tachypnea, tachycardia, interrupted feeding , excessive sweating over head during feed,
repeated chest infections , FTT.
COMPLICATION OF TREATMENT:
 Aspirin /Disprin epigastric pain. GUT bledd, tinntis, vertigo, peteche, wheezing.
Aspirin(15,150,300mg).
Disprin (100mg).
 Clopidogril –(usually post-BT shunt)  bleeding episode, GI upset , -jaundice
(Lowplat-75 mg).
 Warfarin alopecia , rash, diarrhea.
(2.5mg/5mg)
 Propranolol  bradycardia , palpitation , bronxhospasm –wheeze
 BIRTH HX 
o Antenatal – maternal SLE/ rash/ DRUG-anticonvulsant /D.M,
o Natal –cyanosis/ delay cry/ 44
 VACCIANTION HX:  EPI/pneumococcal / h.influenza/ paviluzumab –bronchiolitis
 DEVELOPMENTAL HX ( ask in detail each milestones).
 NTUTRITION HX –last 24 hr calories and ususal diet and current diet, growth pattern
 FAMILY HX—consanguiantiy , same issue in sib, mother.

 DISEASE IMPACT –Schooling –play activities, realtion with other peers.
 PARENTS CONCERN
 PARENTS KNOWLEDGE –about management at home and were they advised how to prevent
spells?
 SOCIAL HX—parents eduction , father job . no. of rooms / overcrowding?
 EXAMINATION – (12-13 MIN)

o VITALS
o ANTHROPOMETRICS
o SCARS
o RADIAL PULSE –ABSENT IF B.T SHUNT ON THAT SIDE AND MEAN PATENT
o CONTINOEUS MURMER AT APICES OF LUNG DUE TO SHUNT.
o ANY SCALP SCAR MARK –SURGERY
o CVS EXAMINATION
o RESPO
o ABDOMEN EXAMINATIION
o NEUROLOGICAL EXAMINATION
o DEVELOPMENT/I.Q ASESSMENT
o FUNDOSCOPY
DISCUSSION:
TETRALOGY OF FALLOT
Tetralogy of Fallot is one of the conotruncal family of heart lesions in which the primary defect is an anterior
deviation of the infundibular septum (the muscular septum that separates the aortic and pulmonary outflows).
The consequences of this deviation are the 4 components:
(1) obstruction to right ventricular outflow (pulmonary stenosis).

(2) a malalignment type of ventricular septal defect (VSD).
(3) dextroposition of the aorta so that it overrides the ventricular septum.
(4) right ventricular hypertrophy.
Obstruction to pulmonary arterial blood flow is usually at both the right ventricular infundibulum
(subpulmonic area) and the pulmonary valve.
The main pulmonary artery may be small, and various degrees of branch pulmonary artery stenosis may be
present.
 Complete obstruction of right ventricular outflow (pulmonary atresia with VSD) is classified as an
extreme form of tetralogy of Fallot .
 The degree of pulmonary outflow obstruction determines the degree of the patient's cyanosis and the
age of first presentation.
 In TOFpulmonary blood flow is two thirds normal (Qp:Qs [pulmonary-to-systemic blood flow ratio]
of 0.7 : 1) (Total 3 litre/min/m2 enter in RT atrium –1 litre VSD—lt atrium & 2 litre goes lungs)
45

PATHOPHYSIOLOGY:
o Pulmonary blood flow may be supplied by a patent ductus arteriosus (PDA) or by multiple major
aortopulmonary collateral arteries (MAPCAs) arising from the ascending and descending aorta and
supplying various lung segments.
o The VSD is usually nonrestrictive and large
o The aortic arch is right sided in 20% of cases,
o When the aorta overrides the VSD by more than 50% and if there is a subaortic conus, this defect is
classified as a form of double-outlet right ventricle; however, the circulatory dynamics are the same as
that of tetralogy of Fallot.
o When obstruction to right ventricular outflow is mild to moderate and a balanced shunt is present
across the VSD, the patient may not be visibly cyanotic (acyanotic or “pink” tetralogy of Fallot).
When obstruction is severe, cyanosis will be present from birth and worsen when the ductus begins to
close.
 Infants with mild degrees of right ventricular outflow obstruction may initially be seen with heart
failure caused by a ventricular-level left-to-right shunt.
 cyanosis is not present at birth; but with increasing hypertrophy of the right ventricular infundibulum as
the patient grows, cyanosis occurs later in the 1st yr of life.
 In infants with severe degrees of right ventricular outflow obstruction, neonatal cyanosis is noted
immediately. In these infants, pulmonary blood flow may be partially or nearly totally dependent on
flow through the ductus arteriosus. When the ductus begins to close in the 1st few hours or days of life,
severe cyanosis and circulatory collapse may occur.
 Older children with long-standing cyanosis who have not undergone surgery may have dusky blue skin,
gray sclerae with engorged blood vessels, and marked clubbing of the fingers and toes.
 In older children with unrepaired tetralogy, dyspnea occurs on exertion.
 They may play actively for a short time and then sit or lie down. Older children may be able to walk a
block or so before stopping to rest.
 Characteristically, children assume a squatting position for the relief of dyspnea caused by physical
effort; the child is usually able to resume physical activity after a few minutes of squatting. These
findings occur most often in patients with significant cyanosis at rest.
 Paroxysmal hypercyanotic attacks (hypoxic, “blue,” or “tet” spells) :
o problem during the 1st 2 yr of life.
o The infant becomes hyperpneic and restless, cyanosis increases, gasping respirations ensue,
and syncope may follow.
o The spells occur most frequently in the morning on initially awakening or after episodes of
vigorous crying.
o Temporary disappearance or a decrease in intensity of the systolic murmur is usual as flow
across the right ventricular outflow tract diminishes.
o The spells may last from a few minutes to a few hours.
o Short episodes are followed by generalized weakness and sleep. Severe spells may progress to
unconsciousness and, occasionally, to convulsions or hemiparesis.
o The onset is usually spontaneous and unpredictable.
o Spells are associated with reduction of an already compromised pulmonary blood flow, which,
when prolonged, results in severe systemic hypoxia and metabolic acidosis.
o Infants who are only mildly cyanotic at rest are often more prone to the development of
hypoxic spells because they have not acquired the homeostatic mechanisms to tolerate rapid 46
lowering of arterial oxygen saturation, such as polycythemia.

Rx 
 knee-chest position + remove cloths if tight.

 oxygen (although increasing inspired oxygen will not reverse cyanosis caused by intracardiac
shunting).
 Morphine--subcutaneously in a dose not in excess of 0.2 mg/kg.
 Avoid samplying attempts initially
 Normal saline 10ml/kg.
 NAHCO3 -- when arterial Po2 is <40 mm Hg
o Recovery from the spell is usually rapid once the pH has returned to normal.
o Repeated blood pH measurements may be necessary because rapid recurrence of acidosis may
ensue.
 Drugs that increase systemic vascular resistance, such as:
 intravenous phenylephrine, can improve right ventricular outflow, decrease the right-to-left shunt, and
improve the symptoms.
 Propranolol –i.v (0.1 mg/kg given slowly to a maximum of 0.2 mg/kg) has also been used.
 For spells that are resistant to this therapy intubation and sedation are often sufficient to break the
spell. 
CLINICAL MANIFESTATIONS:
 The pulse is usually normal, as are venous and arterial pressures.

 In older infants and children, the left anterior hemithorax may bulge anteriorly because of long-
standing right ventricular hypertrophy.
 A substernal right ventricular impulse can usually be detected.
 A systolic thrill may be felt along the left sternal border in the 3rd and 4th parasternal spaces. The
systolic murmur is usually loud and harsh.
 . The murmur is generally ejection in quality at the upper sternal border, but it may sound more
holosystolic toward the lower sternal border.
 It may be preceded by a click.
 *The murmur is caused by turbulence through the right ventricular outflow tract.
 It tends to become louder, longer, and harsher as the severity of pulmonary stenosis increases from mild
to moderate; however, it can actually become less prominent with severe obstruction, especially during
a hypercyanotic spell due to shunting of blood away from the right ventricular outflow through the
aortic valve.
 Either the 2nd heart sound is single, or the pulmonic component is soft.
 Infrequently, a continuous murmur may be audible, especially if prominent collaterals are present.
DIAGNOSIS
 CXRAP VIEW boot Shape heart a narrow base, concavity of the left heart border in the area
usually occupied by the pulmonary artery, and normal overall heart size. The hypertrophied right
ventricle causes the rounded apical shadow to be uptilted so that it is situated higher above the
diaphragm than normal and pointing horizontally to the left chest wall.
o The hilar areas and lung fields are relatively clear because of diminished pulmonary blood
flow or the small size of the pulmonary arteries, or both.
o The aorta is usually large, and in about 20% of patients it arches to the right, which results in
an indentation of the leftward-positioned air-filled tracheobronchial shadow in the
47
anteroposterior view.
 ECG RAD+RVH-dominat R wave in v1,2,3 & RsR pattern.-may be only +T wave IN v1 AND v3R./
TALL AND peak T WAVE –Rt ATRIAL HYPERTROPHY.

 ECHOCARDIOGRAPHY.
 CARDIAC CATHATERIZATION /ANGIOGRAPHY –for additional anomelies MAPCAS & IT
demonstrates a systolic pressure in the right ventricle equal to the systemic pressure
 SELECTIVE VENTRICULOGRAPHY.
 CARDIAC CT SCAN.
Complications
 Growth and development may be delayed --particularly when their oxygen saturation is chronically
<70%.
 Puberty may also be delayed in patients who have not undergone surgery.
 Cerebral thromboses:
 usually in the cerebral veins or dural sinuses and occasionally in the cerebral arteries.
 sequelae of extreme polycythemia and dehydration, iron deficiency anemia –all are
common before 2 yr so more common .
 < than 2 yr.
 Rx:
 adequate hydration and supportive measures.
 Phlebotomy and volume replacement with albumin or saline are indicated in
extremely polycythemic patients who are symptomatic.
 BRAIN ABSCESS:
 is less common than cerebral vascular events .
 usually older than 2 yr.
 The onset of the illness is often insidious
 low-grade fever .
 gradual change in behavior.
 headache, nausea, and vomiting. Seizures may occur; localized neurologic signs
depend on the site and size of the abscess and the presence of increased intracranial
pressure.
CT or MRI confirms the diagnosis.
Rx:
 MEDICAL –abscess <2cm/ neurologicaly fit child, no signs of raised ICP, <2 wk duration illness)
o Sulbactum –ampicillin alone
o Or
o 3rd generation cephalosporin + metronidazole (4-6WEEKS)
o Or
o Meropneum +/- vanco to cover MRSA
o Encapsulated abscess—antibiotic +aspiration
Follow up neuro imaging of not decreasing then surgery.
 SURGICAL DRIANAGE:
Indicatons:
o abscess is >2.5 cm in diameter.
o Gas is present in the abscess.
o lesion is multiloculated. 48
o located in the posterior fossa.
o Fungus is identified.

 BACTERIAL ENDOCARDITIS 
o may occur in the right ventricular infundibulum or on the pulmonic, aortic, or, rarely, tricuspid
valves.
o Endocarditis may complicate palliative shunts or, in patients with corrective surgery, any
residual pulmonic stenosis or VSD.
 HEART FAILURE:
o is not a usual feature in patients with tetralogy of Fallot, with the exception of some young
infants with “pink” or acyanotic tetralogy of Fallot. As the degree of pulmonary obstruction
worsens with age, the symptoms of heart failure resolve and eventually the patient experiences
cyanosis, often by 6-12 mo of age. These patients are at increased risk for hypercyanotic spells
at this time.
 ASSOCIATED ANOMALIES
o PDA
o ASD
o Right aortic arch occurs in ≈20% of patients.
o Anomalies of the pulmonary arteries and aortic arch.
o Multiple VSDs.
o artery anomalies are present in 5-10% and can complicate surgical repair.
o may also occur with an atrioventricular septal defect, often associated with Down syndrome.
o Congenital absence of the pulmonary valve produces a distinct syndrome that is usually
marked by signs of upper airway obstruction . Cyanosis may be absent, mild, or moderate;
the heart is large and hyperdynamic; and a loud to-and-fro murmur is present. Marked
aneurysmal dilatation of the main and branch pulmonary arteries results  compression of the
bronchi and produces stridulous or wheezing respirations and recurrent pneumonia. If the
airway obstruction is severe, reconstruction of the trachea at the time of corrective cardiac
surgery may be required to alleviate the symptoms.
o Absence of a branch pulmonary artery, most often the left, should be suspected if the
roentgenographic appearance of the pulmonary vasculature differs on the two sides; absence
of a pulmonary artery is often associated with hypoplasia of the affected lung. It is important
to recognize the absence of a pulmonary artery because occlusion of the remaining pulmonary
artery during surgery seriously compromises the already reduced pulmonary blood flow.
o DiGeorge syndrome /CATCH 22 (cardiac defects, abnormal facies, thymic hypoplasia, cleft
palate, hypocalcemia). Cytogenetic analysis using fluorescence in situ hybridization.
TREATMENT
Goals: improve pulmonary B.flow  prevent hypoxia.
SEVERE TOF IN NEONATE  URGENT MEDICAL AND SURGICAL Rx.

 Blood glucose levels should be monitored because hypoglycemia is more likely to develop in infants
with cyanotic heart disease.
 Neonates with marked right ventricular outflow tract obstruction may deteriorate rapidly because, as
the ductus arteriosus begins to close, pulmonary blood flow is further compromised. The intravenous
administration of prostaglandin E1 (0.01-0.20 ug/kg/min), a potent and specific relaxant of ductal
smooth muscle, causes dilatation of the ductus arteriosus and usually provides adequate pulmonary
blood flow until a surgical procedure can be performed. This agent should be administered
intravenously as soon as cyanotic congenital heart disease is clinically suspected and continued through
the preoperative period and during cardiac catheterization. 49
 Because prostaglandin can cause apnea, an individual skilled in neonatal intubation should be readily
available.

 Infants with less severe right ventricular outflow tract obstruction who are stable and awaiting surgical
intervention require careful observation. Acyanotic patients can fairly quickly progress to having
cyanotic episodes.
 Prevention: or prompt treatment of dehydration is important to avoid hemoconcentration and possible
thrombotic episodes. Oral propranolol (0.5-1 mg/kg every 6 hr) had been used in the past to decrease
the frequency and severity of hypercyanotic spells, but with the excellent surgical results available
today, surgical treatment is now indicated as soon as spells begin.
 Infants with symptoms and severe cyanosis in the 1st mo of life usually have marked obstruction
of the right ventricular outflow tract.
o Two options are available in these infants
o The first is corrective open heart surgery performed in early infancy and even in the newborn
period in critically ill infants. This approach has widespread acceptance today with excellent
short- and long-term results
o Early total repair carries the theoretical advantage that early physiologic correction allows
for improved growth of the branch pulmonary arteries.
 In infants with less severe cyanosis who can be maintained with good growth and absence of
hypercyanotic spells, primary repair is performed electively at between 4 and 6 mo of age.
 Corrective surgical therapy consists of relief of the right ventricular outflow tract obstruction by
resecting obstructive muscle bundles and by patch closure of the VSD. If the pulmonary valve is
stenotic, as it usually is, a valvotomy is performed.
The surgical risk of total correction in major centers is <5%.
Approaches:
o right ventriculotomy was once the standard approach.
o Transatrial-transpulmonary approach is routinely performed to reduce the long-term risks of a
large right ventriculotomy.
 In patients in whom repair has been delayed to childhood, increased bleeding in the immediate
postoperative period may be a complicating factor due to their extreme polycythemia.
 Blalock-Taussig shunt The second option, more common in previous years, is a palliative systemic-
to-pulmonary artery shunt () performed to augment pulmonary artery blood flow.
 The rationale for this surgery, previously the only option for these patients, is to augment pulmonary
blood flow to decrease the amount of hypoxia and improve linear growth, as well as augment growth of
the branch pulmonary arteries.
 The modified Blalock-Taussig shunt is currently the most common aortopulmonary shunt
procedure and consists of a Gore-Tex conduit anastomosed side to side from the subclavian artery to
the homolateral branch of the pulmonary artery .Sometimes the shunt is brought directly from the
ascending aorta to the main pulmonary artery and in this case is called a central shunt.
 The Blalock-Taussig operation can be successfully performed in the newborn period with shunts 3-4
mm in diameter and has also been used successfully in premature infants.
 Postoperative complications after a Blalock-Taussig shunt include chylothorax, diaphragmatic
paralysis, and Horner syndrome. Postoperative pulmonary overcirculation leading to symptoms of
cardiac failure may be caused by too large a shunt.
 Vascular problems other than a diminished radial pulse and occasional long-term arm length
discrepancy are rarely seen in the upper extremity supplied by the subclavian artery used for the
anastomosis.
 After a successful shunt procedure, cyanosis diminishes. The development of a continuous murmur
over the lung fields after the operation indicates a functioning anastomosis. A good continuous
shunt murmur may not be heard until several days after surgery. 50
 As the child grows, more pulmonary blood flow is needed and the shunt eventually becomes
inadequate. When increasing cyanosis develops rapidly, thrombosis of the shunt should be
suspected, often requiring emergent surgery.
 Nutritional rehabilitation –iron supplement keep HB:Hct RATIO OF 1:3

 PROGNOSIS
 After successful total correction, patients are generally asymptomatic and are able to lead unrestricted
lives.
 Uncommon immediate postoperative problems :
o right ventricular failure.
o transient heart block. RBBB > common/ PVC also occur
o residual VSD with left-to-right shunting.
o myocardial infarction from interruption of an aberrant coronary artery.
51

AORTIC STENOSIS
SHORT CASE –displaced apex beat laterally+ suprasternal thrill + first heart sound is normal and
second heart sound is soft with paradoxical splitting on expiration + harsh ESM at RUSB maximium
also radiating to nexk and right midsternal area + poor peripheral pulse and low B.P.
 Congenital aortic stenosis accounts for ≈5% of cardiac malformations

 may be asymptomatic in childhood.
 Aortic stenosis is more frequent in males (3 : 1).
Valvular aortic stenosis (Most common form)
 Left ventricular systolic pressure is increased as a result of the obstruction to outflow. The left
ventricular wall hypertrophies in compensation; as its compliance decreases, end-diastolic pressure
increases as well.
Subvalvular (subaortic) stenosis:
 It is frequently associated  mitral stenosis and coarctation of the aorta (Shone syndrome).
 It is less commonly diagnosed during early infancy .
 Subvalvular aortic stenosis may also be due to a markedly hypertrophied ventricular septum in
association with hypertrophic cardiomyopathy.
Supravalvular aortic stenosis  least common type.
 sporadic, familial, or associated with Williams syndrome which includes mental retardation (IQ
range 41-80), elfin facies (full face, broad forehead, flattened bridge of the nose, long upper lip, and
rounded cheeks) and idiopathic hypercalcemia of infancy Additional features include loquacious
personality, hypersensitivity to sound, spasticity, hypoplastic nails, dental anomalies (partial anodontia,
microdontia enamel hypoplasia), joint hypermobility, nephrocalcinosis, hypothyroidism, and poor
weight gain.
Clinical Manifestations:
 Severe aortic stenosis that occurs in early infancy  critical aortic stenosis and is associated with left
ventricular failure and signs of low cardiac output. Heart failure, cardiomegaly, and pulmonary edema
are severe, the pulses are weak in all extremities, and the skin may be pale or grayish. Urine output
may be diminished. If cardiac output is significantly decreased, the intensity of the murmur at the right
upper sternal border may be minimal.
 Most children with less severe forms of aortic stenosis remain asymptomatic and display normal
growth and development. The murmur is usually discovered during routine physical examination.
Rarely, fatigue, angina, dizziness, or syncope may develop in an older child with previously
undiagnosed severe obstruction to left ventricular outflow. Sudden death has been reported with
aortic stenosis but usually occurs in patients with severe left ventricular outflow obstruction in whom
surgical relief has been delayed.
 The physical findings are dependent on the degree of obstruction to left ventricular outflow.
 Mild stenosis the pulses, heart size, and apical impulse are all normalWith increasing degrees of
severity, the pulses become diminished in intensity and the heart may be enlarged, with a left
ventricular apical thrust.
52
 Mild to moderate valvular aortic stenosis :
o Early systolic ejection click best heard at the apex and left sternal edge Unlike the
click in pulmonic stenosis, its intensity does not vary with respiration.

 Severe stenosis  1st heart sound may be diminished because of decreased compliance of the
thickened left ventricle.
o The 2nd sound may be split paradoxically (becoming wider in expiration).
o 4th heart sound may be audible when the obstruction is severe due to decreased left
ventricular compliance.
o The intensity, pitch, and duration of the systolic ejection murmur are other indications of
severity. The louder, harsher (higher pitch), and longer the murmur, the greater the degree of
obstruction is.
o The typical murmur is audible maximally at the right upper sternal border and radiates to
the neck and the left midsternal border. It is usually accompanied by a thrill in the
suprasternal notch. In patients with subvalvular aortic stenosis, the murmur may be maximal
along the left sternal border or even at the apex.
o Occasionally, an apical short mid-diastolic rumbling murmur is audible; this murmur should
raise suspicion of associated mitral valve stenosis.
Laboratory Findings and Diagnosis
 ECG
o Mild—NORMAL
o MODERATE-SEVERE—LVH (inverted T wave).
 CXR :
o prominent ascending aorta.
o aortic knob is normal.
o Heart size is typically normal.
o Valvular calcification has been noted only in older children and adults.
 ECHOCARDIOGRAPHY.
 CARDIAC CATHATERIZATION:
D/D
COARACTATION OF AORTA –WEAK PULSES IN LOWER EXTREMITIES AND LOW B.P, MURMER AT RT
3RD IC SPACE.
Treatment:
Medical RX –no need of prophylaxis till prosthesis.
Surgical:
 Balloon valvuloplasty
 Ross procedure
 Kono procedure.
moderate to severe valvular aortic stenosis Balloon valvuloplasty gradient between the left
ventricle and aorta exceeds 60-70 mm Hg at rest. surgery a gradient of 40-50 mm Hg or the
presence of aortic insufficiency
balloon valvuloplasty has become the procedure of choice even in the neonatal period.
Surgical treatment is usually reserved for extremely dysplastic aortic valves that are not
amenable to balloon therapy or in patients who also have subvalvar or valvar (also known as
supravalvar) stenosis. 53
 For patients who have aortic stenosis in association with severe tunnel-like subaortic obstruction, the
left ventricular outflow tract can be enlarged by “borrowing” space anteriorly from the right ventricular
outflow tract (the Konno procedure).

 aortic valve replacement is necessary, the choice of procedure often depends on the age of the
patient.—(HOMOGRAFT)—IT MAY CALCIFY
 aortopulmonary translocation (Ross procedure) ; it involves removing the patient's own pulmonary
valve and using it to replace the abnormal aortic valve
PROGNOSIS
 Neonates with critical aortic stenosis may have severe heart failure and deteriorate rapidly to a low-
output shock state. Emergency surgery or balloon valvuloplasty is lifesaving.
 In older infants and children with mild to moderate aortic stenosis, the prognosis is reasonably good,
although disease progression over a period of 5-10 yr is common.
 Patients with aortic valve gradients <40-50 mm Hg are considered to have mild disease.
 In unoperated patients with severe obstruction, sudden death is a significant risk and often occurs
during or immediately after exercise.
 Aortic stenosis is one of the causes of sudden cardiac death in the pediatric age group.
 Patients with moderate to severe degrees of aortic stenosis should not participate in active competitive
sports.
 In those with milder disease, sports participation is less severely restricted. The status of each patient
should be reviewed at least annually and intervention advised if progression of signs or symptoms
occurs.
 Prophylaxis against infective endocarditis is no longer recommended unless a prosthetic valve has
been inserted.
ASSOCIATIONS:
 Marphan syndrome
 Turner syndrome –bicupid aotic valve.
54

RHEUMATIC HEART DISEASE/ FEVER----------------------------------------- ( LONG
CASE)/short case.
PRESENTATIONS: new case/ known case.
NEW CASE APPROACH
Presentations can be:
 Fever
 Joint pain
 Respiratory distress
 Palpitation.
 Generalized body swelling.
 Pallor.
 Chorea
 Altered sensorium/ CVA/ convulsions.
 PUO.
FEVER: duration, onset, character, pattern, documented/not, diurnal variation/ timings, aggravating/ relieving
factors , associations.
JOINT PAIN: duration, onset, migratory/ non migratory, symmetrical/asymmetrical, no. of joints involved, total
no. of joints involved in 6 month?, morning stiffness, joint swelling?,overlying temp and skin change,
aggravating/ relieving factors.
RESPIRATORY DISTRESS: duration, onset, progression, severity, (exertional or at rest or during walking or even
at rest/ lying down?), cyanosis, altered sensorium, cough, PND, chest pain, palpitation.
PALPITATION: duration, onset, timing, aggravating/ relieving factors, any medication before (digoxin usually),
associated with syncope/chest pain.
BODY SWELLING: duration, onset, progression ( start from where and progressed to where with how much
passage of time?), aggravating & relieving factors, associated with respiratory distress, urinary complaint?
PALLOR: duration, onset, associated respiratory distress , peteche, bruise, bleed/ malema/ , blood transfusion?
CHOREA: duration, onset, progression, which part involved most ? is it worsening? Is it involving whole body or
any part/ segment of body? Is it proximal or distal? How it get worse (anxiety, anger, exercise )?, how it sets
down (sleep/ rest/ medication)? , is it associated with emotional lability, dysarthria, dysphagia, dysphasia,
difficulty in eating/ writing etc.?
(ask relevant questions with each presenting complaints)
(LONG CASE HX PROTOTYPE)
Pt...... Yr.....resident of..... Admitted ..... Back thru...... E.R or OPD with PC of..
fever 2 month
body swelling. 1month
respiratory distress. 1month
According to pts mother who is historian he/she was in usual state of health ....back then she had gradual
onset of fever that was undocumented with diurnal variation more At night time relieved by taking medication
but not associated with rigors, chills.
Then 1 month back she had gradual onset of progressive increasing body swelling started from feet to face
with no specific timing relation, with/without aggravating or relieving factors, no associated hx of urinary 55
complaint in form of oligourea, dysurea, headache, then he/she had progressive worsening of respiratory
distress of grade 2 (walking), along with chest pain. Aggravated by walking and running relieved by sitting
down, no hx of nocturnal dyspnea, cough, cyanosis.

No / hx of cough, flu, (URTI), urinary complaint (hematurea), headache,fits, vomiting,altered level of
consciousness,weaknesss of any part of body,hematuria, alopecia/hair loss, oral ulcer, abdominal pain,
photosensitivity ( SLE), l.motions, malena, tenesmus, (IBD), rash, petechae, bruise, bleed,pallor (malignancy),
arthalgia/joint swelling( JIA),, abnormal movements,emotional lability (R.Fever), wt loss, poor appetite, (TB),
jaundice, subcutaneous nodules.
Also he has no/hx of vomiting, inc appetite, palpitation, visual distrubance (steroids+ digoxin), vertigo, tinnitus
,(salicylates),
hospital stay treatment investigations (blood culture/ ECG/ ECHO/ any contineous infusion any change
in management improvement current
status.........................................................................................................................................................................
..................................................................................................................................................................................
..............
Currently he is improved, changed treatment/not,

Parents have fair knowledge regarding disease of pt.
Vaccinated developmentaly normal class ii student, because of his illness, remained absent from school with
significant impact on his family/sibs. parents He is product of consanguious marriage 2nd of 3 siblings no hx of
contact or joint disease/ renal problem in family.his/ her father is labourer by occupation with monthly income
of ......./ month,live in their own house comprising of ....rooms ,kitchen ,washroom,katcha/pakka house,in joint
family system with poor/ proper sanitation/water supply.
KNOWN CASE APPROACH
 Common presenting complaint respiratory distress and that could be due to 1. R.F with
recurrence/activity 2. Anemia 3. I. Endocarditis 4. CHF 5. Intercurent infections which are common.
 Additional information need to ask :
 Complete criteria (E.M, arthritis, chorea, s/c nodules, carditis, fever, arthralgia.)
 When , where diagnosed  what invx done what treatment offered.
 Compliance (detailed medications)
 S/E of medications.
 Advised for prophylaxis to any surgery?
 Advised for dental care?
 Advised ↓salt intake
EXAMINATION APPROACH (COMMON TO BOTH NEW/KNOWN)
Step 1: Hand shake+ gain pts confidence + adequate Exposure.

Step 2: Take height and weight ( ask before for ability to walk and observe gait during this step of height and
weight measurement.)
Step 3: Get back on couch  start Cardiovascular Examination 56
a- Inspection ( look at pts face and chest by side and foot end).
b.Localise apex beat. ( ask about pain before).

c. Trachea position.
d. Left parasternal heave + thrill+ spigastric pulsation+ suprasternal thrill.
e. Auscultation first with diaphragm start at apex then go upto right upper sternal border.
f.auscultate with Bell all areas with same sequenceask to bent left lateral during apex auscultation for M.S-
MDMurmer.
g. ausculate murmer radiation areas.
h. Ask pt to sit and request for leaning forward & breathing inspiration MR >>, on holded expirationfor
A.R>>.
i. look for scar on subscapular on both sides auscultae back for radiation and basal crepts.
j. ask to lie down during this check JVP.
k. Pulse rate then collapsing pulse and comparebrachial pulsefemoral dorsal pedalis Auscultate for
pistol signs
Step 12. Start GPE genereal nutritional statuspalepalmer erythemaclubbingosler nodes janeway
lesionsjoints assessment s/c nodules at extensor elbow jointB.CGB.P Keep thermometer till and
never forget to take back (common mistake ) eyes for jaundice and palor  oral examination with throat (
hygiene) erythema marginatum / rash/ petechae/ bruise over trunk and extremetieslymph node
examinationedema both sacral and pedal.
STEP 13 Full abdomen examination or just for liver and spleen in detail depend upon time.
STEP 14Neurological examination  tonereflexes abnormal movements (chorea) gait already done.
STEP 15 JOINT EXAMINATION IS MUST TO RULE OUT ANY ARTHRITIS/ ARTHRALGIA.
STEP 16 FUNDOSCOPY  Roth spots.
DESCRIPTION OF EXAMINATION:
Examined …… conscious well interactive and co-operative child with maintained I.v line , pink in room
air ,no Obiveous dysmorphism /respiratory distress. ,
pulse rate is………bpm normal in vlume and character , no radio-radial or radio-femoral delay, r/r is ……bpm ,
o
temp is ….. f , b.p ……… mmhg.
rd
height is………cm at 3 centile for his age and gender, wt is……. kg at … centile for his age and gender.
he has obiviously buldging hyperdynamic precordium, no visible scar , pulsation,prominant veins , apex beat is
at 6 th ic space lateral to left MCL, which is heaving in character, with left parasternal heave and thrill however
no evidence of suprasternal thrill and epigasrtic pulsation.
st
1st and 2nd heart sounds are audible, 1 heart sound is soft while S2 of normal intensity , I Hav appreciated
harsh Pansystolic murmer of grade 4/6 audible all over precordium maximium intensity at apical area radiating
towards axilla and accentuating with inspiration . There is also diastolic murmer of 2/4 grade apical area best
heard with Bell of stethoscope, accentuate with holded expiration and leaning forward. with no radiation to
on chest examination there ar bilateral basal crepts.
his pulse rate is 90 bpm it collapsing (high volume) regular with no radio radial or radio femoral delay. B.P.......
mmHg.
he/ she is jaundice, no evidence of pallor, splinter hemorrhage, clubbing ,osler node, Janeway lesions,
peteae,bruise, subcutaneous module, errythema marginatum. Edema and lymphadenopathy.
JVP is raised , oral hygiene is normal.
Abdominal description same.... With abdominal/ epigasrtic pulsation.(A.R)
And there are no pistol signs.
57
Or simply can be used 2 words No signs of CCF/ peripheral stigmata of SBE.
Rest of systemic examination is unremarkable , fundoscope examination is normal.
SUMMARY
K/C of Severe MR & AR most likely due to RHD on secondary prophylaxix now presented with recurrence due

to poor compliance on examination he is failure to thrive afebrile high volume pulse with collapising character,
BP with wide pulse pressure clinical findings suggestive of severe MR & AR with physical stigmatas of IE
NOTE: in RHD long case it is important that along with history ur examination finding of ur pt must be correct
& match with ur examiner & u must be able to read & pick correct CXR &ECG finding b/c RHD is clinical long
case not theoretical however u should know definitions, few big points of managment of RHD
MANAGEMENT
Multi disciplinary Approach
Parental counseling
Rx of heart failure—O2—prop up---Bed rest
Rx of carditis----Anti inflammatory drugs (aspirin/steroids)
Rx of infection—Benzyl pencillins for 10 days
Advice secondary prophylaxis
Good oral hygiene
Prophylaxis against IE
Primordial prophylaxis
Nutritional rehabilitation
Physosocial support
Regular Monitoring &follow up
DISCUSSION:
Q: can u Summarize your pt?

Q: What is your impression?
Q: Is it RHD or R.Fever?
Q: If it is Primary R.F? OR R.F with recurrence?
Q: What are your differentials ?
A: What is the reason of admission ?
Q: How will you investigate?
Q: How will you manage?
Q: What is prognosis of this child?
Q: What is rheumatic fever?

58
A: acute non suppurative immune mediated multisystem inflammation that usually develops 2-3 weeks after
pharangitis caused by rheumatogenic strains (1, 3, 5, 7, 18, and 24) of GABH streptococcus. (Examiner Q) or
Acute illness which fulfill the Bence jones criteria with or without cardiac involvement.

Q: What is prevalence in Lahore & rahimyar khan?
A: urban area schools of inner Lahore studies show 22/ 1000 & rural schools of RYK 4/1000
Q: How many cases have preceding hx of URTI?
rd rd
A: 2/3 have while 1/3 have not.
Q: What is suspected case SABH infection?
A: Any pt <15 yr of age with hx of fever and absence of cough and on examination tonsillar swelling/ exudate
or tender anterior cervical lymph nodes ( 4/5 present then likehood of infection is 50%, 3/5 25% & if 2/5
10%.
Q: how would you differentiate between RHD & rheumatic fever?
A: they both present with carditis , but in rheumatic fever  HX would be short+no failure to thrive+no
precordial buldge/ chest deformity+ no evidence of pulmonary HTN or LVD
Q: for how long symptoms of acute infection/RF can persist?
A: as long as 1 yr.
Q: What are the signs of Activity/recurrence?
A: 1. Disproportionate or resting tachycardia.

2. change of murmer ( need progressive documentation)
3. pericardial rub.
4. CCF.
5.carey coombs murmer.
6. E.M & subcutaneous nodules.
Q: What single sign always mean recurrence?
A: sir it is pericarditis and in pericarditis it is pericardial rub most important considered
Q: what are grades of murmer( systolic)?
A: 6 Grades:
1/6= more concentration needed to hear.
2/6= in quite room easially heard.
3/6 = easially heard murmer.
4/6 murmer with thrill.
5/6= heared even with sides of stethoscope.
6/6= can be audible without steth in quite room.
Diastolic
A: 4 Grades:
1/6= more concentration needed to hear.
2/6= easily heard.
3/6 = loud murmur.
4/6 murmur with thrill
Q: What is recrudence?
59
A: when pt on treatment becomes asymptomatic but again become symptomatic during the same treatment
course due to any cause may be drug resistance/ poor compliance/ inadequate dose
Q: what is recurrence?

A: New episode of RF by another GABHS after 8 weeks of stopping TX
Q: what is Rebound phenomenon?

A: Carditis occurs after tapering Tx or after 4-6 weeks of stopping Tx.
.
Q: What is streptozyme test?
A: ASOT+Anti-DNase+anti-Streptokinase+antihyaluronidase+Nicotiamide Adenosine
dinucleotidase+Antistreptococccal esterase(total 6)
Q: What is the sequence of involvement of valves In RHD?
A: The mitral valve is most commonly and severely affected (65-70% of patients), and the aortic valve is second
in frequency (25%). The tricuspid valve is deformed in only 10% of patients and is almost always associated
with mitral and aortic lesions. The pulmonary valve is rarely affected.AR appears after 10-15 yrs in developed
&<2yrs after RF in developing countries & MS after 20 yrs in developed &within 8 yrs of RF in developing
countries (EXAMINER Q)
Q: What is attack rate of R.F?/how many pts with GABHS pharangitis develops RF?
A: 0.3 – 3%.
Q: What is the Immune mediated & cytotoxic theory of GABHS causing RF?
A: GABHS cell wall contains M proteins (M1,5,6,19) which share same epitope(antigens) with Human Myosin &
topomyosin thus cross react causing inflammation of tissues at different sites where as cytotoxic theory states
GABHS Toxin produce enzyme Anti streptolysin which causes RF..
Q: What is recurrence rate of R.F?
A: if on prophylaxis it is 7% if not it is 70%.
Q: What are WHO Criteia for active carditis?
A: 1. Resting tachycardia 2. Changing murmer 3. Pericarditis.
Q: what is the earliest sign of digoxin toxicity?
A: vomiting other are colored haloes,bradycardia /palpitation, torse de points.
(torso depoints is Polymorphic VT causes VF or sudden drop in BP Rx is Mgso4,anti arrhythmic drug,no DC

conversion b/c polymorphic nature)
Q: What is prerequisty to start digoxin?
A: SERUM K level it should not be hypokalemic.+RFT,s
Q: why pt develop Collapsing pulse in A.R?
A: it happens due to combination of forceful left ventricular ejection volume in early systole followed by
regurgitant flow in early diastole.
60
Q: what is reason of the peripheral stigmata of A.R?
A: peripheral vasodilation and wide pulse pressure+high volume pulses

Q: what is difference between PSM and holosystolic murmer?
A: Holosyastolic murmer sustained equally during whole of systole while PSM not.
Q: Where does venous hump heard in precordium?
A: Best heard below clavicle and disappear by lying down pt , and elevating legs.
Q: How would you differentiate between functional murmur and pathological murmur?
A: functional murmer are always systolic, soft, localized, intensity increased with physiological
manoevers that increase cardiac output , never associated with thrill.
Q: What are causes of S3?
A: occurs normally produced in early diastole at time of rapid ventricular filling and audible at apex with bell.
Seen in hyperdyamic circulation like LV failure, M.R, anemia.
Q: What is S4 sound?
A: occurs late in diastole caused by bolus of blood delivered to ventricles by atrial contraction its produced in
pts with stiff and non compliant ventricles.
Q: which murmer do not decrease with valsalva maneuvers?
A: HOCM & MVP.
Q: which murmer do not diminish with standing?
A: HOCM & MVP while most diminish.
Q: Primary prevention for Rheumatic fever?
A: Benzathine pencillin within 9 days of illness recommended however it can prevent after 9 days patient
considered non contagious 24 hour after induction of therapy.
Q: Which drugs are considered for primary prevention?
A: pencillin erythromycin oral cephalosporin.
Q: Is there any role of tonsillectomy in prevention??
A: no
Q: How would u define rheumatic heart disease?
A: a new or old case without acute rheumatic activity with a valvular lesion confirmed either by reliable
auscultation or echo.
Q: how do you assess the compliance of pt with rheumatic HD?
A: By hx suggesting 14 injections out of 16 in a year, mean 90% of total injection / year.

61
Q:what is tertiary prophylaxis of RHD?
A: antibiotic prophylaxis before any surgery.

Q: what are the Risk factors for RF?
A: overcrowding, poverty,poor health, Malnutrition, poor maternal education
Q: what is primordial prevention?
A: -To prevent Risk factors –overcrownding,improve socioeconomic status,prevent malnutrition.

-public education regarding Risk of RF from pharangitis
Q: what do u mean by primary & secondary prophylaxis? (Examiner Q)
A: primary aim is to treat cardiac infection & secondary is to treat pharangitis.
Q: why patient is in cardiac failure?/what is the common presentation of RHD pt in OPD or emergency?
(Examiner Q)
A: failure may be because of complication of RHD like anemia, infection, infective endocarditis and poor
compliace or recurrence of R.F.
Q: How much ASOT should be elevated?
A: > 320 Todds unit/ml But important is to consider rising titre. It is 80% positive.
Q: how much level for anti DNAase ?
A: > 240.
Q: what is classification of IE?
A: Classification according to location of infection, presence or absence of intra cardiac material and
according to mode of acquisition.
Native valve infective endocarditis , prosthetic valve infective endocarditis, device related IE,
Nosocomial IE, non nosocomial IE, Intra venous drug abuse IE.
Q: What is definitive diagnosis of infective endocarditis?
A: Sir when we have 2 major or 1 major and 3 minor criteria or 5 minor criteria to fulfil is considered as
definitive case of infective endocarditis.
Q: What is possible infective endocarditis?
A: When we have 1 major and 1 major or 3 minor criteria we consider as a possible case.
Q: what are echo findings for IE in major criteria?
A: vegetation, abscess, new partial dehiscence of prosthetic valve, new valvular regurgitant flow.
Q: What are the typical organisms in IE?
A: strep.viridians (s.mutans,S.sanguis,S,mitis), Group D Strept (s. bovis, S,faecalis), staph aureus,
Q: Any organism which is suggestive of IE even on a single blood culture? 62
A: C. Burneti or phase 1 IG Antibody >1:800 titre.
Q: what is most frequent sign or symptom of IE?

A: Fever.
Q: What are vascular phenomenon associated with IE? (Examiner Q)
A: arterial emboli, septic pulmonary infarcts, intracranial hemorrhage, conjunctival hemorrhage,
Janewaylesions
Q: What is embolic/immunologic phenomenon associated with IE?
A: Roth’s spot, osler nodes, splinter hemorrhage, glomerulonephritis, rheumatoid factor,petechae,CNS

involvement
Q: what is Osler nodes,Janeway lesions & Roth spot? (Examiner Q)
A: Osler nodes (tender, pea-sized intradermal nodules in the pads of the fingers
and toes), Janeway lesions (painless small erythematous or hemorrhagic lesions on the palms and
soles) & Roth spot is (hemmorage in retina with pale or white center is Roth spot) Examiner Q
Q: what is complicated IE?
A: Any patient with heart failure, stroke, renal failure, septic shock or periannular complications is
considered to be as a complicated IE.
Q: what are the neurological complications of IE?
A: stroke, aneurysm, TIA.
Q: how to evaluate for neurological complications ?
A: clinical history of neurologica S/S if suggestive then plan for CT/MR angio.
Q: what medications are used for Treatment of IE?
A: it depend upon the C/S report whether pencillin sensitive or resistant, and different protocols we use
standard treatment with Pencillin G, or Amoxcillin, or ceftriaxone for 4 weeks.
Q: what is the treatment for pencillin susceptible organisms in IE?
A: Pencillin G, or Amoxicillin, or ceftriaxone with gentamycin or neomycin for 2 weeks.
Q: at what dose we use gentamycin?
A: 3mg/kg/day i.v/i.m in one dose or 3 equall divided doses.
Q: Any pt with beta lactam group allergy/resistant then?
A: Then we use vancomycin 60mg/kg/day in 2-3 divided doses for 4 weeks.

63
Q: what is nosocomial IE?
A: IE after 48 hour hospital admission.

Q: common organism in native valvular IE?
A: Staph.aureus.
Q: Common organism after dental procedure?
A: Viridian group streptococci.(mutans, sanguis, mitis).
Q: common organism in i.v drug abusers?
A: P.aeruginosa and serratia marcescens.
Q: After open heart surgery?
A: fungi (candida sp, aspergillus, H.capsulatum).
Q: bugs in patients with prosthetic valve?
A: Staphylococcus epidermidis.,staph aures,viridians group on basis of common occurance
Q: bugs in patients with indwelling CVP?
A: coagulase negative
Q: What are common bugs associated with native valve or other cardiac lesions?
A: viridans streptococci (mutans, mitis, sanguis), stap.aureus, group D streptococci (s.bovis, fecalis).
Q: what % of patients are culture negative IE?
A: 6%
Q: what micro organisms are associated with prosthetic valve IE?
A: Staph. Epidermidis,S.aureus.
Q: Which organism produce culture negative Endocarditis?
A: Certain fastidious bacteria like C.Burnetti, brucella, C.Trachomatis C.pneumonae, legionella,

bartonella, and fungi like candida, aspergillus. Their detection require atleast 7 to 10 days to culture
or serological testing.
Q: is it important to take hx of exposure to animals?
A: yes it is to rule out the infections caused by other like C.Burnetti(Q fever),
brucella and P.Sittasi.
Q: what are hemodynamic sequences that lead to formation of non bacterial
thrombotic endocarditis (NBTE)?
A: 3 Basic hemodynamic processes ….. 64
1). high velocity jet which strikes endothelium damage & facialates
adhesion of platelets & fibrin

2). Flow from high to a low pressure chamber (LV-LA, LV-RV, LV-AS)
3). Flow across a narrow orifice at high velocity.
-Bacteremia converts NBTE to IE.
- Bactermia rates are highest after trauma to oral mucosa (ginjiva), as compared to GUT, GU,
and respiratory tract.
Q: What are the peripheral stigmata of infective endocarditis?
A: osler’s node, Roths spot, janeway lesions (all three 5-10%) splinter hemorrhage, petechae (10-40%).
Q: What other conditions are associated with oslers node?
A: NBTE, gonococcal infection and hemolytic anemia.
Q: what are other differentials of IE?
A: ruptured codae tendenae, libman sachs endocarditis, rheumatic valvulitis.
Q: indications of surgery in IE?
A: sir indications for surgical manipulation are:
1).valvular heart failure sec to endocarditis.
2). Persistant infection despite of medical therapy.

th
3. Emboli risk (vegetaion > 15mm/1cm and + fungating masses) ref. nelson 19 edition
4. prosthetic infective endocarditis (s.aureus)
5. perivalvular abscess / infection.
6. Fungal IE.
Q: brushing is associated with bacteremia?
A: yes it is in 20-68% associated with transient bacteremia but that can be prevented by maintaing good
oral hygiene, not indicated prophylaxis.
Q: prognosis?
A: 25% mortality and 50% mortality in documented IE.
Q: complications”?
A: -CCF, myocardial abscess & toxic myocarditis.
-Systemic embolization CNS stroke,TIA. 65
-In VSD/TOF pt: pulmonary emboli.
-Mycotic aneurysm.(infective not usually fungal may b cardiac or extra cardiac)

-Rupture of sinus of valsalva.
-Acquired VSD.
-Heart block.
-Meningitis, arthritis, renal abscess, GMN.
Manifestations of Infective Endocarditis
HISTORY
Prior congenital or rheumatic heart disease

Preceding dental, urinary tract, or intestinal procedure
Intravenous drug use
Central venous catheter
Prosthetic heart valve
SYMPTOMS
Fever
Chills
Chest and abdominal pain
Arthralgia, myalgia
Dyspnea
Malaise
Night sweats
Weight loss
CNS manifestations (stroke, seizures, headache)
SIGNS
Elevated temperature
Tachycardia
Embolic phenomena (Roth spots, petechiae, splinter nail bed hemorrhages, Osler nodes, CNS or ocular
lesions)
Janeway lesions
New or changing murmur
Splenomegaly
Arthritis
66
Heart failure
Arrhythmias
Metastatic infection (arthritis, meningitis, mycotic arterial aneurysm, pericarditis, abscesses, septic

pulmonary emboli)
Clubbing
LABORATORY
Positive blood culture ( 90% sensitivity)

Elevated erythrocyte sedimentation rate; may be low with heart or renal failure
Elevated C-reactive protein
Anemia
Leukocytosis
Immune complexes
Hypergammaglobulinemia
Hypocomplementemia (+ve in immune complex glomerulonephritis) (EXAMIER Q)
Cryoglobulinemia
Rheumatoid factor(indicate severity of renal involvement) (EXAMINER Q)
Hematuria
Renal failure: azotemia, high creatinine (glomerulonephritis)( <15% common)
Chest radiograph: bilateral infiltrates, nodules, pleural effusions
Echocardiographic evidence of valve vegetations, prosthetic valve dysfunction or leak, myocardial
abscess, new-onset valve insufficiency (80% sensitivity) (EXAMINER Q)
The Duke criteria help in the diagnosis of endocarditis.
Major criteria include
(1) Positive blood cultures (two separate cultures for a usual pathogen, two or more for less typical pathogens)
(2) evidence of endocarditis on echocardiography (intracardiac mass on a valve or other site, regurgitant flow
near a prosthesis, abscess, partial dehiscence of prosthetic valves, or new valve regurgitant flow).
Minor criteria include
- predisposing conditions.(iv drug users,cardiac etc)

- Fever. 101 F> 5 days
- embolic-vascular signs, immune complex phenomena (glomerulonephritis, arthritis, rheumatoid
factor, Osler nodes, Roth spots).
- a single positive blood culture or serologic evidence of infection, and echocardiographic signs not
meeting the major criteria.
-
Two major criteria, one major and three minor, or five minor criteria suggest definite endocarditis
The following minor criteria are added to those already listed:
- presence of newly diagnosed clubbing. 67

- Splenomegaly.
- splinter hemorrhages.
- Petechiae.
- a high erythrocyte sedimentation rate.
- high C-reactive protein level.

- presence of central nonfeeding lines, peripheral lines.
- microscopic hematuria.
TREATMENT OF INFECTIVE ENDOCARDITIS

- High serum bactericidal levels must be maintained long enough to eradicate organisms that are growing
in relatively inaccessible avascular vegetations.
- Several weeks are required for a vegetation to organize completely; therapy must be continued through
this period so that recrudescence can be avoided.
- A total of 4–6 wk of treatment is recommended
- With highly sensitive viridans group streptococcal infections, shortened regimens that include oral
penicillin for some portion have been recommended.
- In nonstaphylococcal disease, bacteremia usually resolves in 24–48 hr, whereas fever resolves in 5–6
days with appropriate antibiotic therapy. Resolution with staphylococcal disease takes longer.
- Digitalis, salt restriction, and diuretic therapy are used for the treatment of heart failure.
Surgical intervention for infective endocarditis is indicated for severe aortic or mitral valve
involvement with intractable heart failure.
Therapy of Native Valve Endocarditis Caused by Highly Penicillin-Susceptible Viridans Group

Streptococci and Streptococcus bovis
DOSAGE[*] AND DURATION,
REGIMEN ROUTE WK COMMENTS
Aqueous penicillin 4 Preferred in patients with impairment of 8th cranial nerve
crystalline 200,000 U/kg per function or renal function
penicillin G 24 h IV in 4–6
sodium equally divided
doses;
Or
Ceftriaxone 100 mg/kg per 4
sodium 24 h IV/IM 1 dos
Aqueous penicillin 2 2 wk regimen not intended for patients with known
crystalline 200,000 U/kg per cardiac or extracardiac abscess or for those with
penicillin G 24 h IV in 4–6 creatinine clearance of <20 mL/min, impaired 8th cranial
sodium equally divided nerve function, or Abiotrophia, Granulicatella, or
doses; Gemella spp infection; gentamicin dosage should be
adjusted to achieve peak serum concentration of 3–4
Or
μg/mL and trough serum concentration of <1 μg/mL
Ceftriaxone ceftriaxone 100 2 when 3 divided doses are used; nomogram used for
sodium mg/kg per 24 h single daily dosing
IV/IM in 1 dose;
Plus
Gentamicin 3 mg/kg per 24 h 2
sulfate[‡] IV/IM in 1 dose,
or 3 equally
divided doses
Vancomycin Pediatric dose: 4
hydrochloride[¶] 40 mg/kg per 24
68
Vancomycin therapy recommended only for patients
h IV in 2–3 unable to tolerate penicillin or ceftriaxone; vancomycin
equally divided dosage should be adjusted to obtain peak (1 h after
doses infusion completed) serum concentration of 30–45

DOSAGE[*] AND DURATION,
REGIMEN ROUTE WK COMMENTS
μg/mL and a trough concentration range of 10–15 μg/mL
Therapy for Endocarditis Caused by Staphylococci in absence of Prosthetic Valve

DURATION,
REGIMEN DOSAGE[*] AND ROUTE WK COMMENTS
OXACILLIN-SUSCEPTIBLE STRAINS
Nafcillin or nafcillin or oxacillin 200 6 weeks
oxacillin mg/kg per 24 h IV in 4–6 cefazolin may be substituted for nafcillin or
equally divided doses oxacillin in patients with non-immediate-type
hypersensitivity reactions to penicillins
Plus
Gentamicin[†] 3 mg/kg/day IV/IM 2/ 3 3-5 days
ddose
OXACILLIN-RESISTANT STRAINS
Vancomycin 40 mg/kg per 24 h IV in 2 6 weeks Adjust vancomycin to achieve 1-h serum
or 3 equally divided doses concentration of 30–45 μg/mL and trough
concentration of 10–15 g/mL (see text for
gentamicin alternatives)
PREVENTION.
- Antimicrobial prophylaxis before various procedures and other forms of dental manipulation may
reduce the incidence of infective endocarditis in susceptible patients.
- Continuing education regarding prophylaxis is important, especially in teenagers and young adults,
who often have poor knowledge of their own congenital heart lesion.
- Proper general dental care and oral hygiene are most important in decreasing the risk of infective
endocarditis in susceptible individuals.
- Vigorous treatment of sepsis and local infections and careful asepsis during heart surgery and
catheterization reduce the incidence of infective endocarditis.
2007 STATEMENT OF THE AMERICAN HEART ASSOCIATION (AHA): CARDIAC CONDITIONS

ASSOCIATED WITH THE HIGHEST RISK OF AN ADVERSE OUTCOME FROM INFECTIVE
ENDOCARDITIS FOR WHICH PROPHYLAXIS WITH DENTAL PROCEDURES IS REASONABLE
Prosthetic cardiac valve or prosthetic material used for cardiac valve repair
Previous infective endocarditis
CONGENITAL HEART DISEASE (CHD)* 69
Unrepaired cyanotic CHD, including palliative shunts and conduits

Completely repaired CHD with prosthetic material or device, whether placed by surgery or
catheter intervention, during the first 6 mo after the procedure [†]
Repaired CHD with residual defects at the site or adjacent to the site of a prosthetic patch, or
prosthetic device (which inhibit endothelization)
Cardiac transplantation recipients who develop cardiac valulopathy
*
Except for the conditions listed here, antibiotic prophylaxis is no longer recommended by the AHA for any
other form of CHD.
†
Prophylaxis is reasonable because endothelization of prosthetic material occurs within 6 mo after the
procedure.
Recommendations of the American Heart Association for Prophylaxis Against Bacterial Endocarditis
DENTAL AND ORAL PROCEDURES OR SURGERY OF THE UPPER RESPIRATORY tract
For most patients Oral amoxicillin

Adults, 2.0 g, children, 50 mg/kg 1 hr before
procedure
For patients unable to take oral medication IM or IV ampicillin

Adults, 2.0 g, children, 50 mg/kg given within 30 min
before procedure
Ampicillin- and amoxicillin-allergic patients Oral clindamycin
Adults, 600 mg, children, 20 mg/kg 1 hr before
procedure
Or
Oral cephalexin[*] or cefadroxil[*]
Adults, 2.0 g, children, 50 mg/kg 1 hr before
procedure
Or
Oral azithromycin or clarithromycin
Adults, 500 mg, children, 15 mg/kg 1 hr before
procedure
Ampicillin- and amoxicillin-allergic patients unable to IV clindamycin
take oral medications 70
Adults, 600 mg, children, 20 mg/kg given within 30
min before procedure
Or

DENTAL AND ORAL PROCEDURES OR SURGERY OF THE UPPER RESPIRATORY tract
IV cefazolin
Adults, 1.0 g, children, 25 mg/kg given within 30 min

before procedure
High-risk patients: (EXAMINER Q)
- prosthetic heart valves (including homografts)

- previous endocarditis.
- complex cyanotic congenital heart disease (e.g., transposition of great vessels, tetralogy of Fallot,
single ventricle).
- systemic-to-pulmonary artery shunts or conduits.
Moderate-risk patients: most other congenital heart diseases (other than those specifically listed previously
or further on),
- acquired valve dysfunction (e.g., rheumatic heart disease)

- hypertrophic cardiomyopathy.
Negligible-risk patients (prophylaxis not recommended):
- isolated secundum ASD.

- surgical repair of ASD, VSD, or PDA (without residua and beyond 6 mo after repair); previous
coronary artery bypass surger.
- functional heart murmurs.
- previous Kawasaki disease or rheumatic fever without valve dysfunction.
- cardiac pacemakers.
- implantable defibrillators.
NOTE: The risk of mitral valve prolapse is controversial. The latest American Heart Association
recommendations categorize mitral valve prolapse with regurgitation or thickened leaflets, or both, as a
moderate risk; mitral valve prolapse without regurgitation is categorized as negligible risk.
PROCEDURES AND ENDOCARDITIS PROPHYLAXIS (EXAMINER Q)

ENDOCARDITIS PROPHYLAXIS ENDOCARDITIS PROPHYLAXIS NOT
RECOMMENDED[*] RECOMMENDED
Dental Dental
Tooth extractions Restorative dentistry[‡] (operative and prosthodontic)
with or without retraction cord[§]
Periodontal procedures, including surgery, Local anesthesia injections (non-intraligamentary)
scaling and root planing, probing, and recall
maintenance
Dental implant placement and re-implantation Intracanal endodontic treatment, after placement and
of avulsed teeth buildup
Endodontic (root canal) instrumentation or Placement of rubber dams
surgery only beyond the apex
Subgingival placement of antibiotic fibers or Postoperative suture removal 71
strips
Initial placement of orthodontic bands but not Placement of removable prosthodontic or orthodontic
brackets appliances

Intraligamentary local anesthesia injections Taking of oral impressions
Prophylactic cleaning of teeth or implants Fluoride treatments
when bleeding is anticipated
Respiratory Tract Taking of oral radiographs
Orthodontic appliance adjustment
Tonsillectomy or adenoidectomy, or both
Shedding of primary teeth

Surgical operations that involve respiratory
mucosa
Bronchoscopy with a rigid broncoscope Respiratory Tract

Endotracheal intubation
Bronchoscopy with a flexible bronchoscope, with or

without biopsy[§]
Tympanostomy tube insertion

NOTE:It is not for any gastro or genitourinary procedures nowadays
DIFFERENCE BETWEEN ACUTE & SUBACUTE INFECTIVE ENDOCARDITIS
Acute Infective Endocarditis v/s Subacute Infective Endocarditis
1- s.aureus most common cause 1- strept viridans (most common cause )

2- previous normal valve 2- previous abnormal valve
3- large bulky vegetation 3- small vegetation
4- IV drug user major RF 4- RF (vsd -stenosis- prosthetic-
5- rapid onset of fever or sepsis 5- slow onset of symptoms

associated with splenomegaly & embolic events.
Infective Endocarditis: Most common infective microorganisms
Here's a mnemonic that can help

natiVe valve ---> Streptococcus Viridans
Prosthetic valve ---> Staphylococcus ePidermidis
Drug Addicts ---> Staphylococcus Aureus
Please note that Viridans group of streptococci include the following:

S. mitis, S. mutans, S. sanguis, and S. salivarius. S. mutans is famous after dental procedures.
DIAGNOSTIC CRITERIA FOR RHEUMATIC FEVER

72
Modified Jones criteria were first published in 1944 by T. Duckett Jones, MD. They have been periodically
revised by the American Heart Association in collaboration with other groups. According to revised Jones
criteria, the diagnosis of rheumatic fever can be made when two of the major criteria, or one major criterion
plus two minor criteria, are present along with evidence of streptococcal infection. Exceptions are chorea ,
indolent carditis and recurrence, each of which by itself can indicate rheumatic fever

Major criteria
- Migratory polyarthritis:( 75%) a temporary inflammation of the large joints, usually lasts for 1-5
days in single joint then disappear, usually starting in the legs and migrating upwards,
asymmetrical extremely painful red ,non deforming but responds well to salicylates (hallmark)
(ARTHRITIS=painfull+swollen+tender where as Arthralgia only pain))
- Carditis: (50-60%) inflammation of the heart muscle usually manifest as pancarditis.Myocarditis
=manifest as congestive heart failure either RVF or LVF with shortness of breath,tachycardia. It
is most common cause of death in RF. pericarditis (fibrinous) manifest as sharp pain localized
relieved on leaning forward (esp feature) with a rub. Endocarditis appears as vegetations on
valve which does not embolize,heals by fibrosis causing residual damage fuse valve cusps
Subcutaneous nodules: (<1%) painless pea size range from 0.5-2cm, firm collections of collagen
fibers over bones or tendons. They commonly appear on the back of the wrist, the outside elbow,
and the front of the knees. They come after 1-2 weeks,persist from days to 1–2 weeks to, rarely,
more than a month. Associated with Severe carditis & recurrence.
- The nodules are not pathognomonic of RF; similar lesions occur inSLE and rheumatoid arthritis
but usually large in size
- Erythema marginatum: (<3%)., appear first as a bright pink macule or papule that spreads
outward in a circular or seripiginouS pattern. The lesions are multiple, appearing on the
trunk or proximal extremities, rarely on the distal extremities, and never on the face.
- They are nonpruritic and nonpainful, blanch under pressure, and are only rarely raised.
- Individual lesions may come and go in minutes to hours,
- they have been described as appearing like “smoke rings” beneath the skin.
- Erythema marginatum usually occurs early in the course of a rheumatic
- attack. It may, however, persist or recur for months or even years, continuing after other
manifestations of the disease have subsided,and it is not influenced by anti-inflammatory therapy.
- This cutaneous phenomenon is associated with chronic carditis but, unlike subcutaneous
- nodules, not necessarily with severe carditis
- Sydenham's chorea (St. Vitus' dance): (10-15%) characteristic series of rapid movements
without purpose of the face and arms. This can occur very late in the disease usually 6-12yeras
after RF common in girls.It is self limiting usually lasts for 6 months to 3 years.CT scan not
routinely advised. Tx is valproic acid 15-20mg/kg/day, carbamazepine 7-20mg/kg/day, both
preferred over haloperidol..
Minor criteria
- Fever -38C
- Arthralgia: Joint pain without swelling
- Raised Erythrocyte sedimentation rate or C reactive protein >30 mm/hr (Normal-10mm/hr)
- Leukocytosis
- ECG showing features of heart block, such as a prolonged PR interval.(Normal PR interval 0.16
sec in 3-12years & 0.18 sec in 12-16 years)
- Supporting evidence of Streptococcal infection: elevated or rising Antistreptolysin O titre >200
Todds unit or DNAase.
- Previous episode of rheumatic fever or inactive heart disease.
PATHOGENESIS:
Rheumatic fever is a systemic disease affecting the peri-arteriolar connective tissue and can
occur after an untreated Group A Beta hemolytic streptococcal pharyngeal infection. It is believed to be
caused by antibody cross-reactivity. This cross-reactivity is a Type II hypersensitivity reaction and is
termed molecular mimicry. Usually, self reactive B cells remain anergic in the periphery without T cell
co-stimulation. During a Strep. infection, mature antigen presenting cells such as B cells present the
bacterial antigen to CD4-T cells which differentiate into helper T 2 cells. Helper T2 cells subsequently
activate the B cells to become plasma cells and induce the production of antibodies against the cell wall 73
of Streptococcus. However the antibodies may also react against the myocardium and joint ], producing
the symptoms of rheumatic fever.

- Not all of the serotypes of GAS can cause rheumatic fever.
- When some strains (M type 4) were present in a very susceptible rheumatic population, no recurrences
of rheumatic fever occurred
- The concept of rheumatogenicity is further supported by the observation that although serotypes of
GAS frequently associated with skin infection are often isolated from the upper respiratory tract, they
rarely cause recurrences of rheumatic fever in individuals with a previous history of rheumatic fever.
- certain serotypes of GAS (M types 1, 3, 5, 6, 18, 24) are more frequently isolated from patients with
acute rheumatic fever than are other serotypes
NOTE: ESR usually remain elevated for 4-8weeks, so used for follow up 1-2 times a week during admission &
1-2 weeks after discharge.It is NON-specific marker during CCF.(EXAMINER Q)..CRP not affected in CCF,
transient rapidly cleared so not significant in follow up..
Q;What are the causes Of Normal ESR in RF?
A: chorea,severe carditis & CCF..
NOTE:ASOT rises after 1-2 weeks max rise 3-6 weeeks after infection ,after 6-8 weeks falls takes 6 months to
1year to become normal where as Anti Dnase max rise 6-8 weeks after infection, falls after 3 months,remains
elevated longer…
Q: what are the causes of Normal ASOT in RF?
- A: Chorea
- 20% pts have negative
- S/C nodule
- Indolent carditis.
- Treated case
- In 1st week or after 5 weeks
Advise : go for AntiDNAse B >98% positive & ASOT is 80% +ve in RF
Q:what is the natural course of RF ?EXAMINER Q
A: All (skin rash,s/c nodules,joints,chorea ,myocaritis,pericarditis) resolve completely,only endocardium heals

by fibrosis causing residual damage
Q:what is indolent (silent ) carditis ? Examiner Q
A: common in our country ,pts presents with persistant features of CCF,cardiomegaly,murmur but no feature of
active carditis OR arthritis with ECHO evidence of MR & AR.
Q:what is subclinical carditis ? EXAMINER Q 74

A: clinical Examination normal,ECHO abnormal ..It occurs in CHOREA

What is carry coombs mumur in RF ?
A:diastolic murmur at Apical area in RF behaves as Mitral stenosis occurs in active carditis due to mitral valve
edema,
Q: what is ECG finding in active RF? EXAMINER Q
A: sinus tachycardia
Prolong PR & QT interval
Narrow QRS complex
Elevation of ST segment
T wave inversion (pericarditis)
Q: what will u see in ECHO in pt of RF? EXAMINER Q
A: Evaluate severity of RF
Measure cardiac (LV) size & Function (EF)
Assess Severity Of MR, AR as mild , moderate & severe MR,AR
Visualize valve Anatomy or valve damage
2002–2003 WHO criteria for the diagnosis of rheumatic fever and rheumatic heart disease (based on the
revised Jones criteria3,4)
Diagnostic categories Criteria

- Primary episode of RF Two major *or one major and two minor**
manifestations plus evidence of a
preceding group A streptococcal infection***.
- Recurrent attack of RF in a patient without Two major or one major and two minor
- established rheumatic heart disease.b manifestations plus evidence of a preceding group
A streptococcal infection.
- Recurrent attack of RF in a patient with Two minor manifestations plus evidence of

established rheumatic heart disease. a preceding group A streptococcal infection
- Rheumatic chorea. Other major manifestations or evidence of

A streptococcal infection not required.
75
- Insidious onset rheumatic carditis.group
Chronic valve lesions of RHD patients Do not require any other criteria to be

mitral stenosis or mixed mitral valve disease. (presenting for the first time with pure
diagnosed as disease and/or aortic valve disease).d having
rheumatic*
Q:what is definite RF ?
A: RF primary or recurrent having 2 major or 1major & 2 minor criteria + ASOT
Q:what is probable RF ?
A:First or recurrent having ↓ 1 major or 1 minor criteria + no ASOT raise but still suspecting RF
CLINICAL SIGNS OF SEVERE M.R( EXAMINER Q)
- Chest deformity.
- High volume pulse
- Wide pressure Bp
- Displaced apex beat.
- Harsh murmer of grade 4/6 (murmer + thrill)
- Pulmonary HTN.
- Apical diastolic rumbling murmer.
- RVH Heave
- RH.Failure.
CLINICAL SIGNS OF SEVERE A.R
- Collapsing pulse with pistol shot femorals , head nodding, dancing carotids, muller sign.
- Grade > 2/4 diastolic murmer.
- Liver + edema.
American Heart Association CLASSIFICATION FOR DYSPNEA
-
Grade:1.on running.
- 2. on upstairing
- 3.normal activity
- 4. sitting
D/D OF A CHILD 5-10 YR WITH POLYARTHRITIS + FEVER
- ARF
- JIA
- IE
- SLE
- LEUKEMIA/MALIGNANCY
Causes of Migratory arthritis
- RF
- Gonococcemia
- Meningococcermia
- Viral arthritis
- Systemic lupus erythematosus
- Acute leukemia
- Whipple’s disease 76
Effusion disproportionately greater than pain
Bacterial endocarditis

- Inflammatory bowel disease
- Giant cell arthritis
- Lyme disease
- Tuberculosis arthritis
Pain disproportionately greater than effusion
- RF
- Familial Mediterranean fever
- Acute leukemia
Positive test for rheumatoid factor
- Rheumatoid arthritis
- Viral arthritis
- Tuberculous arthritis
- Bacterial endocarditis
- Systemic lupus erythematosus
- Sarcoidosis
- Systemic vasculitis
- Viral arthritis
INDICATIONS OF STEROIDS IN RHEUMATIC FEVER
- panCarditis
- carditis+CCF
- Carditis+cardiomegaly
- Carditis+MR.AR murmur
- Not responding to aspirin
RX
- bed rest.
-anti-failure rx.
- steroid ( 2mg/kg)–4 wks good git absorption.
after 4 week if good result by failure improvement activity subsided then start aspirin 1 week
before start of lowering the steroid dose to prevent from rebound phenomenon, then discontinue
steroid, & this started aspirin would be discontinued after 1 month/6 week when all clinical & lab
parameters come towards normality
.
Q:What is the indication of Aspirin In RF?
A: Mild carditis ( only tachycardia)
Arthritis +↑ ESR + ASOT
Arthralgia++↑ ESR + ASOT

77
Dose :100mg/kg/day for 3-5 days then 75mg/kg/day for 4 weeks,If no response in 3 days then start steroids

NOTE: FOR ARTHRITIS we start Brufen or naproxen 10-20mg/kg/day if proven migratory then aspirin for 2
weeks may be for 6 weeks if rebound phenomenon occurs
CRITERIA FOR ENDING ABSOLUTE BED REST AND REDUCING THE DOSE OF SUPPRESSION
THERAPY.
- NORMAL TEMPERATURE.
- ABSENCE OF JOINT SYMPTOMS AND SIGNS
- ABSENCE OF RESTING TACHYCARDIA
- NO CCF
- STABLIZATION OF MURMER AND HEART SOUNDS.
- DECREASING HEART SIZE
- ESR < 25 mm.
- NEG CRP
- PR RETURN TO NORMAL
Aim of bed rest is to decrease duration of carditis, prevent cardiomegaly & relapse…
In some books bed rest advised 2 weeks for arthritis and 4 weeks for carditis
SECONDARY PREVENTION OF RHEUMATIC FEVER
Route of Administration Antibiotic Dose Frequency
Intramuscular Benzathine penicillin G 6- 1,200,000 U
Every 3-4 wk
OralPenicillin V250 mgTwice daily
Sulfadiazine500-1000 mgOnce daily
Erythromycin250 mgTwice daily
FOLLOW UP RHD AFTER PROPHYLAXIS
1 yearly Dr Review
1 yearly Dental Review 78
2 yearly ECHO in children
3 yearly in Adults

FACTORS PRECEPITATE CCF IN RHD
- Poor compliance
- Recurrence
- Intercurent infection
- Anemia
- Infective endocarditis
- Arrhythemia
- Decompensation of valve.
-
Q: how would u check sensitivity Of B.pencillins ?
A:Empty the vial of B.pencillins, ,insert 5ml of D/W take 0.1ml of it inject S/C or put drop of it in eye to check
sensitivity.
Q: what is the side effect of B.pencillin?
A: Pain
MITRAL REGURGITATION (MR)
- During acute rheumatic fever with severe cardiac involvement CCF occurs due to pancarditis and MR,
initially signs of left heart failure then spontaneous improvement usually occurs even in pt with severe
MR at onset.
- Acute M.R ½ Pts have no murmer after 1 yr.
- Chronic M.Rmild-moderateasymptomatic.
SevereUltimately go into RHF.
CLINICAL PRESENTATION:
- MILD CASES: only have holosystolic murmer which radiate to axilla with no thrill even , no signs of
CCF, and quite precordium.
- SEVERE M.R they have Signs of Chronic CCF enlarged heart, heaving apex, loud 2nd heart
sound, apical systolic thrill+, and holosystolic murmer which radiate to axilla, other additional murmer
is short mid diastolic rumbling murmer ( due to inc flow across mitral valve due to insufficiency.) this
murmer should be well differentiated because it may arise the question of M.S which had an opening
snap and diastolic murmer of greater length comparatively, takes years to develop+taping apex beat .
ECG findings:
- Mild= normal
- Severe=bifid P wave(P-mitrale) LAD+ LVH&RVH if pulm HTN develops.
CXR findings: LA enlarged/ LV dilated indicate severity.
D/D:
- RHD leading to M.R pts age is supportive+ more prevalent cause of M.R is Rheumatic and Typical
findings of M.R with radiation to axilla. 79
- DCMP with M.R muffled heart sounds+poor pulses.
- CONGENITAL M.Rrare same feature (cleft in mital valve)
- CONGENITAL MVPlate systolic murmer with ejection click.
TREATMENT:

- Mild= Secondary prophylaxis only
- Severe= Medical Rx of CCF, IE. (Antifailure + antibiotics)
- Surgery = indications:
 Recurrent CCF despite of medical Rx.
 FTT.
 Pul HTN.
 Cardiomegally.
 Exercise intolerance
 E.F <60%.
o Annuloplasty good results.
o Valve replacement.
- PROGNOSIS acute M.R >50% Regress.
AORTIC REGURITATION (AR)
- Presentation: palpitation, excessive sweating, heat intolerance, dyspnea on exertion, orthopnea,

pulmonary edema.
- Nocturnal attack: sweating, tachycardia, chest pain, HTN may occur.
- On examination:
- wide pulse pressure.
- bounding peripheral pulse,
- displaced downward and outward + ill sustained heaving apex beat (severe A.R), soft A2, (We say
soft S1 on examination).
- Early diastolic murmer on A2 area that can be audible along left sterna border , it is high pitched
accentuate during expiration, During examination ask the patient to lean forward and hold breath on
expiration.
- A mid diastolic murmer may be heard at apex (Austin flint murmer which occurs due to large flow
from AR during diastole that prevents from mitral valve to open).
- There may be ejection systolic murmer because of inc stroke volume.
Murmers audible in A.R
- diastolic murmer aotic areaaccentuate with expiration and leaning forward
- mid diastolic murmer apex
PERIPHERAL SIGNS OF A.R (Produced due to wide pulse pressure).
- water hammer pulse high volume collapsing pulse .
- quincke’s sign: visible capillary pulsation checked by applying pressure to tip of fingers or nails
result in alternate flushing and pallor of nail bed. (other less practical method is by glass slide when
pressed over everted lower lip  produces alternating redness and blanching.
- prominat digital pulsation: flex finger feel pulsations at tip.
- blood pressure: wide pulse pressure with low diastolic pressure.
- corrigan’s sign: dancing carotids in neck
- de mussets sign: head nodding due to carotid pulsation.
- traube’s sign: pistol shot sign heard over femoral with steth diaphragm.
- hills sign: (very important and specific sign for A.R)increase in femoral systolic B.P > 20 mmHg
above the brachial artery systolic pressure. (normal –within 20mmHg, if > 60 mmHg then indicate
severe A.R).
- muller sign: pulsation in uvula .
- There are also other signs but practically not common like duroziez’s sign diastolic murmer on distal
compression of femoral artery. Bosenbacks sign pulsation in liver/ Gerhardts sign pulsation in
enlarged spleen.
DIFFERENTIALS:
- VSD with A.R systolic murmer of VSD and diastolic A.R
- PDAcontinous murmer with systolic thrill
- MR systolic murmer at apex transmitted to axilla , no peripheral stigmata like A.R.
- Reduced peripheral resistance:AV fistula, anemia , hyperthyroidism. 80
- IE +A.R
TREATMENT:
- Medical: antifailure Rx. (ACEI)+ sec and tertiary prophylaxis.
- Surgical : Indications:
 severe AR with intractable CCF inspite of Absence of carditis

 Dec E.F.
 when early signs of CCF develop or pt develop angina changes detected by ST/ T
wave changes.
- valve replacement
- PROGNOSIS: unlike M.R , AR does not regress, like any pt with acute rheumatic fever with
combined findings of M.R and AR the M.R would be regressed in 50% cases while A.R will persist.
MITRAL STENOSIS
Takes 10 yr or more to develop but in developing countries it can be early

M.SPressure and enlarged LABlood goes to pulm. Veins pressure inc  pulmonary vascular
resistance, pulmonary HTN RV+atrial dilatation right side heart failure.
CLINICAL PRESENTAION:
- MILD Asymptomatic.
- SEVERE dyspnea, orthopnea, exercise intolerance.
- AUSCULATATION: loud 1st HS, tapping apex beat, opening snap of MV, Low pitched
rumbling mid diastolic murmer with pre systolic accentuation at apex more during left
lateral position, holosystolic murmer due to TR may be +.
LAB:ECG—RAD+RVH (prominent R in V1,S wave in V5)+P-MITRALE+LAH

CXR: left heart border straight+pulmonary edema+prominent
pulmonary trunk
TREATMENT: Indications of surgery in MS
Grade 3 MS
Symptomatic MS
MS with pandiastolic Murmur
MS with PH
EF slope <15 mm
Rx; surgical valvotomy or balloon catheter mitral
valvuloplasty./PTMC(percutaneous transmitral commisurectomy)
GRADES OF MS
Grade 1
Asymptomatic
With Signs of MS
Gradient <5 mmHg
Grade 2
Dyspnea on exertion
With signs of MS
Gradient 5-15mmHg
Grade 3
Dyspnea at rest
Severe PH
Intractable CCF
With signs of MS
Gradient >15mmHg
MISCELLANEUS FACTS R.F/RHD.

81
- Streptococci may be alpha (partial hemolysis green coloured) beta (complete hemolysis clear)
and gamma (no hemolysis).
- Indication of surgery  apex beat displace >0.5 cm/yr.
- Rt sided heart lesion accentuate on inspiration/ left sideexpiration.

- Murmer of M.R,VSD, AR increase with handgrip exercise.
- 3 components of pericardial rub 1 is systolic 2 are diastolic
- Pericardial rub can be systolic (louder), diastolic and audible even holded breathing  point to
differentiate for pleural rub.
- Friction rub is best heard in maintained expiration with patient leaning forward
- Apex beat is defined as the lower most and outermost part of the heart where definite pulsation of
heart.
- The rate of development of rheumatic fever in individuals with untreated strep infection is
estimated to be 3%. The incidence of recurrence with a subsequent untreated infection is
substantially greater (about 50%.
- -absence of emboli does not rule out the IE, Coz vegetations are not often visualized in early phase
of disease and in pts with complex congenital heart disease.
- -Endocarditis is rare in infancy if occours it is usually due to indwelling cathaters or open heart
surgery.
- -high pressure gradient lesion more susceptible to IE.
- -Pathogenesis of IE:
- turbulent blood flow-endothelial traumafibrin and platelete depositionformation of non
bacterial thrombotic embolus (NBTE) , While in prosthetics valves, cathaters or pacemaker wires a
biofilm formed over their surface any episode of transient bacteremia  colonize the
NBTEBacterial surface antigen such as Fim A antigen in viridians act as adhesive factor to
NBTE or biofilmrapid proliferation.
- -high velocity blood flow lesions such as VSD And ASmore risk of IE.
- -surgical corrections of congenital heart lesions do not eliminate risk of infective endocarditis
except ASD or PDA closure without prosthetic material.
- -only in 30% pts we identify the predisposing factors.
- -10 -20% after dental procedure usually 1-6 moth later presentation after any dental procedure, this
is so controversy is to not include in absolute risk of infective endocarditis.
- In 90% of cases of endocarditis, the causative agent is recovered from the 1st two blood cultures.
The laboratory should be notified that endocarditis is suspected so that, if necessary, the blood can
be cultured on enriched media for longer than usual (>7 days) to detect nutritionally deficient and
fastidious bacteria or fungi. Antimicrobial pretreatment of the patient reduces the yield of blood
cultures to 50–60%.
- Three to five separate blood collections should be obtained after careful preparation of the
phlebotomy site. Contamination presents a special problem inasmuch as bacteria found on the skin
may themselves cause infective endocarditis. The timing of collections is not important because
bacteremia can be expected to be relatively constant.
- Subcutaneous nodules are almost always associated with cardiac involvement and are found more
commonly in patients with severe carditis
- Polyarthritis and Sydenham’s chorea virtually never occur simultaneously due to the disparity in
the latency period following the antecedent streptococcal infection. Chorea may, however, occur
after arthritis has subsided.
- Carditis and arthritis frequently coexist during an RF episode, and demonstrate an inverse
relationship between the severity of arthritis and carditis.
- Marantic endocarditis: non bacterial thrombotic endocarditis seen in malignancy and wasting.
- Libman sachs ebdocarditis : seen in SLE Mitral valve mostly.
- Indolent carditis: coomon in our country persistant features of CCF, cardiomegally, murmer.
- A pleural friction rub has only 2 components
- Pericardial friction rub has 3 components (early and late diastole and then systole)
- Arthirits and chorea can’t occur simultaneously .
82
CAUSES OF HEMOPTYSIS IN RHD
- Pulmonary apoplexy rupture of thin wall dilated bronchopulmonary veins usually as a

consequence of a sudden rise in left atrial pressure.
- PND
- Pulmonary edema
- Pulmonary infarction late presnt/ M.Sheart failure.
- Recurrent bronchitis/ bronchiectasis.
- .
- ANY CHILD KNOWN CASE OF RHD IF PRESENT WITH ACTIVITY BEST DIFFERENTIAL
WOULD BE:
 RHD with IE.
- INDOLENT CARDITIS Rx ONLY WITH STEROID NOT ASPIRIN.
- Indolent carditis mean pt presented aftr long time with already established complicated problem
like MS/A.S.
- there is no change in cbc of pts with carditis except may have anemia..
- IN RHD pt we do invx , cbc, cultures, just to rule out the other causes of activity.
- SECONDARY PROPHYLAXIS IS NOT GIVEN AFTER VALVULAR REPAIR.
- BUT TERTIARY PROPHYLAXIS IS GIVEN EVEN AFTER PROSTHESIS.
- Rheumatic fever pt have rarely pericardial effusion—it is in favour of RHD.
- ESTABLISHED RHD PT HAVE CCF-- THINK OF:
 CCF DUE TO ACTIVITY.
 IE
 PERICARDIAL EFFUSION. ---START STEROID
83

VSD--------------------------------------------------------------------SHORT CASE
Command: Do precordial & relevant.
Step 1: intro+consent+exposure. Steps –Same as other .
DIFFERENTIAL
1. CONGENITAL MVP.—preceding click with systolic murmer-usually associated with marfan / may be
isolated.
2. CONGENITAL M.R
HOW WILL U UNVESTIGATE?
 ECG
 CXR
 ECHO
 CARDIAC CATHETERIZATION.
HOW WILL U MANAGE?
Dx councelling
SMALL VSD: --( HARSH PANSYSTOLIC MURMER WITH THRILL / NO FTT)
 reassurance for spontaneous closure

 no restriction of activities
 prophylaxis for IE
 follow up with ECHO, ECG, and for pul HTN.
MODERATE / LARGE VSD:--(BLOWING PSM +/- THRILL + FTT+PULM HTN, BULGE)
 Rx of CCF
 Prevention of Pul.HTN –preload/afterload
 Nutritional rehab
 IE Prophylaxis
 Palliative treatment in case—PA BANDING
 complicated cases
 very premature infants
 muscular septum VSD apical.
 Surgery if no improvement in 1st year—patch closure.
Indications:
1. FTT at any age

2. 6m – 1 yr large VSD with Pul HTN.
3. >24 month after Qp:Qs ratio >2:1.
4. Supracrystal VSD at any age.
5. Recurrent CCF- failure of medical treatment.
PROGNOSIS:
84
 Small—50% close before 4 yr of age
 80% --muscular
 35%--perimembraneous
 Large—8% close

PDA -----------------------------------------------------------------------------SHORT CASE
COMMANDS:
1. DO CARDIOVSCULAR EXMINATION OF THIS PT—( COMMON)—BECAUSE OF HIGH

VOLUME PULSE.
2. DO PRECORDIAL AND RELEVANT.
STEP 1. Intro+ consent + exposure.
Step 2. Inspection –stand back.
Step 3. Make a repo with patient by holding hand–talk
Step 4. Take pulse –note rate , rhthym , volume, character, regularity, & compare with other radial and
femoral + collapsing pulse
Step 5. Brachial pulse.
Step 6. Take B.P of pt  increase mean B.P.
Step 7. Check for JVP.
Step 8. Polpliteal
Step 9. Dorsalis pedalis  if palpable mean shunting/ large PDA.
Step 10. Start same protocol as like precordial examination.
Cover with thanks
Offer ANTHROPOMETRICS, FUNDOSCOPE & RELEVANT EXTENDED EXAMINATION.
DESCRIPTION:
st nd
Pulse description then come to precordial description he had Normal 1 and 2 heart sound and there is a
contioneous murmer of grade …./6 audidible all over precordium but maximum intensity at left lower sterna
area with no radiation at other area. no evidence of pulmonary HTN.
No signs of CCF & IE.
DIFFERENTIALS:
 ACYNOTIC CONGENITAL HEART DIEASE—MOST LIKELY PDA.

 OTHER DIFFERENTIALS I WOULD LIKE TO ENTERTAIN ARE:
1. VENOUS HUM disappear with elevating legs/ down of face.
2. AP WINDOW DEFFECT—systolic murmer rt sternal area.
3. SUBAORTIC VSD –(VSD + AR Collapsing pulse.
4. AV MALFORMATION –( localized murmer).
5. RUPTURE OF SINUS OF VALSALVA emergency comdition pt usually sick. 85
Other can beAbbernt aoronary arteries/ collaterals, M.R +A.R
HOW WILL U INVESTIGATE

 ECG—(LVH-/ BVH).
 CXR.
 ECHO.
 CARDIAC CATHATERIZATION –When associated other cardiac lesions present.
 CBC + BLOOD C/S, URINE C/E.
COMPLICATIONS
 CCF
 IE
 FTT
 PULM HTN
 RECURRENT CHEST INFECTIONS.
MANAGEMENT:
 After establishing DX counceling

 Treatment of current acute problems
 Anti-failure Rx.
 Nutritional rehab.
 Antibiotics for chest infection
 Prophylaxis for IE.
 Definitive surgery advise—Irrespective of sge
 closed heart PDA ligation—usually less than 1 yr indicated/ <1% mortality .
 Transcathater device closure.
Rubella –PDA association.
Down syndrome—PDA.
86

ADDISONS DISEASE
PC:
 FITS.
 UNCONSIOUSNESS.
 HYPERPIGMENTATION
 VOMITING
(AFTER PC MAKE DIFFERENTIALS AT ONCE AND PROCEED SEQUENTIALLY).
HOPC:
HX OF DIFFERENTIALS:
HX OF COMPLICATIONS OF MOST LIKELY DISEASE.
MANAGEMENT DETAILS
- Episodes of hypoglycemia, addisons crisis?

- Growth and htn hx
- Dietry changes? ( advise for salt addition with amount of 6 mmol/kg/day,
- B .p monitoring.
- Gone thru any lab workup? (renin level.)
IN HX MAKE SEQUENCE OF TO TAKE HX OF DISEASE COMPLICATIONS FIRST THEN IN LAST RULE OUT
DIFFERENTIALS.
Must make the logic of current reason of admission and improvement.
Hx of salt craving,virilization (21 OH deff), FITS (hypoglycemic, Hypotension, arrhythmia dt elec imbalance,
(ALD) Oral ulcers, tetany, polyurea, polydypsia, weight loss, sweating, tremors, faintness (APS-I&II), Dyspnea
(Met.acidossis dt dec aldosterone), regression of milestones (ALD), Muscle weakness(AMLD), Muscular spasms
(K dec), Hypothermia+Palpitation+Somnolence+Insomnia (HASHMITOS THYROIDITIS), cutaneous changes+ dec
sweating+alopecia+epigastric pain (AEPECD), Contact (TB ETIOLOGY) loose motions (CELIAC), joint pain,
0
petechae , bruise, bleed, transfusion ( Autoimmune process). history of symptoms of steroid toxicity.
NOTE: if patient presents with hx of fits it is important to ask about l.p and c.t ever done and also encounter
the details of differentials and management in hospital and any unconsiousness if yes then how much duration
and was he cathaterized.
NOTE: must ask about the cxr and mantoux test done before start of treatment if pt is k/c.
FAMILY HISTORY.
DETAILS OF DISEASE IMPACT.
DEVELOPMENT HX.
VACCINATION HX.
87
DRUG HX.
SOCIOECONOMIC HISTORY.

DESCRIPTION OF LAST HX POINTS: VACCINATED CHILD HE IS DEVELOPMENTALLY NORMAL STUDENT OF
RD
CLASS…, PRODUCT OF CONSANGUIS PARENTS 3 NO. OF 4 SIBS, NO SIGNIFICANT HX OF SUCH FAMILY ISSUE,
D/D:
-auto immune polyendocrinopathy type i (apced) /ii (schimidts +hashmitos thyroiditis),

carpenter(d.m)
-adrenoleukodystrophy/ adrenomyeloleukodystrophy.
-fanconi anemia
-Mc cune Albright syndrome
-Hemochromatosis.
DISORDERS OF THE ADRENAL GLANDS
PHYSIOLOGY OF THE ADRENAL GLAND
The adrenal gland is composed of 2 endocrine tissues:
 Medulla  chromaffin cells of the adrenal medulla are derived from neuroectoderm
 cortex. cells of the adrenal cortex are derived from mesoderm
The adrenal glands and gonads have certain common enzymes involved in steroid synthesis; an inborn error in
steroidogenesis in one tissue may also be present in the other.
The adrenal cortex consists of 3 zones:
1. Zona glomerulosa the outermost zone located immediately beneath the capsule, 15%.
2. The zona fasciculatethe middle zonelargest ¾ of the cortex
3. Zona reticularis the innermost zone, lying next to the adrenal medulla it constitute 10% total.
 The zona glomerulosa synthesizes aldosterone, the most potent natural mineralocorticoid in
humans.
 The zona fasciculata produces cortisol, the most potent natural glucocorticoid in humans.
 Zona fasciculata and zona reticularis synthesize the adrenal androgens.
 The adrenal medulla consists mainly of neuroendocrine (chromaffin) cells and glial (sustentacular)
cells
REGULATION OF THE ADRENAL CORTEX 88
REGULATION OF CORTISOL SECRETION.

 Glucocorticoid secretion is regulated mainly by adrenocorticotropic hormone (corticotropin, ACTH),
produced in the anterior pituitary. It is synthesized as part of a larger molecular weight precursor
peptide known as pro-opiomelanocortin (POMC). This precursor peptide is also the source of β-
lipotropin (β-LPH). ACTH and β-LPH are cleaved further to yield α- and β-melanocyte–stimulating
hormone, corticotropin-like intermediate lobe peptide (CLIP), γ-LPH, β- and γ-endorphin, and
enkephalin.
 ACTH is released in secretory bursts of varying amplitude throughout the day and night. The normal
diurnal rhythm of cortisol secretion is caused by the varying amplitudes of ACTH pulses. Pulses of
ACTH and cortisol occur every 30–120 min, are highest at about the time of waking, are low in late
afternoon and evening, and reach their lowest point 1 or 2 hr after sleep begins.
 Corticotropin-releasing hormone (CRH), synthesized by neurons of the parvicellular division of the

hypothalamic paraventricular nucleus, is the most important stimulator of ACTH secretion. Arginine
vasopressin (AVP) augments CRH action. Neural stimuli from the brain cause the release of CRH and
AVP. AVP and CRH are secreted in the hypophyseal-portal circulation in a pulsatile manner. This
pulsatile secretion appears to be responsible for the pulsatile (ultradian) release of ACTH.
REGULATION OF ALDOSTERONE SECRETION.
 The rate of aldosterone synthesis, which is normally 100- to 1000- fold less than that of cortisol
synthesis, is regulated mainly by the renin-angiotensin system and by potassium levels, with ACTH
having only a short-term effect.
 Renin is a proteolytic enzyme that cleaves angiotensinogen (renin substrate), an α 2-globulin produced
by the liver, to yield the inactive decapeptide angiotensin I. Angiotensin-converting enzyme in the
lungs and other tissues rapidly cleaves angiotensin I to the biologically active octapeptide angiotensin
II. Cleavage of angiotensin II produces the heptapeptide angiotensin III. Angiotensin II and III are
potent stimulators of aldosterone secretion;
REGULATION OF ADRENAL ANDROGEN SECRETION.
 The mechanisms by which the adrenal androgens, dehydroepiandrosterone and androstenedione, are
regulated are not completely understood. Adrenarche is a maturational process in the adrenal gland that
results in increased adrenal androgen secretion between the ages of 5 and 20 yr. The process begins
before the earliest signs of puberty and continues throughout the years when puberty is occurring.
Histologicaly, it is associated with the appearance of the zona reticularis. Whereas ACTH stimulates
adrenal androgen production acutely and clearly is the primary stimulus for cortisol release (see later),
additional factors have been implicated in the stimulation of the adrenal androgens.
ACTIONS OF GLUCOCORTICOIDS.
 Glucocorticoids are essential for survival. Glucocorticoids have multiple effects on carbohydrate, lipid,
and protein metabolism. They also regulate immune, circulatory, and renal function. They influence
growth, development, bone metabolism, and central nervous system activity. 89
 In stress situations, glucocorticoid secretion can increase up to 10-fold. This increase is believed to
enhance survival through increased cardiac contractility, cardiac output, sensitivity to the presser
effects of catecholamines and other pressor hormones, work capacity of the skeletal muscles, and
capacity to mobilize energy stores.

METABOLIC EFFECTS.
CARBOHYDRATE METABOLISM
Increase glucose production by:
1. Increasing hepatic gluconeogenesis.

2. Increase cellular resistance to insulindecreasing entry of glucose into the cell. (adipocytes, muscle
cells, and fibroblasts).
Glucocorticoid excess may cause hyperglycemia, whereas glucocorticoid deficiency may cause hypoglycemia.
FAT METABOLISM:
Glucocorticoids increase free fatty acid levels by:
 Enhancing lipolysis.
 Decreasing cellular glucose uptake and decreasing glycerol production which is necessary for re-
esterification of fatty acids.
 In the patient with glucocorticoid excess fat is lost in the extremities, but it is increased in the trunk
(centripetal obesity), neck, and face (moon facies). This may involve effects on adipocyte
differentiation.
 Glucocorticoids generally exert a catabolic/antianabolic effect on protein metabolism. Proteolysis in
fat, skeletal muscle, bone, lymphoid, and connective tissue increases amino acid substrates that can be
used in gluconeogenesis.
Cardiac muscle and the diaphragm are almost entirely spared from this catabolic effect.
CIRCULATORY AND RENAL EFFECTS.
Glucocorticoids have a positive inotropic influence on the heart, increasing the left ventricular work index.
 Moreover, they have a permissive effect on the actions of epinephrine and norepinephrine on both the
heart and the blood vessels.
 In the absence of glucocorticoids, decreased cardiac output and shock may develop; in states of
glucocorticoid excess, hypertension is frequently observed. This may be due to activation of the
mineralocorticoid receptr, which occurs when renal 11β-hydroxysteroid dehydrogenase is saturated by
excessive levels of glucocorticoids.
GROWTH.
In excess, glucocorticoids inhibit linear growth and skeletal maturation in children.
 This results primarily from the direct inhibitory effect of glucocorticoids on the epiphyses.
 This may in part be mediated by decreasing levels of growth hormone and insulin-like growth factor-1
(IGF-1) and by increasing IGF binding protein-1 (IGFBP-1)which inhibits somatic growth by
decreasing circulating levels of free IGF-1.
 Although excess glucocorticoids clearly impair growth, they are also necessary for normal growth and
development. In the fetus and neonate, they accelerate the differentiation and development of various
90
tissues. These actions include the development of the hepatic and gastrointestinal systems, as well as
the production of surfactant in the fetal lung.
IMMUNOLOGIC EFFECTS.

 Glucocorticoids play a major role in immune regulation They inhibit synthesis of glycolipids and
prostaglandin precursors and the actions of bradykinin. They also block histamine and proinflammatory
cytokine (tumor necrosis factor-α, interleukin-1, and interleukin-6) secretion and effects. These actions
diminish the inflammatory process.
 High doses of glucocorticoids deplete monocytes, eosinophils, and lymphocytes, especially T cells.
 The effects on lymphocytes are primarily exerted on T helper 1 cells and hence on cellular immunity,
whereas the T helper 2 cells are spared, leading to a predominantly humoral immune response.
Pharmacologic doses of glucocorticoids may also decrease the size of immunologic tissues (spleen,
thymus, and lymph nodes).
 Glucocorticoids increase circulating polymorphonuclear cell counts, mostly by preventing their
egress from the circulation. Glucocorticoids decrease diapedesis, chemotaxis, and phagocytosis of
polymorphonuclear cells. Thus, the mobility of these cells is altered such that they do not arrive at the
site of inflammation to mount an appropriate immune response. High levels of glucocorticoids decrease
inflammatory and cellular immune responses and increase susceptibility to certain bacterial, viral,
fungal, and parasitic infections.
EFFECTS ON SKIN, BONE, AND CALCIUM.
 Glucocorticoids inhibit fibroblasts, leading to increased bruising and poor wound healing through
cutaneous atrophy. This effect explains the thinning of the skin and striae that are seen in patients with
Cushing syndrome.
 Glucocorticoids have the overall effect of decreasing serum calcium and have been used in emergency
therapy for certain types of hypercalcemia. This hypocalcemic effect probably results from a decrease
in the intestinal absorption of calcium and a decrease in the renal reabsorption of calcium and
phosphorus. Serum calcium levels, however, generally do not fall below normal because of the
secondary increase in parathyroid hormone secretion.
 The most significant effect of long-term glucocorticoid excess on calcium and bone metabolism is
osteoporosis. Glucocorticoids inhibit osteoblastic activity by decreasing the number and activity of
osteoblasts. Glucocorticoids also decrease osteoclastic activity but to a lesser extent, leading to low
bone turnover with an overall negative balance. The tendency of glucocorticoids to lower serum
calcium and phosphate levels causes secondary hyperparathyroidism. These actions decrease bone
accretion and cause a net loss of bone mineral.
CENTRAL NERVOUS SYSTEM EFFECTS.
 Glucocorticoids readily penetrate the blood-brain barrier and have direct effects on brain metabolism.
They decrease certain types of CNS edema and are frequently used to treat increased intracranial
pressure.
 They stimulate appetite and cause insomnia with a reduction in rapid eye movement sleep. There is an
increase in irritability and emotional lability, with an impairment of memory and ability to concentrate.
Mild to moderate glucocorticoid excess for a limited period of time often causes a feeling of euphoria
or well-being, but glucocorticoid excess and deficiency may both be associated with clinical
depression. Glucocorticoid excess may produce psychosis in some patients.
ACTIONS OF MINERALOCORTICOIDS.
 The most important mineralocorticoids are aldosterone and, to a lesser degree, 11-deoxycorticosterone;
corticosterone and cortisol are normally not important as mineralocorticoids unless secreted in excess.
Mineralocorticoids have more limited actions than glucocorticoids. 91
 Their major function is to maintain intravascular volume by conserving sodium and eliminating
potassium and hydrogen ions.
 They exert these actions in kidney, gut, and salivary and sweat glands. Aldosterone may have distinct
effects in other tissues.

 Mineralocorticoid receptors are found in the heart and vascular endothelium, and aldosterone increases
myocardial fibrosis in heart failure.
 Mineralocorticoids have their most important actions in the distal convoluted tubules and cortical
collecting ducts of the kidney, where they induce reabsorption of sodium and secretion of potassium.
 In the medullary collecting duct, they act in a permissive fashion to allow vasopressin to increase
osmotic water flux. Thus, patients with mineralocorticoid deficiency may develop weight loss,
hypotension, hyponatremia, and hyperkalemia, whereas patients with mineralocorticoid excess may
develop hypertension, hypokalemia, and metabolic alkalosis
SYNTHETIC CORTICOSTEROIDS.
 Many synthetic analogs of cortisone and hydrocortisone are available.

 Prednisone and prednisolone are derivatives with an additional double bond in ring A.
 Like cortisone, prednisone is not an active steroid but it is converted to prednisolone by 11β-
hydroxysteroid dehydrogenase type 1 in the liver.
 Prednisone and prednisolone are 4–5 times as potent in anti-inflammatory and carbohydrate activity
but have slightly less effect on retention of water and sodium than cortisol.
 Halogenated derivatives : Betamethasone and dexamethasone have 25–40 times the glucocorticoid
potency of cortisol but have little mineralocorticoid effect
 Fludrocortisone has about 15 times greater anti-inflammatory activity than does hydrocortisone but
is more than 125 times as active a mineralocorticoid; it is used to treat aldosterone deficiency.
ADRENOCORTICAL INSUFFICIENCY
 In primary adrenal insufficiency, congenital or acquired lesions of the adrenal cortex prevent
production of cortisol and often aldosterone .
 Acquired primary adrenal insufficiency is termed Addison disease.
 Dysfunction of the hypothalamus or anterior pituitary gland may cause a deficiency of corticotropin
(ACTH) and lead to hypofunction of the adrenal cortex; this is termed secondary adrenal insufficiency.
CAUSES OF PRIMARY ADRENAL INSUFFICIENCY

CLINICAL FEATURES IN ADDITION TO
DIAGNOSIS ADRENAL INSUFFICIENCY PATHOGENESIS OR GENETICS
AUTOIMMUNE ADRENALITIS
Isolated autoimmune No other features Associations with HLA-DR, CTLA-4
adrenalitis
Autoimmune adrenalitis as
part of APS
APS type 1 (APECED) Hypoparathyroidism, chronic AIRE gene mutations (21q22.3)
mucocutaneous candidiasis, other
autoimmune disorders
APS type 2 Thyroid disease, type 1 diabetes Associations with HLA-DR, CTLA-4
mellitus, other autoimmune diseases
(rare in children)
APS type 4 Other autoimmune diseases, excluding Associations with HLA-DR, CTLA-4
thyroid disease or diabetes (rare in
children) 92
INFECTIOUS ADRENALITIS
Tuberculous adrenalitis Other organ manifestations of Tuberculosis
tuberculosis

AIDS Other AIDS-associated diseases HIV-1, cytomegalovirus
Fungal adrenalitis Mostly in immunosuppressed patients Cryptococcosis, histoplasmosis,
coccidioidomycosis
GENETIC DISORDERS
LEADING TO ADRENAL
INSUFFICIENCY
Adrenoleukodystrophy, Demyelination of CNS (cerebral Mutation of the ABCD1 gene
adrenomyeloneuropathy adrenoleukodystrophy), spinal cord, or encoding for the peroxisomal
peripheral nerves adrenoleukodystrophy protein
(adrenomyeloneuropathy)
Congenital adrenal
hyperplasia
21-Hydroxylase deficiency Ambiguous genitalia in girls CYP21 mutation
11β-Hydroxylase deficiency Ambiguous genitalia in girls and CYP11B1 mutation
hypertension
3β-HSD type 2 deficiency Ambiguous genitalia in boys, postnatal HSD3B2 mutation
virilization in girls
17α-Hydroxylase deficiency Ambiguous genitalia in boys, lack of CYP17 mutation
puberty in both sexes, hypertension
Congenital lipoid adrenal XY sex reversal Mutations in the steroidogenic acute
hypoplasia regulatory protein (STAR) gene;
mutations in CYP11A (encoding
P450scc) POR mutation
Pyrooxidoreductase deficiency Antley-Bixler syndrome
Smith-Lemli-Opitz syndrome Mental retardation, craniofacial 7-Dehydrocholesterol reductase
malformations, growth failure mutations in gene DHCR7
Adrenal hypoplasia congenita
X-linked Hypogonadotropic hypogonadism Mutation in NROB1 (DAX1)
Xp21 contiguous gene Duchenne muscular dystrophy and Deletion of the Duchenne muscular
syndrome glycerol kinase deficiency dystrophy, glycerol kinase, and
(psychomotor retardation) NROB1 (DAX1) genes
SF-1 linked XY sex reversal Mutation in NR5A1 (SF1)
IMAGe syndrome Intrauterine growth retardation, Unknown
metaphyseal dysplasia, adrenal
insufficiency, and genital anomalies
(IMAGe)
Kearns-Sayre syndrome External ophthalmoplegia, retinal Mitochondrial DNA deletions
degeneration, and cardiac conduction
defects; other endocrinopathies
ACTH insensitivity syndromes Glucocorticoid deficiency, but no
(familial glucocorticoid impairment of mineralocorticoid 93
deficiency) synthesis
Type 1 Tall stature ACTH receptor (MC2R) mutations

Type 2 No other features Unknown
Triple A syndrome (Allgrove's Alacrimia, achalasia; additional Mutations in triple A gene (AAAS)
syndrome) symptoms, including neurologic encoding for a WD-repeat protein
impairment, deafness, mental
retardation, hyperkeratosis
BILATERAL ADRENAL Symptoms of underlying disease Septic shock, specifically
HAEMORRHAGE meningococcal sepsis (Waterhouse-
Friderichsen syndrome); primary
antiphospholipid syndrome
ADRENAL INFILTRATION Symptoms of underlying disease Adrenal metastases, primary adrenal
lymphoma, sarcoidosis, amyloidosis,
hemochromatosis
BILATERAL ADRENALECTOMY Symptoms of underlying disease Unresolved Cushing's syndrome
DRUG-INDUCED ADRENAL No other symptoms Treatment with mitotane,
INSUFFICIENCY aminoglutethimide, etomidate,
ketoconazole, suramin, mifepristone
CAUSES OF SECONDARY ADRENAL INSUFFICIENCY

DIAGNOSIS COMMENT
Pituitary tumors Secondary adrenal insufficiency mostly as part of panhypopituitarism; additional
symptoms (visual-field impairment): generally adenomas, carcinoma is a rarity;
consequence of tumor growth, surgical treatment, or both
Other tumors of the Craniopharyngioma, meningioma, ependymoma, and intrasellar or suprasellar
hypothalamic-pituitary metastases
region
Pituitary irradiation Craniospinal irradiation in leukemia, irradiation for tumors outside the
hypothalamic-pituitary axis, irradiation of pituitary tumors
Lymphocytic hypophysitis
Isolated Autoimmune hypophysitis; most frequently in relation to pregnancy (80%);
mostly hypopituitarism, but also isolated adrenocorticotropic hormone
deficiency
As part of APS Associated with autoimmune thyroid disease and, less frequently, with vitiligo,
primary gonadal failure, type 1 diabetes, and pernicious anaemia
Isolated congenital Pro-opiomelanocortin cleavage enzyme defect?
ACTH deficiency
Pro-opiomelanocortin- Pro-opiomelanocortin gene mutations; clinical triad of adrenal insufficiency,
deficiency syndrome early-onset obesity, and red hair pigmentation 94
Combined pituitary- Mutations in the gene encoding the pituitary transcription factor Prophet of Pit1
hormone deficiency (PROP1), progressive development of panhypopituitarism in the order GH, PRL,
TSH, LH/FSH,(ACTH)

DIAGNOSIS COMMENT
Mutations in the homeo box gene HESX1, combined pituitary hormone
deficiency, optic-nerve hypoplasia, and midline brain defects (septo-optic
dysplasia)
Pituitary apoplexy Onset mainly with abrupt severe headache, visual disturbance, and nausea or
vomiting
(Sheehan's syndrome) Histiocytosis syndromes, pituitary apoplexy or necrosis with peripartal onset,
e.g., due to high blood loss or hypotension
Pituitary infiltration or Tuberculosis, actinomycosis, sarcoidosis, Wegener's granulomatosis
granuloma
Head trauma For example, pituitary stalk lesions
Previous chronic Exogenous glucocorticoid administration for more than 4 weeks, endogenous
glucocorticoid excess glucocorticoid hypersecretion due to Cushing's syndrome
PRIMARY ADRENAL INSUFFICIENCY
 Primary adrenal insufficiency may be caused by genetic conditions that are not always manifested in
infancy and by acquired problems such as autoimmune conditions.
 However, susceptibility to autoimmune conditions often has a genetic basis, and so these distinctions
are not absolute.
INHERITED ETIOLOGIES
INBORN DEFECTS OF STEROIDOGENESIS.
 The most common causes of adrenocortical insufficiency in infancy are the salt-losing forms of
congenital adrenal hyperplasia.
 Approximately 75% of infants with 21-hydroxylase deficiency, almost all infants with lipoid
adrenal hyperplasia, and most infants with a deficiency of 3β-hydroxysteroid dehydrogenase
manifest salt-losing symptoms in the newborn period because they are unable to synthesize either
cortisol or aldosterone.
ADRENAL HYPOPLASIA CONGENITA.
 Hypoadrenalism usually presents acutely in the neonatal period but may be delayed until later
childhood or even adulthood with a more insidious onset.
 The disorder affects primarily boys and is caused by mutation of the DAX1 (NR0B1) gene
 Boys with adrenal hypoplasia congenita  do not undergo puberty owing to hypogonadotropic
hypogonadism; both AHC and hypogonadotropic hypogonadism are caused by the same mutated DAX1
gene.
 Cryptorchidism, often noted in these boys, is probably an early manifestation of hypogonadotropic
hypogonadism.
 AHC also occurs as part of a contiguous gene deletion syndrome together with Duchenne muscular
dystrophy, glycerol kinase deficiency, mental retardation, or a combination of these conditions.
SF-1 DEFICIENCY.
95
 Impaired development of the testes and may appear as females, similarly to patients with lipoid adrenal
hyperplasia.

ADRENOLEUKODYSTROPHY.
 adrenocortical deficiency is associated with demyelination in the central nervous system

 High levels of very long chain fatty acids are found in tissues and body fluids, resulting from their
impaired β-oxidation in the peroxisomes.
 The most frequent form of ALD is an X-linked disorder with various presentations.
 The most common clinical picture is of a degenerative neurologic disorder appearing in childhood or
adolescence and progressing to severe dementia and deterioration of vision, hearing, speech, and gait,
with death occurring within a few years.
 A milder form of X-linked ALD is adrenomyeloneuropathy (ALM), which begins in later adolescence
or early adulthood. Many patients have evidence of adrenal insufficiency at the time of neurologic
presentation, but Addison disease may be present without neurologic symptoms or may precede them
by many years.
 X-linked adrenal leukodystrophy (X-ALD) is caused by mutations in the ABCD1 gene located on
Xq28.
 The gene encodes a transmembrane transporter involved in the importation of very long chain fatty
acids into peroxisomes.
 More than 400 mutations have been described in patients with X-ALD; the majority of X-ALD families
have a unique mutation.
 Prenatal diagnosis by DNA analysis and family screening by very long chain fatty acid assays and
mutation analysis are available.
 Women who are heterozygous carriers of the X-ALD gene may develop symptoms in midlife or
laterAdrenal insufficiency is rare.
 Neonatal ALD is a rare autosomal recessive disorder. Infants have neurologic deterioration and have or
acquire evidence of adrenocortical dysfunction. Most patients have severe mental retardation and die
before 5 yr of age. This disorder is a subset of Zellweger (cerebro-hepato-renal) syndrome, in which
peroxisomes do not develop at all owing to mutations in any of several genes controlling the
development of this organelle.
FAMILIAL GLUCOCORTICOID DEFICIENCY.
 This form of chronic adrenal insufficiency is characterized by isolated deficiency of glucocorticoids,

elevated levels of ACTH, and normal aldosterone production. The salt-losing manifestations present in
most other forms of adrenal insufficiency do not occur; instead, patients mainly have hypoglycemia,
seizures, and increased pigmentation during the 1st decade of life. The disorder affects both sexes
equally and is inherited in an autosomal recessive manner. There is marked adrenocortical atrophy
with relative sparing of the zona glomerulosa.
 A number of mutations in the gene for the ACTH receptor have been described in approximately 40%
of these patients.
 Another syndrome of ACTH resistance occurs in association with achalasia of the gastric cardia and
alacrima (triple A or Allgrove syndrome). These patients often have a progressive neurologic
disorder that includes autonomic dysfunction, mental retardation, deafness, and motor neuropathy. This
syndrome is also inherited in an autosomal recessive fashion, and the AAAS gene has been mapped to
chromosome 12q13. The encoded protein, aladin, may help regulate nucleocytoplasmic transport of
other proteins.
TYPE I AUTOIMMUNE POLYENDOCRINOPATHY (APS-1)
 Although autoimmune Addison disease most often occurs sporadically: it may occur as a component of
2 syndromes.
Each consisting of a constellation of autoimmune disorders.
 Type I autoimmune polyendocrinopathy (APS-1), also known as the autoimmune
polyendocrinopathy/candidiasis/ectodermal dystrophy (APECED) syndrome.
96
inherited in mendelian autosomal recessive manner.
 Chronic mucocutaneous candidiasis is most often the first manifestation of APS-1, followed by
hypoparathyroidism and then by Addison disease, which typically develops in early adolescence.
Other closely associated autoimmune disorders include:

 gonadal failure.
 Alopecia.
 Vitiligo.
 Keratopathy.
 enamel hypoplasia.
 nail dystrophy.
 intestinal malabsorption.
 chronic active hepatitis.
 Hypothyroidism.
 Type I diabetes mellitus occur in fewer than 10% of affected patients.
 The presence of anti adrenal antibodies and steroidal cell antibodies in these patients usually
indicates a high likelihood of the development of Addison disease or, in females, ovarian failure.
 Adrenal failure may evolve rapidly in APS-1; death in patients previously diagnosed and unexplained
deaths in siblings of patients with APS-1 have been reported, indicating the need to closely monitor
patients with APS-1 and to thoroughly evaluate apparently unaffected siblings of patients with this
disorder.
 Autoantibodies to the CYP21, CYP17, and CYP11A1 enzymes have been reported in patients
with APS-1.
 The gene affected in APS-1 is designated autoimmune regulator-1 (AIRE1); it has been mapped to
chromosome 21q22.3.
 whereas APS-2 has complex inheritance.
DISORDERS OF CHOLESTEROL SYNTHESIS/METABOLISM.
Patients with disorders of cholesterol synthesis or metabolism, including abetalipoproteinemia with deficient
lipoprotein B–containing lipoproteins, and familial hypercholesterolemia, with decreased or impaired LDL
receptors, have been demonstrated to have limited adrenocortical function. Adrenal insufficiency has been
reported in patients with Smith-Lemli-Opitz syndrome (SLOS), an autosomal recessive disorder presenting
with facial anomalies, microcephaly, limb anomalies, and developmental delay. Mutations in the gene coding
for sterol Δ7-reductase, mapped to 11q12-q13, resulting in impairment of the final step in cholesterol
synthesis with marked elevation of 7-dehydrocholesterol, abnormally low cholesterol, and adrenal
insufficiency, have been identified in SLOS. Wolman disease is a rare autosomal recessive disorder caused by
mutations in the gene encoding human lysosomal acid lipase. Cholesteryl esters accumulate in lysosomes in
most organ systems, leading to organ failure. Infants during the 1st or 2nd mo of life have
hepatosplenomegaly, steatorrhea, abdominal distention, and failure to thrive. Adrenal insufficiency and
bilateral adrenal calcification are present, and death usually occurs in the first year of life. The gene for
lysosomal acid lipase has been mapped to chromosome 10q23.2–23.3; the genetic defects in patients with
Wolman disease have been elucidated.
CORTICOSTEROID-BINDING GLOBULIN (CBG) DEFICIENCY AND DECREASED CORTISOL-BINDING AFFINITY.
These disorders result in low levels of plasma cortisol but normal urinary free cortisol and normal plasma ACTH
levels.
ACQUIRED ETIOLOGIES
AUTOIMMUNE ADDISON DISEASE.
 The most common cause of Addison disease is autoimmune destruction of the glands.—(TB IN OUR
SETUP) 97
 The glands may be so small that they are not visible at autopsy, and only remnants of tissue are found
in microscopic sections. Usually, the medulla is not destroyed, and there is marked lymphocytic
infiltration in the area of the former cortex. In advanced disease, all adrenocortical function is lost,
but early in the clinical course, isolated cortisol deficiency may occur.

 Most patients have antiadrenal cytoplasmic antibodies in their plasma; 21-hydroxylase (CYP21) is the
most frequently occurring autoantigen.
 May occur as a component of 2 autoimmune polyendocrinopathy syndromes.
1. Type I (APS-1).
2. Type II autoimmune polyendocrinopathy (APS-2) consists of:
 (Schmidt syndrome): Addison disease associated with autoimmune thyroid disease)
 (Carpenter syndrome): Addison ds + type 1 diabetes. (CD)
Gonadal failure, vitiligo, alopecia, and chronic atrophic gastritis, with or without pernicious anemia, may occur.
HLA-D3 and HLA-D4 are increased in these patients and appear to confer an increased risk for development of
this disease.
INFECTION.
Tuberculosis was a common cause of adrenal destruction in the past but is much less prevalent now.
The most frequent infectious etiology for adrenal insufficiency is meningococcemiaadrenal crisis from this
cause is referred to as the Waterhouse-Friderichsen syndrome. Patients with AIDS may have a variety of
subclinical abnormalities in the hypothalamic-pituitary-adrenal axis, but frank adrenal insufficiency is rare.
However, drugs used in the treatment of AIDS may affect adrenal hormone homeostasis.
DRUGS.
 Ketoconazoleinhibiting adrenal enzymes.

 Rifampicin.
 anticonvulsive drugs such as phenytoin and phenobarbital reduce the effectiveness and bioavailability
of corticosteroid replacement therapy by inducing steroid-metabolizing enzymes in the liver.
HEMORRHAGE INTO ADRENAL GLANDS.
Neonatal period as a consequence of a difficult labor (especially breech presentation.
 An abdominal mass, anemia, unexplained jaundice, or scrotal hematoma may be the presenting sign.
 Often, the hemorrhage is asymptomatic initially and is identified later by calcification of the adrenal
gland.
Postnatally, adrenal hemorrhage most often occurs in patients being treated with anticoagulants. It may also
occur as a result of child abuse.
98
Primary adrenal insufficiency leads to cortisol and often aldosterone deficiency.
 Hypoglycemia is a prominent feature of adrenal insufficiency.

 It is often accompanied by ketosis as the body attempts to utilize fatty acids as an alternative energy
source. Ketosis is aggravated by anorexia, nausea, and vomiting, all of which occur frequently.
 Cortisol deficiency decreases cardiac output and vascular tone; moreover, catecholamines such as
epinephrine have decreased inotropic and pressor effects in the absence of cortisol.
 These problems are initially manifested as orthostatic hypotension in older children and may progress
to frank shock in patients of any age.
 They are exacerbated by aldosterone deficiency, which results in hypovolemia due to decreased
resorption of sodium in the distal nephron.
 Hypotension and decreased cardiac output decrease glomerular filtration and thus decrease the
ability of the kidney to excrete free water. Vasopressin (AVP) is secreted by the posterior pituitary in
response to hypotension and also as a direct consequence of lack of inhibition by cortisol. These
factors decrease plasma osmolality and lead in particular to hyponatremia. Hyponatremia is also
caused by aldosterone deficiency and may be much worse when both cortisol and aldosterone are
deficient.
 In addition to hypovolemia and hyponatremia, aldosterone deficiency causes hyperkalemia by
decreasing potassium excretion in the distal nephron.
 Cortisol deficiency alone does not cause hyperkalemia.
 Cortisol deficiency decreases negative feedback on the hypothalamus and pituitary, leading to
increased secretion of ACTH. Hyperpigmentation is caused by ACTH and other peptide hormones (γ-
melanocyte-stimulating hormone) arising from the ACTH precursor pro-opiomelanocortin. In patients
with a fair complexion, the skin may have a bronze cast. Pigmentation may be more prominent in
skin creases, mucosa, and scars.
 In dark-skinned patients, it may be most readily appreciated in the gingival and buccal mucosa.
The clinical presentation of adrenal insufficiency depends on the age of the patient, whether both cortisol and
aldosterone secretion are affected, and to some extent on the underlying etiology. The most common causes
in early infancy are:
 inborn errors of steroid biosynthesis.

 Sepsis.
 adrenal hemorrhage
 adrenal hypoplasia congenital.
Infants have a relatively greater requirement for aldosterone than do older children, possibly owing to
immaturity of the kidney and also to the low sodium content of human breast milk and infant formula.
Hyperkalemia, hyponatremia, and hypoglycemia are prominent presenting signs of adrenal insufficiency in
infants.
Ketosis is not consistently present because infants generate ketones less well than do older children.
Hyperpigmentation is not usually seen because this takes weeks or months to develop, and orthostatic
hypotension is obviously difficult to demonstrate in infants.
anorexia, and vomiting before critical electrolyte abnormalities develop.
99
OLDER CHILDREN WITH ADDISON DISEASE:
 Onset is usually more gradual and is characterized by muscle weakness, malaise, anorexia, vomiting,
weight loss, and orthostatic hypotension.

 Hyperpigmentation is often but not necessarily present.
 Hypoglycemia and ketosis are common, as is hyponatremia.
 Hyperkalemia tends to occur later in the course of the disease in older children than in infants. Thus,
the clinical presentation can be easily confused with gastroenteritis or other acute infections.
 Chronicity of symptoms may alert the clinician to the possibility of Addison disease, but this diagnosis
should be considered in any child with orthostatic hypotension, hyponatremia, hypoglycemia, and
ketosis.
 Salt craving is seen in primary adrenal insufficiency with mineralocorticoid deficiency. Fatigue,
myalgias, fever, eosinophilia, lymphocytosis, hypercalcemia, and anemia may be noted with
glucocorticoid deficiency.
LABORATORY FINDINGS.
 Hypoglycemia, ketosis, hyponatremia, and hyperkalemia.

 An electrocardiogram is useful for quickly detecting hyperkalemia in a critically ill child.
 Acidosis is frequently present, and the blood urea nitrogen level is elevated if the patient is
dehydrated.
 Cortisol levels may sometimes be at the low end of the normal range but are invariably low when the
patient's degree of illness is considered.
 ACTH levels are high in primary adrenal .
 aldosterone levels may be within the normal range but inappropriately low considering the patient's
hyponatremia, hyperkalemia, and hypovolemia.
 Plasma renin activity is elevated.
 Blood eosinophils may be increased in number, but this is rarely useful diagnostically.
 Urinary excretion of sodium and chloride are increased and urinary potassium is decreased, but
these are difficult to assess on random urine samples. Accurate interpretation of urinary electrolytes
requires more prolonged (24 hr) urine collections and knowledge of the patient's sodium and
potassium intake.
The most definitive test for adrenal insufficiency is measurement of serum levels of cortisol before and after
administration of ACTH;
1. Resting levels are low and do not increase normally after administration of ACTH.
2. Normal resting levels that do not increase after administration of ACTH may indicate an absence of
adrenocortical reserve.
3. A low initial level followed by a significant response to ACTH may indicate secondary adrenal
insufficiency.
PROCEDURE : this test has been performed by measuring cortisol levels before and 30 or 60 min after giving
0.250 mg of cosyntropin (ACTH) by rapid intravenous infusion.
 Aldosterone will transiently increase in response to this dose of ACTH and may also be measured.

2
A low-dose test (0.5–1 μg ACTH 1–24/1.73 m ) is a more sensitive test of pituitary-adrenal reserve
but has somewhat lower specificity (more false-positive tests). 100

DIFFERENTIAL DIAGNOSIS.
 Gastroenteritis with dehydration or sepsis.

 Fanconi
 Hemochromatosis (short case )
 When congenital adrenal hyperplasia is suspected, serum levels of cortisol precursors (17-
hydroxyprogesterone) should be measured along with cortisol in an ACTH stimulation test.
 Elevated levels of very long chain fatty acids are diagnostic of adrenoleukodystrophy.
 The presence of antiadrenal antibodies suggests an autoimmune pathogenesis.
 Patients with autoimmune Addison disease must be closely observed for the development of other
autoimmune disorders. In children, hypoparathyroidism is the most frequently associated disorder,
and it is suspected if hypocalcemia and elevated phosphate levels are present.
 Ultrasonography, CT, or MRI may help define the size of the adrenal glands.
TREATMENT.
Treatment of acute adrenal insufficiency must be immediate and vigorous. If the diagnosis of adrenal
insufficiency has not been established, a blood sample should be obtained before therapy for determination
of:
 Electrolytes.
 Glucose.
 ACTH.
 Cortisol.
 Aldosterone.
 and plasma renin activity.
 If the patient's condition permits, an ACTH stimulation test can be performed while initial fluid
resuscitation is underway.
Intravenous administration of 5% glucose in 0.9% saline solution should be given to correct hypoglycemia,
hypovolemia, and hyponatremia.
If hyperkalemia is severe, it may require treatment with intravenous calcium and/or bicarbonate, intrarectal
potassium-binding resin (Kayexalate), or intravenous infusion of glucose and insulin.
A water-soluble form of hydrocortisone, such as hydrocortisone sodium succinate, should be given

intravenously.
 10 mg for infants.
 25 mg for toddler.
 50 mg for older children.
 100 mg for adolescents should be administered at 6-hr intervals for the first 24 hr.
101
 These doses may be reduced during the next 24 hr if progress is satisfactory.
Adequate fluid and sodium repletion is achieved by intravenous saline administration, aided by the
mineralocorticoid effect of high doses of hydrocortisone.

Particular caution should be exercised in the rare patient with concomitant adrenal insufficiency and
hypothyroidism, because thyroxine may increase cortisol clearance.
 Adrenal crisis may be precipitated if hypothyroidism is treated without first assuring adequate
glucocorticoid replacement.
 After the acute manifestations are under control, most patients require chronic replacement
therapy for their cortisol and aldosterone deficiencies.
2
 Hydrocortisone (cortisol) may be given orally in daily doses of 10 mg/M /24 hr in 3 divided doses;
2
some patients require 15 mg/M /24 hr to minimize fatigue, especially in the morning.
 Equivalent doses (20–25% of the hydrocortisone dose) of prednisone or prednisolone may be used
and divided and given twice daily.
 ACTH levels may be used to monitor adequacy of glucocorticoid replacement in
primary adrenal insufficiency.
 During situations of stress, such as periods of infection or minor operative procedures, the dose of
hydrocortisone should be increased 2- to 3-fold.
 Major surgery under general anesthesia requires high intravenous doses of hydrocortisone similar to
those used for acute adrenal insufficiency.
 If aldosterone deficiency is present, fludrocortisone (Florinef), a mineralocorticoid, is given orally in
doses of 0.05–0.3 mg daily.
 Measurements of plasma renin activity are useful in monitoring the adequacy of
mineralocorticoid replacement.
Chronic overdosage with glucocorticoids leads to obesity, short stature, and osteoporosis,
whereas overdosage with fludrocortisone results in tachycardia, hypertension, and occasionally hypokalemia.
Replacement of dehydroepiandrosterone (DHEA) in adults remains controversial; prepubertal children do not

normally secrete large amounts of DHEA.
Many adults with Addison disease complain of having decreased energy, and replacing DHEA may improve this
problem, particularly in women in whom adrenal androgens represent approximately ½ of total androgen
secretion. However, large, well-controlled studies are lacking.
Additional therapy may need to be directed at the underlying cause of the adrenal insufficiency in regard to
infections and certain metabolic defects.
Therapeutic approaches to adrenoleukodystrophy include administration of glycerol trioleate and glycerol

trierucate (Lorenzo's oil), bone marrow transplantation, and lovastatin.
SECONDARY ADRENAL INSUFFICIENCY
ETIOLOGY
ABRUPT CESSATION OF ADMINISTRATION OF CORTICOSTEROIDS.

102
 Secondary adrenal insufficiency most commonly occurs when the hypothalamic-pituitary-adrenal axis
is suppressed by prolonged administration of high doses of a potent glucocorticoid and that agent is
suddenly withdrawn or the dose is tapered too quickly. Patients at risk for this problem include those
with leukemia, asthma (particularly when patients are transitioned from oral to inhaled

corticosteroids), and collagen vascular disease or other autoimmune conditions and those who have
undergone tissue transplants or neurosurgical procedures.
 The maximal duration and dose of glucocorticoid that can be administered before encountering this
problem is not known, but it is assumed that high-dose glucocorticoids (the equivalent of >10 times
physiologic cortisol secretion) can be administered for at least a wk without requiring a subsequent
taper of dose.
 On the other hand, when high doses of dexamethasone are given to children with leukemia, it can
take up to 2 mo or longer after therapy is stopped before tests of adrenal function return to normal.
 Signs and symptoms of adrenal insufficiency are most likely in patients who are subsequently
subjected to stresses such as severe infections or additional surgical procedures.
CORTICOTROPIN (ACTH) DEFICIENCY.
 Pituitary or hypothalamic dysfunction can cause corticotropin deficiency.

 usually associated with deficiencies of other pituitary hormones such as growth hormone and
thyrotropin. Destructive lesions in the area of the pituitary, such as craniopharyngioma and
germinoma, are the most common causes of corticotropin deficiency. In many cases the pituitary or
hypothalamus is further damaged during surgical removal or radiotherapy of tumors in the midline of
the brain. In rare instances, autoimmune hypophysitis is the cause of corticotropin deficiency.
 Congenital lesions of the pituitary  septo-optic dysplasia, or de Morsier syndrome. More severe
developmental anomalies of the brain, such as anencephaly and holoprosencephaly, can also affect
the pituitary. These disorders are usually sporadic, although a few cases of autosomal recessive
inheritance have occurred.
CLINICAL PRESENTATION.
Aldosterone secretion is unaffected in secondary adrenal insufficiency because the adrenal gland is, by
definition, intact and the renin-angiotensin system is not involvedThus, signs and symptoms are those of
cortisol deficiency. Newborns often have hypoglycemia. Older children may have orthostatic hypotension or
weakness. Electrolytes are usually normal.
When secondary adrenal insufficiency is due to an inborn or acquired anatomic defect involving the
pituitary, there may be signs of associated deficiencies of other pituitary hormones. The penis may be small
in male infants if gonadotropins are also deficient. Infants with secondary hypothyroidism are often
jaundiced. Children with associated growth hormone deficiency grow poorly after the 1st yr of life.
Some children with pituitary abnormalities have hypoplasia of the midface. Children with optic nerve
hypoplasia may have obvious visual impairment. They usually have a characteristic wandering nystagmus, but
this is often not apparent until several months of age.
 Central cause will be with other associated hormonal defeciencies like growth hormone, dysmorphism, small phallus.
 Peripheral cause –more hyperpigmentation, no dysmorphism, no hypotension?
TREATMENT.
 Iatrogenic secondary adrenal insufficiency (caused by chronic glucocorticoid administration) is best

avoided by use of the smallest effective doses of systemic glucocorticoids for the shortest period of
time. When a patient is thought to be at risk, tapering the dose rapidly to a level equivalent to or
2
slightly less than physiologic replacement (~10 mg/M /24 hr of hydrocortisone) and further tapering
over several wk may allow the adrenal cortex to recover without development of signs of adrenal 103
insufficiency.
 Patients with anatomic lesions of the pituitary should be treated indefinitely with glucocorticoids.
Mineralocorticoid replacement is not required.

 In patients with panhypopituitarism treating cortisol deficiency may cause free water excretion
thus unmasking central diabetes insipidus. Electrolytes must be monitored carefully when initiating
cortisol therapy in panhypopituitary patients.
Why not McCune-Albright syndrome ?
Can be possible differential on basis of hyperpigmentaion but Unlikely to be a case of McCune-Albright

syndrome because that is charachterised by precocious puberty which is hallmark esp in girls and Menstrual
periods may begin in early childhood, long before the breasts or pubic hair develop (which normally occur
first). Puberty and menstrual bleeding may begin as early as 4 - 6 months in girls. Early sexual development
may also occur in boys, but not as often as in girls, Other symptoms include:
 Irregular, large patchy café-au-lait spots
 Gigantism, Acromegaly features,
 Deformities of the bones in the face, Bone fractures.
Treatment
There is no specific treatment for McCune-Albright syndrome. Drugs that block estrogen production, such as
testolactone, have been tried with some success.
Adrenal abnormalities (such as Cushing syndrome) may be treated with surgery to remove the adrenal glands.
Gigantism and pituitary adenoma will need treatment with hormone inhibitors or surgery
WHY NOT A CASE OF AUTOIMMUNE POLYENDOCRINOPATHY I (APECED)?
Can be the case of APECED , On basis of hyperpigmentaion, faintness as a feature of addison disease, and hx of
tetany, alon with hx of oral candidiasis, and symptoms of type 1DM, But the sequence of involvement is
usually candidial infections follwed by hypoparathyroism then addisons disease in last.
 Overview of clinical features

o The 3 major components of polyglandular autoimmune (PGA) syndrome, type I, are (1)
chronic mucocutaneous candidiasis, (2) hypoparathyroidism, and (3) autoimmune adrenal
insufficiency.
o The presence of all 3 components is not required to make a diagnosis; at least 2 components
have to be present in an individual. Additional manifestations, including, among others, type
1A diabetes (documented autoimmune etiology), hypogonadism, pernicious anemia,
malabsorption, alopecia, and vitiligo, may be present as well.
o The first manifestation usually occurs in childhood, and the complete evolution of the 3 main
diseases takes place within the first 20 years of life. Accompanying diseases continue to 104
appear at least until the fifth decade of life.
o Candidiasis usually is the first clinical manifestation, most often presenting in people younger
than 5 years. Hypoparathyroidism occurs next, usually in people younger than 10 years.
Lastly, Addison disease occurs in people younger than 15 years.

o Overall, the 3 components occur in fairly precise chronological order, and they are present in
roughly 40% of cases. As mentioned earlier, however, careful follow-up is mandatory to
watch for the more dreadful manifestations, eg, adrenal insufficiency, regardless of the
reportedly expected pattern of appearance.
 Mucocutaneous candidiasis
o This condition usually occurs earliest and is the most common of the 3 main diseases of PGA-
I.
o Assess any young person with moniliasis for a possible state of T-cell deficiency and PGA-I.
o Between 50 and 100% of patients with PGA-I develop a recurrent monilial infection. Most of
the lesions are limited to the skin (usually < 5% of surface area), nails, and oral and anal
[13]
mucosa. Esophageal involvement may be complicated by strictures and stenosis.
o Even though the presence of candidiasis is consistent with a T-cell defect, no increased
frequency of other opportunistic infections exists.
o Because these patients have a normal B-cell response to candidal antigens, they are spared
from developing disseminated candidiasis.

[4]
Hypoparathyroidism
o This is the first endocrine disease to occur during the course of PGA-I, usually developing
after candidiasis and before Addison disease.
o Antiparathyroid antibodies have been reported in 10-40% of patients with
hypoparathyroidism; however, whether these are being confused with mitochondrial
autoantibodies is still under debate. The pathologic significance of these antibodies is not
clear.
o Other disease states presenting with neonatal hypocalcemia (DiGeorge syndrome or
congenital absence or malformation of the parathyroid) must be differentiated from PGA-I.
DiGeorge syndrome results from a congenital defective disorder of the branchial clefts. It
manifests as hypoparathyroidism and cutaneous candidiasis; unlike PGA-I, DiGeorge
syndrome does not involve the adrenal glands.
o More than 75% of patients develop hypoparathyroidism, which usually presents in persons
younger than 10 years.
o Clinical features may include, among others, (1) tetanic clinical symptoms, such as
carpopedal spasm and paresthesias of the lips, fingers, and feet; (2) seizures; (3)
laryngospasm; (4) leg cramps; (5) diffuse mild encephalopathy; (6) cataracts; and (7)
papilledema. Electrocardiography may show a prolonged QT interval.
 Adrenocortical failure (Addison disease)
o Addison disease typically occurs in people aged 10-30 years (mean, 12-13 y); it usually is the
third disease to appear in PGA-I.
o Mineralocorticoid and glucocorticoid deficiencies usually arise simultaneously, but their
onset can be dissociated by up to 3 years.
o CYP21 appears to be the major autoantigen in isolated Addison disease and Addison disease
associated with PGA-II. Autoantibodies to CYP17 and a side-chain cleavage enzyme
(CYP11A1) have been associated with Addison disease in PGA-I.
o Early symptoms include weakness, fatigue, and orthostatic hypotension.
o Pigmentation usually is increased and may serve as a differentiating point from secondary
hypoadrenalism (primary pituitary failure).
o Anorexia, nausea, vomiting, diarrhea, and cold intolerance often occur.
o Late symptoms include weight loss, dehydration, hypotension, and a small-sized heart.
 Less common clinical manifestations
o Hypergonadotropic hypogonadism
o Type 1 diabetes mellitus
o Autoimmune thyroid disease (not including Graves disease)
o Pernicious anemia
o Chronic atrophic gastritis 105
o Chronic active hepatitis
o Enamel hypoplasia, which occasionally precedes the onset of hypoparathyroidism
o Asplenia
o Keratoconjunctivitis

o Cholelithiasis
o Malabsorption
o Alopecia
o Vitiligo
o Interstitial nephritis
Medical Care
 Mucocutaneous candidiasis
o This condition is treated with oral fluconazole and ketoconazole.
o Absorption of ketoconazole may be compromised if coexistent atrophic gastritis exists.
Ketoconazole may also inhibit adrenal and gonadal synthesis, which could worsen the
coexistent Addison disease and cause hepatitis.
o Fluconazole is preferred, because it does not inhibit steroidogenesis and is less frequently
associated with the development of hepatitis. It is, however, an expensive medication.
 Hypoparathyroidism
o This disorder usually is gradual and permanent, and oral calcium and vitamin D usually are
adequate therapy. Doses of vitamin D range from 50,000-100,000 U/d. Calcitriol (1,25-
dihydroxy D) is a better choice physiologically, but it is more expensive. Other vitamin D
synthetic analogues also are suitable for replacement, but cost again must be considered.
o In cases in which there is coexisting malabsorption, tetany may occur and IV calcium
gluconate and magnesium may be necessary.
o The hypocalcemia seen in PGA-I also has been reported to result from pancreatic
insufficiency, giardiasis (which occurs with increased frequency in PGA-I), and
lymphangiectasia. Each of these requires specific therapy.
 Adrenal insufficiency (Addison disease)
o The treatment of adrenal failure depends mainly on 2 factors.
 Treatment is influenced by the question of whether or not the patient is in crisis
with hypotension and consequently requires IV fluids and IV steroids. Otherwise,
treatment is influenced by the question of whether or not chronic and otherwise
stable oral steroids, eg, prednisone, can be used with or without fludrocortisone.
 Another factor influencing treatment is whether or not a confident diagnosis of
adrenal failure can be made based on the information at hand when the patient is
seen. This may determine what kind of IV steroid is used. If the diagnosis is not
clear, then the physician may opt to use dexamethasone IV, because it does not
interfere with subsequent cortisol measurements required for the diagnosis of
Addison disease. However, if sufficient clinical evidence exists in favor of Addison
disease, then using hydrocortisone is better because of its additional
mineralocorticoid benefit, as an aldosterone defect also is seen. Most of the time, a
mineralocorticoid (eg, fludrocortisone) also is added to the regimen.
o The glucocorticoid dose is changed according to the patient's symptoms. Monitor
electrolytes and the activity levels of plasma renin to assess the efficacy of treatment with
fludrocortisone.
o In cases of intercurrent illness, increase the doses of hydrocortisone.
o In the presence of coexisting diabetes, which is occasionally seen with PGA-I, the daily dose
usually should not exceed 30 mg/d, unless the need for a larger dosage is confirmed. This
necessitates higher doses of insulin; on many occasions, this results in difficulty controlling
glucose levels.
o Other deficiencies seen in association with diabetes and pernicious anemia, eg,
hypothyroidism, can be corrected by replacement therapy.
o Adrenal gland transplants have been successful in experimental rodents and in humans.
o Vitamin and mineral replacement occasionally is needed to complement hormonal 106
replacement.

 Since all of the manifestations of Addison's disease are caused by the lack of cortisol and aldosterone,
the treatment is to replace these with similar steroids.
Cortisol is usually replaced orally by hydrocortisone or cortisone acetate, less often with prednisone
tablets, divided into morning and afternoon doses.
Aldosterone is replaced by an aldosterone-like synthetic steroid, fludrocortisone (Florinef®) tablets

given once daily.
The doses of each of these medications are adjusted for the individual's size and any co-existing
medical conditions.
In emergencies or during surgery, hydrocortisone must be given intravenously.
Patients with Addison's disease should be taught to treat minor illnesses with extra salt, fluids and extra
hydrocortisone. This is especially important if fever, vomiting or diarrhea is present. Persistence of
these signs requires immediate treatment in an emergency room with intravenous saline (salt water) and
hydrocortisone.
Since Addison's disease is a chronic condition, daily replacement medication can never be stopped.
Proper maintenance treatment requires regular visits to a physician for examinations, laboratory tests,
and discussions about symptoms. Certain blood tests, including sodium, potassium, blood counts and
plasma renin are very useful in monitoring the response to adjustments in dosage. There is no single
blood or urine test that is perfect by itself
Patient's Education
 All patients with adrenal insufficiency must receive a structured crisis prevention education together
with their partners or relatives. This should be given at the time of first diagnosis. In addition, each visit
(every 3 or 6 months) the patient should be trained in recognizing typical stressful situations (fever,
infection, stress, surgery or trauma) and symptoms of acute adrenal insufficiency, and instructed on
glucocorticoid dose adjustment in these situations. In case of minor physical stress (infectious diseases
with fever, stress, surgery under local anaesthesia) or major and prolonged psychic stress, the daily
hydrocortisone replacement dose should be doubled or tripled to approximately 40-50 mg/day. When
prednisolone is used as glucocorticoid replacement, standard substitution of 5 mg prednisolone daily
should be increased to 10–15 mg/day. Under conditions of medium or major physical stress (trauma,
surgery with general anaesthesia, delivery) and in case of diarrhoea/vomiting, hydrocortisone needs to
be substituted intravenously (100–250 mg/24 h). As high doses of hydrocortisone have a
mineralocorticoid effect, adjustment of fludrocortisone during these stressful events is not required.
107

ABMBIGOUS GENITALIA -------------------------------------------------( SHORT CASE )/46 XYDSD/
UNDERVIRILIZED MALE.
COMMAND AND EXAMINATION STEPS SAME AS WRIITEN IN 46 XXDSD.
DESCRIPTION:
I have examined pt conscious , cooperative throught my examination with no obv.dysmorphism,

respiratory distress.
Genitalia examination show external
FUSED/ BIFID LABIOSCROTAL FOLD WITH NO/ RUGAE FORMATION.
PHALUS STRECH LENGH IS........
SINGLE / DOUBLE OPENONG .
TESTES PALPABLE IN ..... REGION MEASURING ABOUT ....ml.
Pulse rate is ………..bpm.
Resp.rate is………....bpm.
Afebrile to touch………
B.P is…………………….(raised in 17-hydroxylase deficiency)
There is no evidence of pallor, dehydration ,hyperpigmentation, any asymmetry of limb-(WAGR) , &

normal eye examination-(aniridia) in my child.
Abdomen is soft & nontender with no evidence of visceromegally.
DIAGNOSIS: (DON’T SAY HE/SHE).
Iam considering my pt is the case of XY DSD (Male pseudohermaphroidism/undervirilized male) most

likely secondary to:
1. 5 ALPHA REDUCTASE DEFFECIENCY

2. TESTICULAR FEMINIZING SYNDROME.
3. 17-HYDROXYLASE DEFFECIENCY.
Q: How would u investigate ? 108
A: Karyotyping--/FISH.
USG- abdomen –internal genitalia.

BSR
S.E
ABGs.
S.DHT (AIS  INCREASED)
S.Testosterone, corisol, aldosterone.
HCG stimulation test.
Enzyme assay –
HOW WILL U MANAGE YOUR PATIENT?
After confirming my dx I will councel the parents regarding disease, complication course and
management , & establishing the gender of pt. I will treat the acute problems of pt with correction
of hypoglycemia, dehydration and electrolyte imbalance. & treatment of underlying condition By
involving the mutlidiciplinary approach in which I will envolve myself, surgeon, endocrinologist,
psychotherapist and genetician , we give testosterone injection I.M depot weekly with dose of 25 mg
, then 50 mg till max dose 250 mg, sex of rearing decided on basis of karyptyping and USG of internal
structure. & surgical trx.
DISCUSSION:
3 BASIC DEFFECTS:
1. FAILURE OF GONADAL DIFFERENTIATION,-(denys drash syndrome,WAGR, 46XY gonadal agenesis &

dysgenesis).
2. FAILURE OF TESTOSTERONE BIOSYNTHESIS-(lipoid adrenal hyperplasia, 3-beta hydroxysteroid
dehydronase deff, 17-alpha hydroxylase def)
3. FAILURE OF TESTOSTERONE ACTION-(5 alpha reductase deff, AIS)
------------------------------------------------------×-------------
ANDROGEN INSENSITIVITY SYNDROME (AIS) /TESTICULAR FEMINIZATION SYNDROME
 XLR 1 case per 20,400 liveborn males.

 Unilateral/bilateral inguinal masses which are testes.
 Fused labioscrotal folds.
-------------------------------------------------------------------------
 failure of normal masculinization of external genitalia in chromosomally male individual

(UNDERVIRILIZED MALE)
 Types Complete/partial depending on the amount of residual receptor function. 109
 Both individuals Have offcourse 46,XY karyotypes.
 Individuals with complete androgen insensitivity syndrome have female external genitalia with normal
labia, clitoris, and vaginal introitus.
 In either case, affected individuals have normal testes with normal production of testosterone and

normal conversion to dihydrotestosterone (DHT), which differentiates this condition from 5-alpha
reductase deficiency. Because the testes produce normal amounts of müllerian-inhibiting factor
(MIFaffected individuals do not have fallopian tubes, a uterus, or a proximal (upper) vagina.
 untreated patients have a theoretical risk of malignant degeneration and development of
gonadoblastoma of the testes.
 In newborns most frequent initial finding is unilateral or bilateral masses in the inguinal canals
(testes).
 In adolescent inguinal masses, no pubic and axillary hair, with otherwise scanty body hair, and lack
acne, although breasts are normal as a result of conversion of testosterone to estradiol.
How will u investigate ?
 Karyotyping differentiate an undermasculinized male from a masculinized female.

 fluorescent in situ hybridization (FISH)  rapid alternate of karyotypnig confirm presence of a Y
chromosome
 serum testosterone and dihydrotestosterone (DHT) normal steroidogenesis.
 ratio of testosterone to DHTelevated indicates  5-alpha reductase deficiency,
 ultrasound pelvis: Identification of any müllerian structures, such as uterus or fallopian tubes, is
inconsistent with a diagnosis of complete androgen insensitivity syndrome or partial androgen
insensitivity syndrome
Rx:
 Multidisciplinary approach:
 hormone replacement therapy (HRT) .
 All patients androgen insensitivity syndrome undergo gonadectomy at some point
in their treatment
 For patients with complete androgen insensitivity syndrome, hormone therapy
almost always consists of estrogen replacement.
 Psychological support
 Surgical Care
Orchidectomy prevent malignant degeneration of the testes timing of surgery not clear yet
-----------------------------------------------------------------------
17-HYDROXYLASE (17-OH) DEFICIENCY:
 Can be seen in both genetical gender XX/XY.

 46,XY malesPresent with ambiguous genitalia+ Testes may be undescended or located in the
inguinal canal/ hypertension and hypokalemia.
 46,XX females sexual infantilism
----------
110
 Rare genetic disorder of steroid biosynthesis that causes decreased production of glucocorticoids and
sex steroids and increased synthesis of mineralocorticoid precursors.

 Excessive mineralocorticoid activity hypertension and hypokalemia.
How will u investigate?
All steroids requiring 17-hydroxylase (17-OH) activity for their production are found in very low
concentrations.
 17-hydroxypregnenolone
 Serum /urine 17-hydroxyprogesterone.
 Serum cortisol
 Serum 11-deoxycortisol.
 Dehydroepiandrosterone (DHEA),
 Androstenedione, and testosterone.
 All above are decreased or absent.
 The urinary metabolites 17-hydroxylase corticosteroid and 17-ketosteroid also are decreased or
absent.
 Serum estrogens and urinary estrogens are low.
 11-deoxycorticosterone (11-DOC) and corticosteronemarked elevated
 Aldosterone and plasma renin concentrations are usually low
 adrenocorticotropic hormone (ACTH)  are elevated due to lack of cortisol secretion.
 FSH and LH are elevated secondary to deficient sex steroid production by the gonads.
 Ultrasound pelvis.
Rx:
Exogenous glucocorticoid therapy is the treatment of choice.
 Oral hydrocortisonesuppresses ACTH secretion decreases 11-

deoxycorticosterone and corticosterone levels.
 Potassium and blood pressure abnormalities resolve after suppression of excessive

mineralocorticoid activity.
Hormonal replacement: (start at puberty
 Male patientsrequire testosterone).

 Female patients require cyclic estrogen-progesterone therapy.
 These therapies promote development of secondary sexual characteristics in both sexes and cyclic
menstrual bleeding in 46,XX females.
Surgical Rx:
 who are raised as females Perform a gonadectomy in 46,XY males ( intra-abdominal testes carry a
111
high risk of tumorous and malignant transformation).
-------------------------------------------------------*--------------------

5-ALPHA-REDUCTASE DEFICIENCY.
 autosomal recessive sex

 inability to convert testosterone to the more physiologically active dihydrotestosterone (DHT).
 Because DHT is required for the normal masculinization of the external genitalia in utero, genetic
males with 5-alpha-reductase type 2 deficiency are born with ambiguous genitalia (ie, 46,XY DSD).[1]
 classically present with:

 ambiguity of the genitalia.
 clitoral-like phallus.
 markedly bifid scrotum.
 pseudovaginal perineoscrotal hypospadias.
 Absent female internal genital due to normal MIF

 Testes are intact and are usually found in the inguinal canal or scrotum; however, cryptorchidism is
frequently described with testes occasionally located in the abdomen.
 Wolffian duct differentiation is normal with seminal vesicles, vasa differentia, epididymides, and
ejaculatory ducts.
 The prostate is small, nonpalpable, and rudimentary in adulthood. Neither benign prostate
hyperplasia (BPH) nor prostate cancer has been reported in these patients
 Karyotyping
 17-hydroxyprogesterone, follicle-stimulating hormone (FSH), leuteinizing hormone (LH), testosterone,

dihydrotestosterone (DHT), antimullerian hormone (AMH), electrolytes, and urinalysis
 Abdominopelvic ultrasound to assess for presence of internal male/female structures
 Results should be expedited, ideally available within 48-72 hours.
 In neonates with Y material (46,XY or fluorescent in situ hybridization [FISH] results positive for sex-
determining region [SRY]) and ambiguous genitalia, 5-alpha-reductase type 2 deficiency should be
considered.
 Elevated serum testosterone-to-DHT ratio (T/DHT) is the hallmark of 5-alpha-reductase type 2

deficiency. Typically, testosterone levels are normal to modestly elevated and DHT levels are low to
undetectable.
 HCG stimulation test is needed (after the early infant period of minipuberty) in order to obtain
adequate levels of testosterone and DHT for diagnosis.. 112
 Three common protocols include the following:
o 1500 IU intermuscularly (IM) on days 1, 3, and 5 (short test).
o 1500 IU IM every other day for 7 injections (prolonged test); or
o 5000 IU/m2 IM as a single dose.

 Take baseline HCG and 24 hours after the last dose (stimulated).
INTERPRETATION:
 In healthy newborns and prepubertal children the normal baseline T/DHT ratio is
less than 8.
 in postpubertal patientsthe baseline is less than 17.
 Following hCG stimulation the ratio is less than 17.
 In pt 5-alpha-reductase type deficiencythe post-hCG ratio is typically more than
27.
Rx:
 Hormone replacement therapy should be considered in patients raised in the male gender and is
required in patients raised in the female gender that have undergone gonadectomy
 who are raised as male
 Two doses of testosterone ester (125 mg per dose), 3 weeks apart/used in
prepubertal children and should be considered prior to hypospadias repair.
 Higher dose therapy (250-500 mg 1-2 times per week given for 6-36 mo) has been
used in pubertal or postpubertal patients.
 testosterone or dihydrotestosterone (DHT) therapy increase penile length.
 If testosterone is used in a prepubertal patient, parents should be counseled over
the potential to decrease final adult height secondary to androgen associated
skeletal advancement
 who are raised female estrogen replacement therapy should be initiated at a bone age of 12 years
or once an increase in gonadotropins is observed. Progesterone or cycling of estrogen therapy is not
required due to the absence of a uterus.
------------------------
113

DISCUSSION:
DIABETES MELLITUS
Diabetes mellitus chronic metabolic syndrome characterized by absolute or relative deficiency of insulin
leading to hyperglycemia as a cardinal biochemical feature
Classification:
Type 1 DM: Deficiency of insulin secretion due to pancreatic β-cell damage
Type 2 DM:insulin resistance occurring at the level of skeletal muscle, liver, and adipose tissue, with various
degrees of β-cell impairment.
Etiologic Classifications of Diabetes Mellitus
Type I diabetes (β-cell destruction, usually leading to absolute insulin deficiency)

Immune mediated Idiopathic
Type 2 diabetes (may range from predominantly insulin resistance with relative insulin deficiency to a
predominantly secretory defect with insulin resistance)
Dominant type 2 due to sulfonylurea receptor 1 mutation.
Genetic defects of β-cell function(MODY)

Chromosome 12, HNF-1α (MODY3)
Chromosome 7, glucokinase (MODY2)
Chromosome 20, HNF-4α (MODY1)
Insulin promotor factor–1 (MODY4)
HNF-1β (MODY5)
NEUROD1 (MODY6)
Mitochondrial DNA
Others
Genetic defects in insulin action
Type A insulin resistance
Leprechaunism
Rabson-Mendenhall syndrome
Lipoatrophic diabetes
Others
Diseases of the exocrine pancreas
Pancreatitis
Trauma, pancreatectomy 114
Neoplasia
Cystic fibrosis
Hemochromatosis

Pancreatic resection
Others
Endocrinopathies
Acromegaly
Cushing disease
Glucagonoma
Pheochromocytoma
Hyperthyroidism
Somatostatinoma
Aldosteronoma
Others
Drug-or chemical-induced
Vacor
Pentamidine
Nicotinic acid
Glucocorticoids
Thyroid hormone
Diazoxide
β-Adrenergic agonists
Thiazides
Dilantin
β-Interferon
Others—cyclosporine, tacrolimus
Infections
Congenital rubella
Cytomegalovirus
Others—hemolytic uremic syndrome
Uncommon forms of immune-mediated diabetes
” Stiff-man” syndrome
Cytomegalovirus
Others
Other genetic syndromes sometimes associated with diabetes
Down syndrome
Klinefelter syndrome
Turner syndrome 115
Wolfram syndrome
Friedreich ataxia

Huntington chorea
Laurence-Moon-Biedl syndrome
Myotonic dystrophy
Porphyria
Prader-Willi syndrome
Others/ alstrom syndrome
Gestational diabetes mellitus
Neonatal diabetes mellitus
Transient—without recurrence
Transient—recurrence 7–20 yr later—(ask in hx )
Permanent from onset
Natural history includes 4 distinct stages:
(1) preclinical β-cell autoimmunity with progressive defect of insulin secretion.

(2) onset of clinical diabetes.
(3) transient remission “honeymoon period,”
(4) Established diabetes associated with acute and chronic complications and decreased life
expectancy.
 The onset occurs predominantly in childhood, with median age of 7 to 15 yr, but it may present at any
age.
 T1DM is characterized by autoimmune destruction of pancreatic islet β cells.
 Both genetic susceptibility and environmental factors contribute to the pathogenesis. Susceptibility to
T1DM is genetically controlled by alleles of the major histocompatibility complex (MHC) class II
genes expressing human leukocyte antigens (HLAs).
 It is also associated with autoantibodies :
(1) Islet cell cytoplasm (ICA).
(2) Insulin (IAA). (Insulin autoantibodies)
(3) Antibodies to glutamic acid decarboxylase (GADA or GAD65).
(4) ICA512 (IA2). –(tyrosine hydroxylase antibodies)
 T1DM is associated with other autoimmune diseases such as:

(1) Thyroiditis. –(goiter, cold intolerance, constipation)
(2) Celiac disease.—(chronic diarrhea , abodominal distension)
(3) Multiple sclerosis—(fits, sensations, focal )
(4) Addison disease.—(hyperpigmentation, syncope, hypotension, poor glycemic control)
(5) APS 2 (Carpenter-D.M-1,Addison)
(6) vitiligo
The acute complications:
 Hypoglycemia.
 Hyperglycemia.
 Ketoacidosis.
116

Long-term complications:
 Retinopathy.
 Nephropathy.
 Neuropathy.
 Ischemic heart disease.
 Arterial obstruction with gangrene of the extremities.
Diagnostic Criteria for Impaired Glucose Tolerance and Diabetes Mellitus

IMPAIRED GLUCOSE TOLERANCE (IGT) DIABETES MELLITUS (DM)
*
Fasting glucose 110–125 mg/dL (6.1– Symptoms of DM plus BSR ≥200 mg/dL (11.1 mmol/L)
7.0 mmol/L)
Or
2-hr plasma glucose during the OGTT Fasting plasma glucose ≥126 mg/dL (7.0 mmol/L)
but ≤140 mg/Dl
Or
<200 mg/dL (11.1 mmol/L) 2-hr plasma glucose during the OGTT ≥200 mg/dL
* Symptoms include polyuria, polydipsia, and unexplained weight loss
with glucosuria and ketonuria
 A baseline hemoglobin A1C (HbA1C) allows an estimate of the duration of hyperglycemia and provides
an initial value by which to compare the effectiveness of subsequent therapy.
 In the nonobese child, testing for autoimmunity to β cells is not necessary.
 Other autoimmunities associated with type 1 diabetes should be sought, including
o celiac disease (by tissue transglutaminase IgA and total IgA)
o and thyroiditis (by antithyroid peroxidase and antithyroglobulin antibodies).
o Because significant physiologic distress can disrupt the pituitary-thyroid axis, free thyroxine
(T4) and TSH levels should be checked after the child is stable for a few weeks. (examiner
Q)
NOTE: above are the baseline workup of child with newly diagnosed DM
IMPAIRED GLUCOSE TOLERANCE: refers to a metabolic stage that is intermediate between

normal glucose homeostasis and diabetes.
 A fasting glucose concentration of 99 mg/dL (5.5mmol/L) is the upper limit of “normal.”
 Many individuals with IGT (fasting glucose 100–125 mg/dL) are euglycemic in their daily lives and
may have normal or nearly normal HbA1c levels.
 Individuals with IGT often manifest hyperglycemia only when challenged with the oral glucose load
used in the standardized oral glucose tolerance test.
 IGT is often associated with THE INSULIN RESISTANCE SYNDROME (ALSO KNOWN AS
SYNDROME X OR THE METABOLIC SYNDROME),
(METABOLIC SYNDROME: consists of insulin resistance, compensatory hyperinsulinemia to maintain glucose

homeostasis, obesity (especially abdominal or visceral obesity), dyslipidemia of the high-triglyceride or low- or
high-density lipoprotein type, or both, and hypertension)
117

EPIDEMIOLOGY:
 T1DM accounts for about 10% of all diabetes, affecting 1.4 million in the United States and about 15
million in the world.
 It is one of the most common severe chronic childhood diseases; 40% of individuals with type 1 DM
are younger than 20 yr of age.
 The overall age-adjusted incidence of type 1 DM varies from 0.7/100,000 per year in Karachi
(Pakistan) to about 40/100,000 per year in Finland.
 This represents a more than 400-fold variation in the incidence among 100 populations.
 Data from Western European diabetes centers suggest that the annual rate increase in T1DM
incidence is 3–4%.
 . The increasing rate is greatest among the youngest children; rates of increase in T1DM incidence
as a function of age at onset are 6.3%, 3.1%, and 2.4% in age groups of children 0–4 yr, 5–9 yr, and
10–14 yr, respectively
 Annual incidence of new cases in the United States is about 14.9/100,000 of the child population.
 Girls and boys are almost equally affected; there is no apparent correlation with socioeconomic
status.
Peaks of presentation occur in 2 age groups:
 5–7 yr of age and at the time of puberty.

 A growing number of cases are presenting between 1 and 2 yr of age.
 The 1st peak may correspond to the time of increased exposure to infectious agents coincident with
the beginning of school; the 2nd peak may correspond to the pubertal growth spurt induced by
gonadal steroids and the increased pubertal growth hormone secretion (which antagonizes insulin).
GENES.
 The most important genes are located within the MHC HLA class II region on chromosome 6p21,
formally termed (IDDM1), accounting for about 60% genetic susceptibility for the disease. Their
specific contribution to the pathogenesis of T1DM remains unclear.
 Inheritance of HLA-DR3 or -DR4 antigens appears to confer a 2- to 3-fold increased risk for the
development of T1DM.
 When both DR3 and DR4 are inherited, the relative risk for the development of diabetes is increased
by 7- to 10-fold.
Homozygous absence of aspartic acid at position 57 of the HLA DQ β-chain (non-Asp/non-Asp) confers
an approximately 100-fold relative risk for the development of type 1 diabetes. While heterozygotes at
same position have less susceptibility.
 Thus, the presence of aspartic acid at one or both alleles of DQ β protects against the
development of autoimmune diabetes.
In addition, arginine at position 52 of the DQ β-chain confers marked susceptibility to T1DM. Position 57
of the DQ β and position 52 of DQ β are at critical locations of the HLA molecule that permit or prevent
antigen presentation to T-cell receptors and activate the autoimmune cascade.
type 1 DM seems unique among autoimmune diseases in that, in addition to forming susceptibility, certain
MHC haplotypes provide significant protection.
 The HLA-DRB1*0301, HLA-DRB1*0401, HLA-DQB1*0302, and HLA-DQA1*0301 alleles 118

of MHC (IDDM1) confer high-risk susceptibility in humans.
 other alleles such as HLA-DRB1*0403, HLA-DQB1*0602, and HLA-DQA1*0102 are

negatively associated with type 1 DM and may confer resistance.

The observation that 20% of individuals from Europe or the United States carry protective HLA-DR2
haplotype, yet fewer than 1% of children with type 1 DM are DR2 (DQB1*0602) positive, highlights this
important genetic component.
 T1DM represents a heterogeneous and polygenic disorder.
Factors other than pure inheritance of HLA markers or other genes must also be involved in producing
diabetes.
For example, HLA-DR3 or -DR4 is found in approximately 50% of the general population, and (non-
Asp/non-Asp) is found in approximately 20% of nondiabetic whites in the United States, yet the risk for
type 1 DM in these subjects is only one tenth of that in an HLA-identical sibling of an index case possessing
these markers.
Even siblings sharing only one haplotype have a 6- to 10-fold greater risk of development of type 1 DM
compared with the normal population.
The concordance rate among identical twins is only 30–50%, suggesting either the participation of
environmental triggering factors or other genetic factors.
It can be assumed that in whites, the overall risk to siblings is approximately 6% if the proband is younger
than 10 yr of age and 3% if the proband is older at the time of diagnosis.
The risk to offspring of a diabetic father is 7%,
Diabetic mother is 3 % &
both diabetic risk is 30%
identical twin 50%
HLA identical 20%
Non identical 1%
Hapto identical 5%((examiner Q)
ENVIRONMENT.
 RISK FACTORS:
Protective factors
 Breastfeeding.
 mild early childhood infections (hygiene theory)(examiner Q) or herd immunity to
viruses that can be transmitted transplacentally to the fetus.
 Environmental risk determinants that have been vigorously investigated can be classified as viral
infections, early infant diet, and chemicals.
VIRAL INFECTIONS AND VACCINATIONS.

 coxsackie B3.
 coxsackie B4. 119
 Cytomegalovirus.
 Rubella
 mumps can infect human β cells.
 Only congenital rubella infection is associated with diabetes in later life.

 It is estimated that 10–12% of patients infected with congenital rubella develop T1DM and up to
40% develop impaired glucose tolerance.
 The diabetes induced by rubella resembles T1DM because it is associated with HLA-DR3 and HLA-
DR4 and is mediated by immune responses against β-cell antigens.
SEASONAL ASSOCIATIONS.
 Newly recognized cases appear with greater frequency in the respective autumn and winter months
PUBERTY.
 The pubertal peak in onset of type 1 DM occurs earlier in girls than boys. This sex difference might be
mediated, in part, by estrogen or by genes regulated by estrogen, such as the interleukin-6 (IL6) gene,
and suggests that pubertal changes may contribute to accelerated onset of type 1 DM in genetically
susceptible females.
DIETARY FACTORS.
 Feeding cow's milk to animal models of T1DM has been associated with the development of diabetes
in these animals.
 The likely mechanism is the molecular mimicry between a 17-amino-acid peptide of the bovine serum
albumin and the islet antigen 69. –controversial role
 An initial exposure of infants to cereals before 4 mo of age or after 6 mo of age has been suggested
to increase the risk of islet autoimmunity independent of HLA genotype, family history of T1DM,
ethnicity, and maternal age.
BODY MASS INDEX.
There may be a greater risk of T1DM among individuals who were heavier as young children. The accelerator
hypothesis predicts earlier onset in heavier people, without necessarily a change in risk, and views type 1 and
T2DM as the same disorder of insulin resistance, set against different genetic backgrounds. Insulin resistance is
a function of fat mass, and because increasing body weight in the industrialized world has been accompanied
by earlier presentation (acceleration) of T2DM, proponents of the accelerator hypothesis suggest that the age
at presentation of T1DM is also associated with adiposity. Therefore, limiting excessive weight gain may be as
important for children susceptible to T1DM as for those at genetic risk for T2DM.
CHEMICALS.
 Drugs such as alloxan, streptozotocin (STZ), pentamidine, and Vacor are directly cytotoxic to β cells
and cause diabetes in experimental animals and humans.
 Autoimmunity against β cells has also been reported in humans after intoxication with the human
rodenticide Vacor.
PATHOGENESIS
Autoimmune Injury.
 T1DM is a chronic, T cell–mediated autoimmune disease that results in the destruction of the
pancreatic islets.
 Genetic predisposition and environmental factors lead to initiation of an autoimmune process against
the pancreatic islets.
 The autoimmune attack on the pancreatic islets leads to a gradual and progressive destruction of β cells,
with loss of insulin secretion.
120
 It is estimated that, at the onset of clinical diabetes, 80–90% of the pancreatic islets are destroyed.
 Regeneration of new islets has been detected at onset of T1DM, and it is thought to be responsible for
the honeymoon phase (a transient decrease in insulin requirement associated with improved β-cell
function).

 In young diabetic children, especially those of DR3/DR4 haplotypes, the destruction of β cells is
almost complete during the 1st 3 yr after the onset of hyperglycemia, whereas in older patients
complete β-cell destruction may take up to 10 yr
 Once islet cell autoimmunity has begun, progression to islet cell destruction is quite variable, with
some patients rapidly progressing to clinical diabetes while others remain in a nonprogressive state.
Antigenic/epitope spreading of the autoantibody responses is an important marker of impending
progression; those with but a single autoantibody progress slowly, whereas those with
autoantibodies to multiple antigens most often progress rapidly.
 Most individuals progressing to overt diabetes express multiple anti–islet cell antibodies
(GAD65, ICA512/IA-2, and IAA) before the onset of diabetes, thus used as PRE DIABETIC
SCREENING
The autoimmune response against the pancreatic β cells is believed to consist of 4 phases:
(1) environmental insult.

(2) priming of T cells,
(3) T-cell differentiation
(4) β-cell destruction
PREDICTION AND PREVENTION.
 Autoimmunity precedes clinical T1DM, and indicators of maturing autoimmune responses may
be useful markers for disease prediction.
 Autoantibodies are useful for detecting developing T1DM in close relatives of diabetic patients
whose risk for diabetes is about 3.5–5.0%.
In the 1st-degree relatives of patients with T1DM, the number of positive d-aab can help estimate the risk of
developing T1DM:
 low risk (single d-aab: PPV of 2–6%),

 moderate risk (2 d-aab: PPV of 21–40%),
 and high risk (>2 d-aab: PPV of 59%–80%) over a 5-yr period.
In children carrying the T1DM highest-risk genotype (HLA-DQB1*0201-DQA1*05/DQB1*0302-DQA1*03),

insulitis is almost 10 times more frequent (PPV 21%) than in children with other genotypes (PPV 2.2%).
Children at risk for T1DM develop early IAA, which may progress to multiple islet autoantibodies based on the
degree of IAA affinity to insulin. It has been very difficult to find safe and benign forms of therapy that can be
used in individuals who may never develop T1DM.
IMMUNOTHERAPY IN NEW-ONSET TYPE 1 DM.
Type 1 DM is a T-cell-mediated autoimmune disease that begins, in many cases, 3–5 yr before the onset of
clinical symptoms, continues after diagnosis, and can recur after islet transplantation.
 The effector mechanisms responsible for the destruction of β cells involve cytotoxic T cells as well as
soluble T-cell products, such as IFN-γ and TNF-α. Such observations have led to clinical trials with
immunomodulatory drugs such as cyclosporine, azathioprine, prednisone, and antithymocyte
globulin. these agents do cause transient improvement but their toxicity is more and continues 121
use in healthy child..so all this limits use of these agents.
 Immunotherapy using modified monoclonal antibody against CD3.

 Short-term (6-day) CD3 monoclonal human IgG1 antibody (ChAglyCD3) therapy in patients aged 12
to 39 yr with new-onset T1DM preserved residual β-cell function for at least 18 mo in patients with
recent-onset T1DM. This was associated with a moderate “flu-like” syndrome and transient symptoms
of Epstein-Barr viral mononucleosis.
Examiner Q: how would u prevent & predict DM?
A: PRIMARY PREVENTION FOR DIABETES IS

Prolong breast feeding
Avoid cows milk
Vitamin C,D,E ZINC
Omega -3 fatty acid
Cereals late
Probiotics
MMR vaccination
SECONDARY PREVENTION:
Glucagon like peptide agonist
Anti-CD3 antibody
& predict by pre diabetic screening of family members as well relatives by (detail is
given above)
 Islet cell cytoplasm (ICC)

 Insulin (IAA). (Insulin autoantibodies)
 Antibodies to glutamic acid decarboxylase (GADA or GAD65).
 ICA512 (IA2). –(tyrosine hydroxylase antibodies)
INFLUENCE OF FEEDING (HIGH INSULIN) OR OF FASTING (LOW INSULIN) ON SOME METABOLIC PROCESSES IN
LIVER, MUSCLE, AND ADIPOSE TISSUE
HIGH PLASMA INSULIN (POSTPRANDIAL STATE) LOW PLASMA INSULIN (FASTED STATE)
Liver Glucose uptake Glucose production
Glycogen synthesis Glycogenolysis
Absence of gluconeogenesis Gluconeogenesis
Lipogenesis Absence of lipogenesis
Absence of ketogenesis Ketogenesis
Muscle Glucose uptake Absence of glucose uptake
Glucose oxidation Fatty acid and ketone oxidation
Glycogen synthesis Glycogenolysis
Protein synthesis Proteolysis and amino acid release
Adipose tissue Glucose uptake Absence of glucose uptake
Lipid synthesis Lipolysis and fatty acid release
Triglyceride uptake Absence of triglyceride uptake 122
MECHANISM OF DKA (common examiner Q)

 In type 1 DM there is absolute insulin deficiency which causes Hyperglycemia which produces an
osmotic diuresis (glycosuria) when the renal threshold is exceeded (180 mg/dL; 10 mmol/L). The
resulting loss of calories and electrolytes, as well as the persistent dehydration, produce a physiologic
stress with hypersecretion of stress hormones (epinephrine, cortisol, growth hormone, and
glucagon), which further increases the glucose level by glyconeogenesis & glycogenolysis.This
combination of insulin deficiency and elevated plasma values of the counter-regulatory hormones is
also responsible for accelerated lipolysis of adipose tissue and impaired lipid synthesis, with resulting
increased plasma concentrations of total lipids, cholesterol, triglycerides, and free fatty acids. The
hormonal interplay of insulin deficiency and glucagon excess shunts the free fatty acids into ketone
body formation principally β-hydroxybutyrate and acetoacetate. The rate of formation of these
ketone bodies exceeds the capacity for peripheral utilization and renal excretion. Accumulation of
these keto acids results in metabolic acidosis (diabetic ketoacidosis, DKA) and compensatory rapid
deep breathing in an attempt to excrete excess CO 2 (Kussmaul respiration). Acetone, formed by
nonenzymatic conversion of acetoacetate, is responsible for the characteristic fruity odor of the
breath. Ketones are excreted in the urine in association with cations and thus further increase losses
of water and electrolyte. Keto acids produce abdominal discomfort, nausea, and emesis, preventing
oral replacement of urinary water losses. With progressive dehydration, acidosis, hyperosmolality,
and diminished cerebral oxygen utilization, consciousness becomes impaired, and the patient
ultimately becomes comatose.
When the serum glucose increases above the renal threshold, intermittent polyuria or nocturia begins. With
further β-cell loss, chronic hyperglycemia causes a more persistent diuresis, often with nocturnal enuresis, and
polydipsia becomes more apparent. Calories are lost in the urine (glycosuria), triggering a compensatory
hyperphagia. If this hyperphagia does not keep pace with the glycosuria, loss of body fat ensues, with clinical
weight loss and diminished subcutaneous fat stores. An average, healthy 10-yr-old child consumes about 50%
of 2,000 daily calories as carbohydrate. As that child becomes diabetic, daily losses of water and glucose may
be 5 L and 250 g, respectively, representing 1,000 calories, or 50%, of the average daily caloric intake. Despite
the child's compensatory increased intake of food, the body starves because unused calories are lost in the
urine. This is why children with Type 1DM with poor compliance are thin lean built.(Examiner Q )
Female patients may develop monilial vaginitis due to the chronic glycosuria.
DIABETIC KETOACIDOSIS
o DKA is the end result of the metabolic abnormalities resulting from a severe deficiency of insulin or
insulin effectiveness. The latter occurs during stress as counter-regulatory hormones block insulin
action.
o DKA occurs in 20–40% of children with new-onset diabetes and in children with known diabetes who
omit insulin doses or who do not successfully manage an intercurrent illness.
o DKA may be arbitrarily classified as mild, moderate, or severe
o and the range of symptoms depends on the depth of ketoacidosis. There is a large amount of ketonuria,
an increased ion gap, a decreased serum bicarbonate (or total CO2) and pH, and an elevated
effective serum osmolality, indicating hypertonic dehydration.
123

Classification of Diabetic Ketoacidosis
[†]
NORMAL MILD MODERATE SEVERE
CO2 (mEq/L, 20–28 16–20 10–15 <10
[*]
venous)
[*]
pH (venous) 7.35– 7.25–7.35 7.15–7.25 <7.15
7.45
Clinical No Oriented, alert Kussmaul respirations; Kussmaul or depressed respirations;
change but fatigued oriented but sleepy; sleepy to depressed sensorium to coma
arousable
ALSO
HCO3 22-28 <15 <10 <05
S.Na+ Normal Normal >150meq/L(corrected)
BSR 300-400mg/dl 400-600 >600mg/dl
Severe insulinopenia (or lack of effective insulin action) results in a physiologic cascade of events in 3 general
pathways.
1. Excessive glucose production coupled with reduced glucose utilization raises serum glucose. This
produces an osmotic diuresis, with loss of fluid and electrolytes, dehydration, and activation of the
renin-angiotensin-aldosterone axis with accelerated potassium loss. If glucose elevation and
dehydration are severe and persist for several hours, the risk of cerebral edema increases.
2. Increased catabolic processes result in cellular losses of sodium, potassium, and phosphate.
3. Increased release of free fatty acids from peripheral fat stores supplies substrate for hepatic keto acid
production. When keto acids accumulate, buffer systems are depleted and a metabolic acidosis ensues.
Therapy must address both the initiating event in this cascade (insulinopenia) and the subsequent
physiologic disruptions.
Reversal of DKA or Rx is associated with inherent risks that include hypoglycemia, hypokalemia, and cerebral
edema.
Diabetic Ketoacidosis (DKA) Treatment Protocol

TIME THERAPY COMMENTS
1st hour 10–20 mL/kg IV bolus 0.9% Quick volume expansion;may be repeated.NPO.Monitor
NaCl or LR I/O, neurologic status.Use flow she et.Have mannitol at
Insulin drip at 0.05 to 0.10 μ bedside;1 g/kg IV push for cerebral edema.
/kg/hr
2nd hour until 0.45% NaCl:plus continue
DKA resolution insulin drip
20 mEq/L KPhos and 20
mEq/L KAc
124
5% glucose if blood sugar
<250 mg/dL (14 mmol/L)
If K < 3 mEq/L, give 0.5 to 1.0 mEq/kg as oral K solution OR

TIME THERAPY COMMENTS
increase IV K to 80 mEq/L
Variable Oral intake with No emesis;CO2 ≥ 16 mEq/L;normal electrolytes
subcutaneous insulin
Note that the initial IV bolus is considered part of the total fluid allowed in the first 24 hr and is subtracted
before calculating the IV rate.
Maintenance (24 hr) = 100 mL/kg (for the 1st 10 kg) + 50 mL/kg (for the 2nd 10 kg) + 25 mL/kg (for all
remaining kg)
Sample calculation for a 30-kg child:
1st hour = 300 mL IV bolus 0.9% NaCl or LR
OR
Simply in long case we can say sir i will go for
 Fluid resuscitation
 Insulin therapy
 Monitoring of BSR, Serum electrolytes, ABG, s.urine for ketones
NOTE: (usually BSR 1 hourly, Electrolytes , AbG,s 4 hourly & urine ketones 6 hourly is monitored )
Hyperglycemia is corrected first compare to acidosis during Rx so insulin infusion should be continued till
acidosis corrected.
Children with previously diagnosed diabetes who develop DKA are usually transitioned to their previous
insulin regimen
Q: what electrolytes changes would u expect in pt with DKA?

A:
 ↓s.Na+ (dilutional hyponatremia ) but ↑ corrected Na+
 ↓s.K+
 ↓S.PO4
 Also
 ↑BSR,
 Urine ketones +ve
 ABG,s-Metabolic acidosis
NOTE: corrected Na+= Add 1.6meq for 100mg% BSR above 100mg%
Corrected K+= substract 0.6meq for every 0.1 decrease in PH
Q: indication of NaHCO3 in DKA?
A: usually not given in DKA b/c Soda bicarb leads to paradoxical acidosis –soda bicarb can’t cross BBB –so it
increase PH in blood but not directly in CSF , H2CO3 CO2 + H2O –in this CO2 crosses BBB and enter CSF coz 125
CO2 is an acid thus CSF PH increases….
NAHCO3 in indicated when

 PH is <6.9
 Hco 3 <5meq
 S.k+ ↑ along with ECG changes
Advantages:
 Improve hemodynamics of pt
 ↑ myocardial contraction
 ↓ s.K+
 ↓insulin resistance due to acidosis
REASONS OF HYPOKALEMIA IN DKA
1. Osmotic diuresis –dehydration  increase renin release  increase aldosterone  dec K+

2. During Rx:
 dilutional (N/S bolus)
 Ongoing losses.
 Insulin –shift K + in cell.
REASONS OF CEREBRAL EDEMA IN DKA
 Rapid drop in Glucose level due to early insulin ↓ plasma osmolarity but ↑ CSF
osmolarity.
 Excessive I.V fluids (hypotonic)
 Toxicity of i.v fluids eg Bicarb which ↑ Co 2 in CSF ↓ PH ↑ risk of edema
Clinical signs of cerebral edema
 Poor GCS
 Decorticate/decerebrate posture
 3,4,6 cranial nerve palsy
 Abnormal breathing
RX
 ↓ IV fluids
 Elevate head
 Mannitol 20% 0.5g/kg in 30 min repeat after 1 hour if no response
 Hyperventilation (keep CO2<25)
 Go for CT brain & must check RFTs
Q: how would u prevent DKA?
A: by sick day Rule (explained in the end in detail)….infection increases insulin resistance increase stress
hormones increases BSR thus insulin dose in increased in infection or fever & antibiotics are also given b/c
decreases insulin resistance.
Q: Complications of DKA?
A:
 shock 126
 Thrombosis
 hypoglycemia,
 hypokalemia, and cerebral edema.

Q: why DKA not occurs in Type 2 DM?
A: in type 1 there is absolute insulin deficiency but in type 2 sufficient insu lin is present to suppress ketone
production or lipolysis & fatty acids production
NONKETOTIC HYPEROSMOLAR COMA
This syndrome is characterized by:
 Severe hyperglycemia (blood glucose >800 mg/dL).

 Absence of or only slight ketosis.
 Nonketotic acidosis.
 Severe dehydration.
 Depressed sensorium or frank coma and various neurologic signs that may include grand mal seizures,
hyperthermia, hemiparesis, and positive Babinski signs.
 Respirations are usually shallow, but coexistent metabolic (lactic) acidosis may be manifested by
Kussmaul breathing.
 Serum osmolarity is commonly 350 mOsm/kg or greater.
 This condition is uncommon in children; among adults, mortality rates have been high, possibly in
part because of delays in recognition and institution of appropriate therapy. In children, there has been
a high incidence of pre-existing neurologic damage. Profound hyperglycemia may develop over a
period of days and, initially, the obligatory osmotic polyuria and dehydration may be partially
compensated for by increasing fluid intake With progression of diseasethirst becomes impaired,
possibly because of alteration of the hypothalamic thirst center by hyperosmolarity and, in some
instances, because of a pre-existing defect in the hypothalamic osmoregulating mechanism.The
low production of ketones is attributed mainly to the hyperosmolarity, which in vitro blunts the
lipolytic effect of epinephrine and the antilipolytic effect of residual insulin; blunting of lipolysis
by the therapeutic use of β-adrenergic blockers may contribute to the syndrome. Depression of
consciousness is closely correlated with the degree of hyperosmolarity in this condition as well as in
DKA. Hemoconcentration may also predispose to cerebral arterial and venous thromboses.
TREATMENT:
(1) Rapid repletion of the vascular volume deficit and very slow correction of the hyperosmolar
state.
(2) One half isotonic saline (0.45% NaCl; some use normal saline) is administered at a rate
estimated to replace 50% of the volume deficit in the 1st 12 hr  and the remainder is
administered during the ensuing 24 hr.
 The rate of infusion and the saline concentration are titrated to result in a
slow decline of serum osmolality.
(3) When the blood glucose concentration approaches 300 mg/dL, the hydrating fluid should be
changed to 5% dextrose in 0.2 normal (N) saline.
(4) Approximately 20 mEq/L of potassium chloride should be added to each of these fluids to
prevent hypokalemia.
 Serum potassium and plasma glucose concentrations should be monitored at
2 hr intervals for the 1st 12 hr and at 4 hr intervals for the next 24 hr to
permit appropriate adjustments of administered potassium and insulin.
(5) Insulin can be given by continuous IV infusion beginning with the 2nd hr of fluid therapy.
 Blood glucose may decrease dramatically with fluid therapy alone.
(6) The IV insulin dosage should be 0.05 U/kg/hr of regular (fast-acting) rather than 0.1 U/kg/hr as
advocated for patients with DKA. 127
MANAGEMENT:

Multidisciplinary approach involves pediatric endocrinologist, experienced nursing staff,
dietitians, diabetes educators, and a social worker .As my patient is k/c now presented with DKA
due to poor compliance, I wl counsel them regarding patho physiology of disease ,its Rx,
complications & prognosis
My aim is to maintain tight glucose control keeping random sugar <200mg/dl ,fasting <120mg/dl
, HbA1c ,8% and avoiding hypoglycemia, to to prevent ketoacidosis, and to permit normal
growth and development with minimal effect on lifestyle. Therapy encompasses initiation and
adjustment of insulin, and injecting the correct insulin dose subcutaneously at the proper time,
its storage, monitoring the child's blood glucose and urine ketones, extensive teaching of the child
and caretakers about sick day rule, preparing them recognizing and treating low blood glucose
reactions, and having a basic meal plan , exercise & important is psychosocial support( arrange
kar k donga glucometer 7 strips)
Also I will go for coelic & thyroid workup (usually pts are not compliant & short stature with no
work up previously) & ensure proper compliance & follow up
INSULIN THERAPY
A reasonable dose in the newly diagnosed child, then, is about 60–70% of the full replacement dose based on
pubertal status. Children with long-standing diabetes and no insulin reserve require about:
(1) 0.7 U/kg/d if prepubertal (age 0-5 years)

(2) 1 U/kg/d at midpuberty (5-12years)
(3) 1.2 U/kg/d by the end of puberty(12-18 years)
Most children with new-onset diabetes have some residual β-cell function (the “honeymoon”
period), which reduces exogenous insulin needs
NOTE: (honeymoon period in which residual B cells compensate hypertrophies & increase insulin
production. it usually occurs in 2/3 of cases & 2 weeks after diagnosis, lasts up to months to 1-2
years.Dose used is 0.5U/kg)
Insulin regimen:
1. Twice daily (prebreakfast & pre evening)

2. Twice daily + additional short /ultra short
3. Basal bolus insulin regimen (3 stat Ultrashort acting + long in evening 2 hours after night meal/ or at
bedtime )
4. Pre-mixed – (biphasic) insulin.
5. Insulin pumps.(use only rapid acting, contraindicated in type 2 DM ,used in children <12 years)
STANDARD:
Short acting:
(Regular insulin –plain clear look in bottle)

128
 Onset –30-60 min.
 Peak –2-5 hrs
 Total duration –6-8 hrs

Intermediate acting: (duration 12-18 hours)
 Isophane /NPH(neutral protamine hagedorn)

 Semilente
 Lente discontinued not available now
Long acting: (duration 24 hours)
 Ultra lentediscontinued not available.

 Protamine zinc
Biphasic:
 Pre-mixed (70/30) Milky look in bottle (70% NPH& 30% regular)–->Rs:552)
Onset—30 min
Peak---2-4 hours
Duration--16-24 hours
INSULIN ANALOGUE
Ultra-short acting:
 Lispro.
 Aspart
 Onset: 5-15 min.
 Peak: 30-120 min.
 Total duration: 3.5-6 hrs.
Long acting:
 Glargine –form precipitate s/c –slow insulin release from depot.
Given 30% of long & 70% of ultra short acting
 Onset -2-4 hrs

 Peak less insulin
 Total duration –20-24 hrs.
New insulins :
1. Glulisine—ultra short acting

2. Detemir—long acting given BD.
IMPORTANT TYPES OF INSULINS & REGIMES (common examiner Q)
Standard human insulin – forms hexamers need to convert into monomers before S/C absorption.
129
Standard insulin is available in market of bovine & human (recombinant DNA technology).bovine
costs each vial about Rs 50 & human about 500 Rs where as analogues costs about Rs 1500 each vial.
So most common insulin used in developing countries like Pakistan is standard (Regular or 70/30) &
human usually & Most common method used is twice daily b/c most of families are non compliant &

uneducated. It is very difficult to achieve good glycemic control with this regime & we keep HbA1c
around 8% & which is acceptable in this regime. R has a wide peak and a long tail for bolus insulin &
NPH do not create a peakless background insulin level. When R is combined with NPH the composite
insulin profile poorly mimics normal endogenous insulin secretion. There are broad areas of excessive
insulin effect alternating with insufficient effect throughout the day and night. So This regime does
not achieve good postprandial glucose control, produces prolonged peaks with excessive
hypoglycemic effects between meals, so need snacks in b/w meals and increases the risk of nighttime
hypoglycemia & morning hyperglycemia as well.
 Insulin analogues –don’t forms hexamers & don’t need to convert in monomers,so are absorbed
rapidly s/c. Ultra short acting provides discrete pulses and have short tail effect. The long-acting analog
glargine (G) creates a much flatter 24-hr profile having no peak, no trough It produces a more
physiologic pattern of insulin effect. Acceptable glucose control can be obtained with new insulin
analogs used in a basal-bolus regimen, that is, with slow-onset, long-duration background insulin for
between-meal glucose control and rapid-onset insulin at each meal. This allows better control of post-
meal glucose increase and reduces between-meal hypoglycemia so no need of snacks in b/w & reduces
nighttime hypoglycemia. This is most commonly used method in developed countries & highly
educated people in the world. HbA1c is usually normal in analogues. Poor control glucose or
uncontrolled DM only solution is analogues. it increases the flexibility of time can be given when
eating extra. Its disadvantage is multiple pricks & risk of hypoglycemia, Glargine may be given every
12 hours in young children if a single daily dose of G does not produce complete 24-hr basal coverage

 The BASAL INSULIN GLARGINE should be:
(1) 25–30% of the total dose in toddlers
(2) and 40–50% in older children.
(3) The remaining portion of the total daily dose is divided evenly as bolus injections for the 3
meals.
A simple 3- or 4-step dosing schedule is begun based on the blood glucose level. As soon as the family is
taught to calculate the carbohydrate content of meals, bolus insulin can be more accurately dosed by both the
carbohydrate content of the meal as well as the ambient glucose
Subcutaneous Insulin Dosing

†
BOLUS INSULIN
AGE TARGET TOTAL DAILY BASAL INSULIN, % OF Units Added per 100 Units Added per
*
(YR) GLUCOSE INSULIN (U/KG/D) TOTAL DAILY DOSE mg/dL above Target 15 g at Meal
(MG/DL)
0–5 100–200 0.6–0.7 25–30 0.50 0.50
5–12 80–150 0.7–1.0 40–50 0.75 0.75
[‡]
12– 80–150 1.0–1.2 40–50 1.0–2.0 1.0–2.0
18
Newly diagnosed children who do not use carbohydrate dosing should divide the nonbasal portion of the
daily insulin dose into equal doses for each meal. A dosing scale is then added for each dose.For example:a
6-yr-old child who weighs 20 kg needs about (0.7 units/kg/24 hr × 20 kg) = 14 units/24 hr with 7 units (50%)
as basal and 7 units as total daily bolus. Give basal as glargine at hs. Give 2 units lispro or aspart before each
meal if the blood glucose is within target; subtract 1 unit if below target; add 0.75 unit for each 100 mg/dL
above target (round the dose to the nearest 0.5 unit).
†
‡
130
For finer control, extra insulin may be added in 50-mg/dL increments.
 Frequent blood glucose monitoring and insulin adjustment are necessary in the 1st weeks

Some families may be unable to administer 4 daily injections. In these cases, a compromise may be needed.
A 3-injection regimen combining NPH with a rapid analog bolus at breakfast, a rapid-acting analog bolus at
supper, and NPH at bedtime may provide fair glucose control. Further compromise to a 2-injection regimen
(NPH and rapid analog at breakfast and supper) may occasionally be needed. However, such a schedule would
provide poor coverage for lunch and early morning, and would increase the risk of hypoglycemia at
midmorning and early night.
INSULIN PUMP THERAPY
 Continuous subcutaneous insulin infusion (CSII) via battery-powered pumps provides a closer
approximation of normal plasma insulin profiles and increased flexibility regarding timing of meals
and snacks compared with conventional insulin injection regimens.
 Insulin pump models can be programmed with a patient's personal insulin dose algorithms, including
the insulin to carbohydrate ratio and the correction scale for pre-meal glucose levels. The patient can
enter his or her blood glucose level and the carbohydrate content of the meal, and the pump computer
will calculate the proper insulin bolus dose.
 Insulin pump therapy in adolescents with T1DM is associated with improved metabolic control and
reduced risk of severe hypoglycemia without affecting psychosocial outcomes.
 The use of overnight CSII improves the metabolic control in children aged 7–10 yr.
 CSII has also been useful in toddlers.
INHALED AND ORAL INSULIN THERAPIES
 Preprandial inhaled insulin is being evaluated in adults with T1DM and T2DM.
 Patients taking pre-meal inhaled insulin in combination with once daily bedtime long-acting insulin
(Ultralente) injection achieved similar metabolic control compared with patients taking 2 to 3 daily
injections of insulin.
 There have been reports of pulmonary fibrosis in a small number of patients.
 Bioavailability of inhaled insulin is increased with smoking and reduced with asthma.
PRE-MEAL ORAL INSULIN (ORALIN) has been evaluated in comparison with oral hypoglycemic agents, mostly
in patients with T2DM. The clinical data appear promising, but further evaluation of efficacy in T1DM is
needed.
Insulin side effects:
 Hypoglycemia
 Weight gain
 Allergy –local reaction/anaphylaxis—now eliminated coz of recombinant insulin/analogues.
 Insulin resistance –IgG mediated –now eliminated coz of = = =
 Lipohypertrophy due to same site repeated –Rx –rotate the site b/c area becomes painless (so child
frequently use this area) & it decreases the absorption of insulin
 Lipoatrophy due to impurities in insulin lead to immune complex deposition Rx—inject at
peripheral pointing centres
Insulin absorption
 Abdominal wall >> UL >> LL (fast-Intermediate-slow) 131

 I.M insulin have high peak but short duration( so risk of hypoglycemia)
 Don’t inject in area going to exercise.
 Ultrashort acting insulin can be dangerous in toddlers coz of sudden fall in BSR.only use NPH.
NOTE: insulin bottle is kept in freezer at 36-46F temperature & is discarded every months new is used

even if left in bottle
DIFFERENCE B/W EXOGENOUS & ENDOGENOUS INSULIN
 (1) Exogenous insulin does not have a 1st pass to the liver, whereas 50% of pancreatic portal insulin is
taken up by the liver, a key organ for the disposal of glucose;
 (2) absorption of an exogenous dose continues despite hypoglycemia, whereas endogenous insulin
release ceases and serum levels quickly lower with a normally rapid clearance; and
 (3) Absorption rate from an injection varies by injection site and patient activity level, whereas
endogenous insulin is secreted directly into the portal circulation.
BASIC EDUCATION
 Therapy consists not only of initiation and adjustment of insulin dose but also of education of the
patient and family.
 Teaching is most efficiently provided by experienced diabetes educators and nutritionists.
 In the acute phase, the family must learn the “basics,” which includes monitoring the child's blood
glucose and urine ketones, preparing and injecting the correct insulin dose subcutaneously at the
proper time, recognizing and treating low blood glucose reactions, and having a basic meal plan.
 Written materials covering these basic topics help the family during the 1st few days.
IF THE FASTING BLOOD GLUCOSE IS HIGH:

 Evening dose of long-acting insulin is increased by 10–15% and/or additional fast-acting insulin
(lispro or aspart) coverage for bedtime snack may be considered.
IF THE NOON GLUCOSE LEVEL EXCEEDS SET LIMITS:

 Morning fast-acting insulin (lispro or aspart) is increased by 10–15%.
IF THE PRE-SUPPER GLUCOSE IS HIGH:

 Noon dose of fast-acting insulin is increased by 10–15%.
IF THE PRE-BEDTIME GLUCOSE IS HIGH:
The pre-supper dose of fast-acting insulin is increased by 10–15%.
Reductions in the insulin type and dose should be made if the corresponding blood glucose measurements are
consistently below desirable limits.
Pre-meal and 30-Day Average Blood Glucose Ranges and the Corresponding Hemoglobin A 1c for each Age
Group
AGE GROUP TARGET PRE-MEAL BG RANGE 30-DAY AVERAGE BG RANGE TARGET HBA1C
(YR) (MG/DL) (MG/DL) (%)
<5 100–200 180–250 7.5–9.0
5–11 80–150 150–200 6.5–8.0
12–15 80–130 120–180 6.0–7.5
132
16–18 70–120 100–150 5.5–7.0
A minimum of 4 daily blood glucose measurements should be performed- before breakfast, lunch, and
supper and at bedtime.

 However, some children and adolescents may need to have more frequent blood glucose monitoring
based on their level of physical activity and history of frequent hypoglycemic reactions.
 Families should be encouraged to become sufficiently knowledgeable about managing diabetes.
 They can maintain near-normal glycemia for prolonged periods by self-monitoring of blood glucose
levels before and 2 hr after meals, and in conjunction with multiple daily injections of insulin,
adjusted as necessary, they can maintain near-normal glycemia
NUTRITIONAL MANAGEMENT
CALORIE NEEDS FOR CHILDREN AND YOUNG ADULTS
AGE kcal REQUIRED/kg BODY WEIGHT*

CHILDREN
0-12 mo 120
1-10 yr 100-75
YOUNG WOMEN
11-15 yr 35
≥16 yr 30
YOUNG MEN
11-15 yr 80-55 (65)
16-20 yr
Average activity 40
Very physically active 50
Sedentary 30
SUMMARY OF NUTRITION GUIDELINES FOR CHILDREN AND/OR ADOLESCENTS WITH TYPE 1 DIABETES
MELLITUS
NUTRIENT RECOMMENDATIONS AND DISTRIBUTION
(%) of
NUTRIENT RECOMMENDED DAILY INTAKE
CALORIES
70% should be Complex carbohydrate (starch)

Carbohydrate 55% High fiber, especially soluble fiber like wheat
vegetables, fruits (examiner Q)
Fiber >20g per day
A class proteins (animal derived like egg, meat, 133

Protein 12-20 (15%)
fish)(examiner Q)

Common used is polyunsaturated(examiner Q)
Prefer vegetable fats like margarine instead of butter,
vegetable oil instead of animal oil, poultry/fish instead
Fat <30
of fatty meat. Avoid egg yolk. Reduce cholesterol
Saturated <10
Polyunsaturated 6-8 Oils(soya beans, sunflower, corn oil)
Remainder
Monounsaturated of fat
allowance
Cholesterol 300 mg
Sodium Avoid excessive; limit to 3-4 grams if hypertensive
ADDITIONAL RECOMMENDATIONS
Energy: If using measured diet, reevaluate prescribed energy level at least every 3
mo.
Protein: High-protein intakes may contribute to diabetic nephropathy. Low intakes

may reverse preclinical nephropathy. Therefore, 12-20% of energy is
recommended; lower end of range is preferred. In guiding toward the end of the
range, a staged approach is useful.
Snacks: Snacks vary according to individual needs (generally 3 snacks per day for
children; midmorning, mid afternoon and bedtime snacks for junior high children
or teens).
Alternative sweeteners: Use of a variety of sweeteners is suggested.
TRAFFIC LIGHT DIET PLAN (diet chart given to them for home)
 GREEN –FISH, SOUP, MEAT, COFEE, VEGATABLE. (bilkul khaa sakte hn )

 YELLOW –BREAD, MILK, CEREAL , RICE( kabhi kabhi ya kam amount main khaa sakte hn )
 RED—CHOCOLATE, SOFT DRINK , CAKE, DATE, HONEY.(bilkul bhi nahn khaa sakte)
Diet chart:
 Age: 10years wt: 20kg Required calories: 1500cals

134
CHO 55% 750cals 190gm
Fat 35% 550cals 60gms

Protein 15% 200cals 50gms
Item CHO Protein Fat Calories
Milk (250ml) 12g 8g 10g 150cals
Vegetable (2 10 4 50
cups)
Fruit 5 75 300
Starch 6 90 12 420
(bread, rice)
Chicken 2 28 20 300
boti
6TSF 30 270
vegetable
oil/margarine
Total 187gm 52g 60g 1500cals
 Milk ½ cup (125ml) B.d
 Fruits: peach, pear, guava etc
 Vegetable ½ cup cooked, ½ cup salad
 Starch: chippati 2 B.D, 1 slice, ¾ cup rice
 1 boti, 1 egg (without yolk)
 6 TSF vegetable oil/margarine
 Breakfast: 20%
 Mid: 10%
 Lunch: 20%
 Mid afternoon: 10%
 Dinner: 30%
 Before bed: 10%
 Total: 100%
Breakfast: 1 slice & 1 egg+1 TSF margarine+1/2 cup milk
Midmorning: 2 fruits 135
Lunch: 2 chappati + vegetable ½ cup salad+1boti+2TSF oil
Mid afternoon: 3 fruits

Dinner: 2 chappati+3/4rice+1/2cup cooked vegetable+3TSF oil
Before bed: ½ cup milk
NOTE: simply we say sir The total daily caloric intake i-e 1000 kcal+ 100 kcal /year should include
carbohydrates 55% & 70 % of which is complex carbohydrates, 30% fat mostly polyunsatuarated,15
% proteins mostly animal derived or Class A proteins & divided to provide 20% at breakfast, 20% at
lunch, and 30% at dinner, leaving 10% for each of the midmorning, mid afternoon, and
evening/bedtime snacks ……OR high carbohydrate, high fiber low fat diet in 3 big & 3 small meals in
b/w with no sugar.(sugar free <20 kcal or 5 grams of carbohydrates)
CONCEPT OF PORTION/EXCHANGE =15 G WHICH CONTAIN CARBOHYDRATE UP TO 60
CALORIES/KCAL
Simply in Pakistan we use standard insulin, twice daily regime & calculate diet by calories or kcal &
we use sliding scale (which is nowadays not used in modern world).but in developed countries we
use Analogues, basal bolus regime ,calculate diet by grams & use carbs (carbohydrate) count
instead of sliding scale.
 Different foods are offered to child of same portion /exchange value like we give a chart which contain
different picture and ask child to change like a menu which does pt want. Simply 15 g = 60 kcal And 1
slice,1/2 Roti, 1/3 cup Rice ,1 cup milk, a small orange or peach ,banana ,apple each is equal to 15
grams. Man & woman to maintain normal weight
takes 60-75 grams & 45-60 grams daily respectively. For Activity Add 15 -30 grams to both in
form of snacks.
Roughly we start with carbs to insulin ratio 15 g: 1 unit ultra short acting in normal
10:1 in obese
20: 1 in thin
Then monitor post prandial glucose level after every meal if increased then increase
ratio as 10:1 if low then decrease ratio as 20:1 in normal…
SLIDING SCALE: (we use in children hospital)
BSR INSULIN REGULAR
 <90------------no insulin
 90-180-------0.1 u/kg
 180---270---0.2
 270—360---0.3
 >360---- -----0.4
Exercise
 No form of exercise, including competitive sports, should be forbidden to the diabetic child. 136
Usually it is advised for 30 min /day. A major complication of exercise in diabetic patients is the
presence of a hypoglycemic reaction during or within hours after exercise. If hypoglycemia does not
occur with exercise, adjustments in diet or insulin are not necessary

 The total dose of insulin may be reduced by about 10-15% on the day of the scheduled exercise.
Prolonged exercise, such as long-distance running, may require reduction of as much as 50% or more
of the usual insulin dose. Before going for exercise go for BSR then do accordingly.
BSR
<60--------no exercise
60-100---- take a snack
200-300---normal exercise
300-400---vigorous exercise
>400-------no exercise (b/c of counter regulatory hormones ↑which will ↑ further BSR)
MONITORING
1 Monthly = at each visit

Height
Weight
BP
INj:sites
Joint examination
BSR record (at least twice a day)
School progress
3 monthly= HbA1c
6 Monthly= Fundoscopy (after 5 or 2 years in pre & post puberty)
Yearly = thyroid profile
Coelic profile (TGA Ig A,IgG)
24 hours urine for microalbuminuria
Self-monitoring of blood glucose (SMBG) is an essential component of managing diabetes. Monitoring often
also needs to include insulin dose, unusual physical activity, dietary changes, hypoglycemia, intercurrent
illness and other items that may influence the blood glucose. These items may be valuable in interpreting the
SMBG record, prescribing appropriate adjustments in insulin doses, and teaching the family. If there are
discrepancies in the SMBG and other measures of glycemic control (such as the HbA1c), the clinician should
attempt to clarify the situation in a manner that does not undermine their mutual confidence. Daily blood
glucose monitoring has been markedly enhanced by the availability of strips impregnated with glucose oxidase
that permit blood glucose measurement from a drop of blood.
A portable calibrated reflectance meter can approximate the blood glucose concentration accurately. Many
meters contain a memory “chip” enabling recall of each measurement, its average over a given interval, and
the ability to display the pattern on a computer screen. Such information is a useful educational tool for
verifying degree of control and modifying recommended regimens. A small, spring-loaded device that
automates capillary bloodletting (lancing device) in a relatively painless fashion is commercially available.
Parents and patients should be taught to use these devices and measure blood glucose at least 4 times daily—
before breakfast, lunch, and supper and at bedtime. When insulin therapy is initiated and when adjustments
are made that may affect the overnight glucose levels, SMBG should also be performed at 12 a.m. and 3 a.m.
to detect nocturnal hypoglycemia. Ideally, the blood glucose concentration should range from approximately
80 mg/dL in the fasting state to 140 mg/dL after meals. A continuous glucose monitoring system (CGMS)
records data obtained from a subcutaneous sensor every 5 min for up to 72 hr and provides the clinician with a
continuous profile of tissue glucose levels. The interstitial glucose levels lag 13 min behind the blood glucose
values at any given level.
Glycosylated Hemoglobin (HbA1c)

 A reliable index of long-term glycemic control is provided by measurement of glycosylated
hemoglobin. HbA1c represents the fraction of hemoglobin to which glucose has been nonenzymatically 137
attached in the bloodstream.
 The formation of HbA1c is a slow reaction that is dependent on the prevailing concentration of blood
glucose;

 it continues irreversibly throughout the red blood cell's life span of approximately 120 days. The
higher the blood glucose concentration and the longer the red blood cell's exposure to it, the higher is
the fraction of HbA1c, which is expressed as a percentage of total hemoglobin.
 Because a blood sample at any given time contains a mixture of red blood cells of varying ages,
exposed for varying times to varying blood glucose concentrations, an HbA1c measurement reflects
the average blood glucose concentration from the preceding 2-3 mo.
 It is recommended that HbA1c measurements be obtained 3-4 times per yr to obtain a profile of
long-term glycemic control.
 The more consistently lower the HbA1c level, and hence the better the metabolic control, the more
likely it is that microvascular complications such as retinopathy and nephropathy will be less severe,
delayed in appearance, or even avoided altogether.
 Depending on the method used for determination, HbA1c values may be spuriously elevated in
thalassemia (or other conditions with elevated hemoglobin F) and spuriously lower in sickle cell
disease (or other conditions with high red blood cell turnover).
 Non diabetic individuals < 6%.
 Good metabolic control 6-7.9%.
 Fair control  8.0-9.9%, (unacceptable)
 Poor control 10% or higher.
 Adjustments in target HbA1c should be made for younger children
Diabetes Control and Complications Trial (DCCT)

 This is applied for adults so this is changed for childrens.
 Study conducted 1983-1993.
 This study shows that keeping blood glucose level as close to normal as possible slows the onset and
progression of eye, kidney and nerve damage caused by D.M. it also concluded that any sustained
lowering of blood glucose level helps even if pt has history of poor control.
ELEMENTS:
1. Testing blood glucose level 4 times or more a day.
2. Injecting insulin 3 times daily or insulin pump.
3. Adjust insulin dose according to food intake and exercise.
4. Following a diet and exercise plan.
5. Monthly visits to health care team.
HYPOGLYCEMIC REACTIONS
Hypoglycemia is the major limitation to tight control of glucose levels.
The most important factors in the management of hypoglycemia are an understanding by the patient
and family of the symptoms and signs of the reaction and an anticipation of known precipitating
factors such as gym or sports activities. Tighter glucose control increases the risk. Families should be
taught to look for typical hypoglycemic scenarios or patterns in the home blood glucose log, so that
they may adjust the insulin dose and avert predictable episodes. A source of emergency glucose
should be available at all times and places, including at school and during visits to friends. If possible,
it is initially important to document the hypoglycemia before treating, because some symptoms may
not always be due to hypoglycemia.
 Any child suspected of having a moderate to severe hypoglycemic episode should also be treated
before testing. It is important not to give too much glucose; If CONSCIOUS then give 5-10 g should
be given as juice or a sugar-containing carbonated beverage or candy, and the blood glucose
checked 15-20 minutes later, if still <60mg/dl then take meal or biscuits within half hour.
 An injection kit should be kept at home and school. Patients, parents, and teachers should also be
instructed in the administration of glucagon when the child cannot take glucose orally or
UNCONSCIOUS then. The intramuscular dose is 0 .5 mg if the child weighs less than 20 kg and
1.0 mg if more than 20 kg. This produces a brief release of glucose from the liver. Caretakers must
then be prepared to take the child to the hospital for IV glucose 10% D/W 2ml /kg if still <60 mg/dl 138
after glucagon.
 Mini-dose glucagon (1 unit/yr of age up to a maximum of 15 units subcutaneously) is effective in
treating hypoglycemia in children with blood glucose less than 60 mg/dl who failed to respond to
ORAL GLUCOSE and remained symptomatic.

SOMOGYI PHENOMENON, DAWN PHENOMENON, AND BRITTLE DIABETES
 There are several reasons that blood glucose levels increase in the early morning hours before breakfast
The most common is a simple decline in insulin levels and is seen in many children using NPH as
the basal insulin at supper or bedtime.
 This usually results in routinely elevated morning glucose.
THE DAWN PHENOMENON:

 Due to overnight growth hormone secretion and increased insulin clearance. It is a normal
physiologic process seen in most non diabetic adolescents, who compensate with more insulin
output. A child with T1DM cannot compensate and may actually have declining insulin levels if
using evening NPH
 The dawn phenomenon is usually recurrent and modestly elevates most morning glucose levels.
 Dx –check night time sugar level—hyperglycemia in night 12 am & 3 am.
 Rx –increase night dose of insulin
SOMOGYI PHENOMENON: morning hyperglycemia follow night time hypoglycemia is due to

an exaggerated counter-regulatory response. It is unlikely to be a common cause.
 DxContinuous glucose monitoring systems may help clarify ambiguously elevated morning
glucose levels.
 Rx decrease night time insulin dose.
BRITTLE DIABETES:
Usually an adolescent female, with unexplained wide fluctuations in blood glucose, often with
recurrent DKA, who is taking large doses of insulin. These children usually show normal insulin
responsiveness when in the hospital environment.
Psychosocial or psychiatric problems, including eating disorders, and dysfunctional family dynamics
are usually present, which preclude effective diabetes therapy.
Rx Hospitalization is usually needed to confirm the environmental effect, and aggressive
psychosocial or psychiatric evaluation is essential. Therefore, clinicians should refrain from using
“brittle diabetes” as a diagnostic term.
LIMITED JOINT MOBILITY: -- (LJM)

 Comes after 6 month of disease.
 Due to glycosylation of periarticular tissue.
 40% of IDDM.
 Painless ( need no medicine)
 Hands –small joints –5th finger is usually 1st involved.
 Wrist, elbow, spine, other large joints.
 Significance: correlation between LJM and retinopathy.
 If LJM –increased micro vascular complications
MANAGEMENT DURING INFECTIONS (fever, stress  inc counter regulatory hormones) (common examiner
Q)
GUIDELINES FOR SICK DAY MANAGEMENT

GLUCOSE TESTING AND EXTRA RAPID-ACTING
URINE KETONE INSULIN
COMMENT
STATUS 139
Insulin Correction Doses*
q2 hr
Negative or q2 hr for glucose
[†] (5-10% of rapid acting) 5-10% Check ketones every other void
small >250 mg/dL
of total daily insulin.

GLUCOSE TESTING AND EXTRA RAPID-ACTING
URINE KETONE INSULIN
COMMENT
STATUS
Insulin Correction Doses*
Moderate to q1 hr q1 hr for glucose Check ketones each void. Go to
[‡]
large 10-20% of daily insulin dose. >250 mg/dL hospital if emesis occurs.
Basal insulin: glargine or detemir basal insulin should be given at the usual dose and time.
NPH and Lente should be reduced by one half if blood glucose <150 mg/dL and the oral intake is limited.
Oral fluids: sugar-free if blood glucose >250 mg/dL (14 mmol/L); sugar-containing if blood glucose <250 mg/dL.
Call physician or nurse if blood glucose remains elevated after 3 extra doses; if blood glucose remains less
than 70 mg/dL and child cannot take oral supplement; if dehydration occurs.
Management during Surgery
Stress hormones Decreases insulin sensitivity This increases glucose levels, exacerbates fluid
losses, and may initiate DKA.
On the other hand caloric intake is usually restricted, which decreases glucose levels.
glucose control and avoiding DKA are best accomplished with IV insulin and fluids. A simple The IV
insulin is continued after surgery as the child begins to take oral fluids; the IV fluids can be steadily
decreased as oral intake increases. When full oral intake is achieved, the IV may be capped and
subcutaneous insulin begun. When surgery is elective, it is best performed early in the day, allowing
the patient maximal recovery time to restart oral intake and subcutaneous insulin therapy.
When elective surgery is brief (less than 1 hr) and full oral intake is expected shortly afterward:-
 Monitor BSR hourly and give the dose of insulin analogue according to childs home glucose correction
scale.
 If glargine or detemir is used as the basal insulin  a full dose is given the evening before planned
surgery.
 If NPH or Lente is used  one half of the morning dose is given before surgery.
 Then I will start i.v fluids N/2 + 5% dextrose + 20meq/l of K acetate at 1.5 times maintenance.
 And my aim will be to keep 90-180 mg/dl during and after surgery.
 Give short active insulin as needed as sliding scale
WHEN SURGERY IS MAJOR:

 1 hr BSR measure.
 By keeping same aim.
 Don’t stop insulin infusion if BSR <90 This will cause rebound hyperglycemia.
 So reduce rate of infusion.
 Stop insulin infusion if BSR<55, Frequent monitor BSR.
BEFORE SURGERY:
 Omit morning dose of insulin.
 2 hr before surgery—start I.V fluids and insulin infusion
GUIDELINES FOR INTRAVENOUS INSULIN COVERAGE DURING SURGERY

BLOOD GLUCOSE LEVEL (mg/dL) INSULIN INFUSION (U/kg/hr) BLOOD GLUCOSE MONITORING
<120 0.00 1 hr
121-200 0.03 2 hr
200-300 0.06 2 hr
[†]-urine ketone check
300-400 0.08 1 hr
[†]urine ketone check
400 0.10 1 hr
140
An infusion of 5% glucose and 0.45% saline solution with 20 mEq/L of potassium acetate is given at 1.5 times
maintenance rate.
LONG-TERM COMPLICATIONS: RELATION TO GLYCEMIC CONTROL

Complications into 3 major categories
(1) Micro vascular complications, specifically, retinopathy and nephropathy;
(2) Macro vascular complications, particularly accelerated coronary artery disease,
cerebrovascular disease, and peripheral vascular disease; and
(3) Neuropathies, both peripheral and autonomic, affecting a variety of organs and systems cataracts may
occur more frequently.
SCREENING GUIDELINES (frequently asked in management)
WHEN TO PREFERRED
OTHER SCREENING POTENTIAL
COMMENCE FREQUENCY METHOD OF
METHODS INTERVENTION
SCREENING SCREENING
After 5 yr
duration in
Fluorescein Improved
prepubertal Fundal
Retinopathy 1-2 yearly angiography, mydriatic glycemic control,
children, after 2 photography
ophthalmoscopy laser therapy
yr in pubertal
children
After 5 yr
Improved
duration in 24-hr excretion of
Overnight timed glycemic control,
prepubertal albumin, urinary
Nephropathy Annually urine excretion of blood pressure
children, after 2 albumin/creatinine
albumin control, ACE
yr in pubertal ratio
inhibitors
children
Nerve conduction,
thermal and vibration
Physical Improved
Neuropathy Unclear Unclear threshold,
examination glycemic control
pupillometry,
cardiovascular reflexes
Statins for
Macrovascular hyperlipidemia
After age 2 yr Every 5 yr Lipids profile Blood pressure
disease Blood pressure
control
Thyroid Thyroid peroxidase
At diagnosis Every 2-3 yr TSH (NB) Thyroxine
disease antibody
Tissue
transglutaminase,
Celiac disease At diagnosis Every 2-3 yr Antigliadin antibodies Gluten-free diet
endomysial
antibody
DIABETIC RETINOPATHY:
 Leading cause of blindness in the USA in adults aged 20-65 yr.
 The risk of diabetic retinopathy after 15 yr duration of diabetes is 98% for individuals with T1DM and
78% for those with T2DM.
 Lens opacities (due to glycation of tissue proteins  are present in at least 5% of those younger than
19 yr.
 50% of patients develop proliferative retinopathy.
Non proliferative or background diabetic retinopathy –Earliest

 Microaneurysms.
 Dot and blot hemorrhages.
 Hard and soft exudates. 141
 Venous dilation and beading.
 intraretinal microvascular abnormalities.
Note: These changes do not impair vision. Rx only improve glycemic control

Proliferative diabetic retinopathy—severe form
 Neovascularization.
 Fibrous proliferation.
 Preretinal and vitreous hemorrhages.
Note : Proliferative retinopathy, if not treated, is relentlessly progressive and impairs vision, leading to
blindness.
Rx  panretinal laser photocoagulation
 In advanced diabetic eye disease—manifested by severe vitreous hemorrhage or fibrosis, often with
retinal detachment & glaucoma —vitrectomy is an important therapeutic modality. Eventually,
the eye disease becomes quiescent, a stage termed involutional retinopathy.
 A separate subtype of retinopathy is diabetic maculopathy, which is manifested by severe macular

edema impairing central vision, for which focal laser photocoagulation may be effective.
Ophthalmologist examination required promptly after dx in type 2
While for type 1 as mentioned above (do not required below 10 usually)
DIABETIC NEPHROPATHY: (common examiners Q))

 Leading known cause of (ESRD).
 Most ESRD from diabetic nephropathy is preventable.
 Diabetic nephropathy affects 20-30% of patients with T1DM.
 15-20% of T2DM patients 20 yr after onset.
 The mean 5-yr life expectancy for patients with diabetes-related ESRD is less than 20%.
 The increased mortality risk in long-term T1DM may be due to nephropathy, which may account
for about 50% of deaths.
Risk factors :( NB)
 Long duration of illness.
 Poor metabolic control
 Genetic predisposition to essential HTN.
 Only 30-40% of patients affected by T1DM eventually experience ESRD.

 The glycation of tissue proteins results in glomerular basement membrane thickening(diffuse or focal
glomerulosclerosis ie FSGS)
 The course of diabetic nephropathy is slow.
 An increased urinary albumin excretion rate (AER) of 30-300 mg/24 hr (20-200 ug/min)—
microalbuminuria—can be detected and constitutes an early stage of nephropathy from intermittent
to persistent (incipient), which is commonly associated with glomerular hyperfiltration and blood
pressure elevation.
 As nephropathy evolves to early OVERT STAGE (clinical stage when symptoms appears) with
proteinuria (AER >300 mg/24 hr, or >200 ug/min), it is accompanied by hypertension. Progressive
decline in renal function (declining glomerular filtration rate and elevation of serum blood urea and
creatinine), progressive proteinuria. Progression to ESRD is recognized by the appearance of uremia,
the nephritic syndrome, and the need for renal replacement (transplantation or dialysis).
ADA recommendation for screening of nephropathy:

 Yearly in type 2.
 Yearly in type1 but not before puberty.
Screening test advice:

 24 hr urinary level for albumin excretion and RFTs. If positive then rule out causes of transient
proteinurea and repeat 142
 There is marked day-to-day variability in albumin excretion, so at least 2 of 3 collections done in a 3-
to 6-mo period should show elevated levels before microalbuminuria is diagnosed and treatment is
started.

 Rx Once albuminuria is diagnosed, a number of factors attenuate the effect of hyperfiltration
on kidneys:
(1) Meticulous control of hyperglycemia.
(2) Aggressive control of systemic blood pressure.
(3) angiotensin-converting enzyme (ACE) inhibitors (↑ renal blood flow & ↓ HTN by vasodilation by
efferent arteriolar dilation), ARBS, salt restriction
(4) Dietary protein restriction (because high protein intake increases renal perfusion rate). Tight glycemic
control will delay the progression of microalbuminuria and slow the progression of diabetic
nephropathy.
Q: what are the early features of DM nephropathy & how would u diagnose Any cut off value in ur
mind?
A: no early symptoms there is just microalbuminurea when it is >300mg or 3 grams /24 hrs (cut off) then
clinical features like nephritic/nephrotic syndrome (FSGS) appears as leg, feet or orbital edema
,nausea vomiting & HTN
NOTE: polyuria leads to dehydration,which ↑renin which causes vasoconstriction (survival
mechanism)thus decrease blood 7 nutrient supply to kidneys cause infarction of tissue & renal failure &
HTN)
DIABETIC NEUROPATHY
 Infrequent in children.
 Both the peripheral and autonomic nervous systems can be involved.
 Adolescents with diabetes can show early evidence of neuropathy.
 Even asymptomatic pts can have sensory involvement like tingling sensation, numbness, pain,
parasthesia with poorly controlled diabetes.
 Autonomic instability can be a presenting feature with variable heart rate/ brady/tachy, postural
hypotension, gastroparesis, diarrhea etc.
NOTE: hyperglycemia activate Polyol pathway which ↑ sorbitol,free radicles , ↓ glutathione, Nitric oxide
level(vasodilator),this pathway is dependant of Aldolase reductase enzyme.↓ NO cause vasoconstriction of
vessels supplying vasonervosum thus leads to demyelination and symptoms
Treatment modalities include:
(1) Improvement in metabolic control.

(2) use of aldose reductase inhibitors to reduce byproducts of the polyol pathway.
(3) use of α-lipoic acid (an antioxidant) that enhances tissue nitric oxide and its metabolites.
(4) use of anticonvulsants (e.g., lorazepam, valproate, carbamazepine, tiagabine, and topiramate)
for treatment of neuropathic pain.
MAURIAC SYNDROME:
 Short stature
 Hepatomegally—9glycogen laden enlarged liver)
 Moon face.
 Protruberant abdomen.
 Proximal muscle weakness
 L JM
 Leads to early retinopathy & nephropathy
 Cause: due to poor diabetic control due to underinsulinization now rare because availability of long
acting insulin
D/D – 143
 cushing syndrome.
 Hypothyroidism.
D/D of short stature in DM pt (Examiner Q)

 Mauriac
 Hypothyroidism
 Celiac disease
 Primary pituitary dysfunction
PROGNOSIS OF DIABETIC CHILDRENS:

 Average life span if an individual with D.M is 10 yr shorter.
 Delayed puberty
 Final height may be less than genetic potential.
TYPE 2 DIABETES MELLITUS.
 The children and adolescents with this type of diabetes are usually obese, but don’t have auto
immune destruction of b cells & are not insulin dependent and infrequently develop ketosis.
 Some may develop ketosis during severe infections or other stresses and may then need insulin for
correction of symptomatic hyperglycemia.
 This category includes the most prevalent form of diabetes in adults, which is characterized by insulin
resistance and often a progressive defect in insulin secretion.
 This type of diabetes was formerly known as adult-onset diabetes mellitus, non-insulin-dependent
diabetes mellitus (NIDDM), or maturity-onset diabetes of the young (MODY).
 The presentation of T2DM is typically more insidious than that with T1DM.
 In contrast to patients with T1DM who are usually ill at the time of diagnosis, children with T2DM
often seek medical care because of excessive weight gain and fatigue as a result of insulin resistance
and/or an incidental finding of glycosuria during routine physical examination.
 A history of polyuria and polydipsia is relatively uncommon in these patients.
 Acanthosis nigricans (dark pigmentation of skin creases/flexural areas), a sign of insulin resistance, is
present in the majority of patients with T2DM and is accompanied by a relative hyperinsulinemia at the
time of the diagnosis. However, the serum insulin elevation is usually disproportionately lower than
that of age-, weight-, and sex-matched nondiabetic children and adolescents, suggesting a state of
insulin insufficiency. In some individuals, it may represent slowly evolving T1DM.
 Current recommendation is Fasting sugar as screening (diagnostic tool) tool some recommend
HbA1c.(examiner Q)
 Criteria for diagnosis of DM type 2 is OVER WEIGHT BMI>85 percentile for age & sex PLUS any
2 of the following Risk factors (examiner Q)
o Family history of DM 1or 2
o Sign of insulin resistance (acanthosis nigrans)
o Age at 10 or at onset of puberty
Rx
Oral hypoglycemic agents
Most common is Metformin 500mg BD in adults. It is contraindicated in hepatic & renal
dysfunction.
Q: why not ur pt is a case of type 2 DM? (Examiner Q)
A: sir yes I thought about the possibility but they are obese, usual occurs in adults or age >10 years has +ve
family history, have acanthosis nigrans, use oral hypoglycemic drugs & usually no history of polyuria, polydipsia
144
& don’t usually presents with DKA, but my pt is thin lean built &…….according to case…so I consider it as Type
1 DM.
Q: How would u document resistance in Type 2 DM ?

A: by Acanthosis nigrans
MONOGENIC DIABETES (common examiner Q)
TYPES:
o Neonatal diabetes
o MODY
MATURITY-ONSET DIABETES OF THE YOUNG (MODY)
 Autosomal dominant inheritance & is neither TYPE 1 nor 2

 Strong family history
 There is no apparent autoimmune destruction of β cells (antibodies –ve) and no HLA association.
 Pt usually presents with asymptomatic hyperglycemia on routine checkup, usually not obese, no
DKA occurs in MODY (NB), common in age <15 yrs or can occur in 2 nd to 5 th decade.
 It is a genetic disorder involving mutations of B-cell defect or secretion defect encoding either
pancreatic β-cell and liver glucokinase (MODY 2) or in the nuclear transcription factors hepatocyte
nuclear factor (HNF) (1α (MODY3), 4α(MODY1), 1β (MODY5). Most common is type 2 & 3, A
defect in the gene regulating glucose transport into the pancreatic β cell, the GLUT2 transporter, may
be responsible for other forms of T2DM. The genetic basis of T2DM also includes defects in glycogen
synthase, insulin receptors, Rad (Ras associated with diabetes), and possibly apolipoprotein C-III.
 It is diagnosed by Gene testing.(NB)
Rx
 Dietary changes
 Physical exercise
 Oral hypoglycemic most common is sulphonylurea
 Insulin therapy
Q: Why it is important to diagnose MODY & go for genetic testing?
A:b/c usually in children we say it type 1 & go for insulin ,by diagnosing MODY we may switch to Oral
hypoglycemic drugs & do genetic counseling as well b/c prolong asymptomatic hyperglycemia may cause long
term complications..
Q: why not ur pt is a case of MODY?
A: sir these pts are usually well looking yes obviously not obese but there is a strong family history as AD
inheritance usually asymptomatic with no polyuria polydipsia history,no history of DKA & usually use oral
hypoglycemic agents for treatment. And also no autoimmune destruction of B cells as in Type 2 DM or insulin
antibodies are _ve …
OTHER SPECIFIC TYPES OF SECONDARY DIABETES.
Examples: 145
 diabetes secondary to exocrine pancreatic diseases (cystic fibrosis).

 endocrine diseases (Cushing syndrome)

 and ingestion of certain drugs or poisons (the rodenticide Vacor). Certain genetic syndromes, including
those with abnormalities of the insulin receptor, also are included in this category. There are no
associations with HLAs, autoimmunity, or islet cell antibodies among the entities in this
subdivision.
DIABETES MELLITUS OF NEWBORN
TRANSIENT –50%
 Present in 1st week of life , persist for several weeks to months before spontaneous resolution
 SGA infants –severe hyperglycemia with glycosurea but no ketonurea
 Median period of resolution is 12 weeks.
Rx – 1-2 unit/kg/day of intermediate acting insulin (NPH) only
PERMANENT –more common
 Pancreatic agenesis
 SGA
 Present within 1st month of life
 They are initially euglycemic.
TRAANSIENT WITH RECURRENCE(25% cases) 25% develop permanent diabetes later on in their life 7-20 Yr
MISCELLANEOUS FACTS ABOUT DIABETES
A child with peersistant hypoglycemia even on regular insulin with good compliance and proper dose then
think of Addison disease he may hav developed.(examiners Q)
HLA=DQA1/B1 –Protective genes against diabetes
HLA-DR2 if +ve –then no chance to develop diabetes 1.
OGTT HOW PERFORMED
 Advise 3 days of well balanced diet whiach contain atleast 50% of carbohydrate
 Then fasting from midnight –at test time give 1.75g/kg (max 75 g ) of glucose.
 Obtain plasma sample one before test and other at 1,2,3 hr.
 If fasting BG Level < 126 mg/dl
Or
 2 hr post prandial >126 but <200
If above reading it is impaired GTT.
New advances in diabetes:

Nano Drugs( examiner Q)
Insulin vaccine –3 doses within 6 month of Dx –pt improve—(based on mechanism that it is a peptide 146
which downregulate the immune system which destroy B cells).
Gene therapy ---virus contained corrected genes against the mutated genes are injected in person they
go and attach on site specific defect and start to function normal.
Stem cell therapy
Islet cell transplantation

CSCII –continuous subcutaneous insulin infusions
Edmonton protocol: we infuse islet pancreatic cell directly in portal vein.
Examination:
Sir My pt is conscious co-operative obliviously thin lean during my examination with no respiratory
distress. Vitals…..Height, weight….he has normal joint mobility & has injection sites visible at finger
tips, abdominal wall & both thighs, there is a evidence of macro & micro nutrient deficiency in my pt,
no evidence of nail dystrophy, hyper or hypopigmentation, oral candidiasis ,thyroid enlargement in my
pt. eyes examination is normal with no cataract, squint & nystagmus, no hepatomegaly, CNS
examination including reflexes, vibration, touch, position are intact.
Q: Emergencies in DM/ usual presentation pt DM pts in emergency? Examiner Q
A: DKA (Abdominal pain, vomiting, unconsciousness)
Infection (UTI,s meningitis, loose motions)
Hypoglycemia
Hypernatremic dehydration
Q: C- peptide level?
A: pancreas forms pro insulin which dissociates in insulin+C-peptide..Sopeptide level is ↓or absent in
type 1 DM, normal or increased in type 2 DM.
Q: causes of abdominal pain in DM pts?
A:
 injection sites,
 DKA.
 coelic
 UTI.
 Pancreatitis(Cystic fibrosis)
Q: what are the clinical signs of uncontrolled DM?
A: H/o polyuria, ↓Height, weight, thin lean, delayed puberty, joints involvement, hepatomegaly,↑HbA1c
Q: how would u assess insulin requirement in ur pt?
A: by sliding scale
Q: which antibody is specific for diagnosis of type 1 DM, any single out of 4?
A:……? ( if antibodies are negative then we will confirm diagnosis by c-peptide levels asked by examiner )
Availability :
Lispro (lily company trade name humalog 1 vial contain 10 ml and 1ml =100 units (Rs-1300)
Aspartate Novolog (Rs-3400)
Glargine (lentis =2500?)
Mixtard 70/30—premixed insulin. 147

GOITER----------------------------------------------------- (SHORT CASE).
Commands:
1. Do neck and relevant examination.

2. Child with excessive nervousness do GPE and relevant.
COMMANDS:
 Do the neck examination/thyroid examine/GPE and relevant/ child with irritability AND nervousness
do relevant examination.
Approach
Step 1. Intro + consent+ exposure.
Step 2. Communicate verbally and shake hand.
Step 3. Stand back and inspection--> obiveous signs of hyperthyroidism ( tremors, exophthalmos),
hypothyroidism ( short stature , fascial myxedema , thyroidectomy scar. )/ hyperpigmentation/ dysmorphism-
associated with turner, down.
Step 3. Neck examination (sitting pt )
- inspect for goitre.
- Swallowing. ( palpate during swallowing)
- tongue protrude.
- pemberton's sign.
-red
Step 4. Palpation
- site , size, shape, symmetry, surface, consistency, mobility, tenderness, thrill, check cervical lymph
nodes only which drain.
Step 5. Percussion across upper portion of manuberni sterni from right to left for retrosternal goitre.
Step 6. Auscultate for brui.
Step 7. Access the direct effects of gland on surroundings.
- Horner syndrome. 148
- voice ( recurrent laryngeal nerve paralysis).

- pemberton's sign ( ask to raise both arms and observe few sec later for fascial plethora+ distended
neck veins+ inspiratory striodor.
Step 8.Eye examination.
- movements. ( lid lag, lid retraction.)
- Vision acuity.
- accommodation.
Step 9 GPE –palms, hand –(sweating) move ur hand till elbow for any dryness, pulse –(note wide/not),
B.P, temp, eye examination –acuity, accommodation, EOM, lid lag—(hold head with ur opposite hand)
oral exam—lingual tonsiledema.
Step 10. ToneReflex.
Step 11. Abdomen—look for umbilical hernia-(commonly missed) + liver (autoimmune)
Step 11. Gait  Gower anthropometric if possible time.
Step 11. Cover with thanks.
Step 12. Offer anthropometrixs/ whatever left
DESCRIPTION:
I have examined …. Conscious & co-operative during my examination with no obivious dysmorphism/
respiratory distress, he/she had normal voice.
There is a bilobular symetrical swelling infront of neck with no visible pulsation, scar , prominent veins, it
is moving with swallowing , but not with tongue protrusion , & negative pamberton sign.—(gap 2 sec) it
is firm nontender diffuse measuring of ….. ×……cm, normal temp of overlying skin , lower limit can be
reachable , there is no audible brui. Both carotids are normally palpable, & no cervical lymphadenopathy.
Pulse rate is 80 bpm normal in volume , temp is ……., B.P is …….mmHg-which is age and gender
appropriate for him/her .
Height is ……, wt is………, OFC is ……….
There is no evidence of pallor, jaundice, coarse thick /dry skin, edema, hyperpigmentation, eye
examination is normal in form of visual acuity, accommodation & EOM & no lid lag,exopthalmos, normal
reflexes.
Or simply say I could not appreciate any signs of hypo/hyperthyroidism in my pt. 149

DIFFERENTIALS:
Case of Goiter- euthyroid
Could be secondary to:

 Hashimitos thyroiditis.
 Simple colloid goiter –(more in prepubertal girls).
 May be graves disease on treatment .
Why euthyroid ?
 Sir because normal vitals , height, wt, temp , no brui, DTR, and no ophthalmic complications in form
of lid lad, exopthalmos, dry/sweaty hands all favour my first provisional dx of euthyroid goiter.
Why not hypothyroidic?
 Sir they have myxedamatous facies with rough, dry skin and hoarse voice,coarse hairs , bradycardia
with low systolic B.P, hypotonic and slow relaxation of DTR.
WHY NOT HYPERTHYROIDISM?
 They are thin , sweaty hands, with fime tremors on outstretching of hands, wide pulse pressure with
elevated systolic blood pressure, with brui and ophthalmic signs like lid lag, exopthalmos.
HOW WILL YOU INVESTIGATE THIS CHILD?
 I WILL GO FOR
 FREE T4 & T3 LEVEL + TSH.
 ULTRASOUND OF THYROID – For location, presence/not, focal nodularity.
 Thyroid scintiography –TC99, radiolabelled iodine –for uptake,
 Antithyroid antibodies-(anti-microsomal/anti-thyroglobulin antibodies).
How will u Manage?
 councelling
 As my pt is euthyroid I will keep monitor of TSH level Periodically and clinically by regular follow up.
Keys.
 Inspection
 Palpation
 Swallowing
 Retrosternal goitee 150
 Eye lid lag
 Vision acuity.
 Accomodation
 Brui

 Pulse with arm elevated
 Reflexes
 Proximal.myopathy.
 Pretibial edema
 Oral exinatiion for pigmented buccal mucosa ,lingual thyroid.
 Cover thanks.
ADDITIONAL DIFFERENTIALS OF SWELLING IN NECK
 TG cyst—move with tongue protrusion.

 Cystic hygroma—lateral side usually unilateral.
 Hemangioma ---obivious reddish/ vascular with hum+/-
 SCM tumor-unilateral
 Lymph node –on sides and no focal infection found.
 Brachial cyst –
GRADES OF THYROMEGALLY.
 Grade -0  no goiter
 1agoiter palpable but not seen with normal neck position.
 1bgoiter seen after maximium dorsiflexion of neck.
 2 goiter visible with normal position.
 3  visible at a distance.
ASSOCIATIONS OF GOITER:
 Turner, noonan , down syndrome.

 Addison disease, SLE, pernicious anemia, Rheumatoid arthritis.
CAUSES OF GOITER
EUTHYROID WITH GOITER:
 Euthyroid autoimmune thyroidits.

 Simple colloidal goiter.
 Infective –viral/bacterial.
HYPOTHYROID WITH GOITER.
151
 Autoimmune thyroiditis.
 On anti-thyroid drugs.
 Iodine deeciency----(rule out by urinary iodine excretion).
 Thyroid dyshormonogenesis.—(iodine uptake and discharge perchlorate test).

 HYPERTHYROID WITH GOITER
 Graves disease—( diffuse toxic goiter).

 Hashmitos thyroiditis –(hyperthyroid state).
 Exogenous TH .
Euthyroid sick syndrome
 Birth trauma, acidosis, hypoxia, hypoglycemia, acidosis, infection.

 T4 & T3.
 Normal TSH.
 No treatment required.
-------------------------------------------------------------
152

SHORT STATURE
DESCRIPTION:
My patient conscious and co-operative during my examination with obvious short stature and infantile facies
and voice
Consistent with GH deficiency in form of
1. Infantile facies
2. Infantile voice
3. Cherubic facies
4. Central obesity
5. Micro phallus
6. Cryptorchidism
7. Midline defects (cleft palate ,single central maxillary incisor )
8. Prolonged JNN
9. Hypoglycemia
Her total height is....... which is proportionate Which is obvious below 3rd centile for his age but I would like
to confirm it by plotting on centile chart, with upper segment measuring of ……cm , weight is ........,
OFC is............,
Vitals are......
He/she had no evidence of pale, cyanosis, clubbing, Palmer erythema, jaundice, edema, lymphadenopathy and
sigs of micro and micronutrient deficiency.
No obvious signs skeletal deformity, rickets, Renal osteodystrophy & hypothyroidism.
BCG scar is seen.SMR are prepubertal
Normal thyroid examination, /no evidence of hypothyroidism.
While rest of systemic examination is unremarkable.
 I need parent’s height for MPH.

 I want x rays of left wrist joint for bone age.
 I want progressive percentile charts of child
 Fundus examination.
CAUSES OF GH DEFICEINCY
ISOLATED
Deficiency
153
Insensitivity
PART OF PANHYPOPITUITARISM
Congenital

Acquired
INVESTIGATION
a. IGF1 and IGF1BP3

b. GH level dec with 2 provocative test
i. Insulin , arginine, glucagon, clonidine
ii. Peak level of GH <10ng/ml in each of two procative test compatible with GH
deficiency
c. GHRH stimulation test
d. TSH,ACTH ,T4 , Steroids hormone level , FSH AND LH LEVEL
e. Isolated inc prolactin level
i. Indicated hypothalamic lesion
f. CT /MRI Sull and brain
i. Suprasellar calcification ……….. craniopharyngioma
ii. Lytic lesion ………………………….. histiocytosis
g. X RAY for bone age
h. GH insensivity
i. High GH
ii. Normal IGF1
iii. Normal IGF1BP3
MANAGEMENT
Indication
1. GH deficiency
2. Sever constitutional delay
3. Tuner, Noonan ,P.W.S
4. ESRD
5. IUGR
6. Idiopathic short stature
Side effects
1) Leukemia
2) Pseudo tumor cerebri
3) Slipped capital femoral epiphysis
4) Gynecomastia
5) Worsening of scoliosis
6) Type 2 DM
7) Hypothyroidism
8) Adrenal insufficiency
9) Creutzfeldt-Jakob disease
THERAPY continued till
1. Near final height is achieved

2. Decision of pt that he /she is tall enough
3. Growth rate < 1inc/year
4. Bone age >14y in girls and >16y in boys
TREATMENT 154
A. rhGH
a. .18-.3mg/kg/week s/c 6 divided doses
b. High doses needed in puberty

c. Maximum response in first year of treatment
th
d. Growth velocity in first year >95 centile
th
e. If growth velocity fall below 25 centile then compliance should be cheked before
increasing dose
B. GHRH AGONIST
a. TO interrupt or delay puberty …….to delay epiphyseal closure and prolong growth
b. Can increases the adult height
C. Recombinant IGF1
a. S/c twice daily
b. For growth hormone receptor abnormality
D. Multiple pituitary hormone deficiency
a. Thyroxin
b. Hydrocortisone
c. Testosterone, estrogen. Progesterone
155

THALESMIA------------------------------------------------------------------------------------------------- LONG CASE-
(USUALLY KNOWN CASE).
BIODATA:
P/C:
 REGULAR TRANSFUSION
 PALOR
 RESPIRATORY DISTRESS.-------------------------------------D/D PNEUMONIA/DCMP/PALLOR
 SWELLING OF BODY
 ORTHOPNEA
 FEVER
 ABDOMINAL PAIN.
 JAUNDICE
(ASK MOTHER TO TELL U ALL ABOUT PROBLEM)
HOPC:
DETAILS OF P.C
ELICT THE CAUSE OF CURRENT ADMISSION.
D/D OF CURRENT PRESENTING COMPLAINTS.
CURRENT MANAGENT & PROGRESS.
PAST HX:
-INITAIL DIAGNOSIS:
 WHEN / AT WHICH AGE PRESENTED / WHAT WERE INITIAL MANIFESTATIONS.

 WHERE DIAGNOSED & TREATED
 WHAT RX OFFERED THAT TIME.
-TREATMENT HX:
-BLOOD TRANSFUSION HX:
 WHEN IT WAS STARTED

 AT WHAT AGE FIRST TRANSFUSION GIVEN
 FREQUENCY OF TRX
 IS FREQUENCY INCREASING?
 HOW BLOOD IS ARRANGED?
 WHO DONATES BLOOD? 156
 BLOOD GROUP OF PT?
 ANY REACTION OBSERVED?
 SCREENING/ CROSS MATCHING?
 ANY HX OF PLATELLTE TRNX?

(HERE U ESTABLISH THE QUNATITY & VOLUME OF TRNSFUSION)
CHELATION
 WHETHER IT IS STARTED/ NOT?

 WHEN IT WAS STARTED?
 HOW OFTEN CHELATION (FREQUENCY).
 WHICH FORM OF CHELATION (I.V/S/C, ORAL, and CONTINEOUS).
 HOW IT IS ARRANGED?
 HOW FREQUENT SERUM FERITIN IS MONITORED?
 WHAT IS THE LAST S.FERITIN REPORT?
 ACESS THE COMPLIANCE.
OPTION FOR BMT GIVEN/NOT.
ANY OTHER TRX—FOLIC ACID, VITAMIN C, INSULIN , Ca/VIT D , HORMONE FOR STATURE, INSULIN.
ANY PROCEDURE
 LIVER BIOPSY.--------------------------(NOT FOR IRON OVERLOAD JUST MAY BE FOR

DECARVELLI CLASSIFICATION AND CLD)
 AUDITORY ACESSMENT -------------------(CASE DEPENDANT IF EARLY DISEASE THENO
DON’T ASK)
 VISUAL ASSESSMENT.------------------(CASE DEPENDANT IF EARLY DISEASE / NO I.V/SC
CHELATION THEN DON’T ASK)
QUESSTIONS REGARDING COMPLICATION OF DISEASE
 HEARING IMPAIRMENT
 CONSTIPATION, COLD INTOLERANCE, WT GAIN ,PALPITATION—(HYPOTHYROIDISM)
 POLYUREA, POLYDYSIA, WT LOSS—(D.M after 10 yr)
 JAUNDICE, HEMATEMESIS, EPISTAXIS, MALENA, ABDOMINAL DIATENSION—(CLD)
 TETANY, BONE PAIN, FITS—(HYPOPARATHYROIDISM).
 POOR GROWTH.
 PUBERTY STATUS.
QUESTIONS REGARDING COMPLICATIONS OF TREATMENT:
 VISUAL DISTURBANCE----------------------(CASE DEPENDANT RELEVANCE)

 HEARING IMPAIRMENT---------------------( CASE DEPENDANT RELEVANCE).
 BONY DEFORMITIES.
 DCMP
 ALLERGIC REACTIONS
 BODY SWELLING, PALPITAION, RESP. DISTRESS, SYNCOPE,PND, ORTHOPNEA –(DCMP).
 JAUNDICE 157
 HYPERPIGMENTATION
 B.M SUPRESSION—(SUDDEN PALLOR , PETECHAE, BRUISE, BLELED)
 ABDOMINAL PAIN, VOMITING, MALENA –(YERSENIA).

BIRTH HX:
 HX OF PROLONG JAUNDICE, XCHANGE TRX.
DEVELOPMENT HX:
VACCINATION DETAILS:
 HEP B, OTHER THAN EPI VACCINATIONS
NUTRITIONAL HX
 CALCULATE CALORIES
 ANY DIETRY RESTRICTION/ MODIFICATION/ ADVISE---/BLACK TEA SUGGESTION IN
BETWEEN MEAL.
FAMILY HX.
 FAMILY TREE.
 ANY OTHER FAMILY MEMBER WITH SAME ISSUE.
 HX OF TRNASFUSION IN FAMILY.
 HX OF EARLY DEATH OF SIB?
 IS FAMILY COMPLETE OR WILLING TO CONCIEVE FURTHER.
PARENTS KNOWLEDGE:
DISEASE IMPACT—CHILD SCHOOLING
PERSONAL HX OF CHILD—PLAY ACTIVITIES/AODL
PARENTS CONCERN
SOCIOECOMIC HX:
 DETAILS ABOUT EARNINGS.

 HOME.
 ANY ZAKAT FORM
 THALESMIA SOCIETY JOINED/NOT.
EXAMINATION :
CHECK LIST:
 GPE—THYROID, SMR, LEG ULCERS, JVP, PERIUMBLICAL SCAR MARKS, BONE PAINS.
 OTHER DETAILED SYSTEMIC EXAMINATION.
 FUNDUS EXAMINATION.
158
MAKE A QUESTION IN MIND THAT WILL MY PT BE A SUITABLE CASE FOR BMT.

DESCRIPTION:
HE IS KNOWN CASE OF THALESMIA SINCE THE AGE OF ..YEARS WITH POOR COMPLIANCE AND
FOLLOWUP, NOW PRESENTED WITH FEVER FOR LAST 15 DAYS IT WAS GRADUAL IN ONSET LOW-
HIGH GRADE UNDOCUMENTED INTERMITTANT WITH NO RIGORS, CHILLS , RELIEVE BY TAKING
ANTIPYRETICS , ALONG WITH HX OF RESPIRATORY DISTRESS PROGRESSIVELY INCREASING STARTED
FROM FEET THEN GENERALIZED INVOLVENT UPTO FACE WITHIN 2 DAYS OF ONSET IT WAS NOT
ASSOCIATED WITH ANY PALPITAION , OTHOPNEA, PND, JAUNDICE, URINARY COMPLAINT , LOOSE
MOTION , VOMITING, ABDOMINAL DISTENSION, PAIN.
ACTUAL HX DATES BACK WHEN HE WAS 1 YEAR OF AGE PARENTS NOTICED PALLOR WITH
RESPIRATORY DISTRESS AND FACIAL PUFFINESS , THAT WERE GRADUALLY WORSENING NOT
ASSOCITAED WITH FEBRILE ILLNESS,PETECHAE, BRUISE,BLEED FROM ANY SITE , URINARY
COMPALINT, THEY WENT TO PERIPHERAL HOSPITAL WHERE HE WAS ADMITTED AND INVESTED IN
FORM OF …………………………………………, AND MANAGED WITH BLOOD TRANSFUSION , SINCE THEN HE
HAS BEEN ADVISED REGULAR TRANSFUSION ONCE /MONTH WITH CBC MONTIOTRING AND
REGULAR CHELATION.
BLOOD IS ARRANGED BY PARENTS/HOSPITAL & NO HX SUGGESTIVE OF COLICATIONS RELATED TO

TRANSUFION IN FORM OF ALLERGY, BODYSWELLING, RASH.
HE WAS PUT ON ORAL/S/C CHELATION THERAPY SINCE THE AGE OF 2 YEAR IN A …5DAYS/WEEK
THAT WAS GIVEN BY MOTER/HIMSELF , IT WAS ARRANGED BY ……,BUT NOT REGULARLY
MONITORED WITH SERM FERRITIN LEVEL.. HOWEVER THERE IS NO HX OF ANY OTHER
PRECHELATION EVALUATION APART FROM SERUM FERRITIN LEVEL.
PARENTS HAVE POOR KNOWLEDGE REGARDING THE DISEASE , COMPLICATION , COURSE AND
MANAGEMENT , THEY HAD BEEN ADVISED FOR BMT – BUT STILL NOT ARRANGED ANY MATCHED
DONOR NOR PROCEED FURHTER WORKUP. ALSO THEY HAD BEEN ADVISED FOR ANNUAL
EYE/AUDITORY ASSEMENT .
HX/NO HX OF -- OF POLYUREA, POLYDYPIA, WT LOSS, HEADACHE, FITS, ALTERED SENSORIUM ,

FOCAL NEUROLOGICAL DEFICIT, WEAKNESS OF ANY PART OF BODY, PALPITATION, CONSTIPATION,
COLD INTOLERANCE, THYROID SWELLING, BODYS WELLING,RESPIRATORY DISTRESS, SYNCOPE,
ORTHOPNEA, PND, PETECHAE, BRUISE , BLEED FROM ANY SITE, TETANY, BONY PAINS, JOINT
SWELLING, BACHEACHE, SCOLIOSIS, NUMNBNESS , WEAKNESS OF LOWER LIMBS, GROWTH FAILURE,
LEG ULCERS, OR ANY SURGERY BEFORE.
NO HX OF ALLERGY TO MEDICATION, HYPTENSION, BURNING, TINGLING SENSATION, VISUAL

DISTURBANCE, HEARING IMPAIRMENT, L/M , VOMITING, ABDOMINAL PAIN, BONY DEFORMITIES
DIFFERNTIALS
159
K.CASE OF THE THALESMIA MAJOR NOW PRESENTED WITH COMPLICATION DUE TO POOR
COMPLAINCE AND FLLLOW UP.
OTHER DIFFERNTIAL I CAN ENTERTAIN APART FROM HIS ESTABLISHED DX :

MIXED HEMOGLOBINPATHIES –(THALESMIA C, THEALESMIA Punjab D)
HEREDIATARY SPHEROCYTOSIS
DIAMOND BLACKFAN ANEMIA.—(PRESET AT under 6 month , skeletal abnormalities they had hx of

steroid intake and BMA.)
DISCUSSION:
THALESMIA:
 Total Pakistan population – over 170 million est.

 Gene frequency –5.5 %.
 Gene frequency in targeted families –31%.
 One beta thalesmic born every hour.
 Nearly 11000 beta thalesmic born every year.
 Average life span is 10 yr
 Our population is carrier 5-6%.
 World wide homozygous beta thalesmia carrier – 3%.
 200 mutations
 8 mutations in Pakistan –FR8-9 is most common.
THALESMIA MAJOR
 A.R –1/4 Chance .

 Gene on Chromosome 16  alpha.
 Gene on Chromosome 11  beta.
 Mutataion  quantitative defective in production of beta chain of Hb  imbalance between alpha and
beta chain  hemolysis of RBCs.
Production of Beta chain or excess of free globin chain (alpha)


Chain precipitate  cell membrane damage
 
RBC –Hemolysis BM (Ineffective eryhtropoeisis)
 
Anemia
  
Increase EPO Increase iron absorption blood Tx
 
BM expansion iron load
 
Skeletal changes cardiac death
DIAGNOSIS OF THALESMIA:
 Hx –examination –investigation.
HISTORY:
 Progressive pallor, lethargy , irritability.
 Frequent infrection , FTT.
 Onset of anemia –early onset –major/ childhood –intermedia. 160
 <1 yr –received > 2 BTx
 Anemia unresponsive to hematenics
 Family hx of anemia , jaundice, gallstones

Examination :
 Pallor, fasial features, visceromegally,

 Chronic leg ulcers –intermedia.
Investigations:
 CBC –Hb , MCV --  <25fl, MCH-25 pg, Retix  /N-(d/t ineffective
erryhtropoeisis).
Target cells, anisocytosis, pokilocytosis.
Retic (4-8%) usually but relatively decreased compared to degree of anemia coz of
ineffective erythropoeisis.
 HB electrophoreisis  Hb F –50-80%-(Th.major) / Hb F - <50% -(intermedia).
 DNA analysis.
 PCR –(In case of strong clinical suspicion when all other test are normal).
 Ineffective erythropoisis : active eryhtropoisis with premature death if RBC a decrease output of RBC
from BM resulting in anemia.
CBC AND HB-ELECTROPHORESIS INTERPRETATION:
NORMAL B-THALESMIA TRAIT ALPHA –THALESMIA
MCV >75 <75 <75
MCH >25 <25 <25
HbA2 <3% >3.5% <3.5
HbF <1.5 0-5% <1.5.
LABORATORY STUDIES DIFFERENTIATING THE MOST COMMON MICROCYTIC ANEMIAS

STUDY IRON DEFICIENCY ANEMIA α OR β THALASSEMIA
Hemoglobin Decreased Decreased
MCV Decreased Decreased
RDW Increased Normal
RBC Decreased Normal-increased
Serum ferritin Decreased Normal
Total Fe binding capacity Increased Normal
Transferrin saturation Decreased Normal
Free Eryth. Protoporphyrin Increased Normal
Transferrin receptor Increased Normal
Reticulocyte hemoglobin concentration Decreased Normal
BETA THALESMIA MAJOR :

161
 Usually present between 2 month – 2 year of age
 Early age transfusion dependant.
 Those pt who have no effective production (homozygous 0 beta thealesmia ) or severly limited
production of beta globin – they have starting of transfusion in forst year of life.

 Also called cooley’s anemia.
 HB-ELECTROPHORESIS –( HbA1  , Hb F >90 %, HbA2—3-5%.).
BETA THALESMIA MINOR
 Also called thalesmia trait.

 Heterozygous parents lead to single gene defect lead to this trait –reduced beta globin chain production.
 Usually asymptomatic mild anemic accidentally discovered.
 HB-ELECTROPHORESIS –( HbA1-90%, HbA2 >3%, HbF>5%.)
BETA THALESMIA INTERMEDIA:
 2-6 yr of age –adulthood

 Growth retardation ,typical facies, moderate anemia, mod-sever hepatosplenomegally.
 This is disease of intermediate severity such as those who are compound heterozygous of two
thalessmia variant.
 Same features like major –skeletal abnormality and hepatosplenomegally but their Hb% remain
between 5-10 g/dl.
 HB ELECTROPHORESIS –( Hb-8-10 , retix -  , Hb F 510-50%, HbA2 <3.5).
INDICATION OF TRANSFUSION IN T.INTERMEDIA:
 Growth failure.
 Thalesmia facies.
 Osteoporosis / fractures.
 Cardiac complications.
 Hypersplenism.
COMPLICATIONS :
 Osteoporosis—more common in non-ttransfused thalesmia intermedia than major.

 Leg ulcers.—(Stasis +hypoxia due to chronic anemia)
 Thrombophillia.—(increased plt activation and coagulation cascade by damaged RBCs)
 Extramedullary erythropoitic masses.
 Gall stones.—(50-70% after 15 yr due to ch.hemolysis)
TREATMENT:
 Hydroxyurea –25mg/kg/day –raise HbF –Delay Trx.

 Splenectomy -- >10yr who never treated may be candidate for splenectomy.
 Transfusions : once regular trx started they behave like major.
 Iron chelation –(desferoxamine 2-3 DD) > start when ferritin >1000 .
 Avoid iron rich food
 Add tea/ coffee in between meals –dec iron absorption.
 Rx of leg ulcers –regular transfusions, raise leg for 1-2 hr /day, raise bed end 10 cm durin sleep,
hydrourea / erythropoietin.
 Rx of Osteoporosis –diet , exercise, vitamin D, Ca+, regular trx, bisphosphonates. 162
BLOOD TRANSFUSION IN THALESMIA MAJOR

 START WHEN Hb is <7g/dl on 2 occasions 2 week apart
OR
 >7 g/dl + symptoms of extramedullary hematopoeisis.
TYPES OF BLOOD USED :
 IDEALLY LEUKODEPLETED PCV TRANSFUSION ( <5 × 106 wbc/ul).

 Washed RBCs – ( for those who experience Repeated blood transfusion reaction).
 Fresh blood –(attach drip set and let RBCs to settle down by hanging in refrigerator for 2 hours ).
 Irradiated RBCs  best for prevention of GVHD
 Screend blood transfusion for hep-B,C,HIV, CMV.
 Crossed matched for minor group.
TRANSFUSION REGIEMENS:
1. HIGH TRANSFUSION REGIMEN—(pre-transfusion Hb% Kept between 9.5-10.5g.dl—(better

regimen).
Benefits : good growth, no visceromegally, low requirement of blood/year.
2. LOW TRANSFUSION REGIMEN –(= = = = = 4-8 g/dl --(more in

Pakistan).
High transfusion regimen is better so try to shift pt from low to high by weekly transfusion for a
short period.
SAFE TRANSFUSION:
 Carefully crossmatched blood for ABO,Rh, Minor blood groups , kell , duffy, lewis , coombs method.
 Properly screened for HBV, HCV,HIV, & malaria.
 Proper amount whole blood –20ml/kg/ PCV-10ml/kg.
 Proper record & proper time 4 hour .
 Transfusion of 10-15ml/kg –raises Hb 2-3 g/dl.
 Slower rate of tranx in anemic heart failure 1-2ml/kg/hr.
 Transfusion interval can be 2-5 weeks & should not exceed 20ml/kg at one time.
RECORD OF B.Tx
 Pre-& post trx Hb.

 Volume of trx at each visit
 Six, twelve , monthly blood volume consumption and calculation.
 Adverse reactions.
CAUSES OF INCREASE REQUIREMENT OF TRANSFUSION/ FALL IN Hb% RAPID INTERVAL.
 Hyperspelnism--/spenectomy.
 New antibodies against RBCs.
 Low Hct of donor
 Infection –malaria 163
 Chronic blood loss/occult
 Autoimmune hemolytic reaction –back pain
 Old stored blood
 Undertransfusion.

 BM suppression—parvo virus/deferiprone.
COMMON BLOOD TRANSFUSION REACTIONS AND THEIR PREVENTION:
1. --IMMUNE MEDIATED
2. --NON-IMMUNE MEDIATED
IMMUNE MEDIATED
FEBRILE TRANSFUSION REACTION:
 Rx—leucoreduced/leukofiltered blood trx.
ALLERGIC TRANSFUSION REACTION –(2O to plasma proteins).
 Rx—washed PCV / only PCV trx, and give i.v steroids 10-20 mg/kg.
ACUTE HEMOLYTIC REACTION
 Present with loin pain, jaundice, anemia.

 Rx –proper blood grouping & cross match.
AUTOIMMUNE HEMOLYTIC ANEMIA –New antibodies against RBCs.
 Steroid /immunosuppressive therapy /IVIG, + alloimmunization.
DELAYED TRANSFUSION REACTION.
 After 5-10 days –due to delayed hypersensitivity and infections like malaria.
TRANSFUSION RELATED ACUTE LUNG INJURY (TRALI).
 GVHD –common in those pts who received bld from close relatives.
 Rx—O2 + steroids , Diuretics, assisted ventilation.
NON-IMMUNE MEDIATED
 Hep-B,C, HIV, CMV, malaria, EBV. Yersenia enterocoli, G+ --Arthritis , perinephric abscess, G-ve
septicemia. Creutz feldt jakob disease –rare not mention in exams .
TRANSFUSION INDEX (TI)/TRANSFUSION QUOTIENT = Volume of PCV /kg/year
 Advantage—guide need for splenectomy.
IF Hct of donor is 50% then:
 4ml/kg ---------------- 1 g Hb.

 8 ml/kg----------------  2g Hb.
 12 ml/kg--------------  3g Hb.
 16 ml/kg--------------  4g Hb.
164
FORMULA FOR APPROPRIATE VOLUME OF BLOOD.
 Appropriate volume of blood = (Desired Hb – Pts Hb ) × WT × 3.

EFFECTIVE TRANSFUSION ADVANTAGES:
 Promote normal growth.

 Normal physical activity.
 Suppress ineffective erythropoiesis
 Dec bony changes
 Dec hepatosplenomegally.
 Dec iron overload.
THALESMIA CARRIER
 ATYPICAL –(All CBC /Hb electrophoresis all normal due to Cap1 Mutation) –Dx by PCR.
 TYPICAL –( HbA2 Raised).
CAUSES OF ANEMIA IN BETA THALESMIA:
 Death of RBC precursors within BM –intramedullary hemolysis/ineffective erythropoisis.

 Increase destruction of Circulating RBCs—hemolytic anemia.
 Recurrent infections.
 Inadequate nutrition.
CHELATION THERAPY :
Indication of start of chelation:
 Serum ferritin level >100 ug/L.

 After 1st 10-20 transfusions.
 Age >2 yr.
CAUSES OF IRON OVERLOAD:
 Blood transfusions (250 ml =175mg iron).

 Ineffective erythropoisis RBC breakdown –more it released
 Increase iron absorption.
Dietry restricted iron containing food –avoid spinach and mutton.
DESFEROXAMINE –S/C INFUSION SLOWLY 5 NIGHTS/WEEK. –8-10 hrs. (inj desferol 500mg)
 Time is important not dose.

 Dose –20-40mg/kg/day.
 Routes –S/C / I.v
 Diluent used –water sterile –> less local irritiant
 Bind to NTBI—toxic to tissues.
 Half life is very short --20-30 min so given continuous infusion s/c to slowly absorb and overnight.
Side effects :
–local reaction –itching /erythema, redness—may be due to hypertonic sol, impure distilled water, 165
wrong diluents, intradermal injected  Rx hydrocortisone 5-10 mg mix in infusion.
 Severe allergy-rare
 Rapid infusion –shock
 Interstitial pneumonitis –rarely.

 Dose related side effects : (>4mg/kg/day if used) for long period of time.
 Hearing problems (tinnitus, deafness—High frequency SND)
 Visual problems –night blindness/ colour vision impairment , dec visual acuity.
 Skeletal problems –rickets like changes in metaphysic , vertebrae—microfractures –which lead to
reduce sitting height and bak pain + growth retardation –short trunk it is due to early chelation
therapy <3 yr of age and high doses given.
INDICATIONS OF CONTINEOUS INFUSION (50mg/kg/day).
1. Ferritin >2500 ug/l

2. Cardiac dysarrthemias.
3. Dec ventricular EF
4. Active Hep-C
5. Plan for BMT.
6. Hepatic iron content >15 mg/gram dry wt.
 It is given once/twice per month if>2500 feritin level.
 Add vitamin C Within 1st hour of chelation single dose and after 1 month of chelation –it increase free
iron mobilization from tissue to circulation for chelation.
<10 yr= 50 mg/ >10 yr =100mg single dose.
DEFERIPRONE: (FERIPROX) 75mg/kg/day in 3 DD/ ORAL / —(effective in removing cardiac iron
overload)
 Tablet – 500mg.
 SYP – 100mg/1ml.
 ADVANTAGE :- used for cardiac iron removing and adjunct along with desferoxamine.
 S/E:- neutropenia, agranulocytosis, ALT , arhtropathy.
 MONITORING : Weekly CBC .
 Monthly –LFTS , RFTS, TFT,
DEFERESIROX –(ASUNRA) /ORAL /100/400mg(Rs. 125/395) --FOR TISSUE AND CARDIAC IRON
REMOVAL.
 10-20mg/kg/day OD
 Take on empty stomach
 Dispersible tablets diluted in water.
 Better than deferiprone –coz > effective in selective mobilization of tissue iron
 S/E – MINIMAL , transient nausea and vomiting.
COMBINATION REGIMEN:
Indication : cardiac toxicity
 DESFEROXAMINE + DEFERIPRONE
 desferoxamine – 4DD/week.
 Deferiprone –7D/week.
 Combination regimen lead to rapid depletion of Ca , Cu, Zn –so should be supplemented along.
MONITORING IRON OVERLOAD

166
 S.Ferritin level –3-6 monthly.
o False positive –acute infections/hepatitis.
o False negative –vitamin C deffeciency.

 Cardiac MRI
 Liver biopsy –iron content –( this facility unfortunately we don’t have)—otherwise is best among all.
MONITORING THERAPEUTIC INDEX FOR DESFEROXAMINE TO DECREASE SIDE EFFECTS:
 Therapeutic index = actual dose received in each occasion × doses/week = ans ÷ ferritin ug/L
÷7
 Aim of TI < 0.025

 If increase = mean increase dose is being given so decrease dose.
CAUSE OF GROWTH FAILURE IN THALESMIA:
1. Hypothyroisim
2. Dec nutrition
3. Hypoparathyroidism
4. Hypogonadotrophic hypogonadism
5. Anemia
6. Dec GH
7. Genetic.
SPLENECTOMY :
 During splenectomy also advise for cholecystectomy, appendicetomy and liver biopsy at same time.
 Ideal age is after 5 year because after that risk of capsulated organism related is decreased.
 Required in low transfusion regime pts
 Transfusion independent thalesmia intermedia –2nd or 3rd decade
Indications:
1. Growth failure
2. Thalesmic facies
3. Mechanical discomfort
4. Hypersplenism
Pre-requisties
 Hb  --(so of pt on low trx regime then shift to high trx by weekly trx –it lead to dec spleen sixe easy
to remove).
 Vaccine –(2-4 week before surgery) pneumococal, meningococcal, h.influenza (against encapsulated
organisms).
Post splenectomy:
1. Erythromycin BD for 3-5 yrs

2. 125/250 mg = <10/>10 yr.
3. Aspirin –if plt increased 167
4. Sepsis > chances –treat accordingly.
HYPERSPLENISM:

1. Increase PCV consumption 220ml /kg/yr –earliest sign
2. Initially leucopenia then thrombocytopenia late.
COMPLICATIONS OF THALESMIA MAJOR
CARDIAC COMPLICATIONS
 Pericarditis
 Myocarditis
 Dilated CMP
 Arythemias –SVT
 Most death due to this complications
 No correlation with serum ferritin or liver iron content with cardiac iron iron content
 So aim is to keep ferritin level < 2500 ug/L for lifetime
 It is reversible damage but if untreated with time it is irreversible.
 S/S –palpitaion, syncope, eoigastric pain, dec exercise intolerance, edema
 LABS –ECG , ECHO for E.F , CXR. 24 holter –arythemia monitor , MRI T-2 cardiac.
 Newer –SQUID –super conductive quantum interferon device technique.
MANGEMENT:
 Maintiance of pre-trx Hb 10-12 once cardiac disease set in

 Regular iron chelation –continuous i.v chealtion with 50 mg dose
 Surveillance for other causes of cardiomyopathy –hypothyroidism, Hypoparathyroidism, vitamin C
deff, B1 –berri berry.
 CCF –Commonest among all give diuretics, digoxin, ACEI.
 PERICARDITIS –self limiting ,4-5 weeks, steroids and salicylates.
 DCMP –sudden CVS, Failure, SVT, VT, pulm edema.
 ARRYHTEMIA –mostly SVT –Rx with beta blockers amiodarone (SVT/VT)
 Offcourse bed rest is adviseable .
ENDOCRINE COMPLCATIONS :-----------------(IRRVERSIBLE & APPEAR AFTER 1ST DECADE).
Main causes:
 Chronic anemia.
 Iron overload.
 Late chelation.
1. HYPOTHALMIC PITUATARY DYSFUNCTION ---90%.

2. OSTEOPENIA/OSTEOPORESIS---------------------90%.
3. D.M------------------------------------------------------40%.
4. HYPOPARATHYROIDISM----------------------------37%. 168
5. HYPOTHYROIDISM -----------------------------------27%.

CAUSES OF GROWTH RETARDATION –SHORT STATURE.
 Growth is normal till 12 yr nut then pubertal growth spurt do not occur
 Chronic anemia.
 Hypogonadism
 Hypothyroidism/hypotparathyroidism
 Genetic factors.
 GH deffeciency/ resistance
 Chelation toxicity/ desferal
 Hyperdsplenism
 Genetic factors
 Folate deff
 Zinc deff
Pshycosocial.
INVESTIGATION FOR SHORT STATURE:
 First I will take MPH and plot on centile charts.

 Advise for BONE AGE –x-ray L wrist joint .
 And will exclude the other causes by requesting T3,T4,TSH, sex hormone level –LH,FSH,GnRh, GTT
, Ca, PO4, ALP levels, Zn level and GH level by insulin stress test.
TREATMENT:
 Better growth can be achieved by regular transfusions with proper and adequate chelation , moreover if
osteoporosis then I will treat with advise of regular exercise, Ca,Vit D supplement, diet , and
bisphoshonates with regular trnx,
 If sec to thyroid deff then thyroxine supplement
 If sex steroid deff then accordingly.
 But if my pts age is > 10 yr , arrested growth on 6 month followup and chronological age –bone age >2
yr gap then I will go for G.H therapy and endocrine opinion.
DELAYED PUBERTY
 Female ---13 yr called DP

 Male ---14 yr Called DP
 Hypogonadotropic hypogonadism
 Hypogonadism –male –testicular vol <4 ml / female absent breast development by 16 yr.
 Arrested puberty –when lack of pubertal groeth over a year or longer .
 Tanner staging should be done every 3 monthly.
INVESTIGATIONS:
 Growth parameters and bone age

 T4,TSH level’
 LH, FSH, TESTOSTERONE LEVEL 169
 GnRH stimulation test for LH,FSH.
 Pelvic USG –Ovaries, uterine size.
 GH stimulation if required.

MONITORING:
 Serial montoring of growth and puberty

 Sitting and standing height –monthly,
 Bone age –biannualy after 10 yr
 Standing X-RAY spine –to exclude microfractures
 SMR –3 monthly for puberty staging.
TREATMENT:
 MALE - Testosterone propionate I.M monthly for 6 months with dose of 25 mg/m2.
 FEMALE –INDCUE estrogen supplement –conjugate esters
o Ethinyl estradiol for 6 month.
o During treatment monitor growth and bone age annually.
o If puberty doesn’t occur then increase dose of both above’monthly pelvis USG for uterine size
and when uterine wall size > 45mm then add progesterone  menarche . if doesn’t occur then
estrogen = progesterone both use.
HYPOTHYROIDISM :
 TYPICAL S/S
 LAB DX: T4 ,  TSH
 Rx – thyroxine 3-8 ug/kg/day. (thyroxine tab 50 ug)
 Monitoring – 6 month TFT , bone age annually.
HYPOPARATHYROISM:
 Ca+  PO4, /N ALP  CHECK PTH  LOW.

 Rx ca, vitamin D, Avoid high phosphate diet—egg, milk, cheese, phosphate binders-
sevelemir
D.MELLITUS : (HbA1C can’t be used for monitoring coz already deficient and dec RBC survival)
 Rx – diabetic diet, chelation, metformin—helpful in early stage of D.M
THALESMIC BONE DISEASE:
Common feature of thalesmia in both intermedia and major
Manifestations are:
 Thalesmic facies
 Osteoporosis/osteopenia
 Spinal cord compression –vertebral compression.
OSTEOPENIA/OSTEOPOROSIS:
WHO DEF FOR OSTEOPOROSIS
 T SCORE ON BONE DENSITY OF <-2 S.D. (BONE DENSITY ON DEXA 170

SCAN)
 Z SCORE + 2S.D IN RELATION TO AGE OF PT
 T SCORE BTWEEN -1.5 TO -2.5 –> OSTEOPENIA.


CAUSES OF OSTEOPORESIS:
 Hypogonadotrophic hypogonadism
 Low Ca+, vitamin D , PTH.
 Hypothyroidism
 Anemia
 Chelation
 Genetic factors
INVESTIGATION:
 LH,FSH.
 T4,TSH.
 Ca,PO4,ALP,PTH.
 24 urine Ca.
 LFTs
 Spine –XRAY Lateral /AP view.
 DEXA scan –spine/hip , radius , ulna –annually.
TREATMENT :
 Diet containing Ca+ adequate.

 Regular exercise.
 Ca+, Vit D supplement.
 Rx for hypogonadism before shifting to bisphosphonate therapy.
 Bisphosphonates: (2-4 yr only coz of S/E)
o Clondronate
o Alendronate
o Palmidronate --- Monthly for 6 yrs.
BONE MARROW TRANSPLANTATION:
 Only curable Rx.
Lu-cavaelli’s classification for BMT
Components class-1 class ii/iii

Regular yes No
chelation
Hepatic fibrosis no Yes
Hepatomegally no Yes
Prognosis Offer BMT Councell 30%
97% long Mortality
term survival
Class I 
 100 % cases have 10 yr survival rate.

171
 97% have long tern survival rate.
 Recurrence rate –8%.
 Mortality ---3%.

Younger pt have increase rate of recurrence
Older pt have increased mortality.
DETAIL OF BMT IN LEUKEMIA –SAME PROTOCOL.
POPULATION SCREENING FOR CARRIERS OF THALESMIA:
 Screen targeted population

1. CBC with P.S
2. Hb electrophoresis.
3. Single tube osmotic fragility test—(cheap way of mass screening) based on concept of thin cells which
increase absorb water and increase resistance to hemolysis.
RECOMMENDED FOLLOW UP VISITS AND INVESTIGATIONS:
 PRE-SCHOOL CHILD ---MONTHLY OPD VISIT

 SCHOOL AGE –6 MONTH
 S.FERRITIN 3-6 MONTHLY.
 6 MONTHLY FOLLOWING :
o Ca+, PO4, ALP, Mg, LFTs, RFTs, TFT.
ANNUALLY FOLLOWING:
1. Chelation s/e –slit lamp eye examination, audiometry.

2. Cardiac assessment –after 10 yr of DxECG,ECHO.
3. Dental assessment.
4. Growth assessment –after 13 start to screen annually.
ANTENATAL DX –preimplantation genetic analysis/CV SAMPLING dx and counceling
MISCELLANEOUS FACTS ABOUT THALESMIA:
Mentizer index = MCV ÷ RBC count interpretation - >14 iron def anemia <14 –thalesmia.
172

HEMOPHILLIA --------------------------------------------------------------------------------------LONG CASE
USUALLY KNOWN CASE
BIODATA:
P/C CAN BE:
 Bleeding episode (joint bleed)

 Factor –VIII replacement therapy
 Gum bleed
 Epistaxis
 Psoas bleed
 Intra-cranial bleed.
 Upper airway bleed
 Rarely hematemsis.
HOPC:
Precipitating fctors for current bleed
Amount of bleed
Colour of blood
How stopped
Any S/S suggestive of hypovolumia
For how long bleeding continued before coming to hospital
Any specific Rx/ surgical intervention required
Course in hospital and current status.
D/D
 Previous hx of bleeding episodes

 Peteche/bruises
 Hematemisis/ malena.
 Hematurea
 Gum bleed.
SYSTEMIC INQUIRY
Complications of disease:
Hemarthrosis: 173
 Joint involved in detail

 Sequence

 Extent of joint involvement
 Any target joint
 Deformity
 Functional capability.
Intra-cranial bleed:
 Seizure
 Headache
 Unconsciousness
 Weakness of any part of body
Psoas bleed:
 Abdominal pain
 Abdominal distention
 Vomiting.
COMPLICATIONS OF TREATMENT:
 Inhibitor
 Hep-B/C.
 Liver disease
 Desmopressin if use –flishiin/ hypotension/ edema,seizure, body swelling.
MANAGEMENT HISTORY:
How bleeding episode controlled
Factor 8 replacement herapy
Primary
Secondary
Given during hemarthrosis or other bleeding event
Hx of jaundice
Any surgery done and how managed/ planned
Parents knowledge regarding disease complication, carrier detection, home management .
PAST HISTORY:
When ,where, how, what invx….
Family hx:
Birth hx: 174
Vaccination hx:
Socioeconomic hx.

Examination:
All protocol + JIA maneuvers if evidence of arthropathy
DESCRIPTION OF LONG CASE HEMOPHILIA :
My pt…… known case of hemophilia A/B on factor VIII prophylaxis/on demand with good/poor
compliance and follow up now presented with complaint of ……..
He was diagnosed at the age of …., when he presented with hx of recurrent bleeding episodes from
different sites , these episodes were spontaneous as well as post-traumatic , there was hx of
petechae, bruise, palplable lumps and bleeding after injections , parents also give hx of prolong
bleeding from the umbilical stump, post circumcision , during vaccination and tooth eruption,
however no hx of.
There is also hx of joint swellings (recurrent/first episode ) when pt became mobile involving …joints
, spontaneous/post-traumatic without any migrating pattern or morning stiffness but associated
with sever pain and restriction of activity , there was no hx of fever, rash, photosensitivity , oral
ulcers, diarrhea, urinary complaint , red eyes , generalized weakness , palpitation, respiratory
distress , skin nodules, also there is no hx of epistaxis , gum bleed , hematurea, malena, altered
sensorium , fits , choking, delayed wound healing and pain in abdomen.
--------------------------------------------------------------------------------------------------------------------------------------
----
HEREDITARY CLOTTING FACTOR DEFICIENCIES (BLEEDING DISORDERS)
FACTOR I,II,V,VII,VIII,IX,X,XI,XIII,anti-plasmin/plasminogen activator inhibitor deficiency.
HEMOPHILIA A (factor VIII deficiency) and HEMOPHILIA B (factor IX deficiency) are the most
common and serious congenital coagulation factor deficiencies.
175
HEMOPHILIA C is the bleeding disorder associated with reduced levels of factor XI .
 PARAHEMOPHILLIA –factor V deficiency

 AUTOSOMAL HEMOPHILLIA –vwF 2N

The clinical findings in hemophilia A and hemophilia B are virtually identical.
HEMOPHILIA A / B
Deficiencies of factors VIII and IX are the most common severe inherited bleeding disorders.
Pathophysiology
 Factors VIII and IX participate in a complex required for the activation of factor X.  Together with
phospholipid and calcium, they form the “tenase,” or factor X–activating, complex. In vivo, the
complex of factor VIIa and tissue factor activates factor IX to initiate clotting.
 In the laboratory, prothrombin time (PT) measures the activation of factor X by factor VII and is
therefore normal in patients with factor VIII or factor IX deficiency.
 After injury, the initial hemostatic event is formation of the platelet plug, together with the generation
of the fibrin clot that prevents further hemorrhage. In hemophilia A or B, clot formation is delayed and
is not robust. Inadequate thrombin generation leads to failure to form a tightly cross-linked fibrin clot
to support the platelet plug. Patients with hemophilia slowly form a soft, friable clot. When untreated
bleeding occurs in a closed space, such as a joint, cessation of bleeding may be the result of tamponade.
With open wounds, in which tamponade cannot occur, profuse bleeding may result in significant blood
loss. The clot that is formed may be friable, and rebleeding occurs during the physiologic lysis of clots
or with minimal new trauma.
Neither factor VIII nor factor IX crosses the placenta.
 Bleeding symptoms may be present from birth or may occur in the fetus.
 Only 2% of neonates with hemophilia sustain intracranial hemorrhages.
 30% of male infants with hemophilia bleed with circumcisionThus, in the absence of a positive
family history (hemophilia has a high rate of spontaneous mutation), hemophilia may go undiagnosed
in the newborn.
 Obvious symptoms such as easy bruising, intramuscular hematomas, and hemarthroses begin when the
child begins to cruise.
 Bleeding from minor traumatic lacerations of the mouth (a torn frenulum) may persist for hours or days
and may cause the parents to seek medical evaluation.
 Even in patients with severe hemophilia, only 90% have evidence of increased bleeding by 1 yr of age.
 Although bleeding may occur in any area of the body, the hallmark of hemophilic bleeding is
hemarthrosis.
 Bleeding into the joints may be induced by minor trauma; many hemarthroses are spontaneous.
 The earliest joint hemorrhages appear most commonly in the ankle.
 In the older child and adolescent, hemarthroses of the knees and elbows are also common.
 They complain of a warm, tingling sensation in the joint as the first sign of an early joint hemorrhage.
 Repeated bleeding episodes into the same joint in a patient with severe hemophilia may become a
“target” jointRecurrent bleeding may then become spontaneous because of the underlying pathologic
changes in the joint.
 Although most muscular hemorrhages are clinically evident owing to localized pain or swelling,
bleeding into the iliopsoas muscle requires specific mention. A patient may lose large volumes of blood 176
into the iliopsoas muscle, verging on hypovolemic shock, with only a vague area of referred pain in the
groin.

 The hip is held in a flexed, internally rotated position owing to irritation of the iliopsoas. The
diagnosis is made clinically from the inability to extend the hip but must be confirmed with
ultrasonography or .
 Life-threatening bleeding in the patient with hemophilia is caused by bleeding into vital structures
(central nervous system, upper airway) or by exsanguination (external trauma, gastrointestinal
or iliopsoas hemorrhage). If head trauma  Simply put: “Treat first, image second!”
 Life-threatening hemorrhages require replacement therapy to achieve a level equal to that of normal
plasma (100 IU/dL, or 100%).
 mild hemophilia  VIII or factor IX levels > 5 IU/dL usually do not have spontaneous
hemorrhages These individuals may experience prolonged bleeding after dental work,
surgery, or injuries from moderate trauma.
LABORATORY DIAGNOSIS :
SPECIFIC:
 FACTOR LEVELS—VIII+ IX.

 APTT –(PROLONG) in severe -2-3 times >>normal. (screening test)
 platelete count.
 B.T
 prothrombin time
 Thrombin time
 mixing studies –(if doesn’t correct it mean inhibitor is formed)
 Bethesda test –(quantitative test that measure antibody titre-- inhibitor)
25-35% pt who receive factor viii/ix develop antibodies—inhibitor.
Differential Diagnosis
1. Severe thrombocytopenia.
2. Severe platelet function disorders, such as Bernard-Soulier syndrome and Glanzmann Thrombasthenia.
3. Type 3 (severe) von Willebrand disease.
4. vitamin K deficiency
GENETICS AND CLASSIFICATION
 Hemophilia occurs in approximately 1 : 5,000 males, with 85% having factor VIII deficiency and 10-
15% having factor IX deficiency.
 By definition, 1 IU of each factor is defined as that amount in 1 mL of normal plasma referenced
against a standard established by the World Health Organization (WHO); thus, 100 mL of normal
plasma has 100 IU/dL (100% activity) of each factor.
 Factor concentrates are also referenced against an international WHO standard, so treatment doses are
usually referred to in IU.
 Severe hemophilia is characterized as having <1% activity of the specific clotting factor, and bleeding
is often spontaneous.
 moderate hemophilia have factor levels of 1-5% and usually require mild trauma to induce bleeding. 177
mild hemophilia have levels >5%, may go many years before the condition is diagnosed, and
frequently require significant trauma to cause bleeding.
 hemostatic level for factor VIII is >30-40%, and for factor IX, it is >25-30%.

 The lower limit of levels for factors VIII and IX in normal individuals is approximately 50%.
 The genes for factors VIII and IX are carried near the terminus of the long arm of the X chromosome
and are therefore X-linked traits.
 The majority of patients with hemophilia have reduced clotting factor protein; 5-10% of those with
hemophilia A and 40-50% of those with hemophilia B make a dysfunctional protein.
 In the newborn, factor VIII values may be artificially elevated because of the acute-phase response
elicited by the birth process This artificial elevation may cause a mildly affected patient to have
normal or near-normal levels of factor VIII while Patients with severe hemophilia do not have
detectable levels of factor VIII.
 In contrast, factor IX levels are physiologically low in the newborn If severe hemophilia is present in
the family, an undetectable level of factor IX is diagnostic of severe hemophilia B.
 In some patients with mild factor IX deficiency, the presence of hemophilia can be confirmed only after
several weeks of life.
 Through lyonization of the X chromosome, some female carriers of hemophilia A or B have sufficient
reduction of factor VIII or factor IX to produce mild bleeding disorders Levels of these factors
should be determined in all known or potential carriers to assess the need for treatment in the event of
surgery or clinical bleeding.
 Because factor VIII is carried in plasma by von Willebrand factor, the ratio of factor VIII to von
Willebrand factor is sometimes used to diagnose carriers of hemophilia. When possible, specific
genetic mutations should be identified in the propositus and used to test other family members who are
at risk of either having hemophilia or being carriers.
Treatment
 When mild to moderate bleeding occurs, values of factor VIII or factor IX must be raised to hemostatic
levels, in the 35-50% range.
 For life-threatening or major hemorrhages, the dose should aim to achieve levels of 100% activity.
 dose required of VII (IU) =% Desired (rise in F VII) × Body weight × 0.5
 dose required of IX (IU) =% Desired (rise in Plasma F IX) × Body weight × 1.4
TREATMENT OF HEMOPHILIA
TYPE OF
HEMOPHILIA A HEMOPHILIA B
HEMORRHAGE
[†]
50 IU/kg factor VIII concentrate on day 1; then
80-100 IU/kg on day 1; then 40 IU/kg
20IU/kg on days 2, 3, 5 until joint function is
on days 2, 4. Consider additional
Hemarthrosis* normal or back to baseline. Consider additional
treatment every other day for 7-10
treatment every other day for 7-10 days. Consider
days. Consider prophylaxis.
prophylaxis.
Muscle or [‡]
50 IU/kg factor VIII concentrate; 20 IU/kg every- 80 IU/kg factor IX concentrate ;
significant
other-day treatment may be needed until treatment every 2-3 days may be
subcutaneous
resolved. needed until resolved.
hematoma
[‡]
Mouth, deciduous 40 IU/kg factor IX concentrate ;
20 IU/kg factor VIII concentrate; antifibrinolytic [?]
tooth, or tooth antifibrinolytic therapy ; remove
therapy; remove loose deciduous tooth.
extraction loose deciduous tooth.
Apply pressure for 15-20 min; pack with Apply pressure for 15-20 min; pack
178
petrolatum gauze; give antifibrinolytic therapy; 20 with petrolatum gauze; antifibrinolytic
Epistaxis
IU/kg factor VIII concentrate if this treatment therapy; 30 IU/kg factor IX
[‖] [‡]
fails. concentrate if this treatment fails.
[‡]
Major surgery, life- 50-75 IU/kg factor VIII concentrate, then initiate 120 IU/kg factor IX concentrate , then

TYPE OF
HEMOPHILIA A HEMOPHILIA B
HEMORRHAGE
threatening continuous infusion of 2-4 IU/kg/hr to maintain 50-60 IU/kg every 12-24 hr to maintain
hemorrhage factor VIII >100 IU/dL for 24 hr‘ then give 2-3 factor IX at >40 IU/dL for 5-7 days, and
IU/kg/hr continuously for 5-7 days to maintain the then at >30 IU/dL for 7 days.
level at >50 IU/dL and an additional 5-7 days to
[?]
maintain the level at >30 IU/dL.
[‡]
120 IU/kg factor IX concentrate ; then
50-60 IU/kg every 12-24 hr to maintain
50 IU/kg factor VIII concentrate, then 25 IU/kg
Iliopsoas factor IX at >40 IU/dL until patient is
every 12 hr until asymptomatic, then 20 IU/kg
hemorrhage asymptomatic; then 40-50 IU every
every other day for a total of 10-14 days.**
other day for a total of 10-14
[††]
days.**
Bed rest; maintenance fluids; if not
Bed rest; maintenance fluids; if not controlled in
controlled in 1-2 days, 40 IU/kg factor
1-2 days, 20 IU/kg factor VIII concentrate; if not [‡]
Hematuria IX concentrate ; if not controlled, give
controlled, give prednisone (unless patient is HIV-
prednisone (unless patient is HIV-
infected).
infected).
[‡]
30-50 IU/kg factor IX concentrate
20-40 IU/kg factor VIII concentrate every other
Prophylaxis every 2-3 days to achieve a trough
day to achieve a trough level ≥1%.
level ≥1%.
 With the availability of recombinant replacement products, prophylaxis is the standard of care for most
children with severe hemophilia, to prevent spontaneous bleeding and early joint deformities.
 If target joints develop, “secondary” prophylaxis is often initiated.
 With mild factor VIII hemophilia, the patient's endogenously produced factor VIII can be released by
the administration of desmopressin acetate (DDAVP).
 In patients with moderate or severe factor VIII deficiency, the stored levels of factor VIII in the body
are inadequate, and desmopressin treatment is ineffective. The risk of exposing the patient with mild
hemophilia to transfusion-transmitted diseases and the cost of recombinant products warrant the use of
desmopressin, if it is effective.
 A concentrated intranasal form of desmopressin acetate, not the enuresis or pituitary replacement dose,
can also be used to treat patients with mild hemophilia A. The dose is 150 ug (1 puff) for children
weighing <50 kg and 300 ug (2 puffs) for children and young adults weighing >50 kg.
 Most centers administer a trial of desmopressin to determine the level of factor VIII achieved after its
infusion.
 Desmopressin is not effective in the treatment of factor IX–deficient hemophilia.
PROPHYLAXIS
 Many patients are now given lifelong prophylaxis to prevent spontaneous joint bleeding.
 The National Hemophilia Foundation recommends that prophylaxis be considered optimal therapy for
children with severe hemophilia.
 Usually, such programs are initiated with the first joint hemorrhage.
 Young children often require the insertion of a central catheter to ensure venous access. Such programs
179
are expensive but are highly effective in preventing or greatly limiting the degree of joint pathology.
 Treatment is usually provided every 2-3 days to maintain a measurable plasma level of clotting factor
(1-2%) when assayed just before the next infusion (trough level).

 Whether prophylaxis should be continued into adulthood has not yet been adequately studied. If
moderate arthropathy develops, prevention of future bleeding will require higher plasma levels of
clotting factors.
 In the older child who is not given primary prophylaxis, secondary prophylaxis is frequently initiated if
a target joint develops.
SUPPORTIVE CARE
 should avoid trauma.

 Effective measures include anticipatory guidance, including the use of car seats, seatbelts, and bike
helmets.
 Older boys should be counseled to avoid violent contact sports, but this issue is a challenge.
 Boys with severe hemophilia often sustain hemorrhages in the absence of known trauma.
 Patients with hemophilia should avoid aspirin and other nonsteroidal anti-inflammatory drugs that
affect platelet function.
 The child with a bleeding disorder should receive the appropriate vaccinations against hepatitis B, even
though recombinant products may avoid exposure to transfusion-transmitted diseases.
 Patients exposed to plasma-derived products should be screened periodically for hepatitis B and C,
HIV, and abnormalities in liver function.
CHRONIC COMPLICATIONS
 Chronic arthropathy.
 Development of an inhibitor to either factor VIII or factor IX.
 Risk of transfusion-transmitted infectious diseases.
Chronic arthropathy has been the major long-term disability associated with hemophilia. The natural
history of untreated hemophilia is one of cyclic recurrent hemorrhages into specific joints, including
hemorrhages into the same (target) joint.
In the older patient with advanced arthropathy, bleeding into the target joint, with its thickened
synovium, causes severe pain, because the joint may have little space to accommodate blood.
Once a target joint is seen to be developing, the patient is usually given short-or long-term
prophylaxis to prevent progression of the arthropathy and reduce inflammation.
Inhibitor Formation
Infusion of the deficient clotting factor may initiate an immune response in patients with either
factor VIII or factor IX deficiency. Inhibitors are antibodies directed against factor VIII or factor IX
that block the clotting activity.
Failure of a bleeding episode to respond to appropriate replacement therapy is usually the first
sign of an inhibitor.
180
Inhibitors develop in approximately 25-35% of patients with hemophilia A; the percentage is
somewhat lower in patients with hemophilia B, many of whom make an inactive dysfunctional
protein that renders them less susceptible to an immune response.

Highly purified factor IX or recombinant factor IX seems to increase the frequency of inhibitor
develope.
low inhibitor lose it with continued regular infusions.
higher titer of antibody with subsequent infusions and may need to go through desensitization
programs/immune tolerant programme in which high doses of factor VIII for hemophilia A or
factor IX for hemophilia B are infused in an attempt to saturate the antibody and permit the body
to develop tolerance.
 Factor IX immune tolerance programs have resulted in nephrotic syndrome in some patients.
Rituximab has been used, off label (i.e., in a use not approved by the U.S. Food and Drug
Administration [FDA]), as an alternate therapy for patients with high inhibitor titers in whom
immune tolerance programs have failed.
If desensitization fails, bleeding episodes are treated with either recombinant factor VIIa or
activated prothrombin complex concentratesThe use of these products bypasses the inhibitor in
many instances but may increase the risk of thrombosis.
Very important  Patients with inhibitors require referral to a center that cares for many such
patients and has a comprehensive hemophilia program.
COMPREHENSIVE CARE
Today, patients with hemophilia are best managed through comprehensive hemophilia care centers.
Such centers are dedicated to patient and family education as well as to the prevention and/or
treatment of the complications of hemophilia, including chronic joint disease and inhibitor
development as well as infection, such as hepatitis B and C or HIV. Such centers involve a team of
physicians, nurses, orthopedists, physical therapists, and psychosocial workers, among others.
MANAGEMENT OF MUSCULOSKELETAL BLEED:
AS MY PT HAVE HEMOPHILIC ARTHROPATHY MY GOALS WILL BE TO MAINTAIN NORMAL

FUNCTION AND TO PREVENT DEFORMITY AND CONTRACTURE BY ADVISING REGULAR
PHYSIOTHERAPY AND FACTOR PROPHYLAXIS , PREVET RECURRENCE , AND PROVIDE ANELGESIA.
RICE –(REST, IMMOBLIZATION ,ICE, COMPRESSION , ELEVATION)
ANELGESIA  HEMARTHROSIS IS VERY PAINFUL SO WE DO IMMOBLIZE BY SPLINTS, ANELGESIA BY

PARACETAMOL AND AVOID ASPIRIN/NARCOTICS, FACTOR REPLACEMENT , IF SEVERE PAIN THEN
JOINT ASPIRATION WITH FACTOR COVER MAY BE NEEDED TO RELIEVE PAIN.
181
PREVENTION OF IATROGENIC PROBLEMS:
Apply pressure for 10 min after any injection.

Immunization by small guage needles + deep s/c injections and NO I.M injections & during this no
factor replacement required.
If undergoing for L.P then raise level of deficient factor to 50% , 30 minutes before procedure.
CHRONIC PROBLEMS :
 ARTHROPATHY
 NEUROLOGIX SEQUELE –50% MORBIDITY –(seizures, motor and cognitive impairment), AND
50% MORTALITY.
Joint  arthritis  inflammation  erosion of cartilage /bone  chronic synovitis  hypertrophic

synovium  destruction of cartilage and narrow joint space and bone resorption /cyst formation 
anatomical joint instability + chronic pain + disuse = osteoporosis.:
RADIOLOGIC STAGES OF HEMPHILIC ARTHROPATHY:
STAGE 1: Soft tissue swelling due to hemorage in joint.
STAGE 2: Overgrowth of epiphysis.
STAGE 3: joint disorganized.
STAGE 4: narrow joint space + cartilage destroyed.
STAGE 5: fibrous contracture, loss of joint space , loss of joint.
Diagnosis: MRI best to assess early changes and synovial hypertrophy.
Optimal Rx:
Prevetion of hemarthrosis by:
(1): prophylaxis which ideally should start at 1-3 yr of age by keeping factor level >1%. Which
decreases no. of bleeds per year.
Oral steroids (1-4 weeks) in case of severe synovitis.
NSAIDs –ibuprofen –but can lead to increase bleeding in some cases.
New COX-2 Inhibitors.
Surgery :
 Synovectomy (remove synovium)—

o Arthroscopic (preffered)
o Open
o Isotopic/chemical—(IA injections of chemical).
182
Complications of surgery:
o Re-bleed.
o Long rehab
o Potential requirement of joint replacement.

PROPHYLAXIS:
1. PRIMARY
2. SECONDARY
3. FULL DOSE
4. PARTIAL DOSE
PRIMARY:
 Starting before any joint bleed/ or after 1st joint bleed.

 <2 yr usually around 12 month.
 It is long term 52 weeks/yr.
 Recombinant F-8 – 3 times/week. 25-40 units/kg ( earlier it will start less chance to bleed later).
Advantages:
1. Prevent hemarthrosis
2. Chronic joint disease.
3. Pain.
Disadvantage:
1. Port in young children

2. Increase injections
3. Early inhibitor
4. Cost
5. Poor compliance
It doesn’t prevent all bleeds
Need to continue till 18 yr of age/ life long.
SECONDARY:
o Specified period of regular transfusion of F-8 after joint bleed has been established.
o Used for particular event like surgery, sternous exercise/Activity.
FULL DOSE:
o F-8 2-3 times/week

o >46 wks/yr.
PARTIAL DOSE:
o 3-45 wks/yr
CVAD/PORT
o No lower age limit 183

o For insertion hospitalize child 1-3 days before
o Complications:
o Infection –Rx once infection –sterlization/antibiotics. If >2 time then change.
o Thrombosis -50% by 4 yr.

ELECTIVE SURGERY PROPHYLAXIS:
100% Level required for all procedures.
Pre-op dose : 50 units/kg then 3 units /kg/ hr continous infusion during surgery.
Note: F-8 is stable for only 24 hr after reconstitution and it is adherent to plastic bags so we use
syringe.
FOR KNEE REPLACEMENT:
 Maintain 100%.
 80% (48 hr)
 60% (next 4-5 days).
 10% (rehab)
INHIBITORS:
o 20-30% of Hemophilia A
 35-50% low responders (low level antibody)
 50-65% high responders.
o 1-4% of hemophilia B.
LOW RESPONDERS: May benefit infusions at greater dose / more frequent infusions.
HIGH RESPONDERS: will not benefit from standard clotting factor concentrate so they need :
Factor VII-a 90-120 ug/kg every 2 hourly until bleeding stops or for at least 24 hr for major surgery.
IMMUNE TOLERANCE THERAPY :
 Recurrent exposure of factor-8,9 –Eradicate inhibitor by manipulating immune system.

 Plasma derived F-8 40 units/kg/3 times/week.
If pt fail to ITT then:
 Rituximab, Steroids, Cyclophosphamide, IVIG, plasmapharesis, protein A adsorption.
PATIENT UNDERGOING FOR DENTAL EXTRACTION THEN:
 Tranexamic acid : start 4 hr before surgery with dose of 15-25 mg/kg 8 hourly and continue for 5-10
days.
 Factor 8 replacement = 1 hr Before surgery (30-60% is target).
GENETIC COUNCELLING :
 DNA Analysis : Detect abnormal gene on chromosome

 CARRIER DETECTION 184
 CVS –9 weeks –A/N detection. – 1% risk of abortion.
PROGRESS :

 Cure seen in pt of liver transplantation
 Recent advance ;Gene therapy.
CORTICOSTEROIDS ARE GIVEN FOR HEMATUREA AND JOINT BLEEDS  1-4 WEEKS . ALONG WITH
FACTOR REPLACEMENT.
 FFP 1ml = 2%.

 10 ml/kg =20%.
 50 ml/kg =100%.
Factor supplement given according to severity
 Mild – 1-2 / may not be needed –desmopressin effective in A type and tranexamic acid helpful.
 Moderate: 3-6 doses needed.
 Severe: upto 12
 ICH = upto 15 .
What to do when major surgery planned ?
 Maintain 100% factor activity before surgery.

 Next 4 day 60%.
 Upto sutures – 20-40%
------------------------------------------------------------------------
 Bleeding disorders—superfiical mucosal bleeds

 Clotting disoreders –deep bleed
 Can this be ITP?
 Present with peteche, but since neonatal life they don’t.
 Why not platelete function disorder?
 They present early so but their bleeding doesn’t stop without platelete transfusion.
 Hemophilia 90% present within 1st year of life.
 Target joint we say when >2 time bleed at same joint
 Normal B.T is 3-4 min
 In case of hemophilia if FFP Rx doesn’t give response then it mean diagnosis is wrong or inhibitor is
formed.
RECENT ADVANCES OF HEMOPHILIA
 GENE THERAPY
 LIVER TRANSPLANTION
 Long acting factor VIII which may remain in body for 1 ½ yr –pipe line study.
FACTOR XI DEFICIENCY (HEMOPHILIA C)
 Factor XI deficiency is an autosomal deficiency associated with mild to moderate bleeding symptoms.
 The bleeding tendency is not as severe as in factor VIII or factor IX deficiency. 185
 The bleeding associated with factor XI deficiency is not correlated with the amount of factor XI.
 Some patients with severe deficiency may have minimal or no symptoms at the time of major surgery.
No approved concentrate of factor XI is available in the USA; therefore, the physician must use fresh
frozen plasma (FFP).

 Bleeding during minor surgery can be controlled with local pressure.
 Patients undergoing dental extractions can be monitored closely and may benefit from treatment with
fibrinolytic inhibitors like aminocaproic acid, with plasma replacement therapy used only if
hemorrhage occurs.
 In a patient with homozygous deficiency of factor XI, PTT is often longer than it is in patients with
either severe factor VIII or factor IX deficiency.
Diagnosis : factor level.
Treatment:
 Plasma infusions of 1 IU/kg usually increase the plasma concentration by 2%. Thus, infusion of plasma
at 10-15 mL/kg will result in a plasma level of 20-30%, which is usually sufficient to control moderate
hemorrhage. Frequent infusions of plasma would be necessary to achieve higher levels of factor XI.
Because the half-life of factor XI is usually ≥48 hr, maintaining adequate levels of factor XI commonly
is not difficult.
 Chronic joint bleeding is rarely a problem in factor XI deficiency, and for most patients, the deficiency
is a concern only at the time of major surgery unless there is a second underlying hemostatic defect
(e.g., von Willebrand disease).
DEFICIENCIES OF THE CONTACT FACTORS (NONBLEEDING DISORDERS)
 Prolong APTT
 No bleeding.
 Deficiency of the “contact factors” (factor XII, prekallikrein, and high molecular weight kininogen)
causes prolonged PTT but no bleeding symptoms.
 It is important that individuals with these findings be well informed about the meaning of their clotting
factor deficiency because they do not need treatment, even for major surgery.
FACTOR VII DEFICIENCY
 Factor VII deficiency is a rare autosomal bleeding disorder usually detected only in the homozygous
state.
 Severity of bleeding varies from mild to severe with hemarthroses, spontaneous intracranial
hemorrhage, and mucocutaneous bleeding, especially nosebleeds and menorrhagia.
DIAGNOSIS:
 Markedly prolonged PT but normal PTT. 186

 Factor VII assays show a marked reduction in factor VII.
TREATMENT:

 Concentrate of recombinant factor VIIa has been shown in case reports to be effective in treating some
patients with factor VII deficiency, but this concentrate has not been approved by the FDA for this
indication.
 Because the plasma half-life of factor VII is 2-4 hr, therapy with FFP is difficult and is often
complicated by fluid overload.
FACTOR X DEFICIENCY –(half-life =30 hr)
 Factor X deficiency is a rare autosomal disorder with variable severity.

 Mild deficiency results in mucocutaneous and post-traumatic bleeding.
 severe deficiency results in spontaneous hemarthroses and intracranial hemorrhages.
 Factor X deficiency is the result of either a quantitative deficiency or a dysfunctional molecule.
 DIAGNOSIS: prolongation of both PT and PTT. + Factor level.
 Rx –FFP/Recombinant factor viia.
 Association –amyloidosis.
PROTHROMBIN (FACTOR II) DEFICIENCY
Prothrombin deficiency is caused either by a markedly reduced prothrombin level

(hypoprothrombinemia)
(dysprothrombinemia) functionally abnormal prothrombin.
LABORATORY : shows prolonged PT and PTT. Factor II, or prothrombin, assays show a markedly
reduced prothrombin level.
Mucocutaneous bleeding in infancy and post-traumatic bleeding later are common.
Rx  with either FFP or, rarely, prothrombin complex concentrates. In prothrombin deficiency, FFP
is useful, because the half-life of prothrombin is 3.5 days. Administration of 1 IU/kg of prothrombin
will increase the plasma activity by 1%.
FACTOR V DEFICIENCY
 autosomal recessive.
 mild to moderate bleeding disorder that has also been termed parahemophilia.
 Hemarthroses occur rarely; mucocutaneous bleeding and hematomas are the most common symptoms.
Severe menorrhagia is a frequent symptom in women.
LABORATORY :
 Prolonged PTT and PT.

 Specific assays for factor V show a reduction in factor V levels. 187
Rx FFP is the only currently available therapeutic product that contains factor V.
 Factor V is lost rapidly from stored FFP.

 Patients with severe factor V deficiency are treated with infusions of FFP at 10 mL/kg every 12 hr.
FIBRINOGEN (FACTOR I) DEFICIENCY
 Congenital afibrinogenemia is a rare autosomal recessive disorder in which there is an absence of

fibrinogen.
 Patients with this disorder do not bleed as frequently as patients with hemophilia and rarely have
hemarthroses.
 Affected patients may present in the neonatal period with gastrointestinal hemorrhage or hematomas
after vaginal delivery.
 prolongation of PT and PTT, thrombin time is prolonged. In the absence of consumptive
coagulopathy, an unmeasurable fibrinogen level is diagnostic. In addition to the quantitative
deficiency of fibrinogen, a number of dysfunctional fibrinogens have been reported
 (dysfibrinogenemia). Rarely patients with dysfibrinogenemia present with thrombosis.
 Rx
 Currently, no fibrinogen concentrates are commercially available—(Because the plasma half-life of
fibrinogen is 2-4 days, treatment with either FFP or cryoprecipitate is effective).
 The hemostatic level of fibrinogen is >60 mg/dL. Each bag of cryoprecipitate contains 100-150 mg of
fibrinogen.
 Some clinical assays for fibrinogen are inhibited by high doses of heparin. Thus, a markedly prolonged
thrombin time associated with a low fibrinogen level should be evaluated with determination of
reptilase time. Prolonged reptilase time confirms that functional levels of fibrinogen are low and that
heparin is not present.
FACTOR XIII DEFICIENCY (FIBRIN-STABILIZING FACTOR OR TRANSGLUTAMINASE

DEFICIENCY)
 Because factor XIII is responsible for the cross linking of fibrin to stabilize the fibrin clot, symptoms of
delayed hemorrhage are secondary to instability of the clot.
C/F 
 Typically, patients have trauma 1 day and then have a bruise or hematoma the next day. Clinical
symptoms include mild bruising, delayed separation of the umbilical stump beyond 4 wk in neonates,
poor wound healing, and recurrent spontaneous abortions in women.
 Rare kindreds with XIII deficiency with hemarthroses and intracranial hemorrhage have been
described. Results of the usual screening tests for hemostasis are normal in patients with factor XIII
deficiency.
DIAGNOSIS:
 Screening tests for factor XIII deficiency are based on the observation that there is increased
solubility of the clot because of the failure of cross linking. The normal clot remains insoluble in
the presence of 5M urea, whereas in a patient with XIII deficiency, the clot dissolves. More
specific assays for factor XIII are immunologic.
Rx
o Because the half-life of factor XIII is 5-7 days and the hemostatic level is 2-3% activity, 188
infusion of FFP or cryoprecipitate will correct the deficiency in patients with factor XIII
deficiency. Plasma contains 1 IU/dL, and cryoprecipitate contains 75 IU/bag. In patients with
significant bleeding symptoms, prophylaxis can be achieved with infusion of cryoprecipitate
every 3-4 wk.

ANTIPLASMIN OR PLASMINOGEN ACTIVATOR INHIBITOR DEFICIENCY
 Deficiency of either antiplasmin or plasminogen activator inhibitor, both of which are antifibrinolytic
proteins, results in increased plasmin generation and premature lysis of fibrin clots.
 C/F Affected patients have a mild bleeding disorder characterized by mucocutaneous bleeding but
rarely have joint hemorrhages.
 DIAGNOSIS
 results of the usual hemostatic tests are normal further work-up of a patient with a positive bleeding
history should include  euglobulin clot lysis time (if available), which measures fibrinolytic activity
and yields a shortened result in the presence of these deficiencies.
 Specific assays for α2-antiplasmin and plasminogen activator inhibitor are available.
 Rx  FFP; bleeding in the oral cavity may respond to aminocaproic acid.
189

ITP ----------------------------------------------------------------------------------------------LONG CASE/SHORT CASE.
The most common cause of acute onset of thrombocytopenia in an otherwise well child is
(autoimmune) idiopathic thrombocytopenic purpura (ITP).
 In a small number of children, estimated about 1 in 20,000.

 1-4 wk after exposure to a common viral infection autoantibody directed against the platelet surface
develops with resultant sudden onset of thrombocytopenia.
 A recent history of viral illness is described in 50-65% of cases of childhood ITP.
 The peak age is 1-4 yr, although the age ranges from early in infancy to the elderly.
 In childhood, males and females are equally affected.
 ITP seems to occur more often in late winter and spring after the peak season of viral respiratory
illness.
PATHOGENESIS
 unknown.
 The exact antigenic target for most such antibodies in most cases of childhood acute ITP remains
undetermined.
 In chronic ITP most  antibodies against the platelet glycoprotein complexes, α11b-B3 and GPIb.
 After binding of the antibody to the platelet surface circulating antibody-coated platelets are
recognized by the Fc receptor on splenic macrophages ingested  destroyed.
Most common viruses :
 Epstein-Barr virus and HIV.

 measles, mumps, rubella vaccine
 h.pylori
Epstein-Barr virus-related ITP usually of short duration and follows the course of infectious
mononucleosis.
HIV-associated ITP is usually chronic.
 The classic presentation of ITP is a previously healthy 1-4 yr old child who has sudden onset of
generalized petechiae and purpura.
 bleeding from the gums and mucous membranes, particularly with profound thrombocytopenia
(platelet count <10 109/L).
 There is a history of a preceding viral infection 1-4 wk before the onset of thrombocytopenia.
 physical examination normal, other than the finding of petechiae and purpura.
 Splenomegaly, lymphadenopathy, bone pain, and pallor are rare.
190
classification system has been proposed from the U.K. to characterize the severity of bleeding in
ITP on the basis of symptoms and signs, but not platelet count:

1 No symptoms
2 Mild symptoms: bruising and petechiae, occasional minor epistaxis, very little interference with daily
living
3 Moderate: more severe skin and mucosal lesions, more troublesome epistaxis and menorrhagia
4 Severe: bleeding episodes—menorrhagia, epistaxis, melena—requiring transfusion or hospitalization,

symptoms interfering seriously with the quality of life
 The presence of abnormal findings such as hepatosplenomegaly, bone or joint pain, or remarkable
lymphadenopathy suggests other diagnoses (leukemia).
 When the onset is insidious, especially in an adolescent, chronic ITP or the possibility of a systemic
illness, such as systemic lupus erythematosus (SLE), is more likely.
OUTCOME
 Severe bleeding is rare (<3% of cases in 1 large international study).

 < 1% of patients develop an intracranial hemorrhage
 In 70-80% of children who present with acute ITP, spontaneous resolution occurs within 6 mo.
 Therapy does not appear to affect the natural history of the illness.
 There is no evidence that therapy prevents serious bleeding.
 Approximately 20% of children who present with acute ITP go on to have chronic ITP.
 The outcome/prognosis may be related more to age, as ITP in younger children is more likely to
resolve whereas the development of chronic ITP in adolescents approaches 50%.
LABORATORY FINDINGS
 CBC for Hb, differentials , platelets and p.smear.
 ANTI-PLATELETE ANTIBODY TEST –(ACUTE)
 ANA—(SLE)
 H.PYLORI
 COOMBS TEST –(OEVAN SYNDROME)
 BMA
 Severe thrombocytopenia (platelet count <20  is common, and platelet size is normal or increased
 reflective of increased platelet turnover .
 In acute ITP, the hemoglobin value, white blood cell (WBC) count, and differential count should be
normal.
 Hemoglobin may be decreased if there have been profuse nosebleeds or menorrhagia.
 Bone marrow examination shows normal granulocytic and erythrocytic series, with
characteristically normal or increased numbers of megakaryocytes.
Indications for bone marrow aspiration/biopsy:
o Abnormal WBC count or differential or unexplained anemia as well as findings on history and
physical examination suggestive of a bone marrow failure syndrome or malignancy.
Platelet antibody testing is seldom useful in acute ITP. 191

A direct antiglobulin test (Coombs) should be done if there is unexplained anemia to rule out Evans
syndrome (autoimmune hemolytic anemia and thrombocytopenia) or before instituting therapy with
IV anti-D.
DIAGNOSIS/DIFFERENTIAL DIAGNOSIS
 APLASTIC ANEMIA MAY BE ACQUIRED/ CONGENTIAL-fanconi

 DRUG INDUCED THROMBOCYTOPENIA
 TAR
IF WITH SPLEEN ;
 HYPERSPLENISM.
 PVT
Autoimmune thrombocytopenia may be an initial manifestation of SLE, HIV infection, common

variable immunodeficiency, or rarely lymphoma.
Wiskott-Aldrich syndrome must be considered in young males found to have thrombocytopenia

with small platelets, particularly if there is a history of eczema and recurrent infection.
TREATMENT
There are no data showing that treatment affects either short- or long-term clinical outcome of ITP.
Many patients with new-onset ITP have mild symptoms with findings limited to petechiae and
purpura on the skin, despite severe thrombocytopenia.
treatment appears to be capable of inducing a more rapid rise in platelet count to the theoretically
safe level of >20 × 109/L, although there are no data indicating that early therapy prevents
intracranial hemorrhage.
Antiplatelet antibodies bind to transfused platelets as well as they do to autologous platelets

Thus, platelet transfusion in ITP is usually contraindicated unless life-threatening bleeding is present.
Initial approaches to the management of ITP include the following:
1 No therapy other than education and counseling of the family and patient for patients with
minimal, mild, and moderate symptoms, as defined earlier. This approach emphasizes the
usually benign nature of ITP and avoids the therapeutic roller coaster that ensues once
interventional therapy is begun. This approach is far less costly, and side effects are minimal.
2 Intravenous immunoglobulin (IVIG). IVIG at a dose of 0.8-1.0 g/kg/day for 1-2 days induces a
rapid rise in platelet count (usually >20 ×109/L) in 95% of patients within 48 hr IVIG appears 192
to induce a response by downregulating Fc-mediated phagocytosis of antibody-coated
platelets. IVIG therapy is both expensive and time-consuming to administer. Additionally,
after infusion, there is a high frequency of headaches and vomiting, suggestive of IVIG-induced
aseptic meningitis.

3 Intravenous anti-D therapy.
 For Rh positive patients.

 IV anti-D at a dose of 50-75 ug/kg causes a rise in platelet count to >20 × 10 9/L in 80-90% of
patients within 48-72 hr.
 When given to Rh positive individuals, IV anti-D induces mild hemolytic anemia.
 RBC-antibody complexes bind to macrophage Fc receptors and interfere with platelet
destruction thereby causing a rise in platelet count.
 IV anti-D is ineffective in Rh negative patients.
 Rare life-threatening episodes of intravascular hemolysis have occurred in children and adults
following infusion of IV anti-D.
4 PREDNISONE:
 acute and chronic ITP in adults and children.

 Doses of prednisone of 1-4 mg/kg/24 hr appear to induce a more rapid rise in platelet count than
in untreated patients with ITP.
 Whether bone marrow examination should be performed to rule out other causes of
thrombocytopenia, especially acute lymphoblastic leukemia, before institution of prednisone
therapy in acute ITP is controversial.
 continued for 2-3 wk or until a rise in platelet count to >20 × 109/L has been achieved, with a
rapid taper to avoid the long-term side effects.
Each of these medications may be used to treat ITP exacerbations, which commonly occur several
weeks after an initial course of therapy.
In case of intracranial hemorrhage, multiple modalities should be used, including platelet

transfusion, IVIG, high-dose corticosteroids, and prompt consultation by neurosurgery and
surgery.
Splenectomy in ITP should be reserved for 1 of 2 circumstances.
1. older child (≥4 yr) with severe ITP that has lasted >1 yr (chronic ITP) and whose symptoms are
not easily controlled with therapy is a candidate for splenectomy.
2. must also be considered when life-threatening hemorrhage (intracranial hemorrhage) complicates
acute ITP, if the platelet count cannot be corrected rapidly with transfusion of platelets and
administration of IVIG and corticosteroids.
CHRONIC IDIOPATHIC THROMBOCYTOPENIC PURPURA
20% of patients who present with acute ITP have persistent thrombocytopenia for >12 mo and are
said to have chronic ITP.
At that time, a careful re-evaluation for associated disorders should be performed, especially for
autoimmune disease, such as SLE; chronic infectious disorders, such as HIV; and nonimmune
causes of chronic thrombocytopenia, such as type 2B and platelet-type von Willebrand disease, 193
X-linked thrombocytopenia, autoimmune lymphoproliferative syndrome, common variable
immunodeficiency syndrome, autosomal macrothrombocytopenia, and WAS (also X-linked). The
presence of co-existing H. pylori infection should be explored and, if found, treated.

Rx
Supportive
Specific:
 IVIG, corticosteroids, IV anti-D. Rituximab, a chimeric monoclonal anti–B cell antibody, effectively
induces a remission in 30-50% of children with chronic ITP
 Splenectomy is successful in inducing complete remission in 64-88% of children with chronic
ITP. This effect must be balanced against the lifelong risk of overwhelming postsplenectomy
infection. This decision is often affected by lifestyle issues as well as the ease with which the child
can be managed using medical therapy, such as IVIG, corticosteroids, IV anti-D. Rituximab, a
chimeric monoclonal anti–B cell antibody, effectively induces a remission in 30-50% of children
with chronic ITP. Two new effective agents that act to stimulate thrombopoiesis, romiplastin and
eltrombopag have been approved by the Federal Drug Administration to treat adults with
chronic ITP. There are no data regarding either drug's safety or efficacy in children.
194

APLASTIC ANEMIA --------------------------------------------------------------------------------------------LONG CASE
THE ACQUIRED PANCYTOPENIAS
 Drugs, chemicals, toxins, infectious agents, radiation, and immune disorders can
result in pancytopenia A careful history of exposure to known risk factors should be
obtained for every child presenting with pancytopenia.
 Even in the absence of the classic associated physical findings, the possibility of a
genetic predisposition to bone marrow failure should always be considered .
 The majority of cases of acquired marrow failure in childhood are “idiopathic,”
 These are probably immune-mediated through activated T lymphocytes and cytokine
destruction of marrow progenitor cells.
 The overall incidence of acquired aplastic anemia is relatively low, with an
approximate incidence in both children and adults in the USA and Europe of 2-6
cases/million/yr.
 The incidence is higher in Asia, with as many as 14 cases/million/yr in Japan.
ETIOLOGY OF ACQUIRED APLASTIC ANEMIA
Radiation drugs and chemicals:
Predictable: chemotherapy, benzene, INSECTICIDES.
Idiosyncratic: chloramphenicol, antiepileptics, gold; 3,4-

methylenedioxymethamphetamine
Viruses:
 Cytomegalovirus
 Epstein-barr
 Hepatitis b
 Hepatitis c
 Hepatitis non-A, non-B, non-C (seronegative hepatitis)
 HIV
Immune diseases:
Eosinophilic fasciitis
Hypoimmunoglobulinemia
Thymoma
195
Pregnancy

Paroxysmal nocturnal hemoglobinuria
Marrow replacement:
Leukemia
Myelodysplasia
Myelofibrosis
Autoimmune
Other:
Cryptic dyskeratosis congenita (no physical stigmata)
 A number of viruses can either directly or indirectly result in bone marrow failure.
 Parvovirus B19 is classically associated with isolated red blood cell (RBC) aplasia,
but in patients with sickle cell disease or immunodeficiency, it can result in transient
pancytopenia.
 Prolonged pancytopenia can occur after infection with many of the hepatitis
viruses, herpes viruses, Epstein-Barr virus, cytomegalovirus, and HIV .
 Patients with evidence of bone marrow failure should also be evaluated for
paroxysmal nocturnal hemoglobinuria, and collagen vascular diseases, although
these are uncommon causes of pancytopenia in childhood.
 Pancytopenia without peripheral blasts may be caused by bone marrow replacement
by leukemic blasts or neuroblastoma cells.
PATHOLOGY AND PATHOGENESIS
The hallmark of aplastic anemia is peripheral pancytopenia, coupled with hypoplastic or

aplastic bone marrow.
Severe aplastic anemia is defined as a condition in which 2 or more cell components have
become seriously compromised (absolute neutrophil count [ANC] <500/mm 3, platelet count
<20,000/mm3, reticulocyte count <1% after correction for hematocrit) in a patient whose
bone marrow biopsy material is moderately or severely hypocellular.
Moderate aplastic anemia (65%) (ANC 500-1,500/mm3, platelet count 20,000-

196
100,000/mm3, reticulocyte count <1%)

Bone marrow failure may be a consequence of a direct cytotoxic effect on hematopoietic
stem cells from a drug or chemical or may result from either cell-mediated or antibody-
dependent cytotoxicity.
There is strong evidence that many cases of idiopathic aplastic anemia are caused by an
immune-mediated process, with increased circulating activated T lymphocytes producing
cytokines (interferon-γ) that suppress hematopoiesis.
Abnormal telomere length and telomerase activity in granulocytic precursors in patients with
aplastic anemia suggest that early apoptosis of hematopoietic progenitors may play a role in
the pathogenesis of this disease.
CLINICAL MANIFESTATIONS, LABORATORY FINDINGS, AND DIFFERENTIAL DIAGNOSIS
 Petechae, bruises, bleed

 Infections-any
 No liver/spleen
INVESTIGATIONS
 CBC –differentials, P.S, retix, atypical cells.

 BMA + Bx –microscopy, Cytogenic, immunohenotyping,flow cytometry.
 Chromosome breakage study—Fanconi.
 Erthyrocyte for CD55 And CD 59 –PNH
 Other is baseline + according to symptoms.
D/D
 ITP/ACUTE/CHRONIC.
 EARLY STAGE ACUTE LEUKEMIA
TREATMENT
 GENERAL MEASURES: infection control/transfusions/barriernursing +
hygiene care.
 SPECIFIC MEASURES:
For patients without a sibling donor
 the major form of therapy is immunosuppression with antithymocyte globulin (ATG)

and cyclosporine, with a response rate of 60-80%.
 The median time to response is 6 mo.

 As many as 25-30% of “responders” experience relapse after discontinuation of
immunosuppression, and some patients must continue cyclosporine for several years
to maintain a hematologic response.
197
 Among those who have relapse after immunosuppression, about 50% show response
to a second course of ATG and cyclosporine.

 To accelerate neutrophil recovery, a hematopoietic colony-stimulating factor (e.g.,
granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating
factor) is sometimes added to ATG and cyclosporine for treatment of patients with
very severe neutropenia (absolute neutrophil count <200/mm3)
 In a few cases, tacrolimus has been given successfully with ATG for treatment of
aplastic anemia in a patient unable to tolerate cyclosporine.
 High-dose cyclophosphamide has been used successfully in the treatment of patients
with newly diagnosed aplastic anemia and in patients without adequate response to
immunosuppression.
 For patients who show no response to immunosuppression or who experience relapse
after immunosuppression, matched unrelated donor marrow/stem cell transplant is a
treatment option, with a response rate approaching 80%
 Other therapies that have been used in the past with inconsistent results include
androgens, corticosteroids, and plasmapheresis.
 Disadvantage of ATG/CYCLO,: There is an increased risk of clonal bone marrow

disease in pts <10% especially among those with abnormal karyotype at 6,7,8. , such
as leukemia, myelodysplasia (MDS), or PNH after immunosuppression
 For patients with an HLA-identical sibling marrow donor, allogeneic bone
marrow transplantation (BMT) offers a 90% chance of long-term survival The
risks associated with this approach include the immediate complications of
transplantation, graft failure, and graft versus host disease. Late adverse effects
associated with transplantation may include secondary cancers, cataracts, short
stature, hypothyroidism, and gonadal dysfunction. Only 1 in 5 patients has an HLA-
matched sibling donor, so matched-related BMT is not an option for the majority of
patients.
Prognosis
Spontaneous recovery from pancytopenia rarely occurs.
If left untreated, severe pancytopenia has an overall mortality rate of approximately 50%
within 6 mo of diagnosis and of >75% overall, with infection and hemorrhage being the
major causes of morbidity and mortality.
The majority of children with acquired severe aplastic anemia show response to allogeneic
marrow transplantation or immunosuppression, leaving them with normal or near-normal
blood cell counts.
198

CHRONIC DIARRHEA -------------------------------------------------------------------LONG CASE
DISCUSSION:
Chronic diarrhea is defined as a diarrheal episode that lasts for ≥14 days.
Protracted diarrhea—Diarrhea that last> 14 days due to any infectious etiology.
Pathophysiology
Mechanisms of diarrhea:
Secretory and osmotic/ but often diarrhea is the result of both mechanisms.
Secretory diarrhea:
 large volumes of watery stool.

 persists when oral food is withdrawn
 stool osmolality is normal
 ion gap is <100 mosmols/kg.
active electrolyte and water fluxes toward the intestinal lumen resulting from either the
inhibition of neutral NaCl absorption in villous enterocytes or an increase in electrogenic
chloride secretion in secretory crypt cells due to the opening of the cystic fibrosis
transmembrane regulator (CFTR) chloride channel.
The other components of the enterocyte ion secretory machinery are the Na-K-2Cl
cotransporter for the electroneutral chloride entrance into the enterocyte
Osmotic diarrhea:
 Dependent on oral feeding diarrhea stops on response to fasting.

 Stool volumes are usually not as massive as in secretory diarrhea
 Normal to increase stool osmolality
 Ion gap >100 mosml/kg.
It is caused by nonabsorbed nutrients in the intestinal lumen due to one or more of the following
mechanisms:
1): intestinal damage (such as in enteric infection).
2): reduced functional absorptive surface (such as in celiac disease).
3): defective digestive enzyme or nutrient carrier (such as in lactase deficiency).
4): decreased intestinal transit time (such as in functional diarrhea).
5): nutrient overload exceeding the digestive capacity. 199
 Osmotic diarrhea occurs whenever digestion or absorption is impaired.

 Whatever the mechanism, the osmotic force generated by nonabsorbed solutes drives water into the
intestinal lumen.

 An example of osmotic diarrhea is lactose intolerance. Lactose  if not absorbed in the small
intestine, reaches the colon, where it is fermented to short-chain organic acids, generating an osmotic
overload that overwhelms the absorptive capacity.
 In many children, chronic diarrhea is induced by multiple mechanisms, intersecting each other and
often producing a vicious cycle.
ETIOLOGY :
INFECTIOUS AND NONINFECTIOUS CAUSES OF CHRONIC DIARRHEA

INFECTIOUS ETIOLOGIES
  Bacterial
  Viral and protozoan agents
  Small intestinal bacterial overgrowth
  Postenteritis syndrome
  Tropical sprue
  Whipple disease
ABNORMAL DIGESTIVE PROCESSES:
  Cystic fibrosis
  Shwachman-Diamond syndrome
  Isolated pancreatic enzyme deficiency
  Chronic pancreatitis
  Johanson-Blizzard syndrome
  Pearson syndrome
  Trypsinogen and enterokinase deficiency
  Chronic cholestasis
  Use of bile acids sequestrants
  Primary bile acid malabsorption
  Terminal ileum resection
NUTRIENT MALABSORPTION
  Congenital or acquired lactase deficiency
  Congenital or acquired sucrase-isomaltase deficiency
  Glucose-galactose malabsorption
  Fructose malabsorption
  Congenital or acquired short bowel
IMMUNE AND INFLAMMATORY
 Food allergy (cow's milk or soy proteins, others)
 Celiac disease
 Eosinophilic gastroenteritis
 Inflammatory bowel disease
 Autoimmune enteropathy
 IPEX syndrome
 Primary and secondary immunodeficiencies
STRUCTURAL DEFECTS 200
  Microvillus inclusion disease
  Tufting enteropathy
  Phenotypic diarrhea

  Lymphangiectasia
DEFECTS OF ELECTROLYTE AND METABOLITE TRANSPORT
Congenital chloride diarrhea
Congenital sodium diarrhea
Acrodermatitis enteropathica
Selective folate deficiency
Abetalipoproteinemia
MOTILITY DISORDERS
Hirschsprung disease
Chronic intestinal pseudo-obstruction (neurogenic and myopathic)
Thyrotoxicosis
NEOPLASTIC DISEASES
Neuroendocrine hormone-secreting tumors (APUDomas such as VIPoma)
Zollinger-Ellison
Mastocytosis
Pheochromocytoma
Lymphoma
CHRONIC NONSPECIFIC DIARRHEA
 Functional diarrhea
 Toddler's diarrhea
 Irritable bowel syndrome
Enteric infections:
 most common cause of chronic diarrhea in developing and industrialized countries.

 In developed countries chronic infectious diarrhea usually runs a benign course and the etiology is
often viral.
 Rotavirus and Norovirus are often involved, whereas cytomegalovirus and Clostridium difficile are
emerging agents of severe diarrhea in children.
 Entero-adherent Escherichia coli and Cryptosporidium parvum have been implicated in chronic
diarrhea in developing countries.
 Enteric cryptosporidiosis is the most common cause of severe and protracted diarrhea in AIDS, but
HIV may be directly responsible for diarrhea and for HIV enteropathy.
Small intestinal bacterial overgrowth:
Diarrhea may be the result of either a direct interaction between the microorganism and the
enterocyte or the consequence of the deconjugation and dehydroxylation of bile salts and the
hydroxylation of fatty acids due to an abnormal proliferation of bacteria in the proximal intestine .
201
Postenteritis syndrome:
condition in which small intestinal mucosal damage persists after acute gastroenteritis.

Sensitization to food antigens, secondary disaccharidase deficiency, or an infection or reinfection
with an enteric pathogen is responsible for postenteritis syndrome.
A change of the gut microflora due to the infectious agent and/or antibiotic therapy can contribute
to postenteritis diarrhea.
Celiac disease reduction of intestinal absorptive surface is responsible for diarrhea.
a permanent gluten intolerance that is sustained by a genetic basis affecting as many as 1/100
normal people, depending on geographic origin. Gliadin induces villous atrophy, leading to a
reduction of functional absorptive surface area that is reversible upon implementation of a strict
gluten-free diet
cow's milk protein Allergy:
cow milk and other foods can manifest with chronic diarrhea, especially during infancy.
Hx of atopy, wheezing chest and body swelling , pallor, blood stained stools ( streaks of blood)—
painful.
Eosinophilic gastroenteritis:
is characterized by eosinophilic infiltration of the intestinal wall and is strongly associated with
atopy.
In older children and adolescents:
inflammatory bowel disease including Crohn disease, ulcerative colitis, and indeterminate colitis,
are major causes of chronic diarrhea.
Liver disorders can lead to a reduction in the bile salts, resulting in fat malabsorption. Bile acid loss
may be associated with terminal ileum diseases, such as Crohn disease or disease following ileal
resection. In primary bile acid malabsorption neonates and young infants present with chronic
diarrhea and fat malabsorption due to mutations of ileal bile transporter.
Carbohydrate malabsorption and lactose intolerance:
 may be due to a molecular deficiency of lactase or sucrase-isomaltase, or to congenital glucose-

galactose malabsorption.
 Lactose intolerance is more commonly a consequence of secondary lactase deficiency due to intestinal 202
mucosal damage. A progressive, age-related loss of lactase activity affects about 80% of the nonwhite
population and may be responsible for chronic diarrhea in older children receiving cow's milk.
CHRONIC NONSPECIFIC DIARRHEA:

1. FUNCTIONAL DIARRHEA (or toddler's diarrhea) in children <4 yr of age.
2. IRRITABLE BOWEL SYNDROME in those ≥5 yr.
 The disease is the same with a slightly different age presentation.
 abdominal pain is more common and clearly associated with the diarrhea in older children.
 The hallmark of the syndrome is diarrhea associated with normal weight growth in well-appearing
subjects.
 In younger children diarrhea is often watery, at times containing undigested food particles.
 It is usually more severe in the morning.
 If the child's fluid intake is >150 mL/kg/24 hr fluid intake should be reduced to no more than 90
mL/kg/24 hr.
 persistence with this approach for several more days results in a decrease in the stool frequency and
volume.
 If the dietary history suggests that the child is ingesting significant amounts of fruit juices, then the
offending juices should be decreased.
 Sorbitol, which is a nonabsorbable sugar, is found in apple, pear, and prune juices and it can cause
diarrhea in toddlers.
 Apple and pear juices contain higher amounts of fructose than glucose, a feature postulated to cause
diarrhea in toddlers.
 In older children, irritable bowel syndrome is often associated with abdominal pain and may be
related to anxiety, depression, and other psychologic disturbances.
INTRACTABLE DIARRHEA SYNDROME:
Definition: result of a permanent defect in the structure or function of intestine, leading to

progressive, often irreversible intestinal failure, requiring parenteral nutrition for survival.
The main etiologies of intractable diarrhea include structural enterocyte defects, disorders of
intestinal motility, immune-based disorders, short gut, and multiple food intolerance. The genetic
and molecular bases of many etiologies of intractable diarrhea have been recently identified
MAIN CAUSES OF CHRONIC DIARRHEA ACCORDING TO THE AGE OF ONSET*
0-30 DAYS 1-24 MONTHS 2-18 YEARS
Microvillus inclusion disease Apple juice and pear nectar Apple juice or pear nectar
Autoimmune enteropathy Antibiotic-associated Clostridium difficile colitis
Intestinal infection Intestinal infection
Congenital short bowel syndrome Short gut
Food allergy Lactose intolerance
[†] [‡]
Food allergy Functional diarrhea Irritable bowel syndrome
203
Celiac disease Celiac disease
Hirschsprung's disease Cystic fibrosis

0-30 DAYS 1-24 MONTHS 2-18 YEARS
Malrotation with partial blockage Post-gastroenteritis diarrhea Post-gastroenteritis diarrhea
Neonatal lymphangectasia
Tufting enteropathy
Primary bile-salt malabsorption
Intestinal pseudo-obstruction Intestinal pseudo-obstruction
BIOCHEMICAL MARKERS ASSIST IN GRADING MALNUTRITION .
 The half -life of serum proteins can differentiate between short-term and long-term malnutrition.
 Assessment of body composition may be performed by measuring mid-arm circumference and triceps
skinfold thickness or, more accurately, by bioelectrical impedance analysis or dual emission x-ray
absorptiometry (DEXA) scans.
DEGREE OF MALNUTRITION AS ESTIMATED BY VISCERAL PROTEIN CONCENTRATIONS IN CHILDREN

WITH CHRONIC DIARRHEA
VISCERAL HALF- NORMAL MILD MODERATE SEVERE

PROTEIN LIFE VALUES MALNUTRITION MALNUTRITION MALNUTRITION
Albumin 20 days 30-45 g/L 3.0-2.9 g/L 2.8-2.5 g/L <2.5 g/L
Prealbumin 2 days 0.2-04 g/L 0.2-0.18 g/L 0.17-0.1 g/L <0.1 g/L
Retinol binding
12 hr 2.6-7.6 g/L 2.5-2.0 g/L 1.9-1.5 g/L <1 g/L
protein
Transferrin 8 days 218-411 ?g/dL 200-150 ?g/dL 149-100 ?g/dL <100 ?g/dL
11-19
Serum iron 16-124 ?g/dL 15-13 ?g/dL 12-10 ?g/dL <10 ?g/dL
hr
Consider also the concentrations of the following micronutrients: calcium, zinc, magnesium, iodine,
vitamin A, vitamin C, vitamin B1.
204

STEPWISE DIAGNOSTIC WORK-UP FOR CHILDREN WITH CHRONIC DIARRHEA
STEP 1
Intestinal microbiology
• Stool cultures
• Microscopy for parasites
• Viruses
• Stool electrolytes
• H2 breath test
Screening test for celiac disease (transglutaminase 2 autoantibodies)
Noninvasive tests for:
• Intestinal function
• Pancreatic function and sweat test
• Intestinal inflammation
Tests for food allergy
• Prick/patch tests
STEP 2
Intestinal morphology
• Standard jejunal/colonic histology
• Morphometry
• PAS staining
• Electron microscopy
STEP 3
Special investigations
• Intestinal immunohistochemistry
205
• Anti-enterocyte antibodies
• Serum chromogranin and catecholamines

• Autoantibodies
• Brush border enzymatic activities
• Motility and electrophysiological studies
DISORDERS OF MALABSORPTION
All disorders of malabsorption are associated with diminished intestinal absorption of one or more
dietary nutrients.
Malabsorption can result from a defect in the nutrient digestion in the intestinal lumen or from
defective mucosal absorption.
Malabsorption disorders can be categorized into generalized mucosal abnormalities usually

resulting in malabsorption of multiple nutrients or malabsorption of specific nutrients (carbohydrate,
fat, protein, vitamins, minerals, and trace elements).
Almost all the malabsorption disorders are accompanied by chronic diarrhea
CLINICAL APPROACH:
 The common presenting features, especially in toddlers with malabsorptiondiarrhea, abdominal

distention, and failure to gain weight, with a fall in growth chart percentiles.
 Physical findings include muscle wasting and the disappearance of the subcutaneous fat, with
subsequent loose skinfolds.
 The nutritional consequences of malabsorption are more dramatic in toddlers because of the limited
energy reserves and higher proportion of calorie intake being used for weight gain and linear growth.
 In older children, malnutrition can result in growth retardation, as is commonly seen in children with
late diagnosis of celiac disease.
 If malabsorption is untreated, linear growth slows, and with prolonged malnutrition, death can follow;
edema is usually associated with protein-losing enteropathy.
 digital clubbing with cystic fibrosis and celiac disease.
 perianal excoriation and gaseous abdominal distention with carbohydrate malabsorption.
 perianal and circumoral rash with acrodermatitis enteropathica.
 abnormal hair with Menkes syndrome.
 typical facial features diagnostic of the Johanson-Blizzard syndrome.
 Many children with malabsorption disorders have very good appetites as they try to compensate for the
fecal protein and energy losses.
 In exocrine pancreatic insufficiency, fecal losses of up to 40% of ingested protein and energy do not
lead to malnutrition, as long as they are compensated by an increased appetite.
 In conditions associated with villous atrophy or inflammation (celiac disease, postinfectious
enteropathy), fecal protein and energy losses are usually modest, but associated anorexia and reduced
food intake results in malnutrition.
 Diarrhea is the main clinical expression of malabsorption.
 Onset of diarrhea in early infancy suggests a congenital defect . 206
 In secretory diarrhea due to disorders such as congenital chloride diarrhea and microvillus inclusion
disease, the stool is watery and voluminous and can be mistaken for urine.
 Onset of symptoms after introduction of a particular food into a child's diet can provide diagnostic
clues, such as with sucrose in sucrase-isomaltase deficiency.

 The nature of the diarrhea may be helpful:
 explosive watery diarrhea suggests carbohydrate malabsorption;
 loose, bulky stools are associated with celiac disease;
 and pasty and yellowish offensive stools suggest an exocrine pancreatic insufficiency.
 Stool color is usually not helpful; green stool with undigested “peas and carrots” can suggest
rapid intestinal transit in toddler's diarrhea, which is a self-limiting condition unassociated with
failure to thrive.
DIARRHEAL DISEASES APPEARING IN THE NEONATAL PERIOD

CONDITION CLINICAL FEATURES
Microvillus inclusion disease Secretory watery diarrhea
Tufting enteropathy Secretory watery diarrhea
Congenital glucose-galactose malabsorption Acidic diarrhea
Congenital lactase deficiency Acidic diarrhea
Hydramnion, secretory watery diarrhea
Congenital chloride diarrhea
Metabolic alkalosis
Congenital defective jejunal Na+/H+ exchange Hydramnion, secretory watery diarrhea
Congenital bile acid malabsorption Steatorrhea
Congenital enterokinase deficiency Failure to thrive, edema
Congenital trypsinogen deficiency Failure to thrive, edema
Congenital lipase and/or co-lipase deficiency Failure to thrive, oily stool
GLUTEN-SENSITIVE ENTEROPATHY (CELIAC DISEASE)
 Celiac disease is an immune-mediated disorder elicited by the ingestion of gluten in genetically

susceptible persons and characterized by chronic inflammation of the small intestine.
 It is considered an autoimmune condition because of the presence of anti–TG2 antibodies and the
association with other autoimmune diseases (thyroid, liver, diabetes, adrenal).
 Celiac disease is triggered by the ingestion of wheat gluten and related prolamines from rye and
barley. a few celiac patients have oats prolamine–reactive mucosal T cells that can cause mucosal
inflammation.
 Celiac disease is a common disorder (1% prevalence of biopsy-proven disease).
 Risk factors:
 Family hx.
 Environmental factors:
 Prolonged breastfeeding  reduced incidence of symptomatic disease.
 Ingestion of increased amounts of gluten in the 1st year of life  increase the incidence.
 Infectious agents  frequent rotavirus infections are associated with an increased risk.
 contact with gliadin at a time when there is ongoing intestinal inflammation altered intestinal
permeability, and enhanced antigen presentation can increase the risk of developing the disease, at least 207
in a subset of persons .

GENETICS AND PATHOGENESIS
 A genetic predisposition is suggested by the family aggregation and the concordance in monozygotic
twins, which approaches 100%.
 It is suggested that the primary association of CD is with the DQ  DQA1*05 and the DQB1*02
genes. Such a DQ molecule is present in ≥95% of celiac patients compared with 20-30% of controls.
 DQ2-negative celiac patients are invariably HLA DQ8 positive (DQA1*0301/DQB1*0302).
 A gene dosage effect has been suggested-- HLA DQ2 molecules on gluten peptide presentation to T
cells.
 Other non-HLA genes confer susceptibility to celiac disease.
 some being shared with type 1 diabetes.
 Celiac disease is a T cell–mediated chronic inflammatory disorder with an autoimmune component.
Altered processing by intraluminal enzymes, changes in intestinal permeability, and activation of innate
immunity mechanisms may be involved and precede the activation of the adaptive immune response.
Immunodominant epitopes from gliadin highly resistant to intraluminal and mucosal digestion
incomplete degradation  immunostimulatory and toxic effects.
 Gliadin-specific T-cell responses are enhanced by the action of TG2 the enzyme converts
particular glutamine residues into glutamic acid, which results in higher affinity of these gliadin
peptides for HLA-DQ2 or HLA-DQ8.
 Increased density of CD8+ cytotoxic intraepithelial lymphocytes are a hallmark of celiac disease.
 The most evident expression of autoimmunity is the presence of serum antibodies to TG2.
 However, the mechanisms leading to autoimmunity are largely unknown.
 The finding of IgA deposits on extracellular TG2 in the liver, lymph nodes, and muscles indicates that
TG2 is accessible to the gut-derived autoantibodiesSeveral extraintestinal clinical manifestations of
celiac disease (e.g., liver, heart, nervous system) are possibly related to the presence of autoantibodies.
CLINICAL PRESENTATION AND ASSOCIATED DISORDERS
Intestinal symptoms are common in children whose disease is diagnosed within the 1st 2 years of
life.
 failure to thrive, chronic diarrhea, vomiting, abdominal distention, muscle wasting, anorexia, and
irritability are present in most cases.
 Occasionally there is constipation, rectal prolapse, or intussusception.
later in childhood extraintestinal manifestations and associated disorders, without any

accompanying digestive symptoms, have increasingly become recognized, affecting almost all
organs.
SOME CLINICAL MANIFESTATIONS OF CELIAC DISEASE IN CHILDREN AND ADOLESCENTS
SYSTEM MANIFESTATION (POSSIBLE) CAUSE
 Diarrhea
Distended abdomen
Vomiting
Atrophy of the small bowel mucosa
Gastrointestinal Anorexia 208
Malabsorption
Weightloss
Failure to thrive
Aphthous stomatitis

SYSTEM MANIFESTATION (POSSIBLE) CAUSE
Hematologic Anemia Iron malabsorption
Rickets
Skeletal Osteoporosis Calcium/vitamin D malabsorption
Enamel hypoplasia of the teeth
Muscular Atrophy Malnutrition
Peripheral neuropathy
Neurologic Epilepsy Thiamine/vitamin B12 deficiency
Irritability
Short stature
Malnutrition
Endocrinologic Puberty delayed
Calcium/vitamin D malabsorption
Secondary hyperparathyroidism
Dermatitis herpetiformis
Dermatologic Alopecia areata Autoimmunity
Erythema nodosum
Idiopathic pulmonary
Respiratory
hemosiderosis
RISK GROUPS FOR CELIAC DISEASE CASE-FINDING
1st-degree relatives
Dermatitis herpetiformis
Unexplained iron deficiency anaemia
Autoimmune thyroiditis
Type 1 diabetes
Unexplained infertility
Recurrent abortion
Dental enamel hypoplasia
Cryptic hypertransaminasemia
Autoimmune liver disease 209
Short stature

Delayed puberty
Down, Williams, and Turner syndromes
Irritable bowel syndrome
Unexplained osteoporosis
Sjogren syndrome
Epilepsy with occipital calcifications
Selective IgA deficiency
Addison disease
The most common extraintestinal manifestation of celiac disease is iron-deficiency anemia,

unresponsive to iron therapy.
Osteoporosis may be present; in contrast to the situation in adults, it can be reversed by a gluten-
free diet, with restoration of normal peak bone densitometric values.
extraintestinal manifestations include short stature, endocrinopathies, arthritis and arthralgia,

epilepsy with bilateral occipital calcifications, peripheral neuropathies, cardiomyopathy, chronic lung
disease, isolated hypertransaminasemia, dental enamel hypoplasia, aphthous stomatitis, and
alopecia. The mechanisms responsible for the severity and the variety of clinical presentations remain
obscure. Nutritional deficiencies or abnormal immune responses have been advocated.
Silent celiac disease is being increasingly recognized, mainly in asymptomatic 1st-degree relatives
of celiac patients investigated during screening studies. However, small bowel biopsy in these
people reveals severe mucosal damage consistent with celiac disease. (silent with small biopsy
change only)
Potential celiac diseasepositive screening but without documented celiac disease on small
bowel biopsy. It is important to follow these patients because they can develop established celiac
disease in the future (PPSC –POTENTIAL POSETIVE SEROLOGY )
CLINICAL SPECTRUM OF CELIAC DISEASE
SYMPTOMATIC
Frank malabsorption symptoms: chronic diarrhea, failure to thrive, weight loss
Extraintestinal manifestations: anemia, fatigue, hypertransaminasemia, neurologic disorders, short stature,

dental enamel defects, arthralgia, aphthous stomatitis
210
SILENT

No apparent symptoms in spite of histologic evidence of villous atrophy
In most cases identified by serologic screening in at-risk groups.
LATENT
Subjects who have a normal histology, but at some other time, before or after, have shown a gluten-
dependent enteropathy (KABHI NA KABHI TO AEGI…) ;-)
POTENTIAL
Subjects with positive celiac disease serology but without evidence of altered jejunal histology
It might or might not be symptomatic
ASSOCIATIONS: due to sharing of identical HLA haplotypes
 type 1 diabetes.
 autoimmune thyroid disease.
 Addison disease.
 Sjogren syndrome.
 autoimmune cholangitis.
 autoimmune hepatitis.
 primary biliary cirrhosis.
 IgA nephropathy.
 Alopecia.
 dilated cardiomyopathy.
once those diseases are established, they are not influenced by a gluten-free diet.
Other associated conditions include selective IgA deficiency, Down syndrome, Turner syndrome,
and Williams syndrome.
Patients with celiac disease show increased long-term mortality  the risk rising with delayed
diagnosis and/or poor dietary compliance.
Non-Hodgkin lymphoma is the main cause of death.
Adult patients can develop complications such a refractory celiac disease, ulcerative jejunoileitis, or
enteropathy-associated T-cell lymphoma.
DIAGNOSIS
Serologic tests :
211
 sensitivity of the IgA anti-TG2 is 61-100% (mean, 87%), and specificity is 86-100% (mean, 95%).
 10% of patients whose disease is diagnosed earlier than 2 yr of age show absence of IgA anti-TG2.
For them, the measurement of serum antigliadin antibodies is generally advisedAntibodies
against gliadin-derived deamidated peptides (D-AGA) have been assessed.

 Compared with conventional AGA, the peptide antibodies (IgG and IgA) have a greater
sensitivity and specificity.
 A problem with serology is represented by the association of celiac disease with IgA deficiency (10-
fold increase compared to the general population).
 Serum IgA should always be checked, and in the case of IgA deficiency, D-AGA, IgG anti-
endomysium, or TG2 should be sought. Negative serology should not preclude a biopsy examination
when the clinical suspicion is strong.
Genetic tests have an increasing role in the diagnosis. (indicated in high risk pts)
 < 2% of celiac patients lack both HLA specificities; at the same time, approximately one third of the
“normal” population has one or the other marker; that means that the measurement of HLA DQ2
and/or DQ8 has a strong negative predictive value but a very weak positive predictive value for
the diagnosis of celiac disease. With these limitations the test can prove useful to exclude celiac
disease when the genetic studies are negative in subjects on a gluten-free diet or in subjects belonging
to an at-risk group (e.g., 1st-degree relatives, insulin-dependent diabetics, patients with Down
syndrome) to avoid long-term follow-up.
Small bowel biopsy: The ultimate diagnosis of celiac disease relies on the demonstration of
specific, though not pathognomonic, histopathologic abnormalities in the small bowel mucosa.
According to The European Society for Pediatric Gastroenterology, Hepatology and Nutrition
(ESPGHAN) current criteria:
 2 requirements mandatory for the diagnosis of celiac disease are 1) finding of villous atrophy with
hyperplasia of the crypts and abnormal surface epithelium, while the patient is eating adequate amounts
of gluten, and 2) a full clinical remission after withdrawal of gluten from the diet.
 The finding of circulating IgA celiac disease–associated antibodies at the time of diagnosis and their
disappearance on a gluten-free diet adds weight to the diagnosis.
 A control biopsy to verify the consequences of the gluten-free diet on the mucosal architecture is
considered mandatory only in patients with an equivocal clinical response to the diet.
Gluten challenge is not considered mandatory except:
 in situations where there is doubt about the initial diagnosis, for example, when an initial biopsy was
not performed or when the biopsy specimen was inadequate or atypical of celiac disease.
OTHER CAUSES OF FLAT MUCOSA

Autoimmune enteropathy
Tropical sprue
Giardiasis
HIV enteropathy
Bacterial overgrowth
Crohn disease 212
Eosinophilic gastroenteritis
Cow's milk enteropathy

Soy protein enteropathy
Primary immunodeficiency
Graft-versus-host disease
Chemotherapy and radiation
Protein energy malnutrition
Tuberculosis
Lymphoma
Non-gluten food intolerances
 In some celiac disease patients, only subtle changes of crypt elongation with an
increase in intraepithelial lymphocytes may be present.  In those cases, it is very
important to also evaluate the serology and the HLA typing so as to reach the correct
diagnosis. Analysis of multiple biopsies is also very important.
 many cases of celiac disease are undiagnosed, and the ratio between patients with
diagnosed and with undiagnosed disease may be as high as 1 : 7.
 Case finding by liberal use of anti-endomysium or anti-TG2 antibodies, followed by
confirmatory jejunal biopsy, is more cost effective in primary care than mass
screening is.
TREATMENT
 The only treatment for celiac disease is lifelong strict adherence to a gluten-free diet.
 This requires a wheat-, barley-, and rye-free diet.
 Despite evidence that oats are safe for most patients with celiac disease, there is concern regarding the
possibility of contamination of oats with gluten during harvesting, milling, and shipping.
 There is a consensus that all celiac disease patients should be treated with a gluten-free diet regardless
of the presence of symptoms However, whereas it is relatively easy to assess the health
improvement after treatment of celiac disease in patients with clinical symptoms of the disease, it
proves difficult in persons with asymptomatic celiac disease.
 The nutritional risks, particularly osteopenia, are those mainly feared for subjects who have silent
celiac disease and continue on a gluten-containing diet.
 There are no guidelines concerning the need for a gluten-free diet in subjects with “potential”
celiac disease (patients with positive celiac disease–associated serology but without enteropathy).
 The Codex Alimentarius Guidelines define gluten-free as <20 ppm.
 The data available so far seem to suggest that the threshold should be set to <50 mg/day, although
individual variability makes it difficult to set a universal threshold.
 It is important that an experienced dietician with specific expertise in celiac disease counseling
educates the family and the child about dietary restriction.
 Compliance with a gluten-free diet can be difficult, especially in adolescents.
 It is recommended that children with celiac disease be monitored with periodic visits for assessment of
symptoms, growth, physical examination, and adherence to the gluten-free diet.
 Periodic measurements of TG2 antibody levels to document reduction in antibody titers can be
helpful as indirect evidence of adherence to a gluten-free diet. 213

CHRONIC KIDNEY DISEASE------------------------------------------------------------------------------------------- LONG
CASE
 NEW CASE.
 KNOWN CASE---mostly
PRESENTING COMPLAINTS CAN BE:
 FEVER
 RESPIRATORY DISTRESS.
 PROGRESSIVE PALLOR
 FITS
 ALTERED SENSORIUM
 GENERALISED BODY SWELLING.
 BONY DEFORMITIES.
 FTT
 PETECHAE, BRUISE, BLEEDING.
QUESTIONS REGARDING THE CAUSE OF CRF
RENAL
o HX OF DYSUREA, POLYUREA, URGENCY, INCONTINENCE, POOR STREAM, DRIBBLING, RETENSION,
RECURRENT UTI, ENURESIS, HEMATUREA, PASSAGE OF GRAVEL, POLYUREA, POLYDYPSIA, ANUREA.
GIT
o HX OF SALT CRAVING, ABDOMINAL /FLANK PAIN, VOMITING, ABDOMINAL DISTENSION,
HEMATEMESIS, MALENA, JAUNDICE, ANOREXIA.
HEM
o HX OF PETECHAE, BRUISE, BLEED, PALLOR, BLOOD TRX.
HX OF DEAFNESS, VISUAL DISTURBANCE
RESPIRATORY
o HX OF RESPIRATORY DISTRESS, COUGH, EPISTAXIS, HEMOPTYSIS, EXERTIONAL DYSPENA, ORTHOPNEA,
PND.
CNS
o HX OF HEADACHE , CONVULSIONS, ALTERED SENSORIUM, FOCAL NEUROLOGICAL DEFICIT/ WEAKNESS
OF ANY PART OF BODY, NEUROPATHY, ITCHING (S/C Ca+ DEPOSITION).
OTHER
o HX OF ALOPECIA/ HAIRLOSS, ORAL ULCER, PHOTOSENSETIVITY, JOINT PAIN OR

SWELLING, PERIORBITAL SWELLING OR PUFFINESS, FEVER, HAKEEMS MEDICATIONS.
HX OF CURRENT STATUS AND AODL.
HX OF COMPLICATIONS:
ANY HX OF GROWTH FAILURE, PALLOR, RESPIRATORY DISTRESS, HTN, BODY SWELLING, PALPITATION,
ORTHOPNEA, PND, BONY DEFORMITIES, FRACTURE, RESPIRATORY DISTRESS, FITS, ALTERED SENSORIUM,
FOCAL NEUROLOGIC DEFICIT (CVA), PETECHAE, BRUISE, BLEED, ITCHING.
PAST HISTORY: WHEN, WHERE, WHAT WERE PRESENTING COMPLAINTS, WHAT INITIAL INVESTIGATIONS
DONE, NO. OF HOSPITALISATION, SEQUENCE OF COMPLICATIONS, HOW MANAGED, WHAT DIAGNOSTIC TEST
DONE (DTPA, DMSA, MCUG “TEST WHICH HAS BEEN DONE AFTER INSERTING URINARY CATHATER” , IVP ,
RENAL BIOPSY?
214
WHAT TREATMENT OFFERED SO FOR P.D, HEMODIALYSIS, RENAL TRANSPLANT?

-DRUGS ANTI HYPERTENSIVES, DIURETICS, VITAMIN-D , SODA BICARB, ERYTHROPOEITIN/ ALPHA
DARBOPOETIN, “ASK AS ANY INJECTION GIVEN S/C USED FOR MAKING BLOOD”, HGh “ANY INJECTION FOR
HEIGHT “KAD BADHANAY WALA TEEKA”.
ASK DETAILS OF FOLLOW UP IN HOSPITAL & COMPLIANCE.
BIRTH HX: ANTENATAL USG.
NUTRITIONAL HX: CALCULATE CALORIES, ANY DIETRY RESTRICTION.
VACCINATION: HBsAg BEFORE DIALYSIS.
FAMILY HX: CONSANGUANITY, FAMILY HX OF CKD/ ON RRT, RENAL STONE, TETANY, NIGHT BLINDNESS.
DISEASE IMPACT ON PARENTS, SIBS, PATIENT
SCHOOLING..
SOCIOECONOMIC STATUS:
EXAMINATION -
PROTOTYPE CASE- ESKD.
MY PATIENT ………….11 YR OF AGE RESIDENT OF …………………… ADMITTED…….. DAYS BACK THRU M/E WITH
C/O:
FEVER. 5 DAYS
RESPIRATORY DISTRESS. =
According to pts mother child is known case of CKD since last 5 year with poor compliance and follow up now
presented with hx of gradual onset of low grade fever that was undocumented with diurnal variation more At
night time relieved by taking medication but not associated with rigors, chills.
progressive worsening of respiratory distress , Aggravated by walking and running relieved by sitting down, no
hx of nocturnal dyspnea, cough, cyanosis, chest pain.
he had no hx of rash , sorethroat, ear discharge, loose motions, vomiting, body swelling, urinary complaint.
-For these complaint he admitted in ……. Hospital where he managed with…………
Current his symptoms are improved / not.
Actual hx starts dates back 5 year when he was 6 year of age when he developed gradual onset of progressively
increasing body swelling started from feet to face with no specific timing relation, with/without aggravating or
relieving factors, that was not associated hx of urinary complaint in form of oligourea, dysurea..
During previous course of illness he had/not hx of dysurea, polyurea, urgency, incontinence, poor stream,
dribbling, retension, recurrent uti, enuresis, hematurea, passage of gravel, polyurea, polydypsia, anurea, hx of
salt craving, abdominal /flank pain, vomiting, abdominal distension, hematemesis, malena, jaundice, anorexia.
hx of deafness, visual disturbance, hx of respiratory distress, cough, epistaxis, hemoptysis, exertional dyspena,
orthopnea, pnd, hx of headache , convulsions, altered sensorium, focal neurological deficit/ weakness of any 215
part of body, neuropathy, hx of alopecia/ hairloss, oral ulcer, photosensetivity, joint pain or swelling,
periorbital swelling or puffiness, fever, hakeems medications.

He went to one of tertiary hospital where he investigated with
……………………………………………………………………………………………………………………………………………………….........
Procedures were performed P.D/ H.D/ CVP/ FICTULA/RENAL BIOPSY, DTPA, DMSA, IVP, MCUG,B.P
MONITORING…………….
Treatment started in form

of…………………………………………………………………………………………………………………………………………………………………………
………………………………………………………………………………………………………………………………………………………
Remained with poor/ fair complaint to treatment and follow up.
Parents have poor/fair knowledge regarding the disease, complications, course and management “including
renal transplantation”.
Vaccinated developmentaly normal class ii student, because of his illness, remained absent from school with
significant impact on his family/sibs. parents He is product of consanguious marriage 2nd of 3 siblings no hx of
renal disease, deafness, visual distrubance in family. his/ her father is labourer by occupation with monthly
income of ......./ month,live in their own house comprising of ....rooms ,kitchen ,washroom,katcha/pakka
house,in joint family system with poor/ proper sanitation/water supply.
EXAMINATION:
I have examined a child who is conscious and co-operative and well interactive throughout my examination
with sallow complexion AND malnourished however no aperrent respiratory distress, dysmorphism.
O rd
Hi pulse rate is………………… R/R is ………………bpm, temp is…………. F, B.P is…………………mmHg which is at 3
centile for his/ age gender.
rd
Height is ……………….cm which I below 3 centile for his age and corresponding to age of ….. yr ., wt is……kg
rd
which is <3 centile for his/ her age , intermalleolar distance is……….cm.
He is pale, with tinge of jaundice however no evidence of clubbing, leukonychia, palmer erythema, petechae,
bruise, bleed, wrist widening,Scratch marks, joint pain/ swelling, edema, lymphadenopathy.
Eye examination is normal with no evidence of aniridia, cataract (steroids). Hearing is normal, oral hygiene is
poor ,………..dentination, stained. JVP is ……………………, Thyroid is not enlarged.
Start description of related system with presenting complaints.
Q: why not case of nephronopthisis? (also called medullary sponge disease)
A: unlikley he is the case of nph because they usually present around after 10 yr although can present
before 2 yr ,are ftt, with family hx, & polyurea & polydypsia, with hx of night blidness however no
hypertension.
Q: what are types of nephronopthesis?

216
A: infantile (1-2 yr), juvenile ( 13 yr), adult (16-18 yr).
Q: what is genetic association of nph?

A: nph gene 1,2,3,8,14.
Q: what happens to urine of pts with nph?
A: bland urine.( no rbc, no wbc or their casts) where as active urinary segment contains all.
Q: what othe diagnostic measures are helpful in nph?
A: usg which show small cyst at cm junction, ct scan if usg miss, other is gentic mutation analysis and
bland urine.
Q: what is senior lokin syndrome?
A: it is a variant of nph in which renal and retinal involvemt is there.
Q what are the associations of nph?
A: liver+ cerebellar pathology.
Q: what is closest differential of nph?
A: medulary sponge kidney ds.
Q which vaccines are indicated in pts with who are on coricosteriods or immunosuppresive therapy?
A: pnemococcal, hemophillus and varicella because of increase risk of infection with these organisms.
Q: what are indications of rhgh in ckd pts?
A:
2
o GFR < 30ml/min/1.73m
th th
o height below 25 centile for age or height velocity is below the 25 centile for bone age.
o Age > 10 yrs
o No epiphysial closure
Q: what is dose for rhgh?
2
A: its maximium dose that can be used is 28 units/m per week.
Q: for how long you will continue rhgh in pts with ckd?
A: sir we will continue untill epiphyseal closure or till renal transplantation, other we can discontinue if it
th
is not responsive which we say when child fails to achieve growth velosity atleast 50 centile for bone
age over 6 months.
Q: what is the pathogensis of gh resistance in ckd pts?
A: normal igfbp-3 binds 95% of igfs, igf is active when it is in free /unbound form. ckddecreased
clearance of igfbp-3increase level in blood increase binding with igf-1decreased availability of
free form growth impairment and considered as uremic gh resistance.
Q: what are complications of rhgh therapy?
A: hypercalciurea, asceptic necrosis of femoral head, pseudotumor cerebri,and induction of
malignancy??.
217
Q: what are contraindications of rhgh ?
A: absolute is after epiphyseal closure another not absolute contraindication but it is not considered for
those pts who have received cytotoxic and etiology of ckd sec to wilms tumor becoz it may lead to

induction of malignancy.
Q: what are limitations of gfr calculation?
A: any child who is malnourished / poor muscle bulk, under 2 yr of age, ARF. coz it may overestimate gfr
even at lower level of gfr.
Q: what is good marker of ckd?
A; creatinine is agood marker of ckd than urea, because creatinine is byproduct of muscle metabolism ,
while urea which is filtered somewhat reabsorbed so in decrease gfr there is increase urea absorption
to keep urine concentrated, but creatinine is not absorbed & when increase always indicate chronic
renal injury.
Q: you have a pt 10 yr of age with ckd secondary to puv and you can not have bladder then what is the
reason?
A: ckd decrease urine output bladder empty.
Q: what is most common cause of ckd in our country?
A: in child <5 yr it is obstructive uropathy while in >5 yr nephrolitiasis.
Q: what are the causes of ccf (liver+ ascites+muffled sounds in ckd?
A: anemia, fluid overload, uremic peicarditis, HTN DCMP.
Q: causes of polyurea & polydypsia in ckd?
A: loss of concentrating abillity of kidney , tubular deffects like rta, barter, nephronopthesis.
Q: how uremia causes anemia?
A: acidosis leading to decreased erythropoietin production, second by suppression of marrow by toxic
rd
metabolites & 3 by causing decrease RBC life span
Q: what are the causes of increase uric acid that lead to stone formation?
A: vitamin d intoxication, gout, TLS, GSD.
Q: what is the usual presentation of ideopathic hypercalciurea ?
A: gross hematurea & dysurea.
Q: if the cause is renal calculi how will u investigate that pt?
A: i will investigate by xray plain kub which will show whether radio opaque or leucent stone then if no
visiblility will do ultrasound, then spot urine c/e for ca/ oxalte crystals and urine for citrulin,or 24 hr
urine for ca excretion, ca : creatinine ratio, vit d , serum pth level,urine for oxalate level if pt would be
anureic then i will prescribe serum oxalte level. & offcourse stone analysis will help definate type of
calcli.
Q: how would u differentiate between resp. acidosis due to acidosis or other causes? 218
A: i would look for other causes like pneumonia, fluid overload, and ccf, if these would not be in my pt i
would consider rather acidsis and acidosis have shallow breathing with smell aswell otherwise.

Q: if pt with transplanted kidney again present with deranged rfts then what u would do?
A: in these pts first of all rule out the infection, dehydration, then we may consider recurrence of
underlying illness.
DISCUSSION:
CHRONIC KIDNEY DISEASE

2
DEFINATION: Renal injury (proteinurea) or GFR <60 ml/min/1.73m for more than 3 month.
ETIOLOGY: > 5 YEAR
Well thriving:
1. GMN (30%)
-FSGS, RPGN, MPGN, IgA Neohropathy (berger/HSP), Vascculitis (wegner, PAN.)

Microangiopathy (HUS,TTP), Antibasement membrane antibody disease.
Failure to thrive:
1. Reflux nephropathy
2. Nephronopthisis
3. Alport syndrome
4. Stones
5. PUJ
6. Polycystic kidney diseases
7. SLE
8. Drugs including NSAIDs and hakeem medications.
9. idiopathic.
< 5 YEAR
1. PUV (male).
2. Neurogenic bladder.
3. RTA
4. Polycystic kidney disease
5. Drugs
6. RVT
7. HUS
8. Renal malformations / structural 30% <2 yr. dysplasia, hypoplasia,
aplasia.(usually silent )
9. FSGS
10. Prune belly syndrome
11. Congenital nephrosis
THROUGHOUT CHILDHOOD metabolic disorders

219
1. Cystinosis
2. Hyperoxalurea
3. Cystic kidney disease.

Note: glomerulopathies and certain other conditions like HUS, RVT, RA Stenosis, reflux nephropathies,
pyelonephritis are acquired and considered in group 1 and 4 they progress faster.
While structural and hereditary nephropathies are group 2 and 3 respectively they are congenital and
progress slowly and cause ESRD by year 5-15 .
Structural problems salt and water losing CKD-hypotensive child with polyurea
Glomerular causes salt retention,hypertensive child with anurea
Most important cause of CKD is congenital problem , & FSGS is second most common.
STAGES OF CKD 6 Stages

2
Stage 1.  kidney damage with normal or increased GFR ( >90 ml/min/1.73 m ).
2
Stage 2.  Mild decrease GFR ( 60-90 ml/min/1.73 m ).
2
Stage 3.  Moderate decrease GFR (30-60 ml/min/1.73m ).
2
Stage 4.  severe decrease GFR ( 15-30 ml/min/1.73 m ).
2
Stage 5.  kidney failure (<15 ml/min/1.73m )
Stage 6 ON dialysis or RRT.
2
NORMAL GFR =age variable in newborn it is 45, while childhood is 90- 120ml/min/1.73m .
PATHOGENESIS:
1. HYPERFILTRATION THEORY: as nephrons loss remaining nephrons undergo structural &

functional hypertrophy charachterised by an increase in glomerular blood flow  driving force for
GFR is inceraesd in surviving nephrons this compensatory hypertrophy and hyperfiltration
temporarly preserve total renal function but may cause progressive damage to surviving glomeruli by
direct effect of increase hydrostatic pressure or toxic effect of increased protein traffic across the
capillary wall.
2. Increase protein passage across capillary wall  damage by recuit monocytes and macrophages
increase glomerulosclerosis & tubulointerstitial fibrosis.
3. Hypertension causes arteriolar nephroschlerosis.
4. Hyperphosphatemia causes Ca+ & PO4 deposition in interstitium.
5. Hyperlipidemia causes oxidant mediated injury.
6. Other additional studies shows that pts with adverse intrauterine environment (IURG,SGA, Sepsis)
have increase chance of CRF in adolescent.
CALCULATION OF GFR= Ht (cm) × K where k= constant

-------------------------------------- 0.33= LBW
S. Creatinine (mg/dl) 0.45= FT/AGA infants.
0.55 =children and adolecnt
female
0.70 adolescent males.
GFR is also calculated by DTPA, inulin clearance-
GFR is approximated by Schwartz formula which is based on the relationship between muscle mass and serum
creatinine
220
MANIFESTATIONS OF CKD & CAUSE /Pathophysiology of each in Chronic Kidney Disease ( common
examiner Q)
MANIFESTATION MECHANISMS

Accumulation of nitrogenous waste products Acidosis Decrease in glomerular filtration rate
Decreased ammonia synthesis
Impaired bicarbonate reabsorption
Decreased net acid excretion
Sodium retention Excessive renin production
Oliguria
Sodium wasting Solute dieresis
Tubular damage
Urinary concentrating defect Solute dieresis
Tubular damage
Hyperkalemia Decrease in glomerular filtration rate
Metabolic acidosis
Excessive potassium intake
Hyporeninemic hypoaldosteronism
Renal osteodystrophy Impaired renal production of 1, 25-
dihydroxycholecalciferol
Hyperphosphatemia
Hypocalcemia
Metabolic acidosis
Growth retardation Inadequate caloric intake
Renal osteodystrophy
Metabolic acidosis
Anemia
Growth hormone resistance
Anemia Decreased erythropoietin production
Iron deficiency
Decrease oral intake, anorexia, occult GI blood

loss due to bleeding tendency
Folate deficiency
Vitamin B12 deficiency
Decreased erythrocyte survival
B.M fibrosis due to PTH
Bleeding tendency + Infection Defective platelet function
Defective granulocyte function
Impaired cellular immune functions
Indwelling dialysis catheters
Neurologic symptoms (fatigue, poor concentration, Uremic factor(s)
headache, drowsiness, memory loss, seizures, peripheral Aluminum toxicity
neuropathy) Hypertension
Gastrointestinal symptoms (feeding intolerance, abdominal Gastroesophageal reflux
pain) Decreased gastrointestinal motility
Hypertension Volume overload
Excessive renin production
Hyperlipidemia Decreased plasma lipoprotein lipase activity
Pericarditis/cardiomyopathy Uremic factor(s)
Hypertension
Fluid overload
Glucose intolerance Tissue insulin resistance
221
CLINICAL FEATURES
o
Clinical features are not evident until GFR <25 -30 ML/MIM/1.73 m2.

o IF GFR <5 ml/min/1.73m2 then pt become more symptomatic including uremic encephalopathy, nausea, vomiting and edema.
o Azotemia is pt with incr urea and SYMPTOMATIC. While uremia is only urea level incr while ASYMPTOMATIC.
o Main Clinical features are enlisted above.
o Children and adolescents with CKD from chronic glomerulonephritis (membranoproliferative
glomerulonephritis) may present with edema, hypertension, hematuria, and proteinuria.
o Infants and children with congenital disorders such as renal dysplasia and obstructive uropathy may
present in the neonatal period with failure to thrive, polyuria dehydration, urinary tract infection, or
overt renal insufficiency.
o Children with familial juvenile nephronophthisis may have a very subtle presentation with nonspecific
complaints such as headache, fatigue, lethargy, anorexia, vomiting, polydipsia, polyuria, and growth
failure over a number of years.
INVESTIGATIONS:
Following are general investigations , be specific to diagnosed case / new case according to most likely
etiology.
 CBC with peripheral smear ( look for HB%, anemia which may be normocytic normochromic,
microcytic hypochromic, or macrocytic, and Platelate count.
 S/E =( hyponatremia/hypernatremia, hyperkalemia).
 RFT= ().
 Urine CE= for pus cells, specific gravity (which we aspect fixed at 1010 due to loss of concentration
mechanism lead to plasma with same specific gravity being filtered), protein , RBCs, cast, C/S.
 24 Urine collection for Ca+, Ca oxalate , PO4, urea, creatine, protein.
 Serum complement level C3, ANA & anti-DsDNA.
 S.Ca+ =( normal or ).
 S.PO4= ().
 S.Alk PO4= ().
 S.PTH =(N/).
 VIT D3 Level = (N/).
 X-RAY wrist+hand+knee= (for rickets show osteopenic/osteoporetic pic,fractures+/-).
 X-RAY of abdomen.
 Ultrasound abdomen KUB (for calculi, hydronephrosis / size and shape of kidney).
 ECG/ ECHO.
 DTPA & DMSA scanning/ MCUG study.
 Renal biopsy.
MANAGEMENT :
(GENERAL DESCRIPTION FOR LONG CASE)
After establishing my dx I will councell parents regarding disease its course, complications, management
outcome, & my goals of management would be normal routine life of child with free of uremic symptoms and
must be able to involve with usual activities of daily living it need replacing absent or diminished renal
function, to slow progression of renal dysfunction & renal replacement therapy along with optimium
222
nutritional care and prevention from complications and regular follow up monitoring.
I will correct the electrolyte imbalance , anemia by PCV tranx, with good nutritional care with restricted dietry
salt, water, and protein intalke, they have acid base imbalances I will correct metabolic acidosis and prevent by

regular bicarb supplement , correction of HTN, as they have metabolic bone problems I will keep goal to
prevent pain and deformities and treat with regular calcium supplement (CaCO 3 b/w meals and Phosphate
binder (CaCO3 with meals) and will monitor Alk PO 4 for disease activity and treatment and will go for vitamin
D3 supplement with monitoring of trx by serum PTH by keeping aim to maintain level 2-3 times normal,
treatment of uremia by regular hemodialysis , and care of growth by optimum nutrition, monitoring the bone
disease , correction of acidosis and anemia, avoiding high dose steroids & adequate salt intake , if indicated I
will start recombinant human GH with appropriate dose weekly, I will introduce social service and
pschycotherapist and keep my patient on regular follow up initially monthly then evey 2-3 monthly at each
visit I will monitor for vitals and anthropometrics, complications & lab parameters like HB, Ca, PO4, ALK PO4,
URINE C/E +C/S, X-RAY Wrist +knee.
After treatment of acute problems of child I will involve multidisciplinary approach by myself, expert
nephrologist, nutrtionalist, psychotherapist, social service, nursing.
DISCUSSION OF MANAGEMENT:
PRINCIPLES OF MANAGEMNT ARE:
1. Treatment of reversible kidney dysfunction.
2. Prevent or slow the progression of disease.
2. Treat complication of CKD.
4. RRT aftr preparation
5. Monitoring.
1. TREATMENT OF REVERSIBLE KIDNEY DYSFUNCTION:
 DEC renal perfusion (hypotension , shock, sepsis, dec volume, vomiting, diarrhea)
 Nephrotoxic drugs (aminoglycoside, contrast diagnostic , NSAIDs, AmphoterecinB.)
Prevent above factors.

2. SLOW PROGRESSION OF KIDNEY DISEASE.
 Controll of B.P by ACEI, ARB-II.

 Maintain serum phosphorus normal & Ca+ PO4 Product < 55 m2/dl( to decrease calcium deposit
in renal tissue).
 Prompt treatment of infection and dehydration.
 Correct anemia, hyperlipidemia, avoid obesity, limit use of NSAIDs, smoking.
 Although dietary protein restriction has been shown to be useful in adults, this recommendation is
generally not suggested for children with CKD because of the concern of adverse effects on growth and
development.
3. TREATMENT OF COMPLICATIONS:
223
 FLUID & ELECTROLLYTE BALANCE.

 All ESRD pts regardless of any cause require fluid restriction while in CKD It may
not due to 2 groups of pts may be there: pt with glomerular cause other with
structural or tubular defects.
 SALT & FLUID RESTRICTION (GLOMERULAR CAUSE)
 Advise ‘’ no added salt ‘’ but do not totally restrict.
 In all ESRD and advanced CKD we do .
 In ESRD (on dialysis pt)  they are hyperosmolarincrease thirst even
with intravascular volume increased inc fluid intake leads to edema , fluid
overload, hypertension & wt gain with consequence to CCF.
 HIGH SALT & FLUID INTAKE ( STRUCTURAL/ TUBULAR DEFFECT)
 Require high fluid intake ans sodium supplement.
 CKD Due to congenital renal disease fall in this froup.
 Amount calculated by urinary Na excretion and weight gain.
Note: we decide pt fall in which group among above on the basis of hx which will suggestive of salt
craving, excessive water intake at night time as well, polyurea, B,P, edema, weight gain, urinary Na
excretion.
 HYPERKALEMIA.
 K+ > 7  Emergency
 K+ > 5  dietary potassium restriction.
o TREATMENT:
 Restrict K+ in diet and ongoing fluids.
 Calcium gluconate/ chloride 10% i.v over 2-5 min under ECG monitoring (
cardioprotective by modifying myocardial cell action potential and protect for 30
min).
 NaHcO3 i.v over 30 min alkalosis shift K in cell. (Effective for 2 hours).
 Infusion of 50% dextrose + insulin 0.1 unit/kg over 30 min shift K in cell ( effect
last 2 hrs).
 Salbutamol nabulization/ i.v (rapidly effective and last more).
 Sodium polystyrene sulphonate orally in 70% sorbitol/water. Or if given rectally
then in 1% methylcellulose suspension or 20 % sorbitol. (This bind K+ with ion
exchange resin. It take 2 hours to effect and last 4-6 hrs) ( kayoxalates)
 Acute dialysis
 If not managed a child with chronic hyperkalemia off course definitive treatment is
dialysis and renal transplantation.
Q: Hw hyper or hypokalemia manifest & what ECG changes u expect in both?

(Examiner Q)
A: hypokalemia manifests as muscle weakness,muscle cramps,arrhythmias,flaccid

paralysis, hyporeflexia, respiratory depression where as hyperkalemia
malaise,palpitation,arrhythmias ,sudden cardiac arrest.
ECG: ↓K=depression of ST segment,T wave inversion,prolonged PR interval,large U

wave
K↑=Tall Twave, wide QRS complex,↓size of P wave

224
 HYPERTENSION:
 Fluid overload is the main cause of CKD.
 IT is common in oligouric form of CKD (chr. GMN, HUS, reflux)
 Its tight control is important for slow progression of CKD.

 As fluid overload is the main cause of HTN in ESRD until proved otherwise so pts
who are on dialysis do not require anti hypertensive as they get rid off fluid overload.
If used anti hypertensive along with dialysis they will deteriorate further GFR and
complicate dialysis Due to vasodilation.
 ACEI & ARBs are not used in ESRD they further decline GFR.
o IN CKD HTN:
 Salt restriction 2-3 gram/day.
 Diuretics
 Stage 1-3 thiazide DOC
 Stage 4 loop diuretics DOC. (lose effect when 70% renal function lost.)
 ACEI & ARBs ii  DOC for CKD with proteinura as they prevent
progression of ESRD ( REMEMNER PATHOGENESIS).
 Other drugs : Calcium channel blockers (amlodipine), β blockers
(propranolol, atenolol), and centrally acting agents (clonidine) may be
useful as adjunctive agents in children with CKD whose blood pressure
cannot be controlled using dietary sodium restriction, diuretics, and ACE
inhibitors.
 Amlodipine is better for long term control of B.P 5 mg tablet just dissolve in
calculated water and then required dose given.
 Nifedipine is better for reflux induced but due its breaking off tablet it
become short acting agent so difficult to titrate dose in small children.
ESCAPE trial (Effect of Strict B.P Controll & ACE inhibition on Progression of CRF in pediatric patients.
Concluded by using the fixed dose of ramipril , ADVISED anti-RAS antihypertensive preffereably, that
th
by keeping B.P below 50 centile leading to 3-5 yr delay in CKD, & Optimium B.P control improves 5 yr
renal surviver by 35% in children with CKD.
 Hypertensive emergency: HTN+ its complications/ENCEPHALOPATHY

 Hypertensive urgency: only severe HTN.
 RENAL OSTEODYSTROPHY: (Renal rickets+hyperparathyroidism)

CAUSE : (examiner Q)
Impaired renal production of 1, 25-dihydroxycholecalciferol
Hyperphosphatemia
Hypocalcemia
Metabolic acidosis
ROD
________________________________________
 
HIGH TURNOVER BONE DISEASE (DYNAMIC BONE DS) LOW TURNOVER BONE DISEASE (ADYNAMIC B DS )
 
OSTEITIS FIBROSA CYSTICA OSTEOMALACIA
 
GFR decline 50% 0R CKD III  ↑ INTAKE OF Ca+, PO binders,or vit D,immobility
 
- Activation of vitamin D. SUPPRESSION OF PTH
-  Intestinal Ca absorption  225
-  PTH activity --corrects Ca by bone resorption
DEMINERALIZATION OF BONE
GFR decline to 25%  dec PO4 urinary excretion


Hyperphosphatemia
↓
Further ca+

 PTH (HYPERPARATHYROIDISM)

RENAL OSTEODYSTROPHY
NOTE:(ostietis fibrosa cystica is advanced skeletal manifestation of sec:hyperparathyroidism,when PTH

increase as given above in chart stimulates osteoclasts that breakdown bones to release ca+ in blood thus
increase its level in blood & calcified bone is now replaced by fibrous tissue which weakens softens bone forms
cysts ,decrease bone mass & leads to fractures)
Osteomalacia= also called Adult rickets.
Calciphylaxis: soft tissue calcification if serum PO4 level too high (ca PO4 ratio >56) , cause ischemic necrosis of
muscle , skin and subcutaneous tissue, some time visceral calcification—pulmonary involve—restrictive lung
disease.
CLINICAL FEATURES: (examiner Q) muscle weakness, bone pain, deformity, fractures, growth retardation,
slipped epiphysis, bowing of legs, knock knees, defective enamel, and malformed teeth.
DIAGNOSIS:
 Vitamin D3 level (n/ dec).
 S.Ca level (N/dec)
 S.PO4 level (inc)
 S.alk PO4 level (inc ++)
 Serum PTH level (N/Inc).
 X-ray wrist, knee, and hands. (rachitic changes like cupping , splaying, bowing, fraying, increase
epiphyseal & metaphyseal distance at proximal tibia and distal femur+ secondary
hyperparathyroidism changes includes thin bones+ fractures+ cysts+ subperiosteal resorption +
st nd
widening of metaphysic + generalized ospteopenia at Radial 1 & 2 digit). (examiner Q)
Note: weight bearing bones are most affected like hips, knee, ankles annual x-ray advised.
TREATMENT:
CONTROLL OF SERUM PHOSPHATE: (treat hyperphosphatemia before correction of calcium because it alone
may lead to rapid decline in renal function)
 LOW PHOSPHATE IN DIET (Avoid nuts, ice cream, beans, milk/ dairy products).
 PO4 BINDERs
 CALCIUM BASED: ( INCREASES calcification so try to use non ca based)
 CaCO3 with food. (TAB-QALSAN 500 mg (chewable) dose=
1500mg/m2/day.) Keep PO4 5.5 mg/dl. It increases calcium, dec PO4,
antagonize acidosis.
 Ca++acetate.
 NON-CALCIUM BASED:(cause few hypercalcemic episodes)
 Sevelamer=( ca+Al free) (50 Rs Tablet, expensive comparatively advised
when pt refractory to CaCO3. 226
 Aluminum compound.(may cause aluminum encephalopathy)
NOTE: All bind with PO4 excreted in GIT so causes constipation

CALCIUM SUPPLEMENT:

 CaCO3 Give between meals
VITAMIN D SUPPLEMENT
 1,25 (OH)2 D3 (Calcitriol) once a day, / pulse therapy 2-3 times a week.
 IF  25 OH VIT D Then treat with ergocalciferol.
 IF NORMAL 25 OH VIT D BUT  PTH treat with calcitriol (0.01-0.05
ug/kg/day.
Indication of vitamin D:
 25 OH VIT. D Level below that particular stage of CKD.

 Increase PTH level above that CKD Stage.(secondary hyperparathyroidism)
(NB)
Note : Alk PO4 & Serum PTH is used to monitor the treatment response & our aim is to keep PTH the
twice upper limit of normal , higher level indicate healing and risk of overshooting with resultant
hypercalcemia and low level is associated with adynamic bone disease.
NOTE:
 ergcalceferol D2=plant source

 Cholocalceferol D3=sunlight source
 Calcidiol is 25 vit D either 2or 3 (liver form)
 Calcitriol 1,25 vit D 2 or 3(active or kidney form)
PARTIAL PARATHYROIDECTOMY
REGULAR DIALYSIS
Renal osteodystrophy and pseudohypoparathyroidism present with similar biochemical abnormalities only ALK
po4 differentiate which is highr in ROD while normal in Pseudohypoparathyroisdism.
Advisable monitoring of trx  annual X-RAY of long bones, PTH, s.po4. (examiner Q)
condition appearanc calciu Phosphoru Alk:ph PTH Clinical

e m s 4 feature
s
hypoparathyroidism No skeletal ↓ ↑ normal normal
changes
pseudohypoparathyroidism Skeletal ↓ ↑ normal ↑
changes
Pseudopseudohypoparathyroidism/varia Skeletal Normal Normal Normal Norma
nt of Mc Albright changes l
Renal osteodystrophy Skeletal ↓ ↑ ↑ ↑
changes
Osteomalacia/Rickets Skeletal ↓ ↓ ↑ ↑ Softens
changes bone
Osteitis fibrosa cystica Skeletal ↑ ↓ ↑ ↑ Brown
changes tumors
Osteoporosis/osteopenia Skeletal Normal Normal Normal Norma ↓ bone 227
changes l mass
Osteopetrosis/marble bone disease Skeletal changes Normal Normal ↑ Normal

ACIDOSIS: (common cause of arrrythmias in CKD) examiner Q
 It may be acute / chronic both differ in managent.

 It is Due to inability to excrete H+ or inability to retain bicarb
 (Normal production=2-3meq/kg/day).
 In response to acidosis bone salts act as buffer s maintain bicarb level between 14-
18 mEq/L.
 Acute svere acidosis: Rx: dialysis preferred. (coz pts are often fluid overloaded &
HTN, So bicarb will be not effective so much.
 Chronic acidosis: Rx: alkali 2-3 meq/kg/day. If intractable then dialysis. Aim is to
keep NaHco3 level >22meq.
 Tab: sodamint 325mg/650mg (4meq/8 meq)
 NAHCO3 SOLUTION 1ml of 8.4%=1mmol.
Note : pt with ESRD on dialysis don not need Bicarb supplement coz dialysis alone
corrects acidosis.
STATURE / GROWTH RETARDATION
 Poor nutrition / calorie intake.

 Anemia
 Acidosis
 Renal osteodystrophy
 GH resistance.(b/c ↓IGF protein 3 excretion bind more with IGF so less available for growth)
 Infection.
 Salt wasting
 Disease onset from infancy
 Iatrogenic (steroid Rx).
 Polyuria
TREATMENT:
Optimum nutrition , monitoring the bone disease , correction of acidosis & anemia, avoiding high dose steroids
and adequate salt intake may improve growth.
RhGH therapy.
2
Indications of rhGH: 1). GFR <30ml/min/1.73 m
th
2). Height < 25 centile for age.
th
3). Height velocity is below 25 centile for bone age.
2
Dose of rhGH: 0.05 mg/kg/day S/C to max dose of 28 unit/m /week.
th
RhGH Continue till  1). Ht reaches 50 percentile for MPH.
2). Reaches adult ht.
3). Renal transplantation.
4). Epiphyseal closure.
th
RhGH may be discontinued during therapy if fail to achieve atleast 50 centile for bone age within 6 months
Side effects of rhGH: 1) hypercalciuria
2). Aseptic necrosis of femoral head (SCFE).
3). Pseudo tumor cereberi
4). Malignancy induction.
5). Scoliosis
6). Gynaecomastia 228
7). Type 2 DM
NUTRITION: (common Examiner Q)

Calories 100 % (75% carb, 20% fats, 5% proteins)
Carbohydrates 10 g/kg/day
Fats 4 g/kg/day
Protiens 2.5 g/kg/day
LOW NA, LOW K, LOW PHOSPHATE DIET,↓ PROTIENS &↓ FLUIDS
 Use small glasses for drinking, make ice cubes to suck, cold quench better (↓FLUIDS)
 Avoid salty food (Na ↓) ,discourage for tomato, potato, orange, spinach, cold drink like coke, coffee,
tea at meals, dates, fresh juices, banana & other citrus fruits (K+ RESTRICTION), and limited use of
milk, nuts, chocolates, liver, beans , yogurt, cheese ,ice cream ,pudding (Po4 ↓)in addition to I will
supplement iron, zinc, calcium, water soluble vitamins but fat soluble vitamins usually not required
like A,K,E b/c not removed by kidneys nor by dialysis.
 Low K & low phosphate diet include White rice, white egg, barley non diary creams, non cola drinks,
apple,carrots, pine apple, cabbage ,berries & cucumber can be given
 If CKD is advanced and dialysis is imminent as like in stage 4 then protein restriction may be used to
keep urea at acceptable level.
 In children protein restriction not advised because of growth however proteins of high biological value
with RDA 2.5 g/kg/day are advisable like as above
 Milk has high phosphate contents so limited intake advised however certain especial infant formula are
available with low phosphate, and high calorie, high salt contents.
 Dont use espaecial energy supplements like Ensure, osmolyte , as they have high protein and phosphate
content.
 Infant Similiac 60/40 can be advisable coz hav low PO4 Content.
 If fluid restriction is needed like in glomerular disease avoid high volume and replace to high energy
supplemts like suplena / energy plus.
 If fluid restriction is not the problem like in structural defects / dialysis pts then give supplememtal
feeds by NG @ night also.
 Nutritional supplements doesnot catch up growth but just stablise the growth rate.
ANEMIA: (common examiners Q)
o Decreased erythropoietin production

o Iron deficiency
o Decrease oral intake, anorexia, occult GI blood loss due to bleeding tendecy
o Folate deficiency
o Vitamin B12 deficiency
o Decreased erythrocyte survival
o B.M fibrosis due to PTH
INDICATIONS OF ERYTHROPOIETIN:
1). Hb % fall< 10 g/dl.
2). CKD stage iii-iv.
3). Symptomatic anemia.
229
PRE REQUISITE
 Adequate folic acid & vit B12.

 Adequate iron reserve & ferritin 20%

 PTH normal
 No infection
MOA: EPO Inc terminal differentiation of erythroid progenitor cells + inc cellular HB synthesis + inc retics
release from B.M
DOSE: 50-150 mg/kg/dose given subcutaneous 1-3 times /week. Dose adjusted to maintain HB between 12-
13 mg/dl along with oral or i.v iron supplement.
R-HuEPO is given with dose of 50 ug/kg/dose in a child with no dialysis however dose is doubled 80-100
ug/kg/dose when on dialysis
ROUTES: 1). S/C 2). I.V (Less effective than s/c) 3). Intra peritoneal (I/P).
AVAILABLE FORMS OF ERYTHROPOETIN: 3
 EPOEITIN ALPHA (EPREX) –(2-3/wk, given S/C, or IV on dialysis days).
 DARBAPOETIN APLHA (ARANESP)—(S/C /I.V, longer ½ life can be used once/wk or

once fortnightly or monthly, main problem is pain at injection site .Dose 0.45mcg/kg/week
 EPOETIN BETA (NEORECORMON)—(Once/week, less painful than darbapoetin alpha).
ADVANTAGES OF R-HuEPO : 1). Avoidance of transfusion and decrease chances of transfusion related
infection
SIDE EFFECTS OR DISADVANTAGES OF R-HuEPO:
1). Cost
2). HTN
3). Hyperkalemia
4). Iron deff anemia/ pure red cell aplasia.
5). Vascular acess thrombosis.
CAUSES OF FAILURE OF ERYTHROPOEITIN RESPONSE/ STILL ANEMIC CHILD ( ERYTHROPOEITIN RESISTANCE).
1). Iron deficiency anemia / folic acid / B12 deficiency anemia.
2). Blood loss.
3). Hyperparathyroidism ( PTH RESISTANCE).
4). Inflammation/ infection.
5). Improper dose/ faulty technique.
6). Compliance
230
7). Antibodies against erythropoietin formed.
 So it is advisable to check for serum iron level, TIBC, transferring saturation, serum PTH ,
 if transferring saturation (<20%) iron deficiency replace iron (ORAL/ I.V iron sucrose)

IMMUNIZATION:
Child should receive all scheduled standard immunization.
Withhold live attenuated vaccine in glomerulopathies who are on immunosuppresion therapy, but
recommended at low physiological doses/ on alternate tapering therapy of steroids.
MMR can be given before renal Transplantaion as not advisable in immunosupressed pts.
HbSAg vaccine given before transplant given in double dose than normal.
All children should receive yearly influenza vaccine.
ADJUSTMENT OF DRUG DOSES:
Nephrotoxic drugs like aminoglycoside and sulphonamides.
Adjust by either decreasing the dose or by lengthening time interval.
RENAL REPLACEMENT THERAPY:
 MAY BE DIALYSIS OR RENAL TRANSPLANTAION.

th
DIALYSIS (only waiting for renal transplant). It only provides around 1/10 clearance function
of
normal kidneys.
INDICATIONS:
2
1).Usually started when GFR <15ml/min/1.73m (CKD 5)
2).Failure to control by medical treatment of complications (HTN enceph, hyperkalemia, uremic

enceph, fluid overload, uremic pericarditis, urea < 100-150 or rapid rising trend) .
TYPES OF DIALYSIS:
 Hemodialysis
 Continuous ambulatory peritoneal dialysis (CAPD).
 Automated peritoneal dialysis (APD) or Continuous cycling peritoneal dialysis (CCPD).
CAPD
ADVANTAGES:
 Less painful
 Simple & cheap
 Home treatment easily done.
 Continuous dialysis.
 U can do it alone at any location any time to complete exchanges 231
 Don’t need a machine nor have to travel to a center for dialysis
 No ups & downs as in dialysis
DISADVANTAGES:

 No day off.
 Risk of peritonitis.
 Requirement of repeated correction & disconnection.( change of bags 3-4 times/day).
o Volume of dialysis fluid installed is 40-60 ml/kg depend ipon tolerance.
o Fluid remain in peritoneal cavity during day and cycles started in night 5-8 cycles usually.
o Bag size available are 500ml, 1000 ml, 1500 ml, 2000 ml.(prefilled)
o Available solution strength ( different glucose concentration) are 1.5%, 2.3%, 4.25%.
APD/ is form of CCPD:
o Admit pt in hospital & It is performed by inserting peritoneal (tenckhoff) catheter then teach pt and
parents in management of APD/CCPD for 3 weeks.
o Cathater used have life averaging about 9 months.
ADVANTAGES:
 Only one connection or disconnection.

 U can do it at night
 Less risk of infection.
 Decrease time demand on family during day period
 CCPD is associated with best growth, best control of anemia & best pt tolerance.
DISADVANTAGES:
 Peritonitis. (1 in 8 pts months or three times every 2 years)

 Catheter blockage.
 Negative body inage.
 Exit & catheter tunnel infection.
 You need a machine
SIGNS OF PERITONITIS IN CAPD/ APD: abdominal pain, cloudy fluid go for C/S of P.D fluid should be
obtained and I/P antibiotics cephazolin & gentamycin OD should be started. Usually cause is staph aureus
staph epidermidis.
HAEMODIALYSIS:
o 5 Hour session (depend upon condition) cumulative 15 hrs/week.

o 3-4 times/week initially 1-2 hrs & then gradually build to 4-5 hrs/day.
Access:
 Central venous double lumen catheter or simply hem dialysis catheter.

 AV fistula.
Pre-requisites:
 HB level >10 G/dl.

232
 platelets >1 lac,
 Hbs Ag, Anti HCV,
 weight ideal 15 kg

ACUTE COMPLICATIONS OF CKD pt UNDERGOING H.D:
 Hypotension.
 Hypocalcemic tetany.
 Electrolyte imbalance
 Infection (hepatitis B so we go for vaccination before dialysis)
 Disequilibrium syndrome.(b/c more urea is removed from blood than CSf so causes
this)
 Peripheral neuropathy in long term cases
 DEVICE RELATED COMLICATION—Block/ thromboembolism.
AV FISTULA:
SITE: left arm is usually used because if any complication of procedure then rigt arm can be
saved.
 wrist (radial artery & vein)

 Elbow ( brachial artery & vein)
 Groin (femoral artery & vein).
Precautions: do not prick; take B.P prior & after fistula in corresponding limb.
Advise: at least 1 month before fistula formation do exercise with a small ball in hands so that good
blood supply and collaterals can be formed.
COMPLICARTION OF FISTULAE:
 High cardiac output failure

 Aneurysm
 Rupture
 Empty Arm compartment syndrome
 Arm length discrepancy
RENAL TRANSPLANTATION:
PRE-EMPTIVE TRANSPLANTATION: children who undergo renal transplantation as their RRT, before reaching to
ESRD / dialysis.
If available living related donor it is performed USA procedure of choice with good results.
CANDIDATES IN WHICH RENAL TRANSPLANATION NOT HELPFUL:
 Oxalurea
 Cystinosis.
 FSGS (20-40% Recurrence).
 MPGN-II (90%-100%) (While in type-70 %)
233
CONDITIONS IN WHICH RENAL TRANSPLANATION DONE:
 Obstructive uropathy.
 SLE nephritis (5-10% recurrence).
 Alport syndrome. (5-10% recurrence).

Renal transplantation is done from
 Living related donor

 Cadaveric donor (deceased donor)
Living related donor  compatible ABO blood grouping & HLA matching.
 Transplant survival rate is

o 90% at 1 yr.
o 85% at 2 yr.
o 75 % at 5yr.
 Cadaveric donor survival rate is
o 76% at 1 yr.
o 71% at 2 yr.
o 62% at 5 yr.
CRITERIA FOR PERFORMING RENAL TRX:
o Renal failure, chronic/ESRD.

o Age & wt dependant to accommodate, (at least 15 kg wt).
o Adult kidney transplant.
o Good nutritional condition.
o Absence of other chronic condition or systemic illness.
o < 2yr transplantation have poor survival rate because of effects of
immunosuppressive therapy & small space for kidney.
PREREQUISTIES FOR RENAL TRANSPLANTATION FOR RECIPIENT:
o ABO Matching
o HLA matching
o Immunosuppression.
o Pre-transplantation immunization with MMR, VARICELLA.
o CBC, compliment, hepatitis , CMV ,EBVserology.
PREREQUISTIES FOR RENAL TRANSPLANTATION FOR DONOR:
o ABO matching.
o HLA matching.
o Hepatitis, CMV, EBV, Other infection screening.
o RFTs, urine CE, renal USG.
PRETRANSPLANT NATIVE NEPHRECTOMY: before transplantation native kidney one or both are removed to
make space or room for transplant of kidney, performed if any disease going to damage the kidneys.
POST TRANSPLANTATION MANAGEMENT:
o Immunosupression given for long term with prophylaxis against opportunistic infections (septran
prophylaxis against PCP ( 1 month usually)& Gancyclovir for CMV if +ve then give for 3 months). 234
INDUCTION THERAPY: biological agents (ATG/DACLIZUMAB->ANTI-IL2).
MAINTAINCE THERAPY: steroids, tacrolimus, MMF, azathioprine, cyclosporine.

o Most children we suspect rejection because of rising creatinine & is recognized by renal bx.
o Most standard trx is prednisolone+MMF+CSA.
o Quadraple regime: prednisolone+MMF+Tacrolimus+bassiliximub.
o After transplantation keep pt in hospital for 15 days then daliy exam for 1 month
POST RENAL TRANSPLANT FOLLOW UP:
 Check growth & B.P (HTN 85% of tx).

 Look for opportunistic infection.
 Metabolic workup, RFTS, cbc, BONE x-rays
 S/E Of drugs (Cushing  steroids) ( cyclosporine hypertrichosis,gingival
hyperplasia) (MMFdiarrhea/pain in abdomen)
 Malignancy (lymphoma/skin cancer).
 Recurrence.
 Rejection.
ALLOGRAFT LOSS:
 chronic rejection /tender graft,fevr.inc creatinine , increase WBCs. ( 1st

Most common/ no therapy yet)
 Acute rejection (2nd most common cause) Rx high dose steroids 1year
 Vascular thrombosis (3rd most common/calcineurin inhibitor risk dec)
 Recurrent disease. (FSGS-> Common /grft loss quickly.)
POST TRANSPLANT COMPLICATIONS:
 ATN
 Rejection necrosis
 Recurrence of original renal disease.
 Infection (CMV, PCP).-> most common cuase of death within 1 yr.
 Bleeding.
 Malignancy.
------------------------------------------------------------------------------------------------------------------------------------------
HTN EMERGENCY/CRISIS:
TH
severe symptomatic elevated B.P >95 Centile with evidence of acute target organ damage.
Brain  seizures, raised ICP.
Kidney renal insufficiency.
Eyes  papilledema/ retinal hemorrhage.
Heart LV dysfunction.
TREATMENT:
th st
Do not lower B.P >25 % of measured in 1 8 hr.
Mean arterial pressure should be lowered by following:
rd
1/3 in first 6 hrs.
rd
1/3 in next 24-36 hr.
rd 235
1/3 in next 48 hr.
- CCB/ alpha/beta blockers.
- Hydralazine (i.v vasodilator).

HTN URGENCY:
severe elevation of B.P without symptoms / end organ damage.
TREATMENT: Oral anti HTN: nifidipine, clonidine, captopril.
MAP should be lowered by following:
 20% over 1 hr.
 Return to baseline over 48 – 72 hrs.

MALIGNANT HTN: marked HTN with retinal hemorrhage, exudates, or papilledema. (Usually chronic),
HTN ENCEPHALOPATHY: severe HTN with cerebral edema & neurological symptoms of lethargy coma /
seizures.
HYPERTENSIVE RETINOPATHY:
 GRADE-I  arteriolar constriction & silver wiring.

 GRADE-II Grade I findings+ AV nipping+ Boneutt sign.
 GRADE-III Grade ii+ cotton wool exudates+ flame hemorrhage
 GRADE-IV Grade iv + papilledema.
NEUROGENIC BLADDER:
 ATONIC ( off n on Urinary incontinence which is overflow/ dry trouser in btw/ mass in abdomen+ ) 
UTI PYELONEPHRITIS ESRD.
 HIGH PRESSURE( all time incontinence/no mass in abdomen/bladder/wet trouser UTI+ VUR
ESRD.
POSTERIOR URETHRAL VALVE (PUV):
 The most common cause of severe obstructive uropathy in children is posterior urethral
valves, affecting 1 in 8,000 boys.
 The urethral valves are tissue leaflets fanning distally from the prostatic urethra to the
external urinary sphincter.
 A slit-like opening usually separates the leaflets.
 Approximately 30% of patients experience end-stage renal disease or chronic renal
insufficiency.
 The prostatic urethra dilates, and the bladder muscle undergoes hypertrophy.
 Vesicoureteral reflux occurs in 50% of patients.
 and distal ureteral obstruction may result from a chronically distended bladder or bladder
muscle hypertrophy.
 The renal changes range from mild hydronephrosis to severe renal dysplasia.
DIAGNOSIS:
PRENATAL maternal ultrasonography reveals bilateral hydronephrosis, a distended bladder, and, if the
obstruction is severe, oligohydramnios.
Rx : . Prenatal bladder decompression by percutaneous vesicoamniotic shunt or open fetal surgery has been
reported
236
when discovered in the second trimester, carry a poorer prognosis than those detected after birth.
POSTNATAL: palpable distended bladder and the urinary stream is weak, With lesser degrees of obstruction,
children present later in life with difficulty in achieving diurnal urinary continence or with UTI. If the
obstruction is severe and goes unrecognized during the neonatal period, infants may present later in life with
failure to thrive due to uremia or sepsis caused by infection in the obstructed urinary tract. Dx by VCUG or

perineal ultrasonography.
Better prognosis
RX: after confirming dx check RFT, USG (To detect anatomy of upper urinary tract).

Pass NG tube for several days.
 
If RFT normal / return to normal if RFT deranged or inc despite bladder drainage(irreversible renal
damage,renal dysplasia
  
Urethra small Urethra normal length Vesicostomy.
 
Temporarly vesicostomy Transurethtral ablation of valve leaflets.

When older then valve ablation & close vesicostomy.
After valve ablation: prophylaxis required (coz hydronephrosis persist for many years).
+ annual USG, examination, B.P, urine C/E, S.E, RFTs.
Usually these kids do not achieve diurnal continence as other boys however they
achieve after puberty usually.
Favorable prognostic factors
normal prenatal ultrasonogram between 18 and 24 wk of gestation.
 a serum creatinine level <0.8–1.0 mg/dL after bladder decompression.
visualization of the corticomedullary junction on renal sonography.
Unfavorable prognostic factors include the presence of
oligohydramnios .
 hydronephrosis before 24 wk of gestation.
s. creatinine level >1.0 mg/dL after bladder decompression.
 cortical cysts in both kidneys.
persistence of diurnal incontinence beyond 5 yr of age.
 In several situations, a “popoff valve” may occur during urinary tract development, which preserves
the integrity of one or both kidneys. For example, 15% of boys with posterior urethral valves have
unilateral reflux into a nonfunctioning dysplastic kidney, termed the VURD syndrome (valves,
unilateral reflux, dysplasia). In these boys, the high bladder pressure is dissipated into the
nonfunctioning kidney, allowing normal development of the contralateral kidney. 237
 In newborn boys with urinary ascites, the urine generally leaks out from the obstructed collecting
system through the renal fornices, allowing normal renal development.
 A Foley (balloon) catheter should not be used, because the balloon may cause severe bladder spasm,
which may produce severe ureteral obstruction.

 Many boys have significant polyuria resulting from a concentrating defect secondary to prolonged
obstructive uropathy.
 Incontinence may result from a combination of factors, including uninhibited bladder contractions,
poor bladder compliance, bladder atonia, bladder neck dyssynergia, or polyuria.
ANTERIOR URETHRAL VALVES AND URETHRAL DIVERTICULA IN THE MALE
 rare.
 The obstruction is not obstructing valve leaflets as occurs in the posterior urethra., but it is a urethral
diverticulum in the penile urethra that expands during voiding.
 Distal extension of the diverticulum causes extrinsic compression of the distal penile urethra, causing
urethral obstruction.
 Typically there is a soft mass on the ventral surface of the penis at the penoscrotal junction+ urinary
stream often is weak, findings associated with posterior urethral valves often are present.
 DIAGNOSIS: physical examination confirmed by the VCUG.
 TREATMENT: open excision of the diverticulum or transurethral excision of the distal urethral cusp.
VESICOURETERAL REFLUX:
(Most likely he is the case of ESRD/CKD secondary to VUR because as my pt had hx of repeated urinary tract infection by
hx of recurrent febrile illness since birth with no obivious other cause, However even without fever / recurrent urinary
tract infection pt may have VUR, which is some time family hx related that may lead to ESRD/CKD in 20% pts.)
Definition: Retrograde flow of urine from the bladder to the ureter and renal pelvis is referred to as
vesicoureteral reflux.
 The ureter enter bladder in an oblique direction, perforating the bladder muscle (detrusor) laterally and
proceeding between the bladder mucosa and detrusor muscle, creating a flap-valve mechanism that
prevents reflux.
 Reflux occurs when the submucosal tunnel between the mucosa and detrusor muscle is short or absent.
Reflux usually is congenital, occurs in families, and affects approximately 1% of children.
 Reflux nephropathy: scaring of the kidney after inflammatory reaction due to bacteria after VUR.
 Reflux nephropathy once accounted for as much as 15–20% of end-stage renal disease in children and
young adults
Classification.
 Reflux severity is graded I to V and is based on the appearance of the urinary tract on a contrast
voiding cystourethrogram (VCUG).
 Reflux may be primary or secondary.
 Primary vesicoureteral reflux  congenital incompetence of valvular mechanism of VUJ.
 Primry+ other malformations of VUJ i.e urethral duplication, uretrocele, ectopic ureter.
 Secondary due to increase intravesicle pressure (neuropathic bladder/ BOO).
 Secondary to inflammatory process like cystitis, F.B, vesical calculi.
Grading of vesicoureteral reflux.
Grade I: reflux into a nondilated ureter.

238
Grade II: reflux into the upper collecting system without dilatation.
Grade III: reflux into dilated ureter and/or blunting of calyceal fornices.

Grade IV: reflux into a grossly dilated ureter.
Grade V: massive reflux, with significant ureteral dilatation and tortuosity and loss of the papillary impression.
 Among children with reflux, 80% are female, and the average age at diagnosis is 2–3 yr.
 Reflux is present at birth in 25% of children with neuropathic bladder, as occurs in

myelomeningocele, sacral agenesis, and many children with a high imperforate anus.
 Reflux also is seen in 50% of boys with posterior urethral valves.
 Low pressure/passive reflux: reflux during bladder filingless chance of spont. Resolution.
 High pressure/active reflux reflux during voiding good chance of spontaneous resolution.
 Reflux appears to be an autosomal dominant inherited trait.
 Approximately 35% of siblings of children with reflux also have reflux, and reflux is found in nearly
half of newborn siblings.
 The likelihood of a sibling having reflux is independent of the grade of reflux or sex of the index child.
Approximately 12% of asymptomatic siblings with reflux have evidence of renal scarring.
Consequently, many believe that siblings of children with reflux should be screened even if they have
not had a UTI. In addition, 50% of children born to women with a history of reflux also have reflux.
Screening with a radionuclide cystogram of all siblings 3 yr or younger and any sibling with a UTI is
appropriate.
DIAGNOSIS:
 VCUG
o Radionucleotide less exposure to radiation compare to contrast.
o Contrast better anatomy.
 INDIRECT CYSTOGRAPHY (I.V contrast wait in bladdermicturate reflux).
 USG
 DMSA (Scaring).
NATURAL HISTORY:
 With bladder growth and maturation, there is a tendency for reflux to resolve or improve over time.
 Factors favouring reflux resolution are:
 Low grade of reflux.
 Unilateral
 Younger age at dx
Mean age of reflux resolution is 6 yr.
Grade i-ii  spontaneous resolution.
Grade iii  unilateral + young age  resolution.
Bilateral  surgery.
Grade iv-v surgery.
Although reflux is less likely to cause renal injury without infection but certain high pressure reflux such as
secondary to PUV, neurogenic bladder OR Hinman syndrome their sterile reflux can cause renal damage. 239
TREATMENT:
MEDICAL: prophylaxis for UTI , hoping to resolve spontaneously+ Rx of voiding dysfunction & constipation.

SURGICAL: when medical Rx fail or grade iii-iv reflux.
Medical measures:  Successful  failure
 Prophylaxis remain free of infection. UTI breakthrough

 Urine C/E no new scaring  new scar
 VCUG 12-18 monthl reflux resolve spontaneously.  No resolution
 UT imaging
SURGERY: OPEN/ LAPAROSCOPIC/ CYSTOSCOPIC.( needle with cystoscopego to submucosal plane deep to
urethral orifice  injected bulking agent)
URETEROPELVIC JUNCTION OBSTRUCTION:
 USG shows grade 3-4 hydronephrosis without dilated ureters.

 Presentations: maternal USG finding+, mass in newborn/infant, abdominal or flank pain, hematurea.
 60% Left sided, M:F 2:1, 10% B/L, May impair renal function due to pressure atrophy.
UPJ OBSTRUCTION
(A/N USG dilated renal pelvis/ hydronephrosis).

rd rd
Repaeat USG at 3 day of life (3 coz neonatal oligourea-temporarly decompression of pelvis)
O
+ Also do VCUG to R Unilateral VUR.

  
NO dilatation G 1-2 hydronephrosis G 3+> Hydronephrosis
  
Repeat at 1-2 month start prophylaxis amoxicillin <2 m/TMP Start prophylaxis +
+ Serial USG + MAG3 scan(4-6 wk)
 
Usually hydronephrosis disappears. 
_______ _____________________________________
 
Normal MAG3 scan poor drainage/differential rnl
function
 
Serial USG even grade 4 hydronephrosis + prophylaxis pyeloplasty.

No improvement in hydronephrosis

Repeat MAG3 scan T 6-12 Month of age.
Management: prophylaxis + pyeloplasty (success 90-98%).
Indications for prompt surgery:

 abdominal mass.
 B/L severe hydronephrosis.
 Solitary kidney.
 Dec function in involved kd. 240

URINARY LITHIASIS
CALCIUM
STONES
CYSTEINE
STONE
STRUVITE
STONE
URIC
ACID
STONE FORMATION: Most “spontaneous” stones are composed of calcium, oxalate, or phosphate crystals;
others are due to uric acid, cystine, or ammonium crystals, or phosphate crystals, or a combination of these
substances.
CALCIUM STONES (CALCIUM OXALATE AND CALCIUM PHOSPHATE) * COMMONEST
 Hypercalciuria
 Absorptive
 Renal leak
 Resorptive
 Distal renal tubular acidosis, type 1 (calcium phosphate)
 Hyperparathyroidism
 Sarcoidosis
 Furosemide administration
 Vitamin D excess
 Immobilization
 Corticosteroid administration
 Cushing disease
 Hyperuricosuria
 Heterozygous cystinuria
 Hyperoxaluria (calcium oxalate)
 Primary hyperoxaluria, types 1 and 2
 Secondary hyperoxaluria
 Enteric hyperoxaluria
 Hypocitruria
 Renal tubular acidosis.
CYSTINE STONES
 Cystinuria
STRUVITE STONES (MAGNESIUM AMMONIUM PHOSPHATE)
241
 Urinary tract infection (urea-splitting organism)
 Foreign body
 Urinary stasis
URIC ACID STONES

 Hyperuricosuria
 Lesch-Nyhan syndrome
 Myeloproliferative disorders
 After chemotherapy
 Inflammatory bowel disease
INDINAVIR STONES
NEPHROCALCINOSIS
Urine also contains inhibitors of stone formation, including citrate, diphosphonate, and magnesium ion.
Radiopaque stones: calcium, struvite.
Radiolucent: cysteine, xanthine, uric acid.
90% stones are calcified.
LABS: plain X-ray KUB, USG, excretory urogram, nonenhanced spiral CT, urine C/E with citratrate+
oxalate,cysteine.
HYPERCALCIUREA: absorbtive inc Vit D INC Ca absorption from intestine.

Renal  dec Ca tubular absorption Dec Ca+inc PTH inc intestinal Ca
absorption.
Resorptive in pts with primry hyperparathyroidism.
30% to 60 % have hypercalciurea without hypercalcemia.
HYPEROXALUREA: PrimaryA.R(1).Glycolic /common,oxalic & glycolic acid  in urine (jaundice+).

(2).L.glyceric.
Secondary: due to increase intake of oxalate & oxalate precursor e.g vit.c.
Enteric IBD, pancreatic insufficiency, biliary disease—all lead to GI malabsorption
of
+
F.A lead to increase FAwhich combine with intraluminal Ca saltfeaces loss.
Normally Ca + oxalate are combinly excreted if Ca excreted with F.A then dec Ca  oxalate increase absorbed.
TREATMENT role of pyridoxine.
HYPOCITRUEA: excretion of citrate (inhibitor of stone) seen in chronic diarrhea,

malabsorption,RTA,idiopathic.
CYSTEINE STONES:A.R  Absorption of diphasic aminoacids from renal tubules (COAL =

cysteine,ornithine, arginine,lysine) increase excretion of these A.A Stone, acidic urine.
STRUVITE STONE: UTI by urea spiliting organisms (Proteus, klebsiella, E.coli, pseudomonas.)Lead to urine
alkalinization & ammonia production precipitation of Mg+, Ammonium, Phosphate & CaPO4 Filling calyces
with staghorn comfiguration obstructioninfectionrenal damage.
TREATMENT OF RENAL CALCULI: Medical / Surgical

MEDICAL :
 Decrease Ca & Na intake (Ca+ RDA).
 Thiazide diuretics ( Ca+ excretion).
 K+ Citrate (1-2meq/kg/day) inhibitor of Ca+ stones. (home Rx= 4 oz of lemon+ 2 litre of H 2O
urine citrate.
 Alkalinization of urine by sodium bicarb/ sodium citrate.
 For cysteine crystals alkalinize urine upto 7.5 ph, and D.pencillamine.
 For Uric acid alkalinize urine and also allopurinol.
 DRUGSalpha adrenergic blockers (terazocin)/ CCB Facilitate stone passage by decrease pressure 242
below stone and decrease peristalsis.
 SURGERY open/ lithotripsy/scopy.
lithotripsy
 Renal under 2 cm

 Lower pole < 1cm.
 Proximal ureteral.
(Renal mean at area near middle calyces)
Percutaneous nephrostomy
 Renal >2cm
 Lower pole >1cm
Ureteroscpy/cystoscopy
 Distal ureter/ bladder.
QUESTIONS REGARDING STONES ETIOLOGY
 Family hx of stone
 Consangious
 Bone pain (inc PTH)
 Inc use of tea, coffee, spinach (primary hyperoxalura)
 Inc intake of vit C (primary hyperoxalura)
 Ch. Diarrhea/ fat malabsorption (primary hyperoxalura)
 Polyurea (distal RTA)
 Repeated UTI (struvite)
 Joint pain/ gout (uric acid).
NEUROGENIC BLADDER
 Micturation ( urinary bladder) is under control of CNS, ANS (Sympathatic&Parasymp), somatic

NS(pudendal nerve).
 CNS CEREBRAL CORTEX ( Frontal lobe), BRAINSTEM (PONS), SPINAL CORD, SACRAL
SPINAL CORD.
 FRONTAL LOBE  MICTURATION CONTROL CENTRE (MCC)It send inhibitory signals to
PMC.
 PONSPONS MICTURATION CENTER (PMC).
 SPINAL CORD  Act as connection between PMC & sacral.
 SACRAL SPINAL CORD SACRAL REFLEX CENTER. (SRC).
 AUTONOMIC NERVEOUS SYTEM (Lie outside CNS regulate action of internal organs under invol.
controll
o SYMPATHATICrelax bladder& contract internal urinary sphincter + inhibit
parasympathetic
o PARASYMPATHATICcontract bladder (detrusr) & relax sphincter.
 SOMATIC N.S Lie outside central spinal cord regulate the action of muscle under voluntsry control
e.g external urethral sphincter and pelvic diaphragm, in this activation of pudendal nerve lead to
contration of external urethral sphincter.
MORMAL MICTURATION PHENOMENON:
 BLADDER FILLSSRCSPINAL CORDPMCMCC ( FRONTAL LOBE ) HERE BRAIN

ACESS THE AVAILABILTY OF APROPRIATE PLACE TO MICTURATE  IF N/A THEN MCC
SEND INHIBITORY SIGNALS TO PMC TO STOP MICTURATION.
243
 IF PLACE AVAILABLE THEN THE INHIBITORY SIGNALS ARE WITHFRAWN  EXCITORY
PMCSCSRCCONTRACTION OF BLADDER WHILE INTERNAL SPHINCTER RELAX
ALSO PERSON VOLUNTARLY SUPPRESS PUDENDAL NERVE TO RELAX EXTERNAL
URETHRAL SPHINCTR MICTURATION OCCURS.

 IN INFANTS OR CHILDREN <3-4 YR  BRAIN IS NOT MATURE SO MICTURATION BEING
DONE AT LEVEL OF SACRAL REFLEX CENTRE. (BLADDER
DISTENSIONSRCBLADDER & INT SPHINCTER MICTURATION
 AFTER 3- 4 YR BRAIN ATTAINS THE CONTROLL OF MICTURATION & CHILD BECOMES
FREE OF PAMPERS.
Brain lesion above the pons (stroke, hydrocephalus, C.P, Tumor)
 Loss of inhibitory signals to PMC  This PMC is inborn excitatory in nature leading to
detrusor hyperreflexia bladder empties too quickly/ pt rush to washroom and may leak urine
before reaching, thay may wakeup frequently in night to void.
Spinal cord lesion (meningomyelocele/M.S) ( BETWEEN PMC & SRC) Spastic or overactive bladder.
 Urge incontinence is similar to brain lesion except in spinal cord lesion in which there is
paradoxical contraction of external sphincter which leading to dribbling of urine. Also termed
detruser sphincter dysnergia.
Sacral cord injury (LMN lesion) in sacral cord tumor/tethered cord.
 Hypotonic bladder  overflow incontinence.
Clinical presentations:
 Urinary incontinence
 UTI
 Hydronephrosis due to VUR/DSD
 Pyelonephritis
 CRF
Laboratory :
 USG-RENAL (Acess post voidal residual urine.)

 MCUG(After closure of meningomyelocele 25% have VUR/ 15% Have hydronephrosis.
 URODYNAMIC STUDY: ( fill bladder with saline measure bladder volume/pressure and acess
sphincter tone.
TREATMENT:
 ANTICHOLINERGIC (OXYBUTYRIN)+ CIC 3-4 hrly.(cure 80% reflux/grade1-2).

 ANTIBIOTIC PROPHYLAXIS  IF UTI/REFLUX.
 IF SVERE REFLUX CUTANEOUS VESICOSTOMY.
 MORE SEVRE REFLUX
o (1) ENDOSCOPIC REFLUX CORRECTION FOLLOWED BY CIC+OXYBUTYRIN.
o (2) AUGMENTATION ARTERIOCYSTOPLASTY
Check list for CKD
History
244
-p/c
-HOPC
-DIFFERENTIALS
-COMPLICATIONS OF DISEASE & TREATMENT.
-PAST HX WITH DETAILS OF MANAGEMENT.

-CURRENT STATUS AND ENLIST THE POSSIBLE PROBLEMS.
-VACCINATION
-NUTRITIONAL HX
-FAMILY HX.
-GROWTH/PUBERTY.
-PARENTS KNOWLEGDE
-PARENTS CONCERNS.
- DISEASE IMPACT ON ALL INCLUDING CHILD’S SCHOOLING.
-SOCIOECOMIC HX.
EXAMINATION
-OBERVATION
-FACE hirsuitism/ hypertrichosis (cushing & cyclosporine ), Malar rash (SLE), Peri orbital edema
(nephrosis), any hearing aid in (aminoglycoside toxicity/ alport syndrome).
-EYES LOOK FOR cataract (steroids), aniridia (wilms tumor), jaundice (hepatorenal ), band
keratopathy (hypercalecmia), fundus examination for uremic retinopathy and retinitis pigmentosa
(nephronophthisis) and papilledema.
-MOUTH dry in dehydration, and uremic breath in CKD.
-NECKJVP (CCF Due to volume overload), Cervical adenopathy due to lymphoma and CMV if
immunosupressed.
- CHECK GAIT, PROXIMAL WEAKNESS, REFLEXES FOR PERIPHERAL NEUROPATHY AND HIP MOVEMENT
FOR SCPE.
MISCELLANEOUS FACTS OF CKD/ESRD.
-The prevalence of CKD in the pediatric population is approximately 18 per 1 million.
-The prognosis for the infant, child, or adolescent with CKD has improved dramatically over the past 4
decades because of improvements in medical management (aggressive nutritional support,
recombinant erythropoietin, recombinant growth hormone), dialysis techniques, and renal
transplantation.
-rhGH is safe and effective in CKD, While slightly less effective in pts ESRD on dialysis-
 .
 Pakistan 966 dialysis machines are available and 195 centers are there.
 Main cause of death during HD Is cardiac event which is 55% and infections which are 27%
contributing total of 82% main cause of death( data from Pakistan ).
 Bone disease can be detected histologically within 6 months of the onset of ESRD in almost
all pts.
 Bone disease in CKD is due to 3 reasons 1, acidosis coz use of alkanline bone salts as abuffer.
2, secondary hyperparathyroidism 3, dec 1,25, OH vit D.
 Rachitic changes are best seen at the end of rapid growing bones like proximal tibia and tistal
femur.
 Hyperparathyroid component like osteopenia and subperiosteal bone resorption best seen at
radial side of second & 3rd digit. 245
 Sevelamer better to indicated when phosphate level can not be controlled with calcium
carbonate without causing hypercalcemia.
 Use of digoxin is nt a good idea in ESRD pt coz not removed by dialysis.

 Before going for renal transplantation we should look for indications of dialysis like if a pt
with spina bifida, bladder dysfunction will again had same problem.
 If pt after renal translantaion develop CMV infection which may lead to post transplant
lymphoproliferattive disorder .
 If CMV + then treat infection by reducing dose of immunosuppressive therapy and add
gancyclovir and IVIG, however if CNS infection due to that then stop immunosupresive
therapy & continue same rx.
 There are causes of itching in CKD Pts 1, due to uremic toxins irritiating nerve endings, 2, due
to ca deposition S.C Other may be secondary to diasylate solution used during dialysis which
is transient 1-2 hr lasting during dialysis.
 DTPA=diethylene tetra penta acetic acid.
 DMSA=dimercapto succinic acid
 Sallow appearance means= dirty brown due to anemia & urinary pigments
246

AFP
My patient ...... ,boy , resident of ..... , admitted ....... Days back thru opd with complaints of
1. Difficulty in walking for 1 month
2. Nasal regurgitation for last 1 month.
According to pts mother ..... Was in usual state of health... Days back then had weakness of lower
limbs that was sudden onset and progressively increasing started symmetrical in both lower limbs ,
involved upper extremities with .... Days , however she/ he had no Hx of numbness, paresthesia,
altered senasation, myalgia , respiratory distress, altered speech/ hyponasality, urinary retention,
dribbling. Altered sensorium, fits, focal neurological deficit, visual disturbance, palpitation,
respiratory distress, constipation, dark coloured stool, abdominal pain,
Facial weakness, change of voice.
Along with Hx of nasal regurgitation of fluid/ food intake that was sudden onset
No Hx of
Trauma, preceding URTI, loose motion, vomiting, vaccination, Intra gluteal injection, picca, previous
similiar episodes, honey intake, drug intake( vincrostine), Backeache/ painful swelling at back, fits /
unconscious.
----for these complaints admitted to...... Catheterized, NG pass, cardiopulmonary monitoring done,
IVIG given/ not. Stool & CSF examination.
---- during hospital admission he is improved with weakness...
---
His/ her current activities of daily living are........this this...
Vaccinated child according to epi schedule no xtravaccination has been given, developmental
normal, no significant antenatal natal and post natal Hx, parents are related as 1st......cousins, 247
had.....Sibs all are normal with no similar episodes of illness , nutritional Hx is......, parents had
....knowledge regarding disease, complication and course, significant impact on child and parents,

parents concerns are these... Father is..... By occupation earning ... And live in their own/ rented
house. All the siasease expenses are by themselves/ support.
Summary.
Active problems.
Differentials with most likely dx.
IVIG.
Notification to ask .
Must be able to know about ADEM/M.S.
.Knowledge and interpretation of EMG and CSF findings.
Management steps should.remember on tips.
Recent advances and literature reviews are important.
Polio current cases and type of polio vrus causing vaccine derived poliomyelitis.
DISCUSSION:
AFP (WHO) DEFINATION: sudden onset of recent paraplegia or weakness of lower limb in achild <15
yr of age .
Approach to…
Acute Flaccid Paralysis
A patient presents with relatively recent onset of generalized or symmetric limb weakness
Differential Diagnosis: A neuroanatomical approach
1. Muscle (acute myopathies):

248
- Inflammatory myopathy (polymyositis, dermatomyositis)
- Rhabdomyolysis (extreme exertion, drugs, viral myositis, crush injury etc.)

- Acute alcoholic necrotizing myopathy
- Periodic paralyses (hypokalemic, hyperkalemic)
- Metabolic derangements (hypophosphatemia, hypokalemia, hypermagnesemia)
- Thyroid or steroid myopathy
2. Neuromuscular Junction:
- Myasthenia Gravis
- Botulism
- Tick paralysis
- Other biotoxins (tetradotoxin, ciguatoxin)
- Organophosphate toxicity (can also cause neuropathy)
- Lambert-Eaton Myasthenic Syndrome (LEMS)
3. Nerve (acute neuropathies):
- Diphtheria
- Porphyria
- Drugs & Toxins (arsenic, thallium, lead, gold, chemotherapy - cisplatin / vincristine)
- Vasculitis (incl. lupus, polyarteritis)
4. Nerve Roots (acute polyradiculopathies):
- Guillain-Barre Syndrome
- Lyme disease
- Sarcoidosis
249
- HIV
- other viruses (CMV, VZV, West Nile)

- Cauda equina syndrome (lumbar disc, tumour, etc.)
- Plexus lesions (brachial plexitis, lumbosacral plexopathy)
5. Anterior Horn Cell (motor neuron diseases):
- Amyotrophic lateral sclerosis (ALS) - with UMN findings
- Poliomyelitis
- Kennedy's disease (spinobulbar atrophy)
- other spinomuscular atrophies (inherited)
- Anterior spinal artery syndrome (with grey matter infarction)
6. Spinal Cord (corticospinal tract diseases):
- Inflammatory (Transverse myelitis)
- Subacute combined degeneration (B12 deficiency)
- Spinal cord infarction
- other myelopathies (spondylosis, epidural abscess or hematoma)
7. Brain
- Pontine lesions (eg. central pontine myelinolysis, basis pontis infarct or bleed)
- Multifocal lesions (multiple metastases, dissemination encephalomyelitis [ADEM], multiple infarcts

or hemorrhages - eg. DIC, TTP, bacterial endocarditis)
History:
- duration of weakness (ie. hours to days to weeks / months)
=> classify as rapidly progressive, acute, subacute or chronic
- mode of progression (eg. onset in arms, "ascending paralysis")
- sensory involvement (numbness, tingling, loss of balance esp. in dark, pain / burning) 250
- bulbar involvement (change in voice or swallowing)
- facial weakness (trouble chewing, sucking with straw, blowing)

- extraocular muscle weakness (diplopia) or ptosis
- respiratory involvement (dyspnea, orthopnea)
- bladder or bowel involvement
- autonomic involvement (diarrhea, orthostatic dizziness, urinary retention, palpitations)
- systemic symptoms (fever, weight loss, rash, joint pain)
- recent illness or immunization (diarrheal or respiratory tract infection, oral polio vaccine)
- recent travel (out of country, to woods [tick bites])
- precipitating factors (exertion, carbohydrate loading - with periodic paralyses)
- fluctuation in weakness (eg. diurnal variation, fatiguability in myasthenia)
- drug or toxin exposure (canned or 'bad' food, pesticides, 'statins', lead exposure)
- family history (porphyria)
Physical Examination:
* Distribution and Degree of weakness
- MRC grading (0 to 5 out of 5)
- Examine extraocular muscles (? ptosis), facial muscles, neck, arms & legs
- Describe the pattern of weakness (eg. paraparesis, faciobrachial, multifocal) if possible
- Assess for fatiguability
* Sensory loss
- to particular modality (vibration / proprioception vs. pain / temperature)
- is there a sensory level?
* Reflexes
- are the DTRs lost (ie. areflexic), depressed, preserved, or brisk
- do diminished reflexes facilitate with repeated efforts? (LEMS)

251
* General features
- Autonomic testing (postural vitals, abnormal sweating, pupillary response, ileus)

- Skin: rash of Lyme disease (erythema chronicum migrans), lines on nails with arsenic poisoning
(Mee's lines), ticks, photosensitivity, Gottron's papules (on extensor surfaces) & heliotrope
discoloration over eyelids, gynecomastia (Kennedy's)
- Spinal tenderness (with epidural abscess or hematoma, spinal tumour)
- Straight leg raise (radiculopathy)
Priorities of Management:
1. ABCs
- ensure airway protected (if decreased LOC or dysphagic) and adequate ventilation (not shallow
breathing with CO2 retention)
- check BP / HR in case of brady- or tachyarrhythmias or autonomic failure
2. Examination (see above) and classification into pattern (see below)
3. Investigations
- neuroimaging (head or spinal cord)
- lumbar puncture for CSF
- laboratory tests (incl. CK, potassium, magnesium, phosphate, B12, TSH, ANA, RF, ANCA)
- serum protein electrophoresis
- paraneoplastic antibody screen (esp. anti-Hu)
- electrophysiologic testing (nerve conduction studies & electromyography)
- Tensilon test (IV edrophonium to reverse neuromuscular blockade)
General Patterns:
1. Flaccid symmetric quadripareis (+/- bulbar and respiratory involvement) with areflexia and
minimal to profound sensory loss (but often sensory symptoms)
- Acute neuropathy or polyradiculopathy (esp. Guillain-Barre syndrome)
2. Symmetric proximal muscle weakness without sensory symptoms or signs and with preserved
252
reflexes:
- Acute myopathy (eg. polymyositis)

3. Fatiguable muscle weakness with diplopia, ptosis and bulbar dysfunction
- Myasthenia gravis (and other neuromuscular disorders)
4. Flaccid Paraparesis with sensory level (often with reduced lower limb reflexes & bladder
dysfunction)
- Cauda equina syndrome
- Thoracic spinal cord lesions (eg. transverse myelitis, spinal cord infarct)
5. Bulbar predominant involvement:
- Botulism
- Myasthenia gravis
- Motor neuron diseases (ALS, Kennedy's)
- Pontine lesions
6. Ophthalmoplegia with motor weakness:
- Miller-Fischer variant of Guillain-Barre syndrome (areflexia)
- Botulism & Tick paralysis
- Myasthenia gravis
7. Prominent autonomic dysfunction:
- Guillain-Barre syndrome
- Paraneoplastic syndromes
- Organophosphate toxicity (muscarinic cholinergic overstimulation)
- Botulism.
DEFINATION OF GBS (WHO):
Acute onset of floppy weakness in achild less than 15 yr of age , of any cause
Or
Any paralysis in a person of any age when ppolio is suspected. 253
It is always suspected sometime suspected
1. Polio. 1. Muscle hypotonia.

2. GBS. 2. Hypokalemic paralysis.
3. TM 3. Potts disease.
4. Traumatic neuritis. 4. Meningitis/encephalitis.
For notification: onset of paralysis should be within last 6 month.
1. SUDDEN ONSET OF PARPLEGIA

a. Transverse myeltitis.
b. GBS.
c. Trauma / spinal cord compression.
d. Spinal cord abscess.
e. Spinal cord infarction (AVM).
2. PARAPLEGIA (UMN TYPE).
a. Transverse myeltitis.
b. Spinal cord compression –trauma, tumour, abscess.
c. Familial spastic paraplegia.
d. Potts disease.
e. Syringomelia.
f. Friedreich ataxia/subacute combined degeneration of spinal cord.
g. Meningioma/saggital sinus thrombus/hydrocephalus.
3. PARAPLEGIA (LMN TYPE).
a. GBS.
b. Polio.
c. Polyneuropathy.
d. Traumatic neuritis.
e. Spinal cord compression (cauda equine/ conus medullaris)
f. Metabolic
g. Hysterical.
h. Endocrinological causes
i. Cushing
ii. Hypothyroidsm
iii. Addison disease.
iv. D.M.
GUILLIAN BARE SYNDROME
It is acute post infectious polyneuropathy which invole motor (predominantly) & sometime sensory
or autonomic.
 Demyelinating predominantly  ( d/t EBV, CMV, enterovirus, mycoplasma, varicella,

c.jujenae)
 Axonal degeneration sometimes c.jujenae ( most common etiology).
CLINICAL MANIFESTATION:
254
All age , 5-9 yr common
Male > female

Onset of paralysis hrs-days-weeks-months. (usually 8 days to 2 weeks).
Progression : hours to weeks , rapidlt progressive in 24 hr to 48 weeks.
Preceeding respiratory / GIT infection in 2/3rd cases.
Follow vaccines rabies, influenza, OPV, hep B.
Ascending paralysis ( laundary type ) with pain as initial manifestation in half of the cases.
Symmetrical involvement means proximal and distal muscles involved equally . ( asymmetrical in 9%
cases.
Ataxia (25%)
Bulbar involvement (50%).
Urinary incontinence (20%).
Autonomic involvement (25%).
Facial nerve involvement ( B/L LMN type) 35-50% / > Common affected)./ then 9th +10th CN.
VARIETIES:
1. MILLER FISCHER SYNDROME: (occulomotor paralysis+ataxia+areflexia+papiledema).
2. BICKER STIFF ENCEPHALITIS: very similar to GB syndrome. ( hyper reflexia+ unconscious)—

good prognosis.
3. CHRONIC RELAPSING/ UNREMIITING POLYNEUROPATHY: ( pt remain asymptomatic for 8

weeks or more). Chronic variant with/without bulbar involvement.-->good recovery
4. CONGENITAL GB SYNDROME: pt fulfilling all the GBS criteria including EMG, NCV, CSF
findings born to mother without any neuromuscular illness.
 No treatment required at all.
 Just need close observation.
 Weakness improves within first few months and usually no residual weakness after 1 yr.
5. ACUTE MOTOR/SENSORY AXONAL NEUROPATHY ( hyper reflexia, and positive anti GM1 ab)
6. ACUTE PANDYSAUTONOMIA
7. OVERLAP SYNDROME( GB+fischer miller).
SIGNS OF RESP. INVOLMENT:

255
 Anxious expression
 Inablilty to speak.
 Inc resp rate
 flaring of alae nose.

 Weak cough.
 Paradoxical movement.
 Cyanosis at rest.
 Dec intercostals muscle movement.
SIGNS OF IMPENDING RESPIRATORY FAILURE:
 Weak cough/ cry/ voice.

 Cyanosis at rest.
 Dysphagia .
 Facial weakness.
 Pooling of secretions in pharynx.
 Exhaustion and bradycardia.
 Deltoid abduction power poor (C5 involvement).
 FVC < 25% Of predicted.
RESPIRATORY MONITORING BY:
 FVC  4 hourly if < 50% predicted

 ABGs  4 Hrly.
 If nothing available  balloon inflation.
SIGNS TO CHECK RESP: INVOLEMENT:
Look :
 anxious expression.
 Movement of accessory muscles.
 Tachycardia/ Shallow breathing.
ASK:
 To cough.
 Talk  count upto 10 rapidly in one breath.
 Raise arm above head  deltoid weakness.
DO: Manullay splint:
 Thoracic cage  to c diaphragmatic movement.

 Abdomen  to c thoracic cage movement.
POOR PROGNOSTIC FACTORS:
 CN involvement
 Intubation.
 max disability at time of presentation.
INDICATION OF INTUBATION: (<10% cases).
256
FVC < 25 % Predicted.
Cyansis at rest.

ABGs. Inc PCO2 / dec PO2 /SPO2 ( type 2 picture).
Undue exhaustion/ tachycardia .
Suspected aspiration.
INDICATONS OF IVIG:
1. Rapidly progressive course. (Within 24 weakness)

2. Bulbar involvement.
3. Respiratory involvent.
4. Chronic relapsing/ unremitting polyradiculoneuropathy.
5. CN involvement.
IVIG
dose  400mg / kg/day or 2 gram total dose in 3-5 days.
Check B.P Before.
It lead to immunoparesis ( dilute antibodies) + increasing production of cytokines , antagonising IL-1.
INVESTIGATIONS:
 Electrophysiological studies:
o NCS motor velocity reduced. Sensory slow.
o EMG Denervation of muscles.
 CSF examination:
 After 5 days.
 Cytoalbumin dissociation ( WBC < 10 all monocytes + protein > upto 200 g/dl).
 If CSF WBC more than 50 Say thats not GBS.
 CK enzyme levels may be normal or increased.
 STOOL examination.
o 24-48 hr apart.
o 10 gram/ thumb size.
o Maintain cold chain at 8 oC
o for polio virus & c.jujenae.
 Anti ganglioside antibody  against GM1 (in axonal).
 Anti-myelin antibodies.
 Supportive investigations
TREATMENT:
After Confirming diagnosis i will councell parents regarding the disease course, complication, course
257
and management options and admit in ICU for careful vital monitoring & will notify the TO LOCAL
HEALTH DEPARTMENT, & will treat the acute problems of pt & observe for progression of disease if
it is rapidly progressive with signs of impending respiratory failure then i will keep pt on mechanical
ventilation and start IVIG with dose of 400mg/kg/dose for 5 days , if still not responsive to IVIG then

plasmapharesis can be considered, i will envolve the multidisciplinary approach by neurologist,
nutritionalist, physiotherapist & pscychotherapist , occupational therapist social worker & care of
bladder , bowel and physiotherapy & frequent posture change to avoid bed sore.
Other optional treatment consideration is for immunosupression , interferons .
Steroids are not effective.
Recent trials : ECULIZUMAB  On animal studies benefited , still not approved.
Immune adsorption ( still in pipe line).
Pain management  Gabapentin > effective than carbamazepine.
Prognosis :
Natural course of GBS:
 Paralysis  1 week (knee reflex earliest to lost)

 Progress 1 week.
 Static 2 weeks.
 Recovery  starts within 2-3 weeks, total takes median time about 6-12 months. ( Foot
drop last to recover)
Recovery starts in reverse direction of ascending:
Bulbar upper limblower limbDTR (Las to recover).
80%  regain full strength.
20%  some residual weakness( foot drop, wrist drop, walking difficulty, weakness of grip,
symmetrical atropy of peroneal and anterior tibial muscles in legs and thenar / hypothenar .
(DD of CMTD at this stage)
7%  acute relapse.
Which pt have more chance of residual weaknessfemale pt , remained in ICU, hospital stay > 10
days.
Mortality  5% (bulbar, arrythemias, autonomic involvement).
Guarded prognosis in chronic form  major residual sequel.
Good outcome  pts with electrophysiological study showing conduction block.
PLASMAPHARESIS:
 CVP line.
 >10-15 kg child. 258
 4-5 cycles/ 7-10 days for acute / chronic- 10 exch/day.
 Removes antibodies.
 Advantage: decreases severity & shortens illness.

 S/E: autonomic instability, bbleeding diathesis, hypercalcemia, infections.
CHRONIC GBS TREATMENT :
 IVIG.
 Plasma exchange.
 High dose pulse methylprednisolone.
 Prognosis  guarded residual damages.
TRANSVERSE MYELTIS
Transverse myelitis is characterized by abrupt onset of progressive weakness and sensory

disturbances in the lower extremities.
history of a preceding viral infection accompanied by fever and malaise is documented in most
cases.
Several viruses :
 Epstein-Barr.
 Herpes.
 Influenza.
 Rubella.
 Mumps.
 varicella.
 Mycoplasma pneumoniae
 Lyme disease.
Pathogenesis:
Three hypotheses
1. cell-mediated autoimmune response.

2. direct viral invasion of the spinal cord.
3. and autoimmune vasculitis.
-Pathologic examination of the cord shows marked softening and perivascular cuffing by
lymphocytes, supporting an immunologic basis for the disorder.
259

> 4 yr
Fever may be present before AFP. ( rarely during onset).
Early stage (Like spinal shock last 1-2 weeks)
 Low back or abdominal pain, neck pain and paresthesias of the legs are prominent
symptoms.
 The leg muscles are weak and flaccid.
 sensory level is present, usually in the midthoracic region.
 Pain, temperature, and light touch sensation are affected, but joint position and vibration
sense may be preserved.
 Arms may be affected partially (rare).
 Sphincter disturbances are common, retention early  incontinence later.
 Fever and nuchal rigidity are present early in most cases.
 The neurologic deficit evolves for 2–3 days and then plateaus, with flaccidity gradually
changing to spasticity and with the concomitant development of upper motor neuron signs
in the lower extremities.
DIAGNOSYIC CRITERIA
Bilateral not necessarily symmetrical sensorimotor and autonotic spinal cord dysfunction
Clearly defined sensory level.
Progression of nadir of clinical deficits between 4 hours and 21 days after symptom onset.
Demonstration of spinal cord inflammation: CSF pleocytosis or elevated IgG index or MRI revealing
enhanced cord lesion.
Exclusion of compressive, postiradiation, neoplastic and vascular causes.
Possible idiopathic TM Clinical events that areconsistent with TM but are not associated with CSF
abnormalities or abnormalities detected on MRI and have no identifyable underlying cause.
Differential diagnosis:
 Meningitis.
 Infectious polyneuropathy (Guillain-Barré syndrome).
 Poliomyelitis.
 Neuromyelitis optica (Devic disease)
 SOL SPINE Spinal cord neoplasm, potts disease, epidural abscess.
 CSF Examination shows

 moderate lymphocyte pleocytosis and a
 normal or slightly elevated protein level.
 Myelin basic proteins elevated----( do not tell to examiner till asked other wise coz
260
not routinely performed)
 Immunoglobulin levels increased ----( do not tell to examiner till asked other wise
coz not routinely performed)
 MRI- Spine + brain (30% + findings)  also for to rule out other SOL.

 T2-hyperintense.
 T1-iso/hypointense fusiform swelling extending over at least 3–4 vertebral levels,
usually located in the thoracolumbar region.
TREATMENT :
 Spontaneous recovery occurs over a period of weeks or months and is complete in ≈40–50%
of cases.
 Residual deficits include bowel and bladder dysfunction and weakness in the lower
extremities. Management is directed to bladder care and physiotherapy.
 high-dose methylprednisolone therapy early in the course is effective in shortening the
duration of the disease and in improving the outcome.
Prognosis :
 Late recovery: when onset in rapid and fulminant.
 Early recovery: when onset took several days to complete recovery takes 1-5 days after
symptoms peak and may recover complete.
SPINAL CORD TUMORS
≈20%
Intramedullary tumors:
 arise within the substance of the cord and grow slowly by infiltration.
usually in the cervical region.
PRESENT CLINICALLY :
 Back pain
 Gait disturbance
 Senory deficit
 Scoliosis
 Urinary urge/incontinence.
 If tumour at cervical levelLMN sign in upper limbs & UMN signs in LL along with loss of
pain , touch , temperature in LL + cord level.
TUMOURS ARE:
 astrocytoma (The most common intramedullary tumor).
 Ganglioglioma (#2)
 Ependymoma (#3).
INTRADURAL TUMORS:
 tend to be benign.
 arise from neural crest tissue.
CLINICAL PRESENT :
 Back pain
 Difficulty in sleep supine. 261
 Segmental pain, paresthesia if nerve involve.
TUMOURS ARE
 Neurofibroma.
 Ganglioneuroma.

 meningioma.
EXTRAMEDULLARY EXTRADURAL TUMORS:

CLINICALY PRESENT :
 Block CSF pathway flaccid paraplegia, urinary retention, patulous anus.
 characteristically are metastatic lesions.
TUMOURS ARE
 Neuroblastoma.
 Sarcoma.
 lymphoma.
 Hstocytosis.
DIFFERENCE BETWEEN INTRAMEDULLARY & EXTRA MEDULLARY COMPRESSIONS.

INTRAMEDULARY EXTRAMEDULLARY
B/L spastic paraplegia 1. Asymmetric spastic paraplegia.
Dissociated sensory loss. 2. Early sacral loss.
Urge incontinence 3. retension of urine and feces.
No root pain 4. root pain worsen on movement.
DIAGNOSIS: MRI spine

TREATMENT: suportive care + surgical removal.
CARRIES SPINE
 Lower thoracic / upper lumber vertebrae  most common.

 Tuberculous spondylitis combination of osteomyeltitis + arthritis.
 Hematogenous spread.
 Many pt have no evidence of extraspinal TB ( 60-80%.)
 Can spread to adjacent vertebrae/ Intervertebral disc.
 If intervertebrae is involved  IVD collapse , vertebral narrowing and collapse ( anterior
aspect of vertebrae is usually affected.
 In children Disc can be ap primary focus.
C/F:
 Back pain (Commonest)

 Fever
 Night sweats
 Anorexia.
 Wt loss
 Tender local site with spasm of paravertebral muscles+ 262
 Ankle clonus is one of earliest sign ++
 Spinal mass sensory symptoms.
 Kyphosis in children more common due to increase amount of cartilage.
Vertebral deformities:

 Knuckle: when only one vertebrae is involved
 Gibbus : 2.......
 Kyphous: 3 or more........
T.B SPINE PRESENTATIONS:
1. vertebral collapse  SC compression gait difficulty.
2. cold abscess.
3. vertebral deformity.
4. paraplegia.
LOCATIONS:
 Lower thoracic 50%.

 Upper lumber  35%.
 Cervical 10%.
Neurological complications  50%.
 Paraplegia.
 Impaired sensation.
 Root nerve pain
 Cauda equine syndrome
EXAMINATION:
 LOCAL EXAMINATION  MUST LOCATE SITE AND WHICH VERTBRAE INVOLVE AND ITS
SENSORY DERMATOME ( common & favourite examiners Q).
 GPE nutritional status, BCG, L.N.chest (primary).
DIFFERENTIALS:
 SC ABSCESS.
 SEPTIC ARTHRITIS.
 TRAUMA
 FAMILIAL SPASTIC PARAPLEGIA
 T.MYELTIS.
WORKUP:
 CBC +ESR
263
 CXR
 Mantoux test
 X-RAY spine
 Lytic lesions

 Collapse
 Psoas muscle shadow
 CT-SCAN-SPINE
 MRI –SPINE.
 BONE SCAN non specific bcoz inc false neg results.
MANAGEMENT: (DESCRIPTION SAME ).
SPECIFIC TREATMENT: 4 DRUG therapy for 9-12 month.
 Spinal braces.
 Plaster jackets.
SURGERY:
 Anterior decompression:
 Posterior decompression:
 Anterolateral decompression
 Costotransversectomy.
INDICATIONS
 Spinal deformity.
 Neurological deficit.
 No response on medx treatment.
 Large paraspinal abscess.
FOLLOW UP:
 Treatment response.
 Compliance
 S/E of drugs.
 Development / progression of neurologic/ skeletal deformity.
 Follow up till growth potential is complete.
PROGNOSIS:
Depend:
 Compliance.
 Drug resistance.
 Complications.
Paraplegia well response to chemo.
IMPORTAN TO REMEMBER: 264
Disparity between vertebral and degmental spinal cord levels coz child continue to grow spinal cord
slow growth and ultimaltely it end at level of L1-2.

SPINAL CORD LEVEL CORRESPONDING VERTEBRAL BODY
Upper cervical same as cord level.
Lower cervical. 1 level higher
Upper thoracic. 2 level higher (add 2 )
Lower thoracic. 3 level higher.
Lumber T 10-12.
Sacral T12 – L 1.
coccygeal. L1.
SUPERFICIAL REFLEXES OF SPINAL OROGION FOR LOCALIZATION OF LEVEL OF LESION:
REFLEX LEVEL OF CORD CONCERNED
Abdominal T7-12
Cremestric L1-2
Plantar S1
Anal S3-4.
LOCALIZATION SIGNS FOR SPINAL CORD LESION:
Localization by identification of sensory level
S.LEVEL AT NIPPLE - lesion at T4.
S. LEVEL AT UMBLICUS  T10
FAMILIAL SPASTIC PARAPLEGIA
265
Dominant inheritance
 Chronic.
 Progressive

 Normal MRI.
Recessive type:
 Slowly progressive with 3 month total paraplegic.

No bladder, sensory involvement , atrpy.
TRAUMATIC NEURITIS:
 Onset : 1 hr – 5 days after injection intragleutal

 Preceding hx : usually fever due to any illness for which IG injection given.
 Pain in gluteal region or affected leg.
 Atrophy 40-60 days later.
 Knee jerk preserved while absent ankle jerk ( coz schiatic nerve damage )
 Hip / knee strength normal , child walk with foot drop.
 Atrophy never reaches to that of polio.
 Difference in calf muscle not usually exceed 0.5 -1.5cm.
 Rarely both legs can be affected if injections given on both sides.
 Prognosis: good , recovery in 3-9 months with physiotherapy.
POLIOMYELTIS:
ETIOLOGY.
 polioviruses are nonenveloped, positive-stranded RNA viruses belonging to the

Picornaviridae family, in the genus Enterovirus, and include 3 antigenically distinct serotypes
(types 1, 2, and 3).
 Polioviruses spread from the intestinal tract to the central nervous system (CNS), where they
cause aseptic meningitis and poliomyelitis, or polio.
 90–95% of infections are inapparent but induce protective immunity.

 Clinically apparent but nonparalytic illness occurs in about 5% of all infections.
 paralytic polio occurring in about 1/1,000 infections among infants to about 1/100 infections
among adolescents (.01%).
 Poor sanitation and crowding have permitted the continued transmission of poliovirus in
certain poor countries in Africa and Asia
Transmission:
 Humans are the only known reservoir for the polioviruses, which are spread by the fecal-oral 266
route. Poliovirus has been isolated from feces for >2 wk before paralysis to several weeks
after the onset of symptoms.

Pathogenesis:
Virus  enter cell uncoated & releases viral RNA  The RNA is translated to produce proteins
responsible for replication of the RNA, shut-off of host cell protein synthesis, and synthesis of
structural elements that compose the capsid Mature virus particles are produced in 6–8 hr and
are released into the environment by disruption of the cell..
In the contact host, wild-type and vaccine strains of polioviruses gain host entry via the
gastrointestinal tractThe primary site of replication is in the M cells lining the mucosa of the small
intestineRegional lymph nodes are infected, and primary viremia occurs after 2–3 days The
virus seeds multiple sites, including the reticuloendothelial system, brown fat deposits, and skeletal
muscle.
 Wild-type poliovirus probably accesses the CNS along peripheral nerves.

 Vaccine strains of polioviruses do not replicate in the CNS, which accounts for the safety of
the live-attenuated vaccine.
 Occasional revertants (by nucleotide substitution) of these vaccine strains develop a
neurovirulent phenotype and cause vaccine-associated paralytic poliomyelitis (VAPP).
Reversion occurs in the small intestine and probably accesses the CNS via the peripheral
nerves.
 Because poliovirus replicates in endothelial cells, the theory of viremic spread to the CNS
was favored; however, poliovirus has almost never been cultured from the cerebrospinal
fluid (CSF) of patients with paralytic disease, and patients with aseptic meningitis caused by
poliovirus never have paralytic disease.
 The poliovirus primarily infects motor neuron cells in the spinal cord
 the anterior horn cells.
 medulla oblongata (the cranial nerve nuclei).
 dorsal horn and dorsal root ganglia in the spinal cord
 Because of the overlap in muscle innervation by 2–3 adjacent segments of the spinal cord,
clinical signs of weakness in the limbs develop when more than 50% of motor neurons are
destroyed.
 In the medulla, less extensive lesions cause paralysis, and involvement of the reticular
formation that contains the vital centers controlling respiration and circulation may have a
catastrophic outcome.
 Involvement of the intermediate and dorsal horn and dorsal root ganglia in the spinal cord
results in hyperesthesia and myalgias that are typical of acute poliomyelitis.
 Other neurons affected are the nuclei in the roof and vermis of the cerebellum, the
substantia nigra, and occasionally the red nucleus in the pons; there may be variable
involvement of thalamic, hypothalamic, and pallidal nuclei and the motor cortex.
 Active immunity after natural infection is probably lifelong but protects against the
infecting serotype only; infections with other serotypes are possible.
 Poliovirus neutralizing antibodies develop within several days after exposure as a result of
replication of the virus in the M cells in the intestinal tract and deep lymphatic tissues. This
early production of circulating immunoglobulin G (IgG) antibodies protects against CNS
invasion. Local (mucosal) immunity, conferred mainly by secretory IgA, is an important
defense against subsequent reinfection of the gastrointestinal tract.
267

The incubation period 8–12 days ( 5–35 days).
Poliovirus infections with wild-type virus may follow 1 of several courses:
1. inapparent infection (90-95%)

2. Abortive (5%)
3. Non-paralytic.(1%)
4. Paralytic- (0.1%)
inapparent infection (90-95%)
 causes no disease and no sequelae.
Abortive Poliomyelitis.
 5% .
 a nonspecific influenza-like syndrome occurs 1–2 wk after infection, which is termed
abortive poliomyelitis.
 Fever, malaise, anorexia, and headache are prominent features, and there may be sore
throat and abdominal or muscular pain. Vomiting occurs irregularly.
 The illness is short lived, up to 2–3 days.
 The physical examination may be normal or may reveal nonspecific pharyngitis, abdominal
or muscular tenderness, and weakness.
 Recovery is complete, and no neurologic signs or sequelae develop.
Nonparalytic Poliomyelitis.(simply more intense signs of abortive polio+nuchal rigidity)
 In about 1% of patients infected with wild-type poliovirus, signs of abortive poliomyelitis are
present, as are more intense headache, nausea, and vomiting, as well as soreness and
stiffness of the posterior muscles of the neck, trunk, and limbs. Fleeting paralysis of the
bladder and constipation are frequent.
 Approximately ⅔ of these children have :
 1st phase (minor illness)
 short symptom-free period
 2nd phase (CNS disease or major illness). Nuchal and spinal rigidity are the
basis for the diagnosis of nonparalytic poliomyelitis during the 2nd phase.
 Physical examination
 nuchal rigidity+.
 Head drop is demonstrated by placing the hands under the patient's
shoulders and raising the trunk. Although normally the head follows the
plane of the trunk, in poliomyelitis it often falls backward limply, but this is
not due to true paresis of the neck flexors. 268
 Changes in reflexes, either increased or decreased, may precede weakness
by 12–24 hr.
 The superficial reflexes, the cremasteric and abdominal reflexes, and the
reflexes of the spinal and gluteal muscles are usually the 1st to diminish.

 The spinal and gluteal reflexes may disappear before the abdominal and
cremasteric reflexes.
 Changes in the deep tendon reflexes generally occur 8–24 hr after the
superficial reflexes are depressed and indicate impending paresis of the
extremities.
 Tendon reflexes are absent with paralysis.
 Sensory defects do not occur in poliomyelitis.
Paralytic Poliomyelitis.
o 0.1% of persons infected with poliovirus.
o causing 3 clinically recognizable These are
 (1) spinal paralytic poliomyelitis
 (2) bulbar poliomyelitis,
 (3) polioencephalitis.
Spinal paralytic poliomyelitis may occur as the 2nd phase of a biphasic illness,
1st phase of which corresponds to abortive poliomyelitis.
The patient then appears to recover and feels better for 2–5 days.
2nd phase: severe headache and fever occur with exacerbation of the previous systemic
symptoms. Severe muscle pain is present, and sensory and motor phenomena (e.g., paresthesia,
hyperesthesia, fasciculations, and spasms) may develop.
On physical examination:
 the distribution of paralysis is characteristically spotty.

 Single muscles, multiple muscles, or groups of muscles may be involved in any pattern.
 Within 1–2 days, asymmetric flaccid paralysis or paresis occurs. Involvement of 1 leg is
most common, followed by involvement of 1 arm.
 The proximal areas of the extremities tend to be involved to a greater extent than the
distal areas.
 To detect mild muscular weakness, it is often necessary to apply gentle resistance in
opposition to the muscle group being tested.
 Examination at this point may reveal nuchal stiffness or rigidity, muscle tenderness,
initially hyperactive deep tendon reflexes (for a short period) followed by absent or
diminished reflexes, and paresis or flaccid paralysis.
 In the spinal form there is weakness of some of the muscles of the neck, abdomen,
trunk, diaphragm, thorax, or extremities.
 Sensation is intact; sensory disturbances, if present, suggest a disease other than
poliomyelitis.
 The paralytic phase of poliomyelitis is extremely variable; some patients progress during
observation from paresis to paralysis, whereas others recover, which may be slow or rapid.
 Paralysis of the lower limbs is often accompanied by bowel and bladder dysfunction ranging
from transient incontinence to paralysis with constipation and urinary retention.
 The onset and course of paralysis are variable in developing countries. The biphasic course is 269
rare and typically presents as a single phase in which prodromal symptoms and paralysis
occur in a continuous fashion.

 In developing countries, where a history of intramuscular injections precedes paralytic
poliomyelitis in about 50–60% of patients, patients may present initially with fever and
paralysis (provocation paralysis).
 The degree and duration of muscle pain are also variable, ranging from a few days usually to
a week.
 Occasionally spasm and increased muscle tone with a transient increase in deep tendon
reflexes occur in some patients, whereas in most patients flaccid paralysis occurs abruptly.
 Once the temperature returns to normal, progression of paralytic manifestations stops.
 Little recovery from paralysis is noted in the 1st days or weeks, but, if it is to occur, is usually
evident within 6 mo.
 The return of strength and reflexes is slow and may continue to improve as long as 18 mo
after the acute disease.
 Lack of improvement from paralysis within the 1st several weeks or months after onset is
usually evidence of permanent paralysis.
 Atrophy of the limb, failure of growth, and deformity is common and is especially evident in
the growing child.
 Bulbar poliomyelitis:
 may occur as a clinical entity without apparent involvement of the spinal
cord.
 only dominance of the clinical manifestations by dysfunctions of the cranial
nerves and medullary centers.
 The clinical findings seen with bulbar poliomyelitis with respiratory difficulty
(other than paralysis of extraocular, facial, and masticatory muscles) include
(1) nasal twang to the voice or cry caused by palatal and pharyngeal
weakness (hard-consonant words such as “cookie” or “candy” bring this out
best); (2) inability to swallow smoothly, resulting in accumulation of saliva
in the pharynx, indicating partial immobility (holding the larynx lightly and
asking the patient to swallow will confirm such immobility); (3) accumulated
pharyngeal secretions, which may cause irregular respirations that appear
interrupted and abnormal even to the point of falsely simulating intercostal
or diaphragmatic weakness; (4) absence of effective coughing, shown by
constant fatiguing efforts to clear the throat; (5) nasal regurgitation of
saliva and fluids as a result of palatal paralysis, with inability to separate the
oropharynx from the nasopharynx during swallowing; (6) deviation of the
palate, uvula, or tongue; (7) involvement of vital centers in the medulla,
which manifest as irregularities in rate, depth, and rhythm of respiration; as
cardiovascular alterations, including blood pressure changes (especially
increased blood pressure), alternate flushing and mottling of the skin, and
cardiac arrhythmias; and as rapid changes in body temperature; (8) paralysis
of 1 or both vocal cords, causing hoarseness, aphonia, and ulti mately
asphyxia unless this is recognized by laryngoscopy and managed by
immediate tracheostomy; and (9) the rope sign, an acute angulation
between the chin and larynx caused by weakness of the hyoid muscles (the
hyoid bone is pulled posteriorly, narrowing the hypopharyngeal inlet).
 autonomic disturbances are common in bulbar involvement and may persist for a week or
more or may be transient.
 hypertension is followed by hypotension and shock and is associated with irregular or failed 270
respiratory effort, delirium, or coma.
 The course of bulbar disease is variable; some patients die as a result of extensive, severe
involvement of the various centers in the medulla; others recover partially but require
ongoing respiratory support, and others recover completely.

 Cranial nerve involvement is seldom permanent.
 Atrophy of muscles may be evident, patients immobilized for long periods may
develop pneumonia, and renal stones .
Polioencephalitis:
is a rare form of the disease in which higher centers of the brain are severely involved. Seizures,
coma, and spastic paralysis with increased reflexes may be observed. Irritability, disorientation,
drowsiness, and coarse tremors are often present with peripheral or cranial nerve paralysis that
coexists or ensues.
DIAGNOSIS.
Clinical
Lab dx:
 Poliomyelitis should be considered in any unimmunized or incompletely immunized child

with paralytic disease.
 VAPP should be considered in any child with paralytic disease occurring 7–14 days after
receiving the orally administered polio vaccine (OPV).
 VAPP can occur at later times after administration, and should be considered in any child
with paralytic disease in countries or regions where wild-type poliovirus has been eradicated
and the OPV has been administered to the child or a contact.
 The combination of fever, headache, neck and back pain, asymmetric flaccid paralysis
without sensory loss, and pleocytosis does not regularly occur in any other illness.
LABS:
STOOL EXAMINATION (WHO recommendation)
 with specific identification of wild-type and vaccine-type strains.

 2 stool specimens should be collected 24–48 hr apart, as soon as possible after the
diagnosis of poliomyelitis is suspected.
 In suspected cases of acute flaccid paralysisPoliovirus concentrations are high in the
stool in the 1st week after the onset of paralysis, which is the optimal time for
collection of stool specimens.
 Polioviruses may be isolated from 80–90% of acutely ill patients, whereas <20% may
yield virus within 3–4 wk after onset of paralysis.
 Because most children with spinal or bulbospinal poliomyelitis have constipation,
rectal straws may be used to obtain specimens.
 ideally a minimum of 8–10 g of stool should be collected.
 In laboratories that can isolate poliovirus, isolates should be sent to either the
Centers for Disease Control and Prevention or to 1 of the WHO-certified
poliomyelitis laboratories where DNA sequence analysis can be performed to
distinguish between wild poliovirus and neurovirulent, revertant OPV strains. 271
 With the current WHO plan for global eradication of poliomyelitis, most regions of
the world (the Americas, Europe, Australia) have been certified wild-poliovirus free;
in these areas, poliomyelitis is most often caused by vaccine strains. Hence it is
critical to differentiate between wild-type and revertant vaccine-type strains.

CSF EXAMINATION:
 pleocytosis of 20–300 cells/mm3. polymorphonuclear early  mononuclear cells soon

afterward.
 By the 2nd week of major illness, the CSF cell count falls to near-normal values. In contrast,
the CSF protein is normal or only slightly elevated at the outset of CNS disease but usually
rises to 50–100 mg/dL by the 2nd week of illness.
 In polioencephalitis, the CSF may remain normal or show minor changes.
EMG & NCS
 EMG giant denervation potential.
Conditions causing pseudoparalysis: do not present with nuchal-spinal rigidity or pleocytosis.
 unrecognized trauma.
 transient (toxic) synovitis.
 acute osteomyelitis.
 acute rheumatic fever.
 Scurvy.
 congenital syphilis (pseudoparalysis of Parrot).
 Botulism
TREATMENT.
 There is no specific antiviral treatment for poliomyelitis.

 The management is supportive.
 Goal of treatment :
 limiting progression of disease.
 prevention of ensuing skeletal deformities
 and preparation of the child and family for prolonged treatment required
and for permanent disability .
 Pain free.
 Patients with the nonparalytic and mildly paralytic forms of poliomyelitis may be treated at
home.
 All intramuscular injections and surgical procedures are contraindicated during the acute
phase of the illness, especially in the 1st week of illness, because these may result in 272
progression of disease.
Abortive Poliomyelitis.

 Supportive treatment with analgesics, sedatives, an attractive diet, and bed rest until the
child's temperature is normal for several days is usually sufficient.
 Avoidance of exertion for the ensuing 2 wk is desirable, and there should be careful
neurologic and musculoskeletal examinations 2 mo later to detect any minor involvement.
Nonparalytic Poliomyelitis.
 Treatment for the nonparalytic form is similar to that for the abortive form; in particular,
relief is indicated for the discomfort of muscle tightness and spasm of the neck, trunk, and
extremities.
 Analgesics are more effective when they are combined with the application of hot packs for
15–30 min every 2–4 hr.
 Hot tub baths are sometimes useful. A firm bed is desirable and can be improvised at home
by placing table leaves or a sheet of plywood beneath the mattress.
 A footboard or splint should be used to keep the feet at a right angle to the legs.
 Because muscular discomfort and spasm may continue for some weeks, even in the
nonparalytic form, hot packs and gentle physical therapy may be necessary.
 Such patients should also be carefully examined 2 mo after apparent recovery to detect
minor residual effects that might cause postural problems in later years.
Paralytic Poliomyelitis.
 Most patients with the paralytic form require hospitalization with complete physical rest in a
calm atmosphere for the 1st 2–3 weeks.
 Suitable body alignment is necessary for comfort and to avoid excessive skeletal deformity.
 A neutral position with the feet at a right angle to the legs, knees slightly flexed, and hips
and spine straight is achieved by use of boards, sandbags, and, occasionally, light splint
shells.
 The position should be changed every 3–6 hr.
 Active and passive movements are indicated as soon as the pain has disappeared.
 Moist hot packs may relieve muscle pain and spasm.
 Opiates and sedatives are permissible only if no impairment of ventilation is present or
impending.
 Constipation is common, and fecal impaction should be prevented.
 When bladder paralysis occurs, a parasympathetic stimulant such as bethanechol may
induce voiding in 15–30 min; some patients do not respond, and others respond with
nausea, vomiting, and palpitations. Bladder paresis rarely lasts more than a few days. If
bethanechol fails, manual compression of the bladder and the psychologic effect of running
water should be tried. If catheterization must be performed, care must be taken to prevent
urinary tract infections. An appealing diet and a relatively high fluid intake should be started
at once unless the patient is vomiting. Additional salt should be provided if the
environmental temperature is high or if the application of hot packs induces sweating.
Anorexia is common initially.
 Adequate dietary and fluid intake can be maintained by placement of a central venous
catheter.
 An orthopedist and a physiatrist should see these patients as early in the course of the
illness as possible and should assume responsibility for their care before fixed deformities 273
develop.
 The management of pure bulbar poliomyelitis consists of maintaining the airway and
avoiding all risk of inhalation of saliva, food, or vomitus.

 Gravity drainage of accumulated secretions is favored by using the head-low (foot of bed
elevated 20–25 degrees) prone position with the face to one side.
 Patients with weakness of the muscles of respiration or swallowing should be nursed in a
lateral or semi-prone position.
 Aspirators with rigid or semirigid tips are preferred for direct oral and pharyngeal aspiration,
and soft, flexible catheters may be used for nasopharyngeal aspiration.
 Fluid and electrolyte equilibrium is best maintained by intravenous infusion because tube or
oral feeding in the 1st few days may incite vomiting.
 In addition to close observation for respiratory insufficiency, the blood pressure should be
taken at least twice daily because hypertension is not uncommon and occasionally leads to
hypertensive encephalopathy.
 Patients with pure bulbar poliomyelitis may require tracheostomy because of vocal cord
paralysis or constriction of the hypopharynx; most patients who recover have little residual
impairment, although some exhibit mild dysphagia and occasional vocal fatigue with slurring
of speech.
COMPLICATIONS.
 Paralytic poliomye:
 Acute gastric dilatation  respiratory embarrassment immediate gastric
aspiration and external application of ice bags are indicated.
 Melena  superficial intestinal erosions; perforation is rare.
 Mild hypertension for days or weeks vasoregulatory centers in the
medulla and especially to underventilation.
 Dimness of vision, headache, and a lightheaded feeling associated with
hypertension should be regarded as premonitory of a frank convulsion.
 hypercalcemia, nephrocalcinosis, and vascular lesions (immobllization and
HTN).
 Cardiac irregularities are uncommon, but electrocardiographic abnormalities
suggesting myocarditis are not rare.
 Acute pulmonary edema.
 Hypercalcemia occurs due to skeletal decalcification that begins soon after
immobilization and results in hypercalciuria, which in turn predisposes the
patient to urinary calculi, especially when urinary stasis and infection are
present. High fluid intake is the only effective prophylactic measure.
PROGNOSIS.
 The outcome of inapparent, abortive poliomyelitis and aseptic meningitis syndromes is

uniformly good.
 In severe bulbar poliomyelitis, the mortality rate may be as high as 60%, whereas in less
severe bulbar involvement and/or spinal poliomyelitis, the mortality rate varies from 5 to
10%, generally from causes other than the poliovirus infection.
 Maximum paralysis usually occurs 2–3 days after the onset of the paralytic phase of the
illness, with stabilization followed by gradual return of muscle function. The recovery phase 274
lasts usually about 6 mo, beyond which persisting paralysis is permanent.
 Male children but female adults, generally, are more likely to develop paralysis.
 Mortality and the degree of disability are greater after the age of puberty.
 Pregnancy is associated with an increased risk for paralytic disease.

 Tonsillectomy and intramuscular injections may enhance the risk for acquisition of bulbar or
localized disease, respectively.
 Increased physical activity, exercise, and fatigue during the early phase of illness have been
cited as factors leading to an increased risk for paralytic disease.
 Finally, it has been clearly demonstrated that type 1 poliovirus has the greatest propensity
for natural poliomyelitis and type 3 for VAPP.
Postpolio Syndrome.
 After an interval of 30–40 yr, as many as 30–40% of persons who survived paralytic
poliomyelitis in childhood may experience :muscle pain and exacerbation of existing
weakness, or they may develop new weakness or paralysis. This entity, referred to as
postpolio syndrome, has been reported only in persons who were infected in the era of wild-
type poliovirus circulation.
Risk factors for postpolio syndrome:
 increasing length of time since acute poliovirus infection.

 presence of permanent residual impairment after recovery from acute illness.
 female sex.
PREVENTION.
 Vaccination is the only effective method of preventing poliomyelitis.

 Hygienic measures help limit the spread of the infection among young children, but
immunization is necessary to control transmission among all age groups.
 Both the inactivated polio vaccine (IPV), which is currently produced using improved
methods compared with the original vaccine and is sometimes referred to as enhanced IPV,
and the live-attenuated OPV have established efficacy in preventing poliovirus infection and
paralytic poliomyelitis.
 Both vaccines induce production of antibodies against the 3 strains of poliovirus.
 IPV elicits higher serum IgG antibody titers, but the OPV also induces significantly greater
mucosal IgA immunity in the oropharynx and gastrointestinal tract that limits replication of
the wild poliovirus at these sites.
 Transmission of wild poliovirus by fecal spread is limited in OPV recipients.
 The immunogenicity of IPV is not affected by the presence of maternal antibodies, and IPV
has no adverse effects.
 Live vaccine may undergo reversion to neurovirulence as it multiplies in the human
intestinal tract and may cause VAPP in vaccinees or in their contacts.
 The overall risk for recipients is 1 case/6.2 million doses. As of January 2000, the IPV-only
schedule is recommended for routine polio vaccination in the USA. All children should
receive 4 doses of IPV at 2 mo, 4 mo, 6–18 mo, and 4–6 yr of age.
 In 1988, the World Health Assembly resolved to eradicate poliomyelitis globally by 2000,
and remarkable progress had been made toward reaching this target. To achieve this, the
WHO used 4 basic strategies:
 routine immunization.
 National Immunization Days (NIDs). 275
 acute flaccid paralysis surveillance.
 mopping up immunization. (Door to door with ratio of 4 km where case
detected).

AFP Surveillance
 Each case of AFP should be investigated within 48 hours of being reported.

 Steps in investigation are:
1. Collection of demographic and clinical information of the cases.

2. Filling up of case investigation form.
3. Collection of stool specimen 2 samples.
4. Sixty day follow up to see residual paralysis.
5. Outbreak control should cover entire village in rural areas &
municipal area in urban areas.
6. Children under 5 yr should receive highest priority to receive one
dose regardless of immunization status.
 Case detection.
 Notification.
 Evaluation.
 Eradication of any problem.
 The OPV is the only vaccine recommended by the WHO for eradication.
 This strategy has resulted in a greater than 99% decline in poliomyelitis cases.
 in early 2002, there were only 10 countries in the world endemic for poliomyelitis
 As long as the OPV is being used, there is the potential that circulating vaccine-derived
poliovirus (VDPV) will acquire the neurovirulent phenotype and transmission
characteristics of the wild-type polioviruses.
 VDPV emerges from the OPV because of continuous replication in immunodeficient
persons (iVDPVs) or by circulation in populations with low vaccine coverage (cVDPVs).
 The main risk factor for cVDPV circulation appears to be low levels of vaccine coverage.
 It has also been estimated that the global burden of VAPP varies from 250 to 500
annually, now becoming more common than wild-type poliovirus.
 The risk for paralysis in the immunodeficient recipient may be as much as 6,800 times
that in normal subjects.
 Currently there are several countries that are global priorities because they face
challenges in eradication .
 Polioviruses are endemic in India, Pakistan, Afghanistan, Egypt, and Nigeria; transmission
has been re-established in Africa: Niger, Chad, Mali, Cameroon, and Sudan, with
imported outbreaks in Ethiopia, Eritrea, Somalia, Madagascar, Angola, Yemen, and
Indonesia. All of these countries require multilevel eradication activities, but they pose a
problem to surrounding countries because wild-type poliovirus can be imported from
these countries to countries where immunization rates have dropped (and have been
declared poliomyelitis free), such as Yemen and Indonesia.
TYPES OF POLIO VACCINES:
ORAL POLIO VACCINE: (SABIN)
 Mg chloride is stabilizing agent in OPV.

 20OC At state & district level.
276
 In freezer at clinic level.
 Must reach outreach facility at 2 – 8OC in vaccine carriers with ice packs.
 Positive virus take local infection in GIT before an immune response occurs.

Multiple doses of OPV need to give because:
 Take rate low in children.

 Vaccinated children do not participitate in chain of transmission of wild polio virus by a high
level of gut immunity.
 MONOVALENT: attenuated type -1 virus strain only immunize type-1.

 Advantage:
 increased immunity for type-1.
 Stronger response even with first dose.
 If child receive this vaccination  subsequently if exposure to wild-1 virus 
dec virus excretion  dec further transmission.
 BIVALENT: Against strain 1& 3.

 TRIVALENT: contain all three strain
INJECTABLE POLIO VACCINE (SALK).
 Formaldehyde killed.
 Seroconversion 90-95% after two doses & 99% after 3 doses.
 Produces excellent humoral , local and intestinal immunity.
 Safe but not easially available here, expensive also
 Ideal first dose should be given is 8 weeks , interval 8 weeks.
 Vaccine of choice in immunocompromised.
 Pt may experience allergic reaction because it contain trace amount of neomycin,
streptomycin, polymyxin B.
 Heat stable & no risk of VAPP,VDPP compare to OPV.
CAUSES OF POLIO IN FULLY IMMUNIZED CHILD:
 Non maintained cold chain.

 Diarrhea during vaccination.
 Malnutrition & poor sanitation.
 HIV
 Environmental infection –polio like infection
CURRENT UPDATE OF POLIO BY WHO:
2013GLOBAL POLIO CASES 389
2013 SOMALYA  180 CASES .
2013  PAKISTAN 91 CASES #1 FATA=48 CASES, KPK= 10, PUNJAB=7, SINDH=5 .
2014  4 CASES IN January 5, 2014 FATA WAZIRSTAN

277
FEB 2014……………………………………………………..
MARCH 2014…………………………………………………

APRIL 2014………………………………………………………
……………………………………………………………………….
MISCELLANEOUS FACTS ABOUT POLIO:
 SUSPECTED CASE: any child <15 yr with AFP.

 PROBABLE CASE: child with AFP , All other causes of AFP excluded.
 CONFIRMED CASE: if stool C/S +ve OR major residual weakness is present after 60 days
of onset of paralysis.
 DISCARDED CASE: stool C/S-ve & no residual paralysis.
 POLIO ERADICATION: no case of paralytic polio by wild virus in last 3 yr + absence of
polio virus in community , where excellent clinical & virological surveillance exist and
coverage of routine OPV is more than 80 %.
 POLIO ELIMINATION: ZERO cases of paralytic polio by wild virus in one year + other
same as of eradication
 EPI vaccine against all 3 strains.
 NID vaccine is just for 1 & 3.
 Type 2 is eradicated world wide.
 If person develop polio again should be vaccinated coz may be suffering fron one strain &
vaccine is available for strain also.
 More extensive paralysis in first 10 days more severe diasability.
 VAPP is associated with 1st dose only.
 National immunization day iz…………………..
 AFP paralysis within <4 weeks in <15 yr child.
278

ATAXIA------------------------( short case)
Commands:
This child presented with difficulty in walking do relevant examination—(duration may be

informed/not. But concentrate on command)
This child had abnormal gait do motor system & relevant examination.
Step 1. Into+consent+exposure
step2. Inspection.
Step 3. Communicate with child (speech ), then ask for ability to walk.
Step 4. Gait examination maneuvers:--(exposure to mid thigh is must)
Normal gait—(normal walk)wide based gait + more affected side may sag there.
Heel toe walking (cerbellar lesion pt can’t ).
Ask the pt to walk & rapid turn around to come back –(pt feel maintaining balance after rapid turn).

You find obivious ataxic and wide based gait don’t go for rhomberg test just stop gait maneuvers
here and take child to couch in sitting position if he able to & start following sequence:
Step 5. Eye examination make horizontal line then vertical  for h.nystgmus—(fast component
towards lesion).
Step 6. Alternating hand movements of both side handsdysdiadokokinesia.
Step7. Offer something to take from u like pen  note past pointing.
Step 8. Finger nose test + finger –finger test intension tremor & past pointing.
Step 9. Make elbow flexed and face opposite side and ask to resist your pull Rebound
phenomenon—(dt cerebellar hypotonia prevent to stop) ??(optional because some pt may had face
trauma ).
Step10. Knee pendular jerk  note prolong swinging movement of leg after hammer strike—
(indicate severe cases)
279

Step11. Check for tremor  static tremors.


Step 12.Lye down child and look for heel shin test.
Step 13. Do check tone power reflexes –hypotonia,planters normal.
Step 14. Now start GPE VITALSPALLOR, JAUNDICE, PETECHAE, BRUISE , RASH,
TELANGECTASIA OVER NOSE, UPPER CHEST ,EYES, PES CAVUS, HAMMER TOE.
Step 15. Cover with thanks
Step 16. Offer for
Sensory system examination

Fundus
B.P
Anthropometrics
Any drug intake
DESCRIPTION:
I have examined conscious , cooperative child with slurred unintelligible speech , he has obivious
ataxic gait with open eyes and not able to perform heel to toe , I have appreciated signs of cerebellar
lesions in form of nystgmus which is horizontal, dysdiadokokinesia, past pointing & pendular jerk ,
not able to perform smoothly heel shin test & hypotonia, however reflexes and power is normal .
His vitals are stable & there is no any evidence of telangectia, pes cavus, petechae, bruise, bleed,
rash . sir I want to know anthropometrics of child and want to plot on centile chart & fundoscope
DD:
Say that He is the case of cerebellar ataxia ---(don’t say acute or chronic because in hx u don’t the
duration until examiner tell u.) may be acute or chronic I would like to giv certain possible
differentials in my pt:
Acute cerbellar ataxia –(post infectious /varicell, coxsachie,echovirus,drug induced).

Cerebellar SOL (may be tumor(neuroblastoma)/abscess)
Labrynthitis –I thought the possibility of labrynthitis in pt but as obivious signs of cerebellar
involvement are there so unlikely .
HOW WILL U INVESTIGATE?
 CSF analysis –(acute may be normal but as progress it will show elevated lympho+Protein). 280
 MRI brain.
 Calorie test for labrynthitis (mention if kept in differential).

HOW WILL U MANAGE?
 Councelling
 Supportive treatment
 Treat underlying cause.
WHAT IS PROGNOSIS?
It depend upon the cause . acute post viral self limiting usually resolve soon , SOL good after surgery
, if DBD then poor.
DISCUSSION:
 Ataxia is the inability to make smooth, accurate, and coordinated movements, usually due to a disorder
of the cerebellum and/or sensory pathways in the posterior columns of the spinal cord.
 Ataxias may be generalized or primarily affect gait or the hands and arms
 they may be acute or chronic
CAUSES:
CONGENITAL ANOMALIES OF THE POSTERIOR FOSSA:
 Dandy-Walker syndrome.
 Chiari malformation.
 Encephalocele.
 Agenesis of the cerebellar vermis presents in infancy with generalized hypotonia and decreased deep
tendon reflexes. Delayed motor milestones and truncal ataxia are typical.
 Joubert syndrome:
 is an autosomal recessive disorder
 agenesis of the cerebellar vermis, ataxia, hypotonia, oculomotor apraxia, neonatal
breathing problems, and mental retardation.
 Mutations AHI1 gene on chromosome 6, encoding the Jouberin protein.
 MRI  enlargement of the 4th ventricle at the junction between the midbrain and
medulla, creating the “molar tooth sign.”
INFECTIOUS CAUSES OF ATAXIA:
 cerebellar abscess.
 acute labyrinthitis.
 acute cerebellar ataxia.
ACUTE CEREBELLAR ATAXIA:

281
 primarily in children 1–3 yr of age.
 diagnosis by exclusion.
 often follows a viral illness, such as varicella, coxsackievirus, or echovirus infection, by 2–3 wk and is
thought to represent an autoimmune response to the viral agent affecting the cerebellum.

 The onset is sudden, and the truncal ataxia can be so severe that the child is unable to stand or sit.
Vomiting may occur initially, but fever and nuchal rigidity are absent. Horizontal nystagmus is evident
in ≈50% of cases and, if the child is able to speak, dysarthria may be impressive.
INVESTIGATIONS:
CSF typically normal at the onset of ataxia; a pleocytosis of lymphocytes (10–30/mm3) is not
unusual. Later in the course, the CSF protein undergoes a moderate elevation.
MRI  Rule out other
PROGNOSIS: The ataxia begins to improve in a few weeks but may persist for as long as 2 mo. The
prognosis for complete recovery is excellent; a small number have long-term sequelae, including
behavioral and speech disorders as well as ataxia and incoordination.
ACUTE LABYRINTHITIS:
 difficult to differentiate from acute cerebellar ataxia in a toddler.

 The condition is associated with middle-ear infections and intense vertigo, vomiting, and abnormalities
in labyrinthine function, particularly ice water caloric testing.
TOXIC CAUSES OF ATAXIA:
 Alcohol.
 thallium (which is used occasionally in homes as a pesticide).
 anticonvulsants, particularly phenytoin when serum levels reach or exceed 30 μg/Ml.
BRAIN TUMORS:
 tumors of the cerebellum and frontal lobe, as well as neuroblastoma, may present with ataxia. Frontal
lobe tumors may cause ataxia owing to destruction of the association fibers connecting the frontal lobe
with the cerebellum.
 Neuroblastoma may be associated with a paraneoplastic encephalopathy characterized by progressive
ataxia, myoclonic jerks, and opsoclonus (nonrhythmic horizontal and vertical oscillations of the eyes).
METABOLIC DISORDERS:
 Abetalipoproteinemia , arginosuccinic aciduria, and Hartnup disease.
Abetalipoproteinemia : begins in childhood with steatorrhea and failure to thrive (see

Chapter 86.3 ). A blood smear shows acanthocytosis and decreased serum levels of
cholesterol and triglycerides, and the serum β-lipoproteins are absent. Neurologic signs
become evident by late childhood and consist of ataxia, retinitis pigmentosa, peripheral
neuritis, abnormalities in position and vibration sense, muscle weakness, and mental
retardation. Vitamin E is undetectable in the serum of patients with neurologic symptoms.
282
ATAXIA-TELANGIECTASIA:
 autosomal recessive condition. mutations in the ATM gene located at 11q22–q23.

 Most common of the degenerative ataxias.
 Ataxia beginning at about age 2 yr and progressing to loss of ambulation by adolescence.

 Oculomotor apraxia of horizontal gaze, defined as having difficulty fixating smoothly on an object and
therefore overshooting the target with lateral movement of the head, followed by refixating the eyes, is
a frequent finding, as is strabismus, hypometric saccade pursuit abnormalities, and nystagmus.
 The telangiectasia becomes evident by mid-childhood and is found on the bulbar conjunctiva, over the
bridge of the nose, and on the ears and exposed surfaces of the extremities.
 Examination of the skin shows a loss of elasticity.
 Abnormalities of immunologic function that lead to frequent sinopulmonary infections include
decreased serum and secretory IgA as well as diminished IgG2, IgG4, and IgE levels in more than 50%
of patients.
 Children with ataxia-telangiectasia have a 50- to 100-fold greater chance over the normal
population of developing lymphoreticular tumors (lymphoma, leukemia, and Hodgkin disease) as
well as brain tumors.
DIAGNOSIS:
 CHROMOSOMAL BREAKAGE STUDY: increased incidence of chromosome breaks, particularly

of chromosome 14, and elevated levels of α-fetoprotein.
 SERUM IMMUNOGLOBULIN LEVELS: DEC AG / INC E.
 ALPHA PROETIEN LEVEL.
PROGNOSIS: Death results from infection or tumor dissemination.
FRIEDREICH ATAXIA
 autosomal recessive disorder.

 Involving the spinocerebellar tracts, dorsal columns in the spinal cord, the pyramidal tracts, and the
cerebellum and medulla.
 The majority of patients are homozygous for a GAA repeat expansion Mutations cause oxidative
injury associated with excessive iron deposits in mitochondria.
 The onset of ataxia is somewhat later than in ataxia-telangiectasia but usually occurs before age
10 yr. ataxia is slowly progressive and involves the lower extremities to a greater degree than the
upper extremities.
 The Romberg test result is positive.
 Deep tendon reflexes are absent (particularly the Achilles), and the plantar response is extensor.
Patients develop a characteristic explosive, dysarthric speech, and nystagmus is present in most
children.
 Apathic , intelligence is preserved.
 They may have significant weakness of the distal musculature of the hands and feet.
 Marked loss of vibration and position sense caused by degeneration of the posterior columns and 283
indistinct sensory changes in the distal extremities.
 Skeletal abnormalities: including high-arched feet (pes cavus) and hammertoes, as well as
progressive kyphoscoliosis.
 Hypertrophic cardiomyopathy with progression to intractable congestive heart failure

DIAGNOSIS:
 ELECTROPHYSIOLOGIC STUDIES: including visual, auditory brainstem, and somatosensory-

evoked potentials are often abnormal.
 ECG,CXR,ECHO
 SPINE XRAY.
PROGNOSIS: Hypertrophic cardiomyopathy with progression to intractable congestive heart failure

is the cause of death for most patients.
RECENT ADVANCE: Antioxidant therapy with coenzyme Q10 and vitamin E has been reported to
slow progression in some patients.
OTHER DEGENERATIVE ATAXIAS:
neuronal ceroid lipofuscinoses
and late-onset GM2gangliosidosis .
Rare forms of progressive cerebellar ataxia have been described in association with vitamin E
deficienc
Acute or Recurrent Ataxia
Brain tumor
Conversion reaction
Drug ingestion
Encephalitis (brainstem)
Genetic disorders
Dominant recurrent ataxia
Episodic ataxia type 1
Episodic ataxia type 2
Hartnup disease
Maple syrup urine disease
Pyruvate dehydrogenase deficiency
Migraine
Basilar
Benign paroxysmal vertigo
Postinfectious/immune
Acute postinfectious cerebellitis (varicella)
Miller Fisher syndrome 284
Multiple sclerosis
Myoclonic encephalopathy/neuroblastoma

Pseudoataxia (epileptic)
Trauma
Hematoma
Postconcussion
Vertebrobasilar occlusion
Vascular disorders
Cerebellar hemorrhage
Kawasaki disease
Chronic or Progressive Ataxia
-Brain tumors - Cerebellar astrocytoma
- Cerebellar hemangioblastoma (von Hippel-Lindau disease)
- Ependymoma - Medulloblastoma
- Supratentorial tumors - Congenital malformations
- Basilar impression - Cerebellar aplasias
- Cerebellar hemisphere aplasia - Dandy-Walker malformation
- Vermal aplasia - Chiari malformation
- Hereditary ataxias - Autosomal dominant inheritance
Autosomal recessive inheritance - Abetalipoproteinemia
Ataxia-telangiectasia - Ataxia without oculomotor apraxia
Ataxia with episodic dystonia - Friedreich ataxia
Hartnup disease - Juvenile GM2 gangliosidosis
Juvenile sulfatide lipidoses - Maple syrup urine disease
Marinesco-Sjögren syndrome - Pyruvate dehydrogenase deficiency
Ramsay Hunt syndrome - Refsum disease (HSMN IV)
Respiratory chain disorders
X-linked inheritance
285
Adrenoleukodystrophy - Leber optic neuropathy -With adult-onset dementia
With deafness - With deafness and loss of vision

 CEREBRAL PALSY--------------------------------------------------------------------------LONG CASE/
SHORT CASE.
 Biodata :
 P/C can be –(known case defiantly it will present with multiple associated problems
 Seizure disorder
 Pneumonia –aspiration/recurrent
 GIT –GERD/constipation.
 Malnutrition
 Developmental delay
 Orthopedic problems
 Sepsis /UTI
 Fracture/contracture.
 REMEMBER: While doing case cover the following
 Cause –is it antenatal, natal or postnatal.
 Classify:
 Physiological –spastic, atonic, dystonic, mixed.
 Taxonomical –monoplegia, hemiplegia, quadriplegia.
 Rule out progressive nature of disease.
 Associated problems.
 Functional status / mental age.
 HOPC:
Elicit the current reason of admission like if:
 Fever –sort out focus.
 Seizure –detail and reason-is it drug poor compliance if already taking.
 Management details –of current admission
Investigations Rx response  static/improving  parents knowledge  medicines how arranged
and how they give  parents concern.
 PAST Hx
o When diagnosed –till what age pt was alright.
o What were initial events / symptoms ---(HERE ASK THE Q OF DIFFERENTIALS)
o Sudden loss –CP
o Progressive loss –DBD
o Fits –meningitis
o Birth –prematurity/HIE /TORCH/jaundice-kernicterus.
o Petechae, bruise, bleed(CVA)
o What investigations done?
 Neuroimaging
 EEG
 Visual /hearing assessment
 CSF
o What treatment was given?
o Medicine –name with dose , who give
o Response of Rx.
o Follow up –how often , where and by whom?
o Hx of hospitalizations –stay and reasons?
 TREATMENT HISTORY
o What medications has/had been using
o Anti-convulsants
286
o For spasticity
o For nutritional rehabilitations—(muitvitamins)
o For GERD

o Any side effect noticed?
o Any dose changed?
o Blood transfusion given ?
o Any surgical intervention –tenotomy, achillis tendon release, osteotomy, gastrostomy tube
placement, hearing/vision aid ,.
o Bed sores? How managed ?
o Ask about involvement of:
 Pediatrician
 Nutritionalist
 Orthopedician’
 Physiotherapist
 ENT specialist
 Speech therapist
 Occupational therapist
 Surgeon
 Neurologist
 SYTEMIC ENQUIRY;
o Elaborate systemic problems
 GENERAL :
o Anorexia , wt loss, irritability, excessive crying, bed sores.
 GIT –Thrush, caries, dental problems, nasal regurgitation, GERD, Constipation, alternating diarrhea,
swallowing problems –NG FEED?
 RES/SYSTEM: OSA, cough , RTI.
 GENITO URINARY
o Dribbling, burning, retension
 ORHTOPEDIC
o Contracture
o Scoliosis
 DETAIL OF BIRTH HX:
 DETAIL DEVELOPMENT HX –SHOULD BE IN START OF THIS CASE
o Current
o Previous progression
o Assess the functional level
 FAMILY HX
 NUTRITIONAL HX
 DISEASE IMPACT ON SIBS , PARENTS.
 VACCINATION HX
 SOCIOECONOMIC HX
DISCUSSION :
CEREBRAL PALSY
 Permanent Disorder of posture and movement due to insult to the growing brain.
 Many children and adults with CP function at a high educational and vocational level, without any sign
of cognitive dysfunction
287
 A substantial number of children with CP had congenital anomalies external to the central nervous
system (CNS). Fewer than 10% of children with CP had evidence of intrapartum asphyxia. Intrauterine
exposure to maternal infection (chorioamnionitis, inflammation of placental membranes, umbilical
cord inflammation, foul-smelling amniotic fluid, maternal sepsis, temperature >38?C during labor,

urinary tract infection) was associated with a significant increase in the risk of CP in normal
birthweight infants
 The major lesions that contribute to CP are intracerebral hemorrhage and periventricular
leukomalacia (PVL)
CP is generally divided into several major motor syndromes that differ according to the pattern of neurologic
involvement, neuropathology, and etiology .
 The physiologic classification identifies the major motor abnormality.

 topographic taxonomy indicates the involved extremities.
CP is also commonly associated with a spectrum of developmental disabilities, including mental retardation,
epilepsy, and visual, hearing, speech, cognitive, and behavioral abnormalities. The motor handicap may be the
least of the child's problems.
CLASSIFICATION OF CEREBRAL PALSY AND MAJOR CAUSES

MOTOR SYNDROME (APPROX
NEUROPATHOLOGY/MRI MAJOR CAUSES
% OF CP)
Prematurity
Periventricular leukomalacia
Periventricular cysts or scars in Ischemia
Spastic diplegia (35%)
White matter, enlargement of ventricles, squared of Infection
posterior ventricles
Endocrine/metabolic (e.g., thyroid)
Periventricular leukomalacia Ischemia, infection
Spastic quadriplegia (20%) Multicystic encephalomalacia Endocrine/metabolic,
Cortical malformations genetic/developmental
Thrombophilic disorders
Stroke: in utero or neonatal Infection
Hemiplegia (25%) Focal infarct or cortical, subcortical damage Genetic/developmental
Cortical malformations
Periventricular hemorrhagic
infarction
Asphyxia: symmetric scars in putamen and thalamus Asphyxia
Kernicterus: scars in globus pallidus, hippocampus Kernicterus
Extrapyramidal (athetoid,
Mitochondrial: scaring globus pallidus, caudate,
dyskinetic) (15%) Mitochondrial
putamen, brainstem
No lesions: ? dopa-responsive dystonia Genetic/metabolic
Spastic hemiplegia:
 arm > leg .

 Decreased spontaneous movements on the affected side.
 hand preference at a very early age.
 Walking is usually delayed until 18-24 mo, and a circumductive gait is apparent.
 An affected child often walks on tiptoe because of the increased tone in the antigravity gastrocnemius
muscles.
 Affected upper extremity assumes a flexed posture when the child runs.
 Signs of UMN lesions +.

rd
seizure disorder that usually develops in the 1st yr or 2 –(1/3 ). 288
 mental retardation—25%.
 MRI –may show calcifications of TORCH.
CAUSE : Focal cerebral infarction (stroke) secondary to intrauterine or perinatal

Spastic diplegia:
 bilateral spasticity of the legs > arms.

 CAUSE: damage during --20-34 wk of gestationPT/LBWPVL.
 The 1st clinical indication of spastic diplegia is often noted when an affected infant begins to crawl.
 The child uses the arms in a normal reciprocal fashion but tends to drag the legs behind more as a
rudder (commando crawl) rather than using the normal four-limbed crawling movement.
 Scissoring of legs –difficult diaper
 Tip toe walk –delayed walker
 Decrease growth of lower limb.
 Intellectual –normal
 Learning disability and language problem+.
 Examination:
 Atropy of limbs
 Spasticity
 Brisk reflexes.
 Ankle clonus+
 Upgoing babinski sign.
0
 180 scissoring posture
 The prognosis for normal intellectual development for these patients is good, and the likelihood of
seizures is minimal.
 Vision problems+
 MRI PVL-common (70%) with compensatory enlargement of the cerebral ventricles.
Spastic quadriplegia:
 most severe form of CP  all 4 limbs+seizure +MR

 Swallowing difficulties supranuclear bulbar palsies, often leading to aspiration pneumonia.
 SIGNS OF UMN LESION + BULBAR +CN +AUDITORY/VISUAL.
 MRI scanning are severe PVL and multicystic cortical encephalomalacia.
 Children with spastic quadriparesis often have evidence of athetosis and may be classified as having
mixed CP.
ATHETOID CP/CHOREOATHETOID/EXTRAPYRAMIDAL, OR DYSKINETIC CP: ------------(ONLY HYPOTONIC C.P)
 15-20% of patients with CP.

 Arms >legs
 Characteristically:
 hypotonic with poor head control and marked head lag and develop  increased tone with rigidity
and dystonia over several years.
 Feeding may be difficult, and tongue thrust and drooling may be prominent.
 Speech is typically affected because the oropharyngeal muscles are involved. Speech may be absent
or sentences are slurred, and voice modulation is impaired.
 Generally, upper motor neuron signs are not present, seizures are uncommon, and intellect is
preserved in many patients.
 Causebirth asphyxia. lesions in the basal ganglia and thalamus status marmoratus in the basal
ganglia.
 Athetoid CPkernicterus lesions in the globus pallidus bilaterally.
289
D/D -SEGAWA –(dihydroxyphenylalanine (DOPA)-responsive)—DX-Small dose dopa and see response.

DIAGNOSIS
 MRI –BRAIN.
 TORCH TITRE.
 CHROMOSOMAL STUDIES –IF SYNDROMIC
 AUDIOMETRY
 VISUAL ASSESSMENT
 BASELINE
 CXR
MANAGEMENT :
After review of pts investigations I will councell parents regarding condition, complication. Course and
management by involving multidisciplinary approach , I will treat the acute problems of child and teach the
parents how to work their child in daily activities like feeding , bathing, caring, dressing, playing in a way
that limits the abnormal muscle tone.
I will educate them regarding exercise to prevent the contracture particular at achillis tendon.
I will address the chronic problem specifically feeding and nutrition , seizures, constipation, GERD,
neurogenic bladder.
I will regularly monitor for the complication of ds and treatment & my other goal will be psychosocial and
finantial support.
MULTIDISCIPLINARY INVOLVE:
 Myself.
 Social worker.
 physiotherapist
 Speech therapist.
 Occupational therapist.
 Orthopedics
 Psychologist.
GENERAL NURSING CARE OF CHILD
 NG tube
 Rx of GERD
 Rx & prevent bed sores.
 Attention to toilet.
PHYSIOTHERAPY/OCCUPATIONAL THERAPY-SPLINTS/ORTHOSIS.
 Which enable the child to perform daily activities , dressing , walking, toileting, feeding, & bathroom
fiting.
 Serial casting—Over 2-6 weeks calf muscles stretched gradually
 Orhtosis –splints ---soft/hard –act as exoskeleton –prevent contracture development
o Soft orthosis—made from high density foam –used for low tone
o Hard Ankle foot orthosis –most common used—after 3D gait analysis selected accordingly
which to give It improve gait and prevent deformity. 290
 Fixed AFO
 Hinged AFO-allow dorsiflexion.
 In-shoe orthosis –(supramalleolar orthosis)
 Night splinting –beneficial prevent contracture and allow good muscle growth.

SPASTICITY:
 Advise for regular physiotherapy.

 Diazepam
 Baclofen –oral/IT. (10mg baclen – 2mg /kg/day OD/BD) ---(IT NOT USED NOW)
 Botulism toxin-A
o Effective for localized/segmental spasticity.
o Given IM cholinergic nerve take it motor endplate prevent release of Acetylcholine 
prolong reversible relaxation of skeletal muscles.
o Seven types (A-G) clinically ABF used.
o Causes local paralysis in injected muscles witin 1-3 days.
o Duration of action 3-6 month  then new neuromuscular junction generation  again
spasticity develops then injection need to repeated again.
o Indication:
o Dynamic contracture in absence of fixed deformity.
o Targeted muscles are:
 Gastrocnemius soleus complex.
 Tibialis posterior.
 Hamstrings.
 Adductors.
 Illeopsoas
o DISADVANTAGES:
 S/E—axonally absorbed  deterioration in walking, local weakness, increased falls,
aspiration pneumonia-pharyngeal involvement ,dysphagia, bulbar weakness, urinary /
fecal incontinence.
 Cost.
 Repeatative needed.
 It is not effective for extrapyramidal form.
Selective dorsal rhisotomy—cut nerves which increase tone.
 Dantrolene
 Tizanidine
 Newer:repeatative manetic stimulation + use of gabapentin.—adults useful.
RIGIDITY –L-Dopa
Rx OF CONTRACTURES:
 Physiotherapy
 Adductor tenotomy.
 Hamstring release
 Equine –lenghten achillis.
 Single event multi level surgery.
Rx OF GIT PROBLEMS:
 Nutritional rehabilitation
 Constipation –soft diet /high fibre/laxatives
 May need gastrostomy.
Rx OF RESPIRATORY PROBLEMS:
291
 O2
 Nabulization
 Chest physiotherapy.

 Suction bulb
Rx OF EXCESSIVE SALIVATION:
 Excessive drooling Anti-cholinergic-glycopyrrolate S/E-urine retention, constipation, blurring.

 Severe drooling –USG guided BTX-A inj parotid/submandibular
If still salivation
 Surgery – duct into pharynx.

 Gland removal
 Resection of cordae tympani nerve.
SPEECH THERAPY –Dysartria common due to bilateral corticobulbar dysfunction.
CONTROLL OF SEIZURES-antic-convulsants
CORRECTION OF VISUAL IMPAIRMENT
 Squint-30% CP
 Dec visual acuity –spastic quadriplegia
 Visual field defect –hemiplegic CP.
 >nystgmus, optic atropy and refrective errors.
 Refractive errors –give spectacles
 Squint –patch good eye ---prevent amblopia
 VA <6/60  Not correctable by glasses
 Partially sighted VA btw 6/24-6/60  magnifying glasses .
 <3/60  Braille ( blind person teached by objects)
Rx OF HEARING PROBLEMS:
 Mild loss ( 25-45 db) –no Rx needed

 Moderate ( 45-65) – hearing aid
 Sever (65-85db ) –Aid
 Profound (>85db ) special education of deaf.
SCHOOLING  special schooling
SOCIAL IMPLICATIONS
 Behavior problems –ADHD

 Finances
 Social worker.
PROGNOSIS:
OVERALL PROGNOSIS DEPEND UPON
 EXTENT OF M.R
 VISUAL/ HEARING IMPAIRMENT 292
 SEIZURES
 EXTENT OF PHYSICAL INACTIVITY.

PROGNOSIS OF WALKING
 Hemiplegia –100%
 Diplegic –90%.
 Ataxic –88%.
 Quadriplegic –18%.
 Dyskinetic – 0%.
------------------------------------------
Suspect CP
 Moro >3 month

 Stepping >6 weeks
 Landau –absent ( normal 3 m-1.5 yr).
Microcephaly seen in 25% spastic CP.
 CP is clinical dx
 Difficult to dx before 6 month—coz it is evident when brain matures.
Tonic neck reflex
 If sustained >30 sec or persist at 8-10 month –pathological.
CP DIFFERENTIALS:
1. POST MENINGITIC SEQUELE

2. DBD
3. CEREBRAL MALFORMATIONS.
4. CONGENITAL INFECTIONS –TORCH
FUNCTIONAL CLASSIFICATION
 CLASS-I  NORMAL SELF CARE.

 Vocational –school
 Avocational –outdoor activities
 CLASS-II  SELF CARE BUT SLIGHTLY IMPAIRED VOCATIONAL ACTIVITIES
 CLASS III  SLIGHTLY IMPAIRED SELF CARE + MARKED IMPAIRED VOCATIONAL
ACTIVITES.
 CLASS IV  MARKEDLY IMPAIRED SELF CARE.
Q: WHAT ARE ASSOCIATIONS OF C.P?
Q: WHAT PREVENTIVE MEASURES U WILL TAKE TO DECREASE C.PALSY ?

293
Q: ROLE OF HYPOTHERMIA IN PREVENTION OF HIE?

CHOREA------------------------------------------------------------------ ( SHORT CASE)
Command: Do GPE and relevant./ some time motor system and relevant.
Approach considerations:
Step 1: Introduction--> consent--> adequate exposure.
Step 2: Inspection ( 5 sec)--> communicate with child verbally (observe for unintelligible
speech).
Step 3: Shake hand if you observe the chorioform hand
Step 4: Do Maneuvers for signs of chorea (milk maid sign,darting tongue,pronator sign).
Think possible differentials ( Rheumatic , SLE, Wilson)
Start GPE including vitals.
For rheumatic (fever, S/c nodules, erythema marginatum, joint swelling)
For Wilson disease ( jaundice,liver with span, spleen, ascites).
For SLE ( Rash, oral ulcers joint pain/ swelling, petechae, bruise)
Auscultate heart for carditis ( rheumatic).
Do motor system.+ Gait.
OFFER: Ht, Wt, slit lamp examination and B.P. 294

DESCRIPTION: Sir my patient conscious and co operative during my examination ,
emotionally labile with unintelligible speech, and abnormal involuntary movements
involving both extremeties.
(pause 2 sec) , She/he is having the signs of chorea in form of milk maid sign, darting tongue
and pronator sign
( pause 2 sec): He/ she is vitally stable with Ht, wt, appropriate for her age and gender but I
want to plot on the centile charts.
there is no evidence of pallor,jaundice, clubbing, rash, S/c nodule, oral ulcer.
Apex beat is palpable at 5 th IC space medial to MCL, 1st and 2nd heart sounds are normal
with no added sound.
Abdomen is normal in shape, no evidence of visceromegally or free fluid in abdomen.
Comment on gait and motor if performed.
Tell yor findings?
What is your diagnosis?
My clinical examination findings are in the favour of certain differentials,
sydenham.chorea, Wilson ds with chores, SLE.
Why Rheumatic first in your differential?
Sir as my pt is ..... Yr of age , febrile , and common to be considered ,although I could not hav
other evidence of Rheumatic fever. But as a sole presentation I would consider this as my
first differential.
Why not Wilson ?
Unlikly he/she is the case of Wilson disease , because of no other stigmata of CLD, although
Wilson can present with chorea but usually they hav dystonia as a common neurological
presentation.
Why not SLE?

295
Could be SLE , but there is no evidence of oral ulcer, rash, joint swelling/pain, fever, and
serosal involvement

What other possible differentials can be?
PANDAS, TICS, OBSESSIVE COMPULSIVE DISORDERS are the conditions which are associated
with chorea.
What is the possible mechanism of Chorea?
Chorea is likely result.of functional overactivty of dopaminergic system involving caudate

nucleus and sub thalamus.
What is difference btw PANDAS and Rheumatic fever?
PANDAS present with tics & fits within briesf period of illness, while rheumatic not
What is the reason of these abnormal.movements?
Because of hypotonia and dopaminergic overactivity.
Why not athetosis?
Distal abnormal nonpurposive writhing movements due to lesion at putamen.
What is hemiballismus?
Rapid jerky body movement making half circle like, due to lesion at subthalmic nuclei.
Why not tremors?
Tremors are fine oscillatory movements usually distal if it is resting then lesion in substantial
nigra and intension tremor lesion at cerebellum.
How would you investigate?
first I will investigate my patient according to my possible differentials
I.will go for CBC , ESR, CRP, ECG, CXR, ECHO, LFTs, SERUM CERULOPLASMIN LEVEL, 24 HR
URINARY COPPER LEVEL,SLIT LAMP EXAMINATION, USG ABD, ANA, Anti DsDNA, anti
phospholipid antibody level.
How will you manage the patient?

296
After establishing /confirming my diagnosis I will.councell parents regarding the disease,
treatment, complication and outcome, I.will treat the acute problems of pt , like he/ she is

having severe chorea I will.give diazepam, valproic acid , phenobarb, halloperidol,.and
observe for response. and start benzathine pencillin prophylaxis to prevent from rheumatic
chorea.
If it proves to be case of Wilson then I will start dietry restriction of nuts, chocolates,
pencillamine with zinc acetate with follow up monitoring.
What is prognosis of Rheumatic chorea?
It is a self limiting disease which may take 3-6 month and may take 1 yr to resolve. 20%
cases have recurrence of chorea .
297

DBD ------------------------------------------------------------------------------------------------------------------LONG
CASE
KNOWN CASE/NEW CASE.
Differential can be offered according to clinical features:
1. Post meningitic sequele

2. C.palsy
3. Metachromic LD.
4. SOL –slow growing tumors with dementia .
5. No identifiable cause although I considered ……., rule out each by explanation.
P/C CAN BE :
 FITS
 REGRESSION OF MILESTONES
Q—IF THERE IS HX OF REGRESSION THEN FIRST OF ALL ASK IN DETAIL , WHETHER CHILD ACHIEVED
DEVELOPMENTAL MILSETONES AT APPROPRIATE AGE OR NOT?
IF THERE IS DEFINITELY REGRESSION NOW U DECIDE WHTETHER IT IS :
 WHITE MATTER DEGENERATION –(SOAP)

 GRAY MATTER DEGENERATION –( DEMENTIA, ATAXIA –THEN SOAP)
 BASAL GANGLIA –( DYSTONIA, CHORIOATHETOSIS, CHOREA)
 SPINOCEREBELLAR DEGENERATION –(ATAXIA/GAIT PROBLEMS)
what was age at onset of regression?
how parents nnoticed onset of regression ?
which was the area 1st to be affected?
any subtle finding on note to parents before regressions—altered behaviour/poor performance,

slow mentation..
PROGRESSION OF DISEASE:
 Acute / subacute/ progressive/ non-progressive.

 Walking difficulty, clumsiness, frequent falls, falls during sitting/walking.
 Fever
 Visual problems/ visual deterioration.
 Hearing impairment
 Speech, dysarthria, loss of speech.
 Deterioration in school work / intellectual deterioration.
 Dementia 298
 Psudobulbar palsies –(swallowing difficulty, drooling, dysphagia, nasal speech, nasal regurgitation).
 Abnormal movements –( posturing, dystonia )
 Fits –/ myoclonic jerks --(all details ).
 Bladder/ bowl control

 Headache, vomiting, focal fits, altered sensorium, focal defitis, unconsciousness, coma.
 Any Hx of jaundice—(Wilson), rash before 4 yr of age –(if + then detail for Measles),
hyperpigmentation –(XALD).
 Hx of anti-convulsants, lead intoxication, drugs.
 Hypothyroidism –constipation , cold intolerance,-maternal anti-thyroid, prolong neonatal jaundice.
EVALUTE IN DETAIL COURSE AND PROGRESSION OF ILLNESS
Q For Complication of DISEASE :
 Bed sores/ Contracture/wt loss

 GERD
 Loose motion/constipation
 Retention/incontinence
 ADEK deff –nutritional Hx.
 B.P –hypotension –(ALD)
CURRENT STATUS REGARDING:
 functional disablilty
 seizures
 vision , hearing, abnormal movements, speech.
MANAGEMENT DETAILS
 Where admitted
 What diagnostic investigations carried out
 What treatment has been offered so for?
 Has there been any improvement?
 Parents knowledge –(Disease-course-home management.
 Detail about follow up and monitoring .
PAST Hx—any Hx of of smission, signifiacant illness.
BIRTH Hx –(detail antenatal , natal and post natal to rule out CP)
FEDING Hx –Calculate calories
Family hx –( consanguinity , epilepsy, DBD, similar problem)
Disease impact
Socioeconomic:
Examination :
DISCUSSION
NEURODEGENERATIVE DISORDERS OF CHILDHOOD--------(DBD)

299
heterogeneous diseases that result from specific genetic and biochemical defects, chronic viral
infections, and a significant group of conditions of unknown cause.

Previously rectal / brain biopsy used as a neural source now neuroimaging techniques and specific
biochemical or molecular diagnostic tests, these invasive procedures are rarely necessary.
In DBD the main component of diagnosis is hx & examination.
The hallmark of a neurodegenerative disease is progressive deterioration of neurologic function

with loss of speech, vision, hearing, or locomotion, often associated with seizures, feeding
difficulties, and impairment of intellect. The age of onset, rate of progression, and principal
neurologic findings determine whether the disease affects primarily the white or the gray matter.
White matter Upper motor neuron signs are prominent early .—(SOAP)
Gray matter convulsions, intellectual, and visual impairment.—(first Seizure, ataxia)
Once diagnosed is established although fatal for affected child but proper dx can help in preventive
strategies for affected sib & genetic councelling + other sib prevention—(For all conditions in which
the specific enzyme defect is known, prevention by prenatal diagnosis (chorionic villus sampling or
amniocentesis) is possible. Carrier detection is also often possible by enzyme assay.)
Bone marrow transplantation and other forms of cell and gene therapies are also becoming useful
for preventing the progression of disease in presymptomatic individuals.
Heredity and Biochemical Defects in the Neurodegenerative Disorders

NEURODEGENERATIVE MODE OF SPECIMEN FOR
DISORDER INHERITANCE BIOCHEMICAL DEFECT ANALYSIS
SPHINGOLIPIDOSIS
GM1 gangliosidosis AR β-Galactosidase Serum, leukocytes,
skin fibroblasts
GM2 gangliosidosis
Tay-Sachs disease AR Hexosaminidase A Serum, leukocytes,
skin fibroblasts
Sandhoff disease AR Hexosaminidase A and B Serum, leukocytes,
skin fibroblasts
Krabbe disease AR Galactocerebrosidase Leukocytes and skin
fibroblasts
Metachromatic leukodystrophy AR Arylsulfatase A Leukocytes and skin
fibroblasts
NEURONAL CEROID AR Pamitoyl-protein EM of skin biopsy
LIPOFUSCINOSES thioesterase (PPT)
Tripeptidyl peptidasel 1
(TPP1)
ADRENOLEUKODYSTROPHY XLR VLCFA oxidation Plasma, skin
300
fibroblasts
SIALIDOSIS AR Neuraminidase Skin fibroblasts

Select “Intrinsic” Conditions Associated with Developmental Regression
AGE AT ONSET
(Yr) CONDITIONS COMMENTS
<2, with Fructose intolerance Vomiting, hypoglycemia, poor feeding,
hepatomegaly failure to thrive (when given fructose)
Galactosemia Lethargy, hypotonia, icterus, cataract,
hypoglycemia (when given lactose)
Glycogenosis (glycogen storage Hypoglycemia, cardiomegaly (type II)
disease) types I-IV
Mucopolysaccharidosis types I and Coarse facies, stiff joints
II
Niemann-Pick disease, infantile Gray matter disease, failure to thrive
type
Tay-Sachs disease Seizures, cherry red macula, edema, coarse
facies
Zellweger (cerebrohepatorenal) Hypotonia, high forehead, flat facies
syndrome
Gaucher disease type II Extensor posturing, irritability
Carbohydrate-deficient Dysmyelination, cerebellar hypoplasia
glycoprotein syndromes
<2, WITHOUT Krabbe disease Irritability, extensor posturing, optic

HEPATOMEGALY atrophy and blindness
Rett syndrome Girls with deceleration of head
growth, loss of hand skills, hand
wringing, impaired language skills,
gait apraxia
Maple syrup urine disease Poor feeding, tremors, myoclonus,
opisthotonos
Phenylketonuria Light pigmentation, eczema, seizures
Menkes kinky hair disease Hypertonia, irritability, seizures,
abnormal hair
Subacute necrotizing White matter disease
encephalopathy of Leigh
Cerebrooculofacioskeletal Reduced white matter, failure to
syndrome (of Pena and Shokeir) thrive
Canavan disease White matter disease 301
2–5 yr Niemann-Pick disease types III and IV Hepatosplenomegaly, gait difficulty

Wilson disease Liver disease, Kayser-Fleischer ring;
deterioration of cognition is late
Gangliosidosis type II Gray matter disease
Ceroid lipofuscinosis Gray matter disease
Mitochondrial encephalopathies (e.g., Gray matter disease
myoclonic epilepsy with ragged red fibers
[MERRF])
Ataxia-telangiectasia Basal ganglia disease
Huntington disease (chorea) Basal ganglia disease
Hallervorden-Spatz syndrome Basal ganglia disease
Metachromatic leukodystrophy White matter disease
Adrenoleukodystrophy White matter disease, behavior problems,
deteriorating school performance,
quadriparesis
5–15 yr Adrenoleukodystrophy Same as for adrenoleukodystrophy in 2 to 5 yr olds

Multiple sclerosis White matter disease
Neuronal ceroid lipofuscinosis, Gray matter disease
juvenile and adult
Schilder disease White matter disease, focal neurologic symptoms
Refsum disease Peripheral neuropathy, ataxia, retinitis
pigmentosa
Sialidosis II, juvenile form Cherry-red macula, myoclonus, ataxia, coarse
facies
Subacute sclerosing Diffuse encephalopathy, myoclonus; may occur
panencephalitis years after measles
GRAY MATTER DISEASE
Present with : Early dementia / seizures , +/- extrapyramidial features—(cedrebellum +basal ganglia
involvement –(tremors, chorea, athetosis, dystonia,nystgmus)
With viseromegally: without visceromegally
 MPS -Tay sach disease

 Mucolipidosis -Rett syndrome –(female xclusively)
 GM1 gangliosidosis . -Neuronal ceroid lipofusinosis.
 Fucosidosis -mitochondrial –(MELAS, MERRF). 302
 Nieman pick disease
 Gaucher disease

WHITE MATTER DISEASE:
Present with: Spastic, ataxia, optic atrophy, peripheral neuropathy—(early manifestation)
While seizures & dementia late manifestation.
Examples:
 Adrenoleukodystrophy.
 Metachromatic leukodystrophy.
 Krabbe disease.
 Alaxander disease.
 Canavan disease.
 SSPE
 MS
 MPS:
PRESENTATION OF WHITE MATTER DISEASE: Childhood age with enlarge head size presented with
prominent cerbellar signs in form of ataxia, had spasticity, with loss of sensation of touch & pain
(demylinating), absent reflexes, visual impairment, however cognition is normal
Q: HOW CHERRY RED SPOT FORMED WHAT IS CONCEPT BEHIND THAT?
A: (sphingolipid-laden retinal ganglion cells) encircling the normal red fovea :there are ganglion
throught retina except this macula so in this disease the lipid accumulate in ganglions
surround giving yellow appearance background that leads more prominent red look of fovea
cherry red
Why not metachromatic leukodystrophy?
Can be late infantile variant of MCL , They have insidious onset of gait disturbance start at 1-2 yr of
age , present with frequent falls and gradually locomotion is impaired , and on examination they
have hypotonia, with absent /Reduced DTR. And as the time progresses within months of onset they
have decreased intellectual abilities and slurred speech, dyarthria, visual problems become
prominent in form of decrease vision, nystgmus and ultimately as a result of optic atrophy.
So within 1 yr regress of ability to sit , decorticate posture –spasticity, feeding problems –which is
due to pseudobulbar palsy –ultimaltely go into coma and die by 5-6 yr of age as a consequence of
aspiration/bronchopneumonia.
Juvenile –present at 5-10 yr of age with decrease school performance, altered personality , gait
disturbance and urinary incontinence , dysarthria and ataxia, dystonia and tremors and in terminal
stage they develop seizures and death usually ensues at mid adolescence.—( same like Wilson
disease but they present predominantly with extra-pyramidal in form of dystonia, usually present
with neurologically manifestations after 10 yr of age, they have KF rings which I could not appreciate 303
in my pt.

HOW U INVESTIGATE A CASE OF MCLD ?
 MRI-/CT BRAIN – diffuse symmetric attenuation of white matter of cerebrum and cerebellum.
 ELECTROPHYSIOLOGICAL STUDIES –all are reduced
 VEP
 ABRs
 NCV
 CSF EXAMINATION –raised protein.
TREATMENT:
 SUPPORTIVE
 BMT—( EARLY ).
GANGLIOSIDOSES
 Gangliosides are glycosphingolipids, normal constituents of the neuronal and synaptic membranes.
 Abnormalities in catabolism result in an accumulation of the ganglioside within the cell.
 classified into 2 groups:
 GM1 gangliosidoses.
 GM2 gangliosidoses.
GM1 Gangliosidoses:
autosomal recessive trait.
deficiency of acid β-galactosidase –assess in leukocytes and cultured fibroblast.
Prenatal diagnosis –enzyme in cultured amniotic cells.
 The 3 subtypes of GM1 gangliosidoses are classified according to age at presentation:

 Infantile (type 1).
 Juvenile (type 2).
 Adult (type 3).
 Infantile GM1 gangliosidosis:
 presents at birth or during the neonatal period with anorexia, poor sucking, and inadequate weight gain.
 Development is globally retarded, and generalized seizures are prominent.
 The phenotype is striking and shares many characteristics with Hurler syndrome.
 The facial features are coarse, the forehead is prominent, the nasal bridge is depressed, the tongue is
large (macroglossia), and the gums are hypertrophied.
 Hepatosplenomegaly is present early in the course as a result of accumulation of foamy histiocytes,
and kyphoscoliosis is evident because of anterior beaking of the vertebral bodies. The neurologic
examination is dominated by apathy, progressive blindness, deafness, spastic quadriplegia, and
decerebrate rigidity.
 A cherry red spot in the macular region is visualized in approximately 50% of cases.
 The cherry red spot is characterized by an opaque ring (sphingolipid-laden retinal ganglion cells)
encircling the normal red fovea.
 Children rarely survive beyond age 2-3 yr, and death is due to aspiration pneumonia.
Juvenile GM1 gangliosidosis: 304
 Delayed onset beginning about 1 yr of age.

 The initial symptoms consist of incoordination, weakness, ataxia, and regression of language.
Thereafter, convulsions, spasticity, decerebrate rigidity, and blindness are the major
findings.
 No coarse facial features and no hepatosplenomegaly.
 Radiographic examination of the lumbar vertebrae may show minor beaking.
 Children rarely survive beyond 10 yr of age.
Adult GM1 gangliosidosis is a slowly progressive disease consisting of spasticity, ataxia,

dysarthria, and a gradual loss of cognitive function.
GM2 Gangliosidoses
 Tay-Sachs disease (TSD).

 Sandhoff disease.
 juvenile GM2 gangliosidosis.
 adult GM2 gangliosidosis.
Tay-Sachs disease: hexosaminidase A deficiency
 is most prevalent in the Ashkenazi Jewish population.
 mutations in the HEXA gene .
 appear normal until ≈6 mo of age, except for a marked startle reaction to noise that is evident
soon after birth.
 Begin to lag in developmental milestones and, by 1 yr of age, they lose the ability to stand, sit, and
vocalize.
 Early hypotonia develops into progressive spasticity, and relentless deterioration follows, with
convulsions, blindness, deafness, and cherry red spots in almost all patients.
 Macrocephaly becomes apparent by 1 yr of age  the 200- to 300-fold normal content of GM2
ganglioside deposited in the brain.
 Few children live beyond 3-4 yr of age, and death is usually associated with aspiration or
bronchopneumonia.
 An accurate and inexpensive carrier detection test is available (serum or leukocyte hexosaminidase A),
and the disease can be reliably diagnosed by chorionic villus sampling in the 1st trimester of pregnancy
in couples at risk (heterozygote parents).
Sandhoff disease:  hexosaminidase A and B in serum and leukocytes.

305
 very similar to TSD in the mode of presentation, including progressive loss of motor and language
milestones beginning at 6 mo of age.
 Seizures, cherry red spots, macrocephaly, and doll-like facies are present in most patients; however,
children with Sandhoff disease may also have splenomegaly.

 The visual-evoked potentials (VEPs) are normal early in both early then abnormal or absent later.
 The auditory brainstem responses (ABRs)  prolonged latencies.
 Children usually die by 3 yr of age.
Juvenile GM2 gangliosidosis:
 develops in mid-childhoodinitially with clumsiness followed by ataxia.

 Signs of spasticity, athetosis, loss of language, and seizures gradually develop.
 Progressive visual loss is associated with optic atrophy, but cherry red spots rarely occur. deficiency
of hexosaminidase is variable (total deficiency to near normal) in these patients. Death occurs
around 15 yr of age.
Adult GM2 gangliosidosis:
 is characterized by a myriad neurologic signs, including slowly progressive gait ataxia, spasticity,
dystonia, proximal muscle atrophy, and dysarthria.
 Generally, visual acuity and intellectual function are unimpaired.
 Hexosaminidase A activity alone or hexosaminidase A and B activity is reduced significantly in
the serum and leukocytes.
KRABBE DISEASE (GLOBOID CELL LEUKODYSTROPHY):

 A.R
 Severe myelin loss due to its destruction + globoid loss in white matter.
 deficiency of the lysosomal enzyme galactocerebroside β-galactosidase.
 Normally, myelination begins in the 3rd trimester, corresponding with a rapid increase of
galactocerebroside β-galactosidase activity in the brain.
 Pathogensis: Nonmetabolized galactocerebroside stimulates the formation of globoid cells that reflect
the destruction of oligodendroglial cellsoligodendroglial cells are responsible for the elaboration of
myelintheir loss results in myelin breakdown, thus producing additional galactocerebroside and
causing a vicious circle of myelin destruction.
 Clinical features: The symptoms evident in the 1st few months of life and include excessive irritability
and crying, unexplained episodes of hyperpyrexia, vomiting, and difficulty feeding. In the initial stage
children are often treated for colic or “milk allergy” with frequent formula changes. Generalized
seizures may appear early in the course of the diseaseAlterations in body tone with rigidity and
opisthotonus and visual inattentiveness due to optic atrophy become apparent as the disease progresses.
In the later stages of the illness, blindness, deafness, absent deep tendon reflexes, and decerebrate
rigidity constitute the major physical findings.
 Most patients die by 2 yr of age.
 MRI and magnetic resonance spectroscopy are useful for evaluating the extent of demyelination in
Krabbe disease.
 Umbilical cord blood (stem cell) transplantation from unrelated donors in asymptomatic babies
may favorably alter the natural history but will not help patients who already have neurologic
symptoms.
LATE-ONSET beginning in childhood or adolescence.

 Patients present with optic atrophy and cortical blindness,
 condition may be confused with adrenoleukodystrophy.
 Slowly progressive gait disturbances, including spasticity and ataxia, are prominent
 cerebrospinal fluid (CSF) elevated protein content.
 Nerve conduction velocities are markedly delayed due to segmental demyelination of the peripheral
306
nerves.
 VEPs decrease gradually in amplitude with no response in the late stages of the disease.
 ABRs are characterized by the presence of only waves I and II.

 CT scans and MRI  marked decrease in white matter, especially of the cerebellum and centrum
semiovale, with sparing of the subcortical U fibers.
 Prenatal diagnosis is possible by the assay of galactocerebroside β-galactosidase activity in chorionic
villi or in cultured amniotic fluid cells.
NEURONAL CEROID LIPOFUSCINOSES
 Neurodegenerative lysosomal storage disorders characterized by visual loss, progressive dementia,

seizures, motor deterioration, and early death.
 The NCLs are so named because of the intracellular accumulation of fluorescent lipopigments—(
ceroid and lipofuscin).
 Evaluation of neuronal biopsies (either brain, rectal, conjunctival, or skin) was once required for
diagnosis)—but latest is With the advent of enzymatic and molecular testing methods.
Infantile type begins in the 1st yr of life with myoclonic seizures, intellectual deterioration, and
blindness.
 Eye retina findings—optic atrophy + brownish discoloration of the macula Optic atrophy and,
cerebellar ataxia is prominent.
 Death occurs during childhood.
Late infantile type :generally presents with myoclonic seizures beginning between 2 and 4 yr of
age in a previously normal child. Dementia and ataxia are combined with a progressive loss of
visual acuity and microcephaly.
 Examination of the retina marked attenuation of vessels, peripheral black “bone spicule”
pigmentary abnormalities, optic atrophy, and a subtle brown pigment in the macular region.
 The ERG and VEP are abnormal early in the course of disease.
 The autofluorescent material is deposited in neurons, fibroblasts, and secretory cells.
Juvenile type or Batten disease) is the most common form of NCL disease.
 Autosomal recessive mutations.

 Children affected with JNCL tend to develop normally for the 1st 5 yr of life.
 Their initial symptom is usually progressive visual loss and their retinal pigmentary
changes often results in an initial diagnosis of retinitis pigmentosa.
 The funduscopic changes are similar to those for the late infantile type.
 After disease onset, there may be rapid decline with changes in cognition and personality,
motor incoordination, and seizures.
 Myoclonic seizures are not as prominent as in LINCL.
ADRENOLEUKODYSTROPHY
 1/20,000 boys.
 XLR—MALES—ONLY TRANSMITTED BY CARRIER MOTHERS
 Associated with adrenocortical suffieciency.
 mutations in the ABCD1 gene coding for the ALD protein, an adenosine triphosphate (ATP)-
binding cassette half transporter on Xq28. 307
 Classical –CERALD –most common.
 Classic adrenoleukodystrophy (ALD), also called cerebral ALD (CERALD) is considered to be
the most common leukodystrophy.

o Boys present between 5 and 15 yr of age with evidence of academic difficulties,
behavioral disturbances, and gait abnormalities.
 ALD is caused by accumulation of very long chain fatty acids in neural tissue and adrenals
 In 40% of male hemizygotes, the disease presents in its classic form, CERALD, as an
inflammatory demyelinating disease.
PRESENTATION Generalized seizures are common in the early stages.
 UMN signs  spastic quadriparesis and contractures, ataxia, and marked swallowing
disturbances secondary to pseudobulbar palsyThese dominate the terminal stages of the illness.
 Hypoadrenalism –(50%) and adrenal insufficiency characterized by abnormal skin pigmentation
(tanning without exposure to sun) may precede the onset of neurologic symptoms.
CT scans and MRI  periventricular demyelination beginning posteriorly; this advances

progressively to the anterior regions of the cerebral white matter.
ABRs, VEPs, and SSEPs  normal initially but ultimately show prolonged latencies and abnormal
waveforms.
PROGNOSISDeath occurs within 10 yr of the onset of the neurologic signs.
Rx :
 BMT prevent the progression of the disease when done at an early stage before clinical signs
develop.
 LORENZO'S OIL (LO), a mixture of glyceryl trioleate and glyceryl trierucate lowers very long
chain fatty acid (VLCFA) levels by inhibiting synthesis.
 It has not been shown to effectively reverse or slow neurologic deterioration in
CERALD boys.
 it may be effective in slowing onset of cerebral disease when given to asymptomatic
boys with no clinical or MRI findings.
Adrenomyeloneuropathy;
 40% of boys with X-linked ALD.

 presents as a more chronic disorder of the spinal cord and peripheral nerves.
 It begins with a slowly progressive spastic paraparesis, urinary incontinence, and onset of
impotence during the 3rd or 4th decade.
Multiple periodic brain neuroimaging studies which can provide quantitative information about
the progression of adrenoleukodystrophies aids the selection of patients for bone marrow
therapy, and has improved counseling for these disorders.
Neonatal ALD:
 A.R
 marked hypotonia, severe psychomotor retardation, and early onset of seizures.
 Visual inattention is secondary to optic atrophy.
 Results of adrenal function tests are normal. 308
DIAGNOSIS OF ALD:
 Clinical history

 MRI  posterior leukoencephalopathy.
 SERUM VLCFA
In classical and late-onset ALD, the male child is affected, but the carrier mother may show spasticity
of spinal cord origin.
SIALIDOSIS
 A.R
 lysosomal sialidase deficiency, secondary to autosomal recessive mutations in the sialidase (α-
neuraminidase, NEU1) gene on chromosome 6p21.3
 The accumulation of sialic acid–oligosaccharides with markedly increased urinary excretion of sialic
acid–containing oligosaccharides is associated with clinical presentations that range from the milder
sialidosis type I to the more severe sialidosis type II associated with both neurologic and somatic
features.
 Sialidosis type I, the cherry red spot myoclonus syndrome :
o usually presents in the 2nd decade of life, when a patient complains of visual deterioration.
Inspection of the retina shows a cherry red spot, but, unlike patients with TSD, visual acuity
declines slowly.
o Myoclonus of the extremities is gradually progressive and often debilitating and eventually
renders patients nonambulatory.
o The myoclonus is triggered by voluntary movement, touch, and sound and is not
controlled with anticonvulsants.
o Generalized convulsions responsive to antiepileptic drugs occur in most patients.
Sialidosis type II :
patients present at a younger age and have cherry red spots and myoclonus, as well as
somatic involvement, including coarse facial features, corneal clouding (rarely), and
dysostosis multiplex, producing anterior beaking of the lumbar vertebrae.
 Type II patients may be further subclassified into congenital and infantile (childhood) forms.
Patients with sialidosis have been reported to live beyond the 5th decade.
DIAGNOSIS—urinary levels.
ALEXANDER DISEASE
 Rare disorder that causes progressive macrocephaly and leukodystrophy.

 dominant mutations in the glial fibrillary acidic protein (GFAP) gene, on chromosome 17q21 and cases
are usually sporadic in their families.
 Pathologic examination of the brain discloses deposition of eosinophilic hyaline bodies called
Rosenthal fibers in astrocyte processes- accumulate in a perivascular distribution throughout
the brain.
 In the classic infantile form of Alexander disease degeneration of white matter is most prominent
frontally.
PRESENTATION  progressive loss of intellect, spasticity, and unresponsive seizures 309

causing death by 5 yr of age.
 There are milder forms that present later in life and that may not have the characteristic frontal
predominance or megalencephaly.

CANAVAN DISEASE
Inherited as A.R Defeciency of aspartoacyclase  no cleaving of N-acetylaspartic acid—(white

matter)  no available acetate (essential for myelination) no more myelin symthesis.
Excessive amount of N-acetylaspartic acid accumulate in Blood, CSF, urine.
 Spongy degeneration of the white matter of the brainleads to a severe form of leukodystrophy.
 It is more prevalent in Ashkenazi Jewish descent than in other ethnic groups.
PATHOLOGY
 There is striking vacuolization and astrocytic swelling in white matter As the disease progresses, the
ventricles enlarge, owing to cerebral atrophy.
 Infants usually appear normal at birth and may not manifest symptoms of the disease until 3-6 mo of
age, when they develop progressive macrocephaly, severe hypotonia, and persistent head lag As the
infant grows older, delayed milestones become evident. These children become hyperreflexic and
hypertonic; joint “stiffness” and contractures may be encountered, as is commonly seen in cerebral
palsy. As these patients grow older, seizures and optic atrophy develop.
 Feeding difficulties, poor weight gain, and gastroesophageal reflux may occur in the 1st yr of life;
swallowing deteriorates in the 2nd and 3rd yr of life, and nasogastric feeding or permanent gastrostomy
may be required.
 Most patients die in the 1st decade of life; with improved nursing care, they may survive through the
2nd decade.
Atypical Canavan Disease Such patients have very mild delays and are often not suspected of
having Canavan disease. However, the urinary excretion of N-acetylaspartic acid is moderately
increased, which raises the question of Canavan disease. Brain MRI demonstrates increased
signal intensity in the basal ganglia rather than global white matter disease, sometimes leading
to confusion with mitochondrial disease.
In the very young patient with typical Canavan disease, as well, severe white matter disease
may not be seen in the white matter of the brain, and mitochondrial disease may be suspected.
However, the diagnosis will be reached by determining the level of N-acetylaspartic acid in urine
or after magnetic resonance spectroscopy (MRS) of the brain.
DIAGNOSIS
 CT scan and MRI diffuse white matter degeneration, primarily in the cerebral hemispheres with
sparing of arcuate fibres U , with less involvement of the cerebellum and brainstem .—( typical
canavan disease)
 MRS performed at the time MRI is done can show the high peak of N-acetylaspartic acid, suggesting
Canavan disease.
 N-acetylaspartic acid in blood/urine.—(definitive Dx)
 Enzyme level in cultured skin fibroblast.
 The differential diagnosis:
 Alexander disease  they have same macrocephally and white matter feature but are Slowly
progressive and less hypotonic compared to canavan . 310
 Brain biopsies of patients with Canavan disease show spongy degeneration of the myelin fibers,
astrocytic swelling, and elongated mitochondria.

TREATMENT AND PREVENTION
 No specific treatment is available.

 Feeding problems and seizures should be treated on an individual basis.
 Genetic counseling, carrier testing, and prenatal diagnosis are the only methods of prevention.
 Gene therapy for Canavan disease has been attempted but not yet successful.
 There are currently ongoing trials of glycerol-triacetate as a supplement for acetate deficiency; the
results of these trials are not yet available.
MENKES DISEASE.
XLR
 Menkes disease (kinky hair disease) is a progressive neurodegenerative condition .

 The Menkes gene codes for a copper-transporting, P-type ATPase, and mutations in the protein are
associated with low serum copper and ceruloplasmin levels as well as a defect in intestinal copper
absorption and transport.
 Clinical presentation :
 They are FTT children with obivious coarse fasial features and kinky curly friable hairs eith hx of
myoclonic seizures and difficult in feeding they have constant featutre of mental retardation and visual
loss that occur due to optic atrophy, rarely survive beyond 3 year if left untreated,
 The facies are distinctive, with chubby, rosy cheeks and kinky, colorless, friable hair.
 Symptoms begin in the 1st few months of life and include hypothermia, hypotonia, and
generalized myoclonic seizures.
 Microscopic examination of the hair shows several abnormalities, including trichorrhexis nodosa
(fractures along the hair shaft) and pili torti (twisted hair).
 Rx Copper-histidine therapy –effective more when started in early life.
 Presymtptomatic neonates are diagnosed by family history –if positive injection of copper histidine
250ug S/C is given twice daily till 1 year of age then once daily thereafter.
 Optimal response to copper-injection treatment appears to occur only in patients who are identified in
the newborn period and whose mutations permit residual copper-transport activity.
 Copper is essential in the early stages of CNS development, and its absence probably accounts for the
neuropathologic changes
The occipital horn syndrome skeletal dysplasia caused by different mutations in the same
gene as that involved in Menkes disease.
 relatively mild disease.
RETT SYNDROME:
 frequency is ≈1/15,000-1/22,000
 predominantly in girls./ males can be affected very rarely
 This syndrome is not strictly speaking a degenerative disease but a disorder of early brain
development marked by a period of developmental regression and deceleration of brain growth after a
relatively normal neonatal course.
 Development may proceed normally until 1 yr of agewhen regression of language and motor
milestones and acquired microcephaly become apparent.
 An ataxic gait or fine tremor of hand movements is an early neurologic finding.
 Most children develop peculiar sighing respirations with intermittent periods of apnea that may be
associated with cyanosis
 The hallmark of Rett syndrome is repetitive hand-wringing movements and a loss of purposeful and 311
spontaneous use of the hands; these features may not appear until 2-3 yr of age. Autistic behavior is
a typical finding in all patients.
 Generalized tonic-clonic convulsions occur in the majority and are usually well controlled by
anticonvulsants.

 Feeding disorders and poor weight gain are common.
 After the initial period of neurologic regression, the disease process appears to plateau, with persistence
of the autistic behavior.
 Cardiac arrhythmias may result in sudden, unexpected death at a rate that is higher than the general
population.
 Generally girls survive into adulthood.
 The phenotype may be related to failure to suppress expression of genes that are normally silent in the
early phases of postnatal development.
 Some girls have an atypical Rett phenotype associated with severe myoclonic seizures in infancy,
slowing of head growth, and developmental arrest
----------------------------------
SUBACUTE SCLEROSING PANENCEPHALITIS
 Subacute sclerosing panencephalitis (SSPE) is a chronic complication of measles with a delayed onset
and an outcome that is nearly always fatal.
 why this happens so: --(DEEFECTIVE MEASLE VIRUS INTERACT WITH DEFFECTIVE
/IMMATURE IMMUNE SYSTEM—SO THAT’S WHY MORE YOUNG AGE MORE SSPE
CHANCE) It appears to result from a persistent infection with an altered measles virus that is
harbored intracellularly in the CNS for several yr. After 7-10 yr the virus apparently regains virulence
and attacks the cells in the CNS that offered the virus protection. This “slow virus infection” results in
inflammation and cell death, leading to an inexorable neurodegenerative process
 Measles at an early age favors the development of SSPE:50% of patients with SSPE had primary
measles before 2 yr of age, and 75% before 4 yr of age.(VIVA QUESTION COMMON).
 Males are affected twice as often as females, and there appear to be more cases reported from rural
rather than urban populations.
 The number of reported cases has decreased dramatically to 0.06 cases/million population, paralleling
the decline in reported measles cases.—USA figure.
CLINICAL MANIFESTATIONS: SSPE begin insidiously 7-13 yr after primary measles infection.
 initial phase (stage I):

o Subtle changes in behavior or school performance appear, including irritability, reduced
attention span, and temper outbursts.
o Fever, headache, and other signs of encephalitis are absent.
o Mild –usually missed.
 Myoclonic stage ii :
o massive myoclonus—(hallmark) –(coincides with extension of the inflammatory process site
to deeper structures in the brain, including the basal ganglia).
o Involuntary movements and repetitive myoclonic jerks begin in single muscle groups but
give way to massive spasms and jerks involving both axial and appendicular muscles.
o Consciousness is maintained.
 Stage of coma( iii stage):
 involuntary movements disappear and are replaced by choreoathetosis, immobility, dystonia, and
lead pipe rigidity that result from destruction of deeper centers in the basal ganglia. Sensorium
deteriorates into dementia, stupor, and then coma.
 The fourth stage:  loss of critical centers that support breathing, heart rate, and blood
pressure—(bulbar palsy) Death soon ensues.
 Progression through the clinical stages may follow courses characterized as acute, subacute, or chronic
progressive
312
Fundoscopic findings :
 papilledema 20% (early stage of ds).

 Optic atrophy.

 Chorioretinitis.
 and macular pigmentation are observed in most patients.
DIAGNOSIS:
The diagnosis is established by the typical clinical course and 1 of the following:
(1) measles antibody detected in the CSF.

(2) a characteristic electroencephalogram consisting of bursts of high-voltage slow waves interspersed with
a normal background that occur with a constant periodicity in the early stages of the disease.
(3) typical histologic findings in the brain biopsy or postmortem specimen.
 CSF analysis  normal cells but elevated IgG and IgM antibody titers in dilutions >1:8.
 EEG patterns are normal in stage I, but in the myoclonic phase, suppression-burst
episodes are seen that are characteristic of but not pathognomonic for SSPE.
 Brain biopsy is no longer routinely indicated for diagnosis of SSPE.
MANAGEMENT  Management of SSPE is primarily supportive
 clinical trial compared the use of oral inosine pranobex (isoprinosine) alone to oral inosine
pranobex and intraventricular interferon-α2b BOTH tired for 6 month –resulted in 5-10% in
clinical improvement .
 Inosine is available in Karachi.
 Treatment with a series of antiviral agents has been attempted without success.
PROGNOSIS:
 Death occurs usually within 1-2 yr from the onset of symptoms—(due to auntonomic
involvement/infection.
 Measle vaccine virus theoretically said to be associated but not obtained from tissue biopsy. However
wild virus is main  even if no history of measle , may be subclinical measle in past.
DYSTONIA
Definition: Disorder of movement characterized by sustained muscle contraction causing twisting

and repetitive movements or abnormal postures.
Causes:
 Asphyxia
 Kernicterus
 Drugs
 Wilson disease
 SSPE
 primary generalized dystonia.
 Haller vorden spatz disease. 313
 Metablic –glutaric acidurea.
 SEGAWA disease.
INHERITED PRIMARY DYSTONIAS

PRIMARY GENERALIZED DYSTONIA, ALSO REFERRED TO AS PRIMARY TORSION DYSTONIA OR
DYSTONIA MUSCULORUM DEFORMANS.
 Dominant mutation at DYT1

 More than 20 mutations identified
Clinical features:
 group of genetic disorders with onset in childhood.

 intermittent unilateral posturing of a lower extremity, which assumes an extended and rotated
positionUltimately, all 4 extremities and the axial musculature can be affected. Although cranial
involvement can occur.
 If a family history of dystonia is absent, the diagnosis should still be considered, given the intrafamilial
variability in clinical expression.
SEGAWA DISEASE:
 Dopa responsive dystonia.

 the rate-limiting enzyme for tetrahydrobiopterin synthesis, which is a cofactor for synthesis of the
neurotransmitters dopamine and serotonin
 Dominant with female predominance
 Diurnal variation – > symptoms progress—more in morning less in evening --improve with sleep.
 Confused with dystonic C.P
Rx—Levodopa 50-250 mg.
SEGMENTAL DYSTONIA
 Writers cramp
 Blepharospasm
 Buccomandibular dystonia
 > in adults
DRUGS
 Dopamine-blocking agents, including antipsychotics (e.g., haloperidol) and antiemetics (e.g.,

metoclopramide, prochlorperazine), as well as atypical antipsychotics (e.g., risperidone) can
produce acute dystonic reactions or delayed (tardive) DIMD Acute dystonic reactions, occurring
in the 1st days of exposure, typically involve the face and neck, manifesting as torticollis,
retrocollis, oculogyric crisis, or tongue protrusion.
 Therapeutic doses of phenytoin or carbamazepine rarely cause progressive dystonia in children
with epilepsy, particularly in those who have an underlying structural abnormality of the brain
 Severe rigidity combined with high fever, autonomic symptoms (tachycardia, diaphoresis), delirium,
and dystonia are signs of neuroleptic malignant syndrome (NMS) which typically occurs a few days
after starting or increasing the dose of a neuroleptic drug, or in the setting of withdrawal from a
dopaminergic agent. In contrast to acute dystonic reactions, which take place within days, NMS occurs
within a month of medication initiation or dose increase 314
 Delayed onset involuntary movements, tardive dyskinesias, develop in the setting of chronic
neuroleptic use, at least 3 mo in duration. Involvement of the face, particularly the mouth, lips,
and/or jaw with chewing or tongue thrusting is characteristic.

Rx –stop offending drug and Intravenous diphenhydramine, 1-2 mg/kg/dose, may rapidly
reverse the drug-related dystonia.
Cerebral Palsy
 10-15% have a dyskinetic form characterized largely by involuntary movements such as dystonia or
chorea, rather than predominant spasticity.
 Dyskinetic CP is a more common presentation in term infants who suffer from perinatal asphyxia.
 Typically, these signs develop during infancy; though rarely, the onset of dystonia can be delayed by
several years. In patients with delayed-onset dystonia, involvement of the neck spreading to an upper
limb or hemidystonia (involvement of the arm and leg on 1 side of the body) may be the initial
presentation, which differs from the typical presentation of other childhood-onset dystonias. Review of
birth history remains an important component of the evaluation of new onset dystonia, even in
adolescence, when evidence of prior mild motor deficits exists. Birth injury, kernicterus, stroke,
encephalitis, and head trauma are all potential causes of delayed-onset dystonia.
Wilson disease:
 A.R
 inborn error of copper transport characterized by cirrhosis of the liver and degenerative
changes in the CNS, particularly the basal ganglia
 It has been determined that there are multiple mutations in the Wilson disease gene (WND),
accounting for the variability in presentation of the condition.
 The neurologic manifestations of Wilson disease rarely appear before age 10 yr, and the
initial sign is often progressive dystonia.
 Tremors of the extremities develop,  unilaterally at first, but they eventually become
coarse, generalized, and incapacitating.
 Other neurologic signs of Wilson disease relate to progressive basal ganglia disease, such as
parkinsonism, dysarthria, dysphonia, and choreoathetosis. Less frequent are ataxia, and
pyramidal signs.
 The MRI or CT scan shows ventricular dilatation in advanced cases with atrophy of the
cerebrum, cerebellum, and/or brainstem along with signal intensity change in the basal
ganglia, thalamus, and/or brainstem, particularly the midbrain.—(PANDA EYE SIGN)
Rx – pencilamine + zinc acetate + trientene .
HALLERVORDEN-SPATZ DISEASE:
 rare autosomal recessive neurodegenerative disorder.

 Mutations in pantothenate kinase 2 (PANK2) localized to mitochondria in neurons.
 The condition usually begins before 6 yr of age and is characterized by rapidly progressive
dystonia, rigidity, and choreoathetosis. Spasticity, extensor plantar responses, dysarthria,
and intellectual deterioration become evident during adolescence, and death usually occurs
by early adulthood.
 MRI lesions of the globus pallidus low signal intensity in T2 weighted images
(corresponding to iron pigments) and anteromedial area of high signal intensity (tissue 315
necrosis and edema), or “eye-of-the-tiger” sign.
 Biopsy : excessive accumulation of iron-containing pigments in the globus pallidus and
substantia nigra.

 Aceruloplasminemia, have been grouped as disorders of neurodegeneration with brain iron
accumulation (NBIA). Patterns of iron deposition visualized by brain MRI have shown
utility in differentiating these disorders.
Dystonia-deafness optic neuropathy syndrome: Sensorineural hearing loss in early childhood,

Psychosis, Optic atrophy in adolescence
Alternating hemiplegia of childhood (AHC):
 Episodic hemiplegia affecting either side of the body is the hallmark of the disorder.
 Episodes of dystonia, ranging from minutes to days in duration.
 disorder commence at approximately 6 mo of age.
 Infantile onset and the paroxysmal nature of symptoms early in the disease course are key
features to this diagnosis.
 Episodic abnormal eye movements are observed in a large proportion of patients (93%) with
onset as early as the 1st week of life.
 Thought to represent a migraine variant, AHC can similarly be triggered by fluctuations in
temperature, certain foods, or water exposure. Over time, epilepsy and cognitive
impairment emerge, and the involuntary movements change from episodic to constant.
MANAGEMENT OF DYSTONIA :
 Establishment of diagnosis and counceling regarding disease, complication , course and

management and prognosis
 I will treat the acute problems of pt .
 Start of anti-cholinergic for swallowing problems –trihexyphnidyl 2mg/day can be
increased to 60-80mg.
 Others levodopa, carbamazepine , diazepam, bromocriptine.
 For segmental dystonia Botulism A injection
 Intrathecal Baclofen can be used for generalized.
 If proves secondary to drugs then  stop drug & start diphenhydramine.
 Surgery: thalamotomy, pallidectomy.
316

DMD--------------------------------------------------------------------------(SHORT CASE)/LONG CASE
COMMAND:
1. CHILD PRESENTED WITH ABNORMAL GAIT DO RELEVANT EXAMINATION.

2. CHILD PRESENTED WITH DIFFICULTY IN WALKING/AWKWARD MOVEMET DO MOTOR &
RELEVANT.
STEP 1. Intro + consent + exposure.
Step2. Hand shake with patient & greet ( note voice )Ask (can u walk)don’t help child to sit up
note how he sits –(Gowersign).
Step3. Check gait maneuvers—(limited maneuvers till +ve findings / not all maneuvers)
1. Expose legs upto upper thighs –(check thigh wasting).

2. Ask to walk normaly—(stand behind and note his walk—(waddling gait+ lordotic posture+calf
hypertrophy)
3. Ask to sit down and then stand.
Step4. Then take pt to wall and ask to give a pressure to wall with hands—(note scapula winging).
Step5. Take patient for neurological examination on couch.
Step6. Start motor examination
LOWER LIMBS:
 Touch & show examiner that u are watching for calf hypertrophy.
 Bulk
 Tone –(note for contractures aswell++ (very important).
 Power of proximal muscles and distal muscles.—(proximal hip weak power distal good).
 Reflexes.
 Clonus.
 Superficial rreflexes
 Bladder
 Spine –(scoliosis, lordosis)
UPPER LIMBS:
 Same sequence..(offer pad & hand writing for muscle power)

 Cranial nerves
 OFC
Step 7. Cardiac examination –(DCMP, Pulm. HTN).
Sep 8. Thanks and cover pt.
OFFER:
317
1. Formal developmental assessment
2. Anthropometrics
3. B.P

DESCRIPTION:
SIR I have examined ………,….yr child conscious and co-operative during my examination with normal
speech & no apparent respiratory distress/
His has waddling gait with lordotic posture calf hypertrophy and positive gower sign during my
examination but no evidence of winging of scapula.
He has generalized equally proportional bulk in all four limb, normal tone , power of 4/5 in proximal
group of muscles and 5/5 in distal , dimnished reflexes and planters down going, no ankle/patellar
clonus, superficial reflexes are intact , upper limb are not showing any evidence of hypertrophy at
forearm , bulk , tone , reflexes are normal.
Spine is lordotic at lumber level .
All accessible cranial nerves are intact,
Apex beat is located at……………. MCL, with normal heart sounds.
WHAT SRE UR DIFFERENTIALS?
1. DMD
2. BECKER
3. TYPE-3 SMA I considered the posssiblity of type iii SMA but + ankle and palnatar responsive with
calf hypertrophy & no fasciculation os tongue are findings against my 3 rd possible differential .
4. FSCAPULOHUMERAL –contractures+
HOW WILL YOU INVESTIGATE?
 SERUM CK LEVEL (consistently greatly elevated in Duchenne muscular dystrophy, even

in presymptomatic stages, including at birth. The usual serum concentration is 15,000–35,000
IU/L (normal <160 IU/L).
 MUSCLE BIOPSY.
 PCR FOR DYSTROPHIN GENE MUTATION ANALYSIS.
 EMG & NCS ( characteristic myopathic but is not specific feature. No evidence of
denervation is found. Motor and sensory nerve conduction velocities are normal)
 ECG/CXR/ECHO.
 EEG (epilepsy more comman than genral population)
 MRI (cerebral atrophy is demonstrated by MRI late in the clinical course)
318
 Other :serum aldolase and aminotrasferase-less specific.

HOW WILL U MANAGE?
Councelling after establishing dx.

Involve multidisciplinary approach
 Neurologist
 Nutritionalist
 Physiotherapist
 orthopedics
 Cardiologist
 Gentists
 Psychotherapist
 Social worker
 And myself
I will treat acute problems of child and address for the complications and advise for regular physiotherapy and
proper nutritional well balanced diet and cardiac complication monitoring and treat and prevent chest infections.
Start specific treatment with steroids with mucoprotective cover, vit .D Supplement and anti-hypertensive/ACE
if needed.
I will advise for family screening and genetic councelling, Ensure proper compliance and follow up.
DISCUSSION:
MUSCULAR DYSTROPHIES:
dystrophy means abnormal growth, derived from the Greek trophe, meaning “nourishment.
.” A muscular dystrophy is distinguished from all other neuromuscular diseases by four obligatory
criteria:
1. It is a primary myopathy.
2. it has a genetic basis.
3. the course is progressive.
4. degeneration and death of muscle fibers occur at some stage in the disease.
Muscle carntitine deficiency is a metabolic abnormality which is progressive mopathy but doesn’t included in
classification.
DUCHENNE AND BECKER MUSCULAR DYSTROPHIES
 Both diseases : X-linked recessive trait abnormal gene is at the Xp21 locus and is one of
the largest genes.
 incidence is 1 : 3,600 liveborn infant boys.
 Duchenne muscular dystrophy is the most common hereditary neuromuscular disease
 characteristic clinical features progressive weakness, intellectual impairment, hypertrophy of the
calves, and proliferation of connective tissue in muscle.
 Infant boys: rarely symptomatic at birth or in early infancy, some are mildly hypotonic. Poor head
319
control in infancy may be the 1st sign of weakness. Early gross motor skills, such as rolling over,
sitting, and standing, are usually achieved at the appropriate ages or may be mildly delayed.
 Distinctive facies are not a feature because facial muscle weakness is a late event.
 Walking is often accomplished at the normal age of about 12 mo.

 Hip girdle weakness may be seen in subtle form as early as the 2nd yr.
 Toddlers may assume a lordotic posture when standing to compensate for gluteal weakness.
 An early Gowers sign is often evident by age 3 yr and is fully expressed by age 5 or 6 yr. A
Trendelenburg gait, or hip waddle, appears at this time.
 The length of time that a patient remains ambulatory varies greatly.
 Some patients are confined to a wheelchair by 7 yr of age;
 Most patients continue to walk with increasing difficulty until age 10 yr without orthopedic
intervention. With orthotic bracing, physiotherapy, and sometimes minor surgery (Achilles
tendon lengthening), most are able to walk until age 12 yr.
Ambulation is important not only for postponing the psychological depression that accompanies the loss of an
aspect of personal independence but also because scoliosis usually does not become a major complication as
long as a patient remains ambulatory, even for as little as 1 hr per day; scoliosis often becomes rapidly
progressive after confinement to a wheelchair.
 The relentless progression of weakness continues into the 2nd decade.

 The function of distal muscles is usually relatively well enough preserved, allowing the child to
continue to use eating utensils, a pencil, and a computer keyboard.
Respiratory muscle involvement: it is expressed as a weak and ineffective cough, frequent pulmonary
infections, and decreasing respiratory reserve.
Pharyngeal weakness:
 Aspiration.
 Nasal regurgitation of liquids.
 Airy or nasal voice quality.
The function of the extraocular muscles remains well preserved.—(in FACIOSCAPULOHEUMERAL NOT)
 Incontinence due to anal and urethral sphincter weakness is an uncommon and very late event.
 Contractures most often involve: ankles, knees, hips, and elbows.
 Scoliosis is common The thoracic deformity further compromises pulmonary capacity and
compresses the heart. Scoliosis usually progresses more rapidly after the child becomes nonambulatory
and may be uncomfortable or painful.
 Enlargement of the calves (pseudohypertrophy) and wasting of thigh muscles are classic features.
 The enlargement is caused by:
 hypertrophy of some muscle fibers.
 Infiltration of muscle by fat.
 Proliferation of collagen.
 After the calves, the next most common site of muscular hypertrophy is the tongue, followed by
muscles of the forearm. Fasciculations of the tongue do not occur. The voluntary sphincter muscles
rarely become involved.
Unless ankle contractures are severe, ankle deep tendon reflexes remain well preserved until terminal stages.
 The knee deep tendon reflexes may be present until about 6 yr of age but are less
brisk than the ankle jerks and are eventually lost.
 In the upper extremities, the brachioradialis reflex is usually stronger than the
320
biceps or triceps brachii reflexes.
Cardiomyopathy: persistent tachycardia and myocardiac failure, is seen in 50–80% of patients with this
disease.

 The severity of cardiac involvement does not necessarily correlate with the degree of skeletal
muscle weakness.
 Some patients die early of severe cardiomyopathy while still ambulatory; others in terminal
stages of the disease have well-compensated cardiac function. GIT may involve
Intellectual impairment occurs in all patients, although only 20–30% have an IQ <70.
 The majority has learning disabilities.

 A few patients are profoundly mentally retarded, but there is no correlation with the severity of the
myopathy.
 Epilepsy is slightly more common than in the general pediatric population.
 Dystrophin is expressed in brain and retina, as well as in striated and cardiac muscle, though the level,
is lower in brain than in muscle. Abnormalities in cortical architecture and of dendritic arborization
may be detected neuropathologically; cerebral atrophy is demonstrated by MRI late in the clinical
course. The degenerative changes and fibrosis of muscle constitute a painless process.
 Myalgias and muscle spasms do not occur.
 Calcinosis of muscle is rare.
 PROGNOSIS: Death occurs usually at about 18–20 yr of age. The causes of death are respiratory
failure in sleep, intractable heart failure, pneumonia, or occasionally aspiration and airway
obstruction.
BECKER MUSCULAR DYSTROPHY:
 boys remain ambulatory until late adolescence or early adult life.

 Calf pseudohypertrophy, cardiomyopathy, and elevated serum levels of creatine kinase (CK) are similar
to those of patients with Duchenne dystrophy.
 Learning disabilities are less frequent.
 The onset of weakness is later in Becker than in Duchenne dystrophy.
PROGNOSIS: Death often occurs in the mid to late 20s; fewer than half of patients are still alive by age 40
yr; these survivors are severely disabled.
GENETIC ETIOLOGY AND PATHOGENESIS.
 Despite the X-linked recessive inheritance in Duchenne muscular dystrophy, about 30% of patients are
new mutations, and the mother is not a carrier.
 The female carrier state usually shows no muscle weakness or any clinical expression of the disease,
but affected girls are occasionally encountered, usually having much milder weakness than boys.
 These symptomatic girls are explained by the Lyon hypothesis in which the normal X chromosome
becomes inactivated and the one with the gene deletion is active.
 The full clinical picture of Duchenne dystrophy has occurred in several girls with Turner syndrome in
whom the single X chromosome must have had the Xp21 gene deletion.
 The asymptomatic carrier state of Duchenne dystrophy is associated with elevated serum CK values in
80% of cases. The level of increase is usually in the magnitude of hundreds or a few thousand but does
not have the extreme values noted in affected males.
 Prepubertal girls who are carriers of the dystrophy also have increased serum CK values, with highest
levels at 8–12 yr of age. 321
 Approximately 20% of carriers have normal serum CK values. If the mother of an affected boy has
normal CK levels, it is unlikely that her daughter can be identified as a carrier by measuring CK.
Muscle biopsy of suspected female carriers may detect an additional 10% in whom serum CK is not

elevated; a specific genetic diagnosis using PCR on peripheral blood is definitive. Some female
carriers may suffer cardiomyopathy without weakness of striated muscles.
 The molecular defects in the dystrophinopathies vary: intragenic deletions, duplications, or point
mutations of nucleotides. About 65% of patients have deletions, and only 7% exhibit duplications.
 An even milder form of adult onset, formerly known as quadriceps myopathy, is also caused by an
abnormal dystrophin molecule. The clinical spectrum of the dystrophinopathies not only includes the
classic Duchenne and Becker forms but ranges from a severe neonatal muscular dystrophy to
asymptomatic children with persistent elevation of serum CK levels >1,000 IU/L.
 Analysis of the dystrophin protein requires a muscle biopsy and is demonstrated by Western blot
analysis or in tissue sections by immunohistochemical methods using either fluorescence or light
microscopy of antidystrophin antisera
 In classic Duchenne dystrophy, levels of <3% of normal are found; in Becker muscular
dystrophy, the molecular weight of dystrophin is reduced to 20–90% of normal in 80% of
patients, but in 15% the dystrophin is of normal size but reduced in quantity, and 5% have an
abnormally large protein caused by excessive duplications or repeats of codons.
 The diagnosis can thus be confirmed at the molecular genetic level from either the muscle biopsy
material or from peripheral blood, although as many as ⅓ of boys with Duchenne or Becker dystrophy
have a false-normal blood PCR; all cases of dystrophinopathy are detected by muscle biopsy.
 same methods of DNA analysis from blood samples may be applied for carrier detection in female
relatives at risk, such as sisters and cousins, and to determine whether the mother is a carrier or whether
a new mutation occurred in the embryo.
 Prenatal diagnosis is possible as early as the 12th wk of gestation by sampling chorionic villi for DNA
analysis by Southern blot or PCR and is confirmed in aborted fetuses with Duchenne dystrophy by
immunohistochemistry for dystrophin in muscle.
DIAGNOSIS:
 Clinical + lab (written above
TREATMENT.
There is neither a medical cure for this disease nor a method of slowing its progression.
Supportive treatment: to improve the quality of life of affected children.
o Cardiac decompensation:
 often responds initially well to digoxin.
o Pulmonary infections should be promptly treated.
 Patients should avoid contact with children who have obvious respiratory or other
contagious illnesses.
 Immunizations for influenza virus and other routine vaccinations are indicated.
o Nutritional care:
 it is not a vitamin deficiency disease, and excessive doses of vitamins should be
avoided.
 Adequate calcium intake is important to minimize osteoporosis in boys confined to a
wheelchair.
 fluoride supplements may also be given, particularly if the local drinking water is not
fluoridated.
 Dietary restrictions with supervision may be needed to avoid obesity.
322
 Physiotherapy.
 Delays but does not always prevent contractures.
 Contractures may actually be useful in functional rehabilitation. ( If contractures
prevent extension of the elbow beyond 90 degrees and the muscles of the upper limb

no longer are strong enough to overcome gravity, the elbow contractures are
functionally beneficial in fixing an otherwise flail arm and in allowing the patient to
eat and write).
 Surgical correction of the elbow contracture may be technically feasible, but the
result may be deleterious. Physiotherapy contributes little to muscle strengthening
because patients usually are already using their entire reserve for daily function, and
exercise cannot further strengthen involved muscles.
 Excessive exercise may actually accelerate the process of muscle fiber degeneration.
 DRUGS: prednisone, prednisolone, deflazacort, or other steroids.
 Glucocorticoids decrease the rate of apoptosis or programmed cell death of
myotubes during ontogenesis and may decelerate the myofiber necrosis in muscular
dystrophy. Strength usually improves initially, but the long-term complications of
chronic steroid therapy, including considerable weight gain and osteoporosis, may
offset this advantage or even result in greater weakness than might have occurred in
the natural course of the disease.
 One protocol gives prednisone (0.75 mg/kg/day) for the first 10 days of each
month to avoid chronic complications.
 Fluorinated steroids, such as dexamethasone or triamcinolone, should be
avoided because they induce myopathy by altering the myotube abundance of
ceramide.
Muscle biopsy is diagnostic and shows characteristic Myopathic changes include:
1. Endomysial connective tissue proliferation.

2. Scattered degenerating and regenerating myofibers.
3. Foci of mononuclear inflammatory cell infiltrates as a reaction to muscle fiber necrosis.
Who need biopsy?
Still unclear- but Some reasons to perform are:
1. if there is a family history of the disease, particularly in the case of an involved brother whose
diagnosis has been confirmed, a patient with typical clinical features of DMD and high concentrations
of serum CK probably does not need to undergo biopsy.
2. A first case in a family, even if the clinical features are typical, should have the diagnosis confirmed to
ensure that another myopathy is not masquerading as Duchenne dystrophy.
3. Confusing PCR results !
Source of biopsy?
The most common muscles sampled are the vastus lateralis (quadriceps femoris) and the gastrocnemius.
What is biopsy difference in DMD & Becher MD?
 In Duchenne dystrophy, most myofibers express no detectable dystrophin, but a few scattered fibers
known as “revertant fibers” show near-normal immunoreactivity. 323
 In Becker muscular dystrophy, the abnormal dystrophin molecule is expressed as thin, pale-staining of
the sarcolemma in which reactivity varies not only between myofibers but also along the circumference
of individual fibers.
 If PCR is normal still we have clinical suspicion of DMD then?

 if pcr is normal even our clinical suspicion is strong then we should go for dystrophin
immunocytochemistry performed on muscle biopsy sections detects the ⅓ of cases that do not show a
pcr abnormality
EMERY-DREIFUSS MUSCULAR DYSTROPHY / SCAPULOPERONEAL OR SCAPULOHUMERAL MUSCULAR

dystrophy.
 rare X-linked recessive dystrophy.
 May be A.D but extremely rare—present in adult life-with similar manifestations.
The locus is on the long arm within the large Xq28 region that includes other mutations that cause
myotubular myopathy, neonatal adrenoleukodystrophy, and the Bloch-Sulzberger type of incontinentia
pigmenti.
Clinical manifestations:
 Begin at between 5 and 15 yr of age, but many patients survive to late adult life because of the
slow progression of its course.
 Muscles do not hypertrophy.
 Contractures of elbows and ankles develop early, and muscle becomes wasted in a
scapulohumeroperoneal distribution.
 Facial weakness does not occur.
 Myotonia is absent.
 Intellectual function is normal.
 Cardiomyopathy is severe and is often the cause of death, more commonly from conduction defects
and sudden ventricular fibrillation than from intractable myocardial failure.
 The serum CK value is only mildly elevated, further distinguishing this disease from other X-linked
recessive muscular dystrophies.
 Nonspecific myofiber necrosis and endomysial fibrosis are seen in the muscle biopsy. Many
centronuclear fibers and selective histochemical type I muscle fiber atrophy can cause confusion with
myotonic dystrophy. T
 he defective gene in the X-linked form is called emerin
 Emerin and desmin may be demonstrated immunocytochemically in the muscle biopsy for definitive
diagnosis.
 Emerin also may be tested as a genetic marker in blood.
Treatment:
supportive, with special attention to cardiac conduction defects, and can require medications or a
pacemaker.
LIMB-GIRDLE MUSCULAR DYSTROPHIES
 a group of progressive hereditary myopathies that mainly affect muscles of the hip and shoulder girdles
Distal muscles also eventually become atrophic and weak.
 Hypertrophy of the calves and ankle contractures develop in some forms, causing potential confusion
with BMD.
 The initial clinical manifestations rarely appear before middle or late childhood or may be delayed
until early adult life.
 Low back pain may be a presenting complaint because of the lordotic posture resulting from
gluteal muscle weakness. 324
 Confinement to a wheelchair usually becomes obligatory at about 30 yr of age.
 weakness of neck flexors and extensors is universal, facial, lingual, and other bulbar-innervated
muscles are rarely involved.
 As weakness and muscle wasting progress, tendon stretch reflexes become diminished.

 Cardiac involvement is unusual.
 Intellectual function is generally normal.
differential diagnosis :
 juvenile spinal muscular atrophy (Kugelberg-Welander disease).

 myasthenia gravis.
 and metabolic myopathies.
Most cases of LGMD are of autosomal recessive inheritance.
but some families express an autosomal dominant trait-benign
The EMG and muscle biopsy show confirmatory evidence of muscular dystrophy, but none of the findings is
specific enough to make the definitive
FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY / Landouzy-Dejerine disease.
 Autosomal dominant inheritance is the rule; genetic anticipation is often found within several
generations of a family, the succeeding more severely involved at an earlier age than the preceding.
 The frequency is 1:20,000.
 Facioscapulohumeral dystrophy shows the earliest and most severe weakness in facial and
shoulder girdle muscles.
 The facial weakness differs from that of myotonic dystrophy; rather than an inverted V-shaped
upper lip, the mouth in facioscapulohumeral dystrophy is rounded and appears puckered
because the lips protrude.
 Inability to close the eyes completely in sleep is a common expression of upper facial weakness.
 some patients have extraocular muscle weakness, although ophthalmoplegia is rarely complete.
Facioscapulohumeral dystrophy has been associated with Mobius syndrome on rare occasions.
 Pharyngeal and tongue weakness may be absent and are never as severe as the facial involvement.
Hearing loss, which may be subclinical, and retinal vasculopathy (indistinguishable from Coats
disease).
 Scapular winging is prominent, often even in infants.
 Flattening or even concavity of the deltoid contour is seen.
 biceps and triceps brachii muscles are wasted and weak.
 Muscles of the hip girdle and thighs also eventually lose strength and undergo atrophy, and Gowers
sign and a Trendelenburg gait appear.
 Contractures of the extremities are rare.
 Finger and wrist weakness occasionally is the first symptom. Weakness of the anterior tibial and
peroneal muscles can lead to footdrop; this complication usually occurs only in advanced cases with
severe weakness.
 Lumbar lordosis and kyphoscoliosis are common complications of axial muscle involvement. Calf
pseudohypertrophy is not a usual feature but is described rarely.
 Facioscapulohumeral muscular dystrophy can also be a mild disease causing minimal disability.
325
 Clinical manifestations might not be expressed in childhood and are delayed into middle adult
life. Unlike most other muscular dystrophies, asymmetry of weakness is common.

Laboratory Findings
 Serum levels of CK and other enzymes vary greatly, ranging from normal or near normal to elevations
of several thousand.
 ECG should be performed, although the anticipated findings are usually normal.
 EMG reveals nonspecific myopathic muscle potentials.
 Diagnostic molecular testing in individual cases and within families is indicated for prediction.
Treatment
 Physiotherapy is of no value in regaining strength or in retarding progressive weakness or muscle

wasting.
 Foot drop and scoliosis may be treated by orthopedic measures.
 In selected cases, surgical wiring of the scapulas to the thoracic wall provides improved shoulder
stability and abduction of the arm, but brachial plexopathy, frozen shoulder, and scapular fractures are
reported complications.
 Cosmetic improvement of the facial muscles of expression may be achieved by reconstructive surgery,
which grafts a fascia lata to the zygomatic muscle and to the zygomatic head of the quadratus labiae
superioris muscle.
 Exercise of facial muscles can help minimize secondary disuse atrophy. No effective pharmacologic
treatment is available.
326

STROKE/CVA--------------------------------------------------------------------LONG CASE/SHORT CASE
PROTOTYPE CASE:
MY PATIENT …………….. AND …… YR OF AGE RESIDENT OF……….. ADMITTED THRU M/E IN TERTIARY
CARE HOSPITAL …… DAYS BACK WITH HX OF
WEAKNESS OF LEFT SIDE OF BODY  3 DAYS
DIFFICULTY IN TALKING  3 DAYS
ACCORDING TO PT MOTHER …. WAS IN USUAL STATE OF HEALTH 3 DAYS BACK THE HE HAD
SUDDEN ONSET PROGRESSIVELY INCREASING WEAKNESS OF LEFT SIDE OF BODY STARTED FROM
LEFT LOWER LIMB THEN ENVOLVED UPPER LIMB WITHIN FEW HOURS TO WEAKNESS SUCH AN
EXTENT NOT ABLE TO WRITE , EAT, IT WAS ASSOCIATED WITH SUDDEN ONSET OF DIFFICULTY IN
TALKING AND WALKING , THERE IS NO HX OF VISUAL DISTURBANCE ,DIPLOPIA,DROOLING,NASAL
REGURGITATION, DYSPHAGIA, URINARY /FECAL INCONTINENCE, ALTERED SENSORIUM, EXCESSIVE
SALIVATION , TEARING, FASCIAL ASYMMETRY/ WEAKNESS, CHOCKING.
DD HX: HE/SHE HAD NO HX OF FEVER,COUGH, RESPIRATORY DISTRESS , ORTHOPNEA, PALPITATION,

CYANOSIS (CVS) FITS,EARLY MORNING HEADACHE,VOMITING, ALTERED SENSORIUM,(SOL) TRAUMA,
EAR DISCHARGE, SINUSITIS, RHINORHEA/ NASAL DISCHARGE (INFLM), PALLOR, PETECHAE, BRUISE,
BLEED,JAUNDICE, JOINT PAIN, JOINT SWELLING, GLANDULAR SWELLING( HEMAT),DIARRHEA
VOMITING, HEMATUREA, DEC URINE OUTPUT (HUS), REPEATED BLOOD TRANSFUSION, BURNING/
TINGLING SENSATION(SICKLER/THALESMIA) , PREVIOUS EPISODE OF SIMILAR ILLNESS/
FITS(EPILEPSY, TIA, MOYA MOYA, HOMOCYSTINUREA), DRUG INTAKE OR HAKEEM MEDICATION ,
PRIOR VACCINATION (DPT/RABIES), ORAL ULCER , PHOTOSENSITIVITY, ALOPECIA (SLE), POLYUREA,
POLYDYPSIA, WT LOSS,(D.M),
FOR THESE COMPLAINTS HE ADMITTED IN HOSPITAL AFTER…….. TIME INTERVAL OF WEAKNESS

WHERE HE INVESTIGATED WITH BLOOD INVEX, AND C.T SCANING, CSF EXAMINATION, URINARY
CATHATERISATION/NG TUBE, AND TREATED WITH …….. HEPARIN INJ / INFUSION, ASPIRIN,
CURRENTLY HE/SHE IS ABLE TO MOVE LEG/NOT, TOILETING, EATING HIMSELF, ABLE TO HOLD
SPOON/ WRITE, DRESSING/NOT.
DEVELOPMENTALLY NORMAL MILESTONES ACHIEVED VACCINATED ACC TO EPI SCHEDULE NO XTRA

VACCINATION HAS BEEN GIVEN, WITH UNEVENTFUL BIRTH HX , PARENTS ARE CONSANGIOUS HAVE
… SIBS ALL ARE HEALTHY AND ALIVE NO HX OF SIMILAR ILLNESS, CONTACT, BLEEDING PROBLEM,
HTN, D.M, MIGRAINE/ EPILEPSY. PARENTS HAVE POOR / FAIR KNOWLEDGE REGARDING DISEASE /
COMPLICATION/ COURSE AND MANAGEMENT TILL WHAT HAS BEEN DONE SO FOR, DISEASE HAS
SIGNIFICANT IMPACT ON THE PT , SIBS AND PARENTS , NUTRITIONAL HE IS TAKING…………., PARENTS
ARE CONCERNED ABOUT……………, FATHER IS …. BY OCCUPATION EARNING…../ MONTH , LIVE IN
THEIR OWN HOUSE WITH JOINT FAMILY 2 ROOM , PROPER VENTILATION AND SANITATION .
327

ON EXAMINATION
CONSCIOUS, CO-OPERATIVE AND WELL INTERACTIVE THROUGHT MY EXAMINATION WITH

OBIVIOUS PAUCITY OF MOVEMENTS OF LEFT HALF OF BODY , NO DYSMORPHIC (MARFAN), AND
PINK IN ROOM AIR.
PULSE RATE IS………BPM NORMAL IN VLUME AND CHARACTER , NO RADIO-RADIAL OR RADIO-

FEMORAL DELAY, R/R IS ……BPM , TEMP IS ….. OF , B.P ……… MMHG.
HEIGHT IS………CM AT 3RD CENTILE FOR HIS AGE AND GENDER, WT IS……. KG AT … CENTILE FOR HIS
AGE AND GENDER, OFC IS…….. CM AT…. SD.
I HAVE APPRECIATED PALLOR WHILE NO EVIDENCE OF CLUBBING, PALMER ERYTHEMA, SPLINTER

HEMORRHAGE, CYANOSIS, JAUNDICE PETECHAE, BRUISE, BLEED , RASH , HYPO/HYPERPIGMENTED
AREA, AXILLARY/INGUINAL FRECKLING, JOINT PAIN / SWELLING, LYMPHADENOPATHY, EDEMA.
BCG SCAR IS SEEN ORAL HYGIENE IS NORMAL.
NEUROLOGICAL EXAMINATION : BULK TONEPOWERREFLEXESCLONUSSUPERFICIAL

REFLEXESUPPER LIMB EXAMINATION  CO- ORDINATION ALL ACCESSIBLE CN ARE INTACT , NO
SOMI, SPINE IS NORMAL , SENSATIONS ARE INTACT AND GAIT IS HEMIPLEGIC LEFT SIDED. BLADDER
NOT PALPABLE.
ABDOMEN EXAMINATION:
CVS EXAMINATION:
CHEST EXAMINATION:
FUNDOSCOPIC FINDINGS ARE……………………………………………………………
SUMMARY:
HEMIPLEGIA LONG CASE EXAMINATION APPROACH
STEP 1: ADEQUATE EXPOSURE + SHAKE HAND AND TAKE PT IN CONFIDENCE+ COMMUNICATE

(SPEECH )
STEP 2: OBSERVATION ( STAND BACK AND GIVE A LOOK FOR FEW SEC.)
STEP 3: TAKE ANTHROPOMETRICS (LENGTH+WT) ASK BEFORE FOR WALKING ABILITY.
STEP 4: START GPE: PALE, CLUBBING, DACTILTIS, S.HEMRHAGE, XANTHOMA, PULSE WITH
COMPARISON,BCG SCAR, B.P, KEEP THERMOMETER IN AXILLA/ ORAL, OFC, JAUNDICE, EYE
EXAMINATION (PUPIL SIZE,LEISH NODULE, CATARACT, NYSTGMUS, LENSE DISLOCATION)ORAL
EXAMINATIONPRESS FOR SINUSITIS  NASAL EXAMINATION FOR DISCHARGE  EAR 328
EXAMINATION SEARCH PETECHAE/ BRUISE/BLEED/ CAUFE AU LAIT / PATCH/
NEUROFIBROMA/AXILLARY N INGUINAL FRECKLINGLYMPH NODE EXAMINATION EDEMA 
JOINT EXAMINATIONS FOR SWELLINGS/PAIN.

STEP 5: COMPLETE NEUROLOGICAL EXAMINATION  HIGHER MENTAL FUNCTIONS ( APPEARANCE+
BEHAVIOR+ CONSCIOUS LEVEL)+ COGNITION+ INTELLIGENCE AND OFFER PEN AND WRITING PAD
LOOK AT POWER OF SMALL MUSCLES+ SPEECH (DOMINANT HEMISPHERE)  START GAIT WITH
ALL MANOEUVERS BULK  TONE POWER REFLEXES CLONUS SUP REFLEXES UPPER
LIMBS  SPINE  SOMI CEREBELLAR SIGNS  SENSATION  GAIT C.N EXAMINATION.
DETAILED EYE EXAMINATION. (IF CHILD AGE IS <6 MONTH THEN DO COVER TEST AND
DEVELOPMENT ASSESSMENT.)
STEP 6: ABDOMEN EXAMINATION
STEP 7: CVS EXAMINATION
STEP 8: CHEST
STEP 9: DO FUNDOSCOPY.
STROKE 1. ACUTE (1-2DAYS)/ SUBACUTE (DAYS-WEEKS) .
2.CHRONIC NONPROGRESSIVE/STATIC
4. CHRONIC PROGRESSIVE
5. PAROXYSMAL EPILEPSY, MIGRAINE, PERIODIC PARALYSIS.
ACUTE
1. SPONTANEOUS/CATASTROPHIC(in minutes)hemmorhage, embolism, trauma.

2. ACUTE pyogenic meningitis,encephalitis, thrombosis, electrolyte imbalance, toxins.
3. SUBACUTE/INSIDIOUSTBM,malignancies,neuroregression,partial treated meningitis.
CHRONIC STATIC/PROGRESSIVE
STATIC HEMIPLEGIC C.P
PROGRESSIVEDBD (ALD+LATE ONSET GLOBOID LEUKODYSTROPHY) ,SOL & SICKLERS, AVM
DBD=H/O MENTAL RETARDATION,DELAYED AND REGRESSION OF MILESTONES).
SOL EARLY MORNING HEADACHE , VOMITIMG, FOCAL FITS.
Q: SUMMARIZE YOUR PT ?
Q: WHAT IS YOUR IMPRESSION? 329
Q: WHAT IS YOUR DIFFERENTIAL?
Q: WHERE IS THE LESION?

Q: WHAT IS LESION?
Q:IS IT CROSSED/ UNCROSSED?
DISCUSSION:
Q: CAN THIS BE SEC TO POST-TRAUMATIC THROMBOTIC STROKE AT LEVEL OF INTERNAL CAROTID

ARTERY?
A: UNLIKELY SIR SEC TO TRAUMA AS M Y PT DO NOT HAVE HX OF TRAUMA TO PHARYNX, ALTHOUGH

THEY CAN PRESENT WITH TRAUMA AT BARBER SHOP / BEAUITY PARLOR / CHILD ABUSE THAT LEAD
TO ACUTE ANGULATION OF ARTERY INTIMAL DAMAGETHROMBUS FORMATION/ DISSECTING
ANEURYSM EMBOLUS TO BRAIN , THEY USUALLY PRESENT AFTER 24 HOUR PRECEEDING TRAUMA
WITH APHASIA, LETHARGY AND PROGREESIVE HEMIPLEGIA AND FOCAL SEIZURES.
Q: WHY NOT MOYA MOYA DISEASE?
A: UNLIKELY HE/SHE IS THE CASE OF MOYA MOYA DISEASE BECAUSE THESE PT HAVE RECURRENT
EPISODES OF TIA/ HEMIPLEGIA THAT CONDITION IS MORE COMMON IN GIRLS AND OFTEN
PRESENTS WITH HEADACHE AND BILATERAL UPPER MOTOR NEURON SIGNS, ALSO IT MAY ALSO
PRESENT WITH CHOREA. INTERMITTENT EPISODES OF TRANSIENT ISCHEMIC ATTACKS CAN PRODUCE
PROGRESSIVE NEUROLOGIC SIGNS AND SEVERE DISABILITY, I COULD NOT APPRECIATE ANY OF POINT
IN FAVOUR OF MOYA MOYA DISEASE IN MY PT.
Q: WHAT IS LESION IN MOYA MOYA DISEASE?
A: SIR THERE IS BASILAR ARTERY OCCLUSION WITH TELANGECTASIA THAT GIVE ATYPICAL
APPEARANCE OF PUFF OF SMOKE ON ARTERIOGRAM.--> NARROWING/ OCCLUSION OF DISTAL ICA
WITH UNILATERAL OR BILATERAL NETWORK OF VESSELS DISTAL TO OCCLUSION.
Q: WHAT ARE THE CAUSES OF MOYA MOYA DISEASE?
A: PROGRESSIVE OR NON-PROGRESSIVE ARTERIOPATHIES: GENETIC—SICKLE-CELL DISEASE,

NEUROFIBROMATOSIS TYPE 1; TOXIC—RADIOTHERAPY (ESPECIALLY IN NEUROFIBROMATOSIS TYPE 1
CONTEXT); INFLAMMATORY/INFECTIOUS—VARICELLA ZOSTER VIRUS
Q: WHAT ARE THE TREATMENT OPTION FOR MOYA MOYA DISEASE?
A: SYMPTOMATIC TREATMENT / GAMMA KNIFE SURGERY AND SURGICAL PROCEDURES DESIGNED

TO ENHANCE CEREBRAL FLOW (SUPERFICIAL TEMPORAL ARTERY TO MIDDLE CEREBRAL ARTERY
SHUNT AND LAYING THE SUPERFICIAL TEMPORAL ARTERY ON THE ARACHNOID MEMBRANE) HAVE
VARIABLE RESULTS.
330
Q: WHAT IS MEANING OF MOYA MOYA DISEASE ?
A: MOYA MOYA MEAN PUFF OF SMOKE ‘’JAPANESE WORD’’.

Q: WHAT IS TRANSIENT CEREBRAL ARTERIOPATHY?
A: IT IS A NONPROGRESSIVE, USUALLY SELF-LIMITED PROCESS THAT PRODUCES UNILATERAL

INTRACRANIAL ARTERY STENOSIS, USUALLY IN THE MIDDLE ARTERY .THE MOST COMMON,
IDENTIFIABLE ASSOCIATION IS CHICKENPOX WHICH MAY TAKE WEEKS TO MONTH AFTER IT.
IMPROVEMENT OR STABILIZATION IS NOTED IN ∼75% RECURRENT INFARCTION IS RARE. TRANSIENT
CEREBRAL ARTERIOPATHY MAY BE THE MOST COMMON IDENTIFIABLE CAUSE OF NONPROGRESSIVE
STROKES IN CHILDREN, WITH A MEAN ONSET OF STROKE AT 40 MO OF AGE (RANGE 0.3–14.8 YR).
Q: WHY NOT SUBARACHNOID HEMORRHAGE?
A: SUBARACHNOID BLEEDING IS CHARACTERIZED BY SEVERE HEADACHE, NUCHAL RIGIDITY, AND

PROGRESSIVE LOSS OF CONSCIOUSNESS, AND INTRACEREBRAL BLEEDING IS CHARACTERIZED BY
FOCAL NEUROLOGIC SIGNS AND SEIZURES. INTRACRANIAL HEMORRHAGE IS A COMMON EVENT IN
PREMATURE INFANTS
Q: DO YOU THINK THAT YOUR PT CAN BE THE CASE OF STROKE SEC TO AVM ?
A: YES AS MY PT HAD NO EXHISTING IDENTIFIABLE ETIOLOGY INCLUDING SYSTEMIC ILLNESS MOST

LIKELY HE MAY HAV SOL IN FORM OF AVM WHICH MAY BE ASYMPTOMATIC BEFORE AND
SUBSEQUENTLY CAN BE SYMPTOMATIC AT ANY TIME ANY AGE WITH RUPTURE OR BLEED ON
AUSCULTATION OF THE SKULL IS POSITIVE FOR A HIGH-PITCHED BRUIT IN ≈50% OF CASES. RUPTURE
OF AN ARTERIOVENOUS MALFORMATION CAUSES A SEVERE HEADACHE, VOMITING, NUCHAL
RIGIDITY CAUSED BY SUBARACHNOID BLEEDING, PROGRESSIVE HEMIPARESIS, AND A FOCAL OR
GENERALIZED HX OF SEIZURE AND MIGRAINE LIKE HEADACHE WHICH THEY DEVELOP USUALLY..
Q; HOW MIGRAINE OF AVM IS DIFFERENT FROM CLASSICAL MIGRAINE?
A: TYPICAL MIGRAINE ALTERNATES FROM ONE SIDE OF THE HEAD TO THE OTHER, WHEREAS
HEADACHES ASSOCIATED WITH AN ARTERIOVENOUS MALFORMATION CLASSICALLY REMAIN ON
THE SAME SIDE
Q: CAN THIS BE SEC TO RETROPHARYGEAL ABCESS?
A: UNLIKELY AS NO HX OF SORETHROAT, DYSPHAGIA, DROOLING.
Q: WHAT IS PATHOGENESIS OF THROMBOSIS SEC TO RETROPHARYNGEAL ABSCESS?
A: ABSCESS DAMAGE OF ARTERIAL INTEMIA SEC TO INFLAMMATION THRMOBUS OF INTERNAL

CAROTID ARTERY HYPODENSE AREA ON MRI/CT IN TERITORRY.
Q; WHAT IS THE COMMONEST CAUSE OF THROMBOEMBOLIC STROKE IN CHILDREN?

A: CARDIAC CAUSE INCLUDE ASD, PDA, ATRIAL FIB, MYXOMA, PFO.
Q: BELOW 2 YR IN CYANOTIC CHD COMMON LESION WOULD BE?
A: THROMBUS AND MOSTLY IN MIDDLE CERBRAL ARTERY. 331
Q: WHAT IS ACUTE INFANTILE HEMIPLEGIA?
A: TERM USED TILL 4 YR OF AGE BECAUSE GROWTH IS TILL 4 YEAR OF LIFE.

Q:WHAT IS HEMIPLEGIA CRUCIATA?
A: PARALYSIS OF IPSILATERAL LOWER LIMB AND CONTRALATERAL UPPER LIMB  OCCURS DUE TO
ARM FIBRES CROSSING BEFORE LEG FIBRE AT LOWER PART OF MEDULLA.
Q: WHICH CHEMOTHERAPR DRUG IS ASSOCIATED WITH STROKE ?
A: ASPARAGINASE
Q: WHICH TYOE OF ANEMIA HAVE MORE ASSOCIATION WITH STROKE?
A: IRON DEFFECIENCY ANEMIA AND SICKLE CELL ANEMIA.
Q: SICKLE CELL ANEMIA INCREASES HOW MUCH FOLD INCREASE RISK OG STROKE?
A: 400 FOLD.
Q: WOULD YOU CONSIDER DEHYDRATION AND DKA AS ARISK FACTOR IN STROKE?
A: YES
Q: HOW WILL U INVESTIGATE?
A: THE MOST CRITICAL COMPONENT OF THE INVESTIGATION IS A THOROUGH HISTORY AND

PHYSICAL EXAMINATION, SEARCHING FOR AN UNDERLYING DISEASE PROCESS; EVIDENCE OF
TRAUMA; AN INFECTIOUS, METABOLIC, OR HEMATOLOGIC DISORDER; NEUROCUTANEOUS
SYNDROME; INCREASED INTRACRANIAL PRESSURE; OR HYDROCEPHALUS. APPROPRIATE TESTS FOR
INFECTIOUS DISEASES, METABOLIC DISORDERS, AND COAGULATION DISORDERS ARE BASED ON THE
RESULTS OF THE HISTORY AND PHYSICAL EXAMINATION. AN ELECTROENCEPHALOGRAM (EEG) MAY
BE HELPFUL IN LOCALIZING THE DISEASE PROCESS BUT RARELY ESTABLISHES THE DIAGNOSIS. A CT
SCAN CAN DETECT RECENT BLEEDING OR A LARGE AREA OF INFARCTION, BUT DIFFUSION WEIGHTED
MRI, PERFUSION MRI IMAGING, AND MRA AND MRV ARE SUPERIOR FOR EARLY DETECTION OF
CEREBRAL ISCHEMIA AND ASSESSMENT OF CEREBRAL VESSELS. A CEREBRAL ANGIOGRAM MAY BE
USEFUL IN SOME CASES IN WHICH MRI STUDIES ARE NONDIAGNOSTIC, SUCH AS TO DETECT
VASCULITIS OR SITES OF INTRACRANIAL HEMORRHAGE. IN THESE CASES, A FOUR-VESSEL CEREBRAL
ANGIOGRAM IS INDICATED. ELECTROCARDIOGRAPHY AND ECHOCARDIOGRAPHY MAY HELP TO
EXCLUDE INTRINSIC CARDIAC DISEASES OR AN ARRHYTHMIA AS A CAUSE OF THE STROKE. FINALLY,
THE BASIC INVESTIGATIONS FOR A CHILD WITH AN UNEXPLAINED STROKE SYNDROME SHOULD BE
ORGANIZED TO ELIMINATE THE FOLLOWING CONDITIONS: (1) VASCULITIS AND CONNECTIVE TISSUE
DISEASES (ESR, C3, C4, RF, ANA), (2) LIPID DISORDERS, (3) COAGULATION DISORDERS, (4)
HEMATOLOGIC DISORDERS (SICKLE CELL DISEASE, THROMBOCYTOPENIA), (5) METABOLIC
DISORDERS (HOMOCYSTINURIA, FABRY DISEASE, MELAS), AND (6) AN INFECTIOUS ETIOLOGY
(MENINGITIS AND ENCEPHALITIS).
Q: HOW WILL YOU MANAGE?
A: AFTER CONFIRMING MY DIAGNOSIS I WILL COUNCELL THE PARENTS REGARDING THE DISEASE , 332
COMPLICATION ITS COURSE MANAGEMENT AND PROGNOSIS, IT IS A MULTI DISCIPLINARAY
APPROACH AFTER TREATMENT OF ACUTE PROBLEMS OF CHILD ,I WLL START ANTI THROMBOTIC
TREATMENT WITH ANTICOAGULATION WITH HEPARIN INFUSION THEN S/C INJECTIONS WITH 100

UNIT BOLUS THEN 75 UNITS IN 2 DIVIDED DOSES FOR 5 DAYS SUPPORTIVE MEASURES — FOR MOST
PATIENTS WITH SUSPECTED ACUTE ARTERIAL ISCHEMIC STROKE, THE FOLLOWING SUPPORTIVE
MEASURES ARE RECOMMENDED:
 MAINTAIN AIRWAY, BREATHING, AND CIRCULATION (ABCS)

 MAINTAIN NORMOGLYCEMIA AND NORMOTHERMIA; START NORMAL SALINE
INTRAVENOUSLY AT MAINTENANCE RATE
 ALLOW MODEST HYPERTENSION
 PERFORM FREQUENT NEUROLOGIC CHECKS
 BEGIN RESPIRATORY AND OXYGEN SATURATION MONITORING, ALONG WITH
OXYGEN SUPPLEMENTATION TO KEEP OXYGEN SATURATION >95 PERCENT
 UTILIZE CARDIAC MONITORING FOR THE FIRST 24 HOURS AFTER STROKE ONSET
TO LOOK FOR ATRIAL FIBRILLATION OR OTHER POTENTIALLY SERIOUS CARDIAC
ARRHYTHMIAS
 START VENOUS THROMBOEMBOLISM PROPHYLAXIS WITH PNEUMATIC
COMPRESSION DEVICE FOR PATIENTS RESTRICTED TO BED WITH PARALYSIS OR
DIMINISHED CONSCIOUSNESS
 MOST PATIENTS WITH ACUTE ISCHEMIC STROKE SHOULD BE POSITIONED AS FLAT

AS POSSIBLE IN BED FOR AT LEAST THE FIRST 24 HOURS FROM STROKE ONSET,
IDEALLY WITH HEAD-OF-BED ELEVATION KEPT BETWEEN 0 AND 15 DEGREES.
EXACERBATION OF ELEVATED INTRACRANIAL PRESSURE (ICP) MAY OCCUR WITH
FLAT HEAD-OF-BED POSITIONING. SIGNIFICANT AGGRAVATION OF ELEVATED ICP IS
UNLIKELY IN THE FIRST 24 HOURS AFTER ISCHEMIC STROKE ONSET, BUT CAN
OCCUR AFTER 24 HOURS. THUS, PATIENTS WITH LARGE ISCHEMIC INFARCTION OF
UNKNOWN ONSET OR >24 HOURS SINCE ONSET SHOULD BE MAINTAINED AT 30
DEGREES IN BED, ONCE HYPOVOLEMIA HAS BEEN EXCLUDED.
 ALTHOUGH DATA ARE LIMITED AND CONSENSUS OPINIONS CONFLICTING, WE
SUGGEST ASPIRIN 3 TO 5 MG/KG PER DAY RATHER THAN ANTICOAGULATION AS
INITIAL THERAPY FOR MOST CHILDREN WITH ACUTE ARTERIAL ISCHEMIC STROKE
OF UNKNOWN ETIOLOGY. HOWEVER, IN CASES WITH A HIGH CLINICAL SUSPICION
FOR EITHER ARTERIAL DISSECTION OR CARDIOEMBOLISM AS THE ETIOLOGY, WE
SUGGEST SHORT-TERM ANTICOAGULATION WITH LOW MOLECULAR WEIGHT
HEPARIN OR UNFRACTIONATED HEPARIN UNTIL VASCULAR IMAGING AND
ECHOCARDIOGRAPHY ARE OBTAINED. ANTICOAGULATION SHOULD THEN BE
STOPPED AND ASPIRIN INITIATED IF NO INDICATION (EG, A CONFIRMED
CARDIOEMBOLIC SOURCE OR ARTERIAL DISSECTION) IS IDENTIFIED BY THESE
INVESTIGATIONS. EXCEPTIONS TO THE USE OF ANY ACUTE ANTITHROMBOTIC
TREATMENT (IE, ASPIRIN OR ANTICOAGULATION) ARE CHILDREN WITH SICKLE
CELL DISEASE AND THOSE WITH EVIDENCE OF INTRACRANIAL HEMORRHAGE.
CHILDREN WHO ARE ALREADY ANTICOAGULATED AT THE TIME OF ISCHEMIC
STROKE ONSET SHOULD NOT BE TREATED ACUTELY WITH ASPIRIN
 FOR CHILDREN WITH ARTERIAL STROKE DUE TO A CONFIRMED CARDIOEMBOLIC 333
SOURCE, ARTERIAL DISSECTION, OR HYPERCOAGULABLE STATE, WE SUGGEST
INITIAL ANTICOAGULATION TREATMENT (RATHER THAN ASPIRIN) WITH
INTRAVENOUS UNFRACTIONATED HEPARIN (GOAL PTT 60 TO 85) OR

SUBCUTANEOUS LOW MOLECULAR WEIGHT HEPARIN (EG, ENOXAPARIN [1 MG/KG
DOSE EVERY 12 HOURS] TO ACHIEVE A GOAL ANTI-FACTOR XA LEVEL OF 0.5 TO 1.0
U/ML) FOR FIVE TO SEVEN DAYS, FOLLOWED BY TREATMENT WITH LOW
MOLECULAR WEIGHT HEPARIN OR WARFARIN. ASPIRIN (3 TO 5 MG/KG PER DAY)
SHOULD BE GIVEN IF THERE IS A CONTRAINDICATION TO ANTICOAGULATION.
 IN NEONATES, TREATMENT FOR PREVENTION OF A 2ND STROKE IS OFTEN NOT
REQUIRED BECAUSE THE RISK OF RECURRENCE IS LOW. IN CHILDREN, HOWEVER,
THE RECURRENCE RISK IS HIGHER AND LONG-TERM THERAPY WITH LOW-DOSE
ASPIRIN IS OFTEN NEEDED. LOW MOLECULAR WEIGHT HEPARIN OR WARFARIN IS
FREQUENTLY USED FOR SEVERAL MONTHS TO PREVENT STROKE RECURRENCE IN
THE PRESENCE OF CARDIAC EMBOLI, DISSECTION OF AN ANEURYSM, HIGH-GRADE
CEREBRAL ARTERY STENOSIS, SEVERE PROTHROMBOTIC CONDITIONS, OR ASPIRIN
FAILURE. REGULAR BLOOD TRANSFUSIONS REDUCE THE INCIDENCE OF STROKE
IN SICKLE CELL DISEASE. IMMUNOSUPPRESSANT THERAPY IS OFTEN REQUIRED
FOR VASCULITIS. REHABILITATION REQUIREMENTS AFTER A STROKE CAN
INCLUDE SPEECH THERAPY, OCCUPATIONAL AND PHYSICAL THERAPY,
PSYCHOLOGIC SERVICES, AND SPECIAL EDUCATION. THESE TREATMENT
REGIMENS ARE MOST EFFECTIVELY PROVIDED IN A MULTIDISCIPLINARY SETTING.
Q: WHAT ARE TYPES OF STROKE?
A: ISCHEMIC AND HEMORHAGIC / ISCHEMIC MAY BE SEC TO ARTERIAL OR VENOUS THROMBUS

OR EMBOLUS/ IN CHILDREN ISCHEMIC MORE COMMON.
Q: HOW MANY CASES THE CAUSE OF STROKE IS ESTABLISHED?
A: IN 75%.
Q: CHILDREN WITH ISCHEMIC STROKE, PREDICTORS OF POOR OUTCOME ?
A: YOUNG AGE, ALTERED CONSCIOUSNESS AT PRESENTATION ,FEVER AT PRESENTATION,

MIDDLE CEREBRAL ARTERY TERRITORY STROKE VOLUME GREATER THAN 10 PERCENT OF
THE INTRACRANIAL VOLUME ,RIGHT MIDDLE CEREBRAL ARTERY TERRITORY INFARCTION
,BILATERAL ISCHEMIA ,ARTERIOPATHY
MISCELLANOEUS FACTS ABOUT STROKE.
- SICKLERS THROMBUS MCA/ DISTAL ICA.

- CYANOTIC CHDMCA THROMBUS
- THROMBUSSMALL VESSELS OF BRAIN = D.M, RADIATION, DRUG ABUSE,POST
VARICELLA ARTERIOPATHY,HOMOCYSTEINUREA.
- APPROXIMATELY ⅓ OF CHILDREN WITH SICKLE CELL DISEASE HAVE SILENT BRAIN 334
INFARCTIONS THAT MAY LEAD TO COGNITIVE DECLINE
- PATIENTS WITH THROMBOSIS OF SMALL ARTERIES, INCLUDING THE PERFORATING
STRIATE VESSELS, WHICH RESULT FROM POLYARTERITIS NODOSA AND

HOMOCYSTINURIA, GENERALLY HAVE A PROGRESSIVE DEBILITATING COURSE
CHARACTERIZED BY BILATERAL SIGNS AND HIGH MORTALITY RATE.
- ARTERIAL ISCHEMIC STROKE (AIS) IS LEADING CAUSE OF ACQUIRED BRAIN INJURY IN
CHILDREN.
- ACUTE ONSET OF FOCAL NEUROLOGICAL DEFICIT IN ACHILD IS STROKE UNTIL
PROVED OTHERWISE, BECAUSE MANY STROKES MISSED.
- MRI AND DIFFUSION WEIGHTED MRI( DWI) DETECT AIS VERY EARLY EVEN IN
MINUTES.
- ATERIOPATHIES, CARDIAC AND HEMATOLOGICAL CAUSES ARE THE MAIN CONCERNS.
- ARTERIOPATHIES IN MORE THAN 50%  LEADING CAUSE OF CHILDHOOD AIS.
- IDEOPATHIC ARTERIAL STENOSIS OR FOCAL CEREBRAL ARTEIOPATHY OR TRANSIENT
CEREBRAL ARTERIOPATHY OR POST VARICEAL ANGIOPATHY ALL ARE SYNONYMS.
- MOYA MOYA CAN BE IDIOPATHIC OR SECONDARY TO NF1, SICKE CELL ANEMIA,
RADIATION THERAPY TRISOMY 21.
- CARDIAC EMBOLIC STROKE  25% OF CHILDHOOD AIS.--> SPONTANEOUS/ AFTER
CATHATERISATIONOR SURGICAL REPAIR.
- COMPLEX CONGENITAL HEART DISEASE ARE MOST FREQUEBT CAUSE,
- LACUNAR INFARCT<5 MM HYPODENSE  USUALLY TRANSIENT AND RECOVER. IN
D.M AND HTN.
- ALTEPLASE (RT-PA) IS NOT APPROVED IN THE UNITED STATES BY THE FOOD AND DRUG
ADMINISTRATION FOR USE IN CHILDREN LESS THAN 18 YEARS OF AGE WITH ISCHEMIC
STROKE.
- HE AMERICAN ACADEMY OF CHEST PHYSICIANS (ACCP) RECOMMENDS EITHER
UNFRACTIONATED HEPARIN OR LOW MOLECULAR WEIGHT HEPARIN (LMWH) OR
ASPIRIN AS INITIAL THERAPY UNTIL DISSECTION AND EMBOLIC CAUSES HAVE BEEN
EXCLUDED
- THE AMERICAN HEART ASSOCIATION STROKE COUNCIL GUIDELINE STATES THAT IT
MAY BE REASONABLE TO INITIATE ANTICOAGULATION WITH LMWH OR
UNFRACTIONATED HEPARIN IN CHILDREN WITH ARTERIAL ISCHEMIC STROKE
PENDING COMPLETION OF THE DIAGNOSTIC EVALUATION
- THE ROYAL COLLEGE OF PHYSICIANS RECOMMENDS INITIAL THERAPY WITH ASPIRIN.
- VENOUS THROMBOSIS SEPTIC/ NONSEPTIC
- SEPTIC CAUSES OF VENOUS SINUS THROMBOSIS INCLUDE ENCEPHALITIS AND
BACTERIAL MENINGITIS. HEMIPLEGIA IS A RELATIVELY COMMON COMPLICATION OF
BACTERIAL MENINGITIS CAUSED BY THROMBOSIS OF THE SUPERFICIAL CORTICAL
AND DEEP PENETRATING VEINS. ADDITIONAL INFECTIOUS CAUSES OF SEPTIC SINUS
THROMBOSIS IN CHILDREN INCLUDE OTITIS MEDIA AND MASTOIDITIS WITH
INVOLVEMENT OF THE DURAL VESSELS, AS WELL AS RETROGRADE ORBITAL
INFECTIONS PRODUCING CAVERNOUS SINUS THROMBOSIS
- ASEPTIC CAUSES INCLUDE SEVERE DEHYDRATION IN INFANCY, WHICH MAY RESULT
IN THROMBOSIS OF THE SUPERIOR SAGITTAL SINUS AND THE SUPERFICIAL CORTICAL
VEINS DUE TO HYPERVISCOSITY AND SLUDGING OF BLOOD. CONDITIONS RESULTING
IN HYPERCOAGULOPATHY, CYANOTIC CONGENITAL HEART DISEASES, IRON-
DEFICIENCY ANEMIA, AND LEUKEMIC INFILTRATES OF CEREBRAL VEINS ARE
ADDITIONAL CAUSES OF NONSEPTIC ACUTE HEMIPLEGIA OF CHILDHOOD.
PROTHROMBOTIC DISORDERS INCLUDING DEFICIENCIES OF INHIBITORS OF
COAGULATION SUCH AS PROTEIN C, PROTEIN S, AND ANTITHROMBIN III, AND
PROCOAGULANT STATES SUCH AS INCREASED FACTOR VIII LEVELS, ACTIVATED
PROTEIN C RESISTANCE, MUTATIONS IN LEIDEN FACTOR V, ABNORMALITIES OF
LIPOPROTEIN A, MUTATIONS OF THE THERMOLABILE METHYLENE 335
TETRAHYDROFOLATE REDUCTASE GENE, ELEVATED FASTING HOMOCYSTEINE
LEVELS, AND ANTICARDIOLIPIN ANTIBODIES ARE FOUND IN 12–50% OF CASES (SEE
CHAPTERS 478 AND 479 ). VASCULAR MALFORMATIONS ASSOCIATED WITH IMPAIRED

VENOUS DRAINAGE (SUCH AS STURGE-WEBER SYNDROME) MAY PREDISPOSE TO
VENOUS INFARCTS AND STROKELIKE EPISODES.
- INTRACRANIAL HEMORRHAGE MAY OCCUR IN THE SUBARACHNOID SPACE OR THE
BLEEDING MAY BE PRIMARILY LOCATED IN THE PARENCHYMA OF THE BRAIN.
-
- ARTERIOVENOUS MALFORMATIONS RESULT FROM FAILURE OF NORMAL CAPILLARY
BED DEVELOPMENT BETWEEN ARTERIES AND VEINS DURING EMBRYOGENESIS.
ARTERIOVENOUS MALFORMATIONS PRODUCE ABNORMAL SHUNTING OF BLOOD,
CAUSING AN EXPANSION OF VESSELS AND A SPACE-OCCUPYING EFFECT OR RUPTURE
OF A VEIN AND INTRACEREBRAL BLEEDING. ARTERIOVENOUS MALFORMATIONS ARE
TYPICALLY LOCATED IN THE CEREBRAL HEMISPHERE, BUT THEY MAY BE SITUATED IN
THE CEREBELLUM, BRAINSTEM, OR SPINAL CORD.
- AN ARTERIOVENOUS MALFORMATION OF THE VEIN OF GALEN IN INFANCY CAN
CAUSE HIGH-OUTPUT CONGESTIVE HEART FAILURE SECONDARY TO SHUNTING OF
LARGE VOLUMES OF BLOOD OR PROGRESSIVE HYDROCEPHALUS AND INCREASED
INTRACRANIAL PRESSURE SECONDARY TO OBSTRUCTION OF THE CEREBROSPINAL
FLUID (CSF) PATHWAYS. VEIN OF GALEN MALFORMATIONS ARE DIFFICULT TO TREAT
AND ARE ASSOCIATED WITH A POOR PROGNOSIS
- CEREBRAL ANEURYSMS PRODUCING SYMPTOMS IN CHILDREN ARE RELATIVELY
RARE. IN CONTRAST TO THOSE IN ADULTS, ANEURYSMS IN CHILDREN TEND TO BE
LARGE AND ARE LOCATED AT THE CAROTID BIFURCATION OR ON THE ANTERIOR AND
POSTERIOR CEREBRAL ARTERIES RATHER THAN THE CIRCLE OF WILLIS. THE
ANEURYSMAL DILATATION RESULTS FROM A CONGENITAL WEAKNESS OF THE VESSEL
AND, IN SOME CASES, A DEFICIENCY OF TYPE III COLLAGEN HAS BEEN
DEMONSTRATED. IN CHILDREN, THERE IS AN ASSOCIATION BETWEEN CEREBRAL
ANEURYSMS, COARCTATION OF THE AORTA, AND BILATERAL POLYCYSTIC KIDNEY
DISEASE. ALTHOUGH MOST RUPTURED ANEURYSMS BLEED INTO THE SUBARACHNOID
SPACE, CAUSING AN INTENSE HEADACHE, NUCHAL RIGIDITY, AND COMA,
INTRACEREBRAL HEMORRHAGE AND PROGRESSIVE HEMIPARESIS ALSO OCCUR.
- CONTRAST CT SCAN OR MRI WITH GADOLINIUM AND MRA IS USEFUL FOR
IDENTIFYING LARGE ARTERIOVENOUS MALFORMATIONS; HOWEVER, FOUR-VESSEL
CEREBRAL ANGIOGRAPHY IS THE STUDY OF CHOICE FOR INVESTIGATING
ARTERIOVENOUS MALFORMATIONS AND CEREBRAL ANEURYSM
- DIFFERENTIAL DIAGNOSIS OF STROKELIKE EVENTS
 ALTERNATING HEMIPLEGIA OF CHILDHOOD IS OCCASIONALLY ASSOCIATED
WITH MIGRAINE, BUT IN MOST CASES THE CAUSE IS UNKNOWN. IT DEVELOPS
IN INFANTS BETWEEN 2 AND 18 MO OF AGE AND IS CHARACTERIZED BY
INTERMITTENT EPISODES OF HEMIPLEGIA ALTERNATING FROM ONE SIDE OF
THE BODY TO THE OTHER RARELY, BOTH SIDES ARE INVOLVED DURING AN
ATTACK. CHOREOATHETOSIS AND DYSTONIC MOVEMENTS ARE COMMONLY
OBSERVED IN THE HEMIPARETIC EXTREMITY. SIGNS SPONTANEOUSLY
REGRESS WITH SLEEP BUT RECUR WITH AWAKENING. THE HEMIPLEGIA
PERSISTS FOR MINUTES TO WEEKS AND THEN RESOLVES SPONTANEOUSLY.
THE CONDITION HAS A POOR PROGNOSIS, WITH PROGRESSIVE MENTAL
RETARDATION AND DEVELOPMENTAL DISABILITIES. RESULTS OF
NEUROIMAGING AND METABOLIC STUDIES ARE NEGATIVE
 SEVERAL METABOLIC DISEASES ARE ASSOCIATED WITH STROKELIKE EPISODES IN

CHILDREN, INCLUDING MITOCHONDRIAL ENCEPHALOMYELOPATHY , ORNITHINE 336
TRANSCARBAMYLASE DEFICIENCY, PYRUVATE DEHYDROGENASE DEFICIENCY, AND
HOMOCYSTINURIA.
 TODD PARALYSIS MAY BE CONFUSED INITIALLY WITH A STROKE. THE
HEMIPARESIS FOLLOWS A FOCAL SEIZURE, BUT THE WEAKNESS AND

NEUROLOGIC SIGNS DISAPPEAR COMPLETELY WITHIN 24 HR OF THE
CONVULSION. ALTHOUGH THE CAUSE OF TODD PARALYSIS REMAINS
UNKNOWN, THE HEMIPARESIS PROBABLY RESULTS FROM AN INHIBITORY
PHENOMENON, POSSIBLY RELATED TO NEUROTRANSMITTER DYSFUNCTION
 ADDITIONAL CAUSES OF HEMIPARESIS INCLUDE CEREBRAL TUMOR, ENCEPHALITIS

(PARTICULARLY HERPES), FOCAL POSTVIRAL ENCEPHALITIS, AND STATUS
EPILEPTICUS. IN SOME PEDIATRIC SERIES OF UNEXPLAINED STROKE, LIPID
ABNORMALITIES, INCLUDING ELEVATED TRIGLYCERIDES AND LOW LEVELS OF HIGH-
DENSITY LIPOPROTEIN CHOLESTEROL, HAVE BEEN FOUND IN ≈20% OF THE CASES.
THE FAMILY HISTORIES OF THESE CHILDREN REVEAL AN INCREASED INCIDENCE OF
PREMATURE CORONARY HEART DISEASE AND EARLY ISCHEMIC CEREBROVASCULAR
DISEASES. SCREENING OF AT-RISK FAMILIES IDENTIFIES CHILDREN WHO MAY
BENEFIT FROM LONG-TERM DIETARY MANAGEMENT.
AMAUROSIS FUGAX—sudden and brief loss of vision in one eye Obstruction of carotid
circulationOcclusion of the ophthalmic artery is probably symptomless in most cases because of
the rich orbital collaterals, but its transient embolic obstruction can lead to this.
Occlusion of the anterior cerebral artery distal to its junction with the anterior communicating
artery causes weakness and cortical sensory loss in the contralateral leg and sometimes mild
weakness of the arm, especially proximally. There may be a contralateral grasp reflex, paratonic
rigidity, and abulia (lack of initiative) or frank confusion. Urinary incontinence is not uncommon,
particularly if behavioral disturbances are conspicuous. Bilateral anterior cerebral infarction is
especially likely to cause marked behavioral changes and memory disturbances. Unilateral anterior
cerebral artery occlusion proximal to the junction with the anterior communicating artery is
generally well tolerated because of the collateral supply from the other side.
MIDDLE CEREBRAL ARTERY OCCLUSION leads to contralateral hemiplegia, hemisensory loss, and
homonymous hemianopia (ie, bilaterally symmetric loss of vision in half of the visual fields), with the
eyes deviated to the side of the lesion. If the dominant hemisphere is involved, global aphasia is also
present. It may be impossible to distinguish this clinically from occlusion of the internal carotid
artery.
OCCLUSION OF BOTH VERTEBRAL ARTERIES OR THE BASILAR ARTERY leads to coma with pinpoint
pupils, flaccid quadriplegia and sensory loss, and variable cranial nerve abnormalities.
IN PATIENTS WITH HEMIPLEGIA OF PONTINE ORIGIN, the eyes are often deviated to the paralyzed
side, whereas in patients with a hemispheric lesion, the eyes commonly deviate from the hemiplegic
side.
OCCLUSION OF ANY OF THE MAJOR CEREBELLAR ARTERIES produces vertigo, nausea, vomiting,
nystagmus, ipsilateral limb ataxia, and contralateral spinothalamic sensory loss in the limbs.
Saccular aneurysms ("berry" aneurysms) tend to occur at arterial bifurcations, are frequently
multiple (20% of cases), and are usually asymptomatic. They may be associated with polycystic
kidney disease and coarctation of the aorta. Risk factors for aneurysm formation include smoking,
hypertension, and hypercholesterolemia. Most aneurysms are located on the anterior part of the 337
circle of Willis—particularly on the anterior or posterior communicating arteries, at the bifurcation
of the middle cerebral artery, and at the bifurcation of the internal carotid artery.

CHILD WITH UNEXPLAINED STROKE
1. Vasculitis/C.T disorder
2. infection
3. metabolic
4.coagulopathy/ hematological.
5. lipid disorder.
Child with recurrent stroke like episodes.
1. Migraine.
2. AVM/Moya Moya disease
3. Vasculitis.
4. Lipid disorders,
5. Metabolic disorders (MELAS/MERF/overlap/homocysteinurea, fabry , OTC deff, pyruvate
kinase def).
6. Todds paralysis
7. NCutaneous syndromes. (NF-1, SWS, PHACES.)
8. SOL
9. Post varicella arteriopathy.
LIST INVESTIGATIONS FOR STROKE?
FIRST LINE (Advise in first 24 hrs)
1. CBC with ESR & CRP, PT APTT ,

2. CT/MRI BRAIN +ECG+CXR+ECHO
3. ANA , BLOOD C/S, AND CSF EXAMINATION .
4. Lipid profile.
SECOND LINE (advise 1st week of admission)
1. MRA/MRV For vascular details AND EEG for focal lesion.

2. C3 & C4/ RA factor.
3. Protein C ,S, Anti thrombin III, Factor v.
4. Antiphospholipid antibody.
THIRD LINE (As per need according to pt scenario).

338
1. Serum homocysteine level
2. Cerebral angiogram
3. Cardiac MRI.
4. Mycoplasma titre.

HEMIPLEGIA
CROSSED--> CN PALSY ON ONE SIDE & HEMIPLEGIA

OTHER SIDE
UNCROSSED-->CN PALSY & HEMIPLEGIA SAME SIDE
JUST HEMIPLEGIA-->WITH NO CN INVOLVEMENT -->MUST BE LESION

IN SPINAL CORD ABOVE C5 ON SAME SIDE OF WEAKNESS
NATURE OF LESION
CVA SOL
HEMORHAGE-- INFARCTION-->THROMBOTIC/
>INTRACEREBRAL/SUBARACHNOID EMBOLISM
THROMBOSIS LOSS OF CONSCIOUSNESS DOES NOT OCCUR.
EMBOLISMLOSS CONSCIOUSNESS OCCUR BUT UNCOMMON. 339
HEMMORHAGE  INTERNAL CAPSULE MOST COMMON SITE  DENSE HEMIPLEGIA

TYPES OF STROKE
1. TIA.
2. STROKE IN EVOLUTION  INC IN STEPWISE MANNER / RESMBLE SOL
3. COMPLETE STROKE.
UNCROSSED HEMIPLEGIA LESION ABOVE BRAINSTEM LEVEL ON OPPOSITE SIDE OF WEAKNESS.
 IT CAN BE DENSE HEMIPLEGIA LESION IN INTERNAL CAPSULE.

 IF HEMIPARESISLESION CAN BE FROM CORTEX TO JUST ABOVE INTERNAL
CAPSULE.
CROSSED HEMIPLEGIA LESION IS IN BRAINSTEM ON SAME SIDE.
 All muscles supplied by cranial nerves are controlled by motor areas of both sides except
muscles of lower half of face which are supplied by contralateral hemisphere so in
unilateral lesion of UMN tract above brainstem only lower half is involved.
 SIMPLE WORDSIF UMN TYPE FACIAL PALY MEAN LOWER HALF FACE
PARALYSED IT IS ALWAYS ASSOCIATED WITH IPSILATERAL
HEMIPLEGIATHINK THAT LESION IS ABOVE PONS OPOSITE SIDE.
IF BOTH UMN AND LMN FACIAL SIDE WEAKNESS IT IS ALWAYS CROSSED.
IF VII CN PALSY IS LMN TYPE (UPPER FACE )+ CONTRALATERAL

HEMIPLEGIA  THINK THAT LESION IS AT VII CN NUCLEUS WHICH IS AT PONS
ON THE SIDE OF VII CN PALSY.
 IF NO FACIAL NERVE INVOLVED  THINK THAT LESION IS BELOW PONS THAT
LEADED INCOMPLETE HEMIPLEGIA.
 GAG REFLEX TOTAL LOST IN BOTH 9TH AND 10TH CN PALSY, WHILE WRETCH
ATTEMPT IF PRESERVED IT INDICATE PRESERVED 9 TH CN WHICH INDICATE
SENSORY ARC INTACT.
STAGES OF SHOCK
1. STAGE OF NEURAL SHOCK (LAST 2-3 WEEKS)COMA+HYPOTONIA+DTR-VE

2. STAGE OF RECOVERY RECOVERY IN THIS SEQUENCE FACE(EARLIEST)LOWER
LIMB EXTENSORS RECOVER FIRST THEN UPPER LIMB FLEXORS RECOVER FIRST 
DORSIFLEXION OF FOOR FINE MOVEMENTS OF FINGERS.
3. STAGE OF RESIDUAL PARALYSIS.
We diagnosed as uncrossed hemiplegia lesion in
 Motor cortex
 present with incomplete hemiplegia
 only one limb can be involved.
 fits may occur
 Corona radiata:
 Weakness is more marked in one limb. 340
 Whole half is affected.
 Internal capsule:
 Hemiplegia is complete+dysarthria+homonymous hemiopia.
 Note : dysphasia is a feature of uncrossed hemiplegia if lesion is in dominant hemisphere.

 Dominat hemisphere left hemisphere in all persons who are right handed & in left handed it is
50% even.
 Internal capsule has 3 parts ant horn , genu and posterior horn.
 Middle cerebral artery lenticulostriate branch supply to ant horn+genu+posterior 1/3 of post horn.
 Internal carotid  posterior 2/3rd of post horn.
 CROSSED HEMIPLEGIA:
o Lesion in midbrain:  3,4 CN Affected on one side while weakness on other side.
 pons  5,6,7,8 CN involved ,pupils pinpoint/ reactive, & hyperpyrexia +/-
 medulla oblongata 9,10,11,12 CN + weakness on ther side.
 Pupil size:
 dilated/fixed midbrain lesion
 Pinpoint/reactingpons
 Mid position junction of midbrain and pons.
 LOCALIZING SIGNS:
o PRE-FRONTAL LOBEpersonality change+micturation disturbance+grasp reflex +.
o PRE-CENTRAL GYRUS weakness+fits+motor dysphasia.
o PARIETAL LOBE Loss of cortical senses 2 point discrimination+astereognosis
 Homonymous quadrantanopia (lower)
 Apraxia
 Sensory dysphasia
 Spatial disorientation.
o TEMPORAL LOBE Auditory/olfactory hallucination and illusion.
 Homonymous quadranopia (upper)
 Automatism & memory loss
o OCCIPITAL LOBE visual hallucination+homonymous heminopia of opposite side.
--------------------------------------
IMPORTANT QUESTIONS:
 Middle Cerebral Artery lateral surface of brain motor/sensory cortex upper limbs.
 Anterior cerebral artery medial surface of brain motor/sensory cortex lowe limbs.
o If lesion at MCA Total occlusion  hemiplegia / partial hemiparesis and lower limbs
minimally affected.
o If lesion ACA Total occlusion  present same as like MCA lesion otherwise if partial
occlusion it will present with weakness of lower limbs.
 LATERAL MEDULLARY SYNDROME: Occlusion of posterior cerebellar artery present with
ataxia , 6th cranial nerve palsy and ipsilateral horner syndrome and fascial numbness, but contralateral
hemiparesis.
 WEBER SYNDROME: 3rd CN palsy + contraletral hemiplegia. 341
 BENEDICTS SYNDROME: 3RD CN palsy +contralateral hemiplegia + red nucleus manifestation
=tremor , rigidity and ataxia on opposite side. ( weber + red nucleus).
 MILLARD GUBBLERS SYNDROME: 7th CN + Contralateral hemiplegia.
 JACKSON SYNDROME: 12th CN palsy+ contralateral hemiplegia.

 BROWN SEQUARD SYNDROME: Hemisection of the spinal cord below level of lesion would be
o Ipsilateral UMN weakness and loss of sense of position and vibration.
o Contralateral loss of pain amd temp sensation.
 Hemiplegia in a comatose patient:
o -hyoptonia+
o -raise arm  fall sudden / while not in normal comatose
o -supraorbital pain pressure facial deviation may be
o -planter reflex unilateral upgoing../ bilateral upgoing is normal in deep comatose.
 SPINAL CORD
 UMN lesion is usually bilateral
 But if unilateral  lesion is on side of weakness.
 If upper limb involvedlesion above C5 spinal segment.
 If all abdominal reflex absentlesion above T8 Spnal segment.
 Evidence of LMN involvement+ sensory dermatome loss lesion at same segment.
 DIPLEGIA BILATERAL HEMIPLEGIA OF CORTICAL ORIGION WHERE LOWER LIMB>>

WEAK THAN UPPER.
 DOUBLE HEMIPLEGIA UPPER LIMB>> THAN LOWER LIMBS
 STROKE IS DEFINED BY SUDDEN ONSET OF FOCAL/GLOBAL NEUROLOGICAL DEFICIT
LASTING MORE THAN 24 HOUR.
 APOPLEXY IS TERM RESERVED FOR THOSE STROKE PATIENT WITH LOSS OF
CONSCIOUSNESS IT OCCURS DUE TO CESSATION OF VEREBRAL CIRCULATION.
342

MENINGOMYELOCELE (SHORT CASE/ CAN BE A LONG CASE).
COMMANDS:
1. CHILD PRESENTED WITH SWELLING OVER BACK DO RELEVANT EXAMINATION.

2. CHILD WITH PAUCITY OF MOVEMENTS OF LOWER LIMBS DO MOTOR SYSTEM & RELEVANT EXAM.
3. GPE & RELEVANT.
STEP 1. Intro + consent + exposure.
Step 2. Observation (5sec).
Step 3. Swelling examination (site, size, shape, surface, mobility, transillumination test)-localize
by palpating lower rib and count.
Step 4. Head examination (continue same protocol like hydrocephalus).
Step final: offer fundus, anthropometrics.
DISCUSSION :
MENINGOMYELOCELE/ SPINAL DYSRAPHISM; SPINA BIFIDA.
Failure of closure of the neural tube allows excretion of fetal substances (α-fetoprotein [AFP],
acetylcholinesterase) into the amniotic fluid, serving as biochemical markers for a neural tube
defect.
Incomplete closure of the vertebral column during embryogenesis, thus exposing meninges and
spinal cord
 Always associated with Chiari II malformation which include:

 small posterior fossa.
 hindbrain herniation into the upper cervical spinal canal.
 dysgenesis or agenesis of the corpus callosum.
 neuronal migration disorders of varying degree, and hydrocephalus
 during the 1st 4 weeks of gestationfaulty formation of the neural tubeChiari II abnormality is
associated with meningomyelocele, anencephaly, and encephalocele, all of which belong to a group of
disorders known as neural tube defects.
 Postneurulation defects develop after 25 days of intrauterine life, that is, after neurulation is
complete: Lesions include simple meningocele, lipo meningomyelocele, diastematomyelia,
Characterized by intact skin over the underlying lesion
Risk Factors:
343
 Use of valproic acid and derivatives (valproate sodium) during the 1st gestational trimester
 High-risk pregnancy: Previous children with spina bifida
 Insufficient maternal levels of folic acid

Genetics:
 multifactorial inheritance.
 Parents of an affected infant have a 1:30 chance of producing a 2nd affected child.
 An affected patient, if able to bear children, has a 3–4% chance of having an affected child.
 Parents with 2 affected children run a 7–8% risk of having a 3rd child so affected.
 2nd-degree relatives of an affected person (e.g., nephews, nieces) have a 1:100 risk.
 the risk for 1st cousins is 1:200.
General Prevention
 Adequate folate intake (0.4 mg per day) by sexually active women at least 1 month before pregnancy
and through 1st trimester
 For women with prior pregnancy of child with neural tube defect: 4 mg per day of folate before
conception and through 1st trimester.
Prenatal diagnosis:
 Amniocentesis: Elevated alpha-fetoprotein in amniotic fluid (by 14 weeks’ gestation) suggests open
neural tube defects.-not raised in encephalocele
 Ultrasound:
 MRI:
 Maternal serum alpha-fetoprotein levels. Elevated alpha-fetoprotein level at 16–18 weeks
Newborn:
 Cranial ultrasound is the most efficient way .

 MRI
Treatment
General Measures
 Multidisciplinary approach: Pediatric neurosurgery, orthopedics, urology, nursing, social services,

pediatrics, and physical therapy
 Most patients with meningomyelocele have neurogenic bladder, necessitating intermittent
catheterization to prevent severe secondary urologic disorders.
344

Surgery
 CSF diversion (ventriculoperitoneal shunt).

 Meningomyelocele repair, usually within 24–48 hours of birth
 While the Chiari II malformation (i.e., hindbrain herniation into the upper cervical spinal canal) rarely
requires surgical decompression, infants with clinical evidence of hindbrain compression despite
adequate CSF diversion require prompt posterior fossa decompression:
 Surgical hindbrain decompression, if done promptly after onset of symptoms of hindbrain
compression, may reverse or alleviate stridor, respiratory distress, or laryngomalacia, but these
syndromes are often confused with respiratory infections, delaying treatment.
 Urologic consultation is essential.
follow-up
usually once or twice a year to assess:
 Head circumference (infants)

 Ocular status
 Developmental status
 Motor status, including grasp strength in cooperative patients
 Urologic and orthopedic status
Diet
 Obesity is a major cause of morbidity in patients with meningomyelocele.

 Modified as needed to facilitate bowel and bladder training
 Patient Education
 Genetic counseling
 Signs and symptoms of shunt malfunction.
Prognosis
 >80% of treated patients with open neural tube defects have normal IQ.
 Shunt infection and malfunction have become less frequent, but remain major causes of morbidity.
 Infants with head circumference >50 cm at birth (e.g., severe hydrocephalus) have dismal cognitive
prognosis.
Complications
 Meningitis
 Neurodevelopmental problems
 Tethering  progressive back pain and decline in neurologic performance in the lower extremities
and sphincters for patients who retain lower extremity function and bowel and bladder continence.
For paraplegic, incontinent patients, progressive severe pain in the midthoracic and lumbar region is
most common
 Shunt obstruction:
 Neurogenic bladderDisruption of the neural axis between the pons and the sacral spinal cord by the 345
myelomeningocele may cause uninhibited detrusor contractions or dyssynergia, a lack of coordination
of the external bladder sphincter that causes involuntary sphincter activity during detrusor
contraction. Myelomeningocele in the sacral area can produce a lower motor neuron lesion, resulting
in detrusor areflexiaCKDESRD

 Seizures may result from cortical migration disorders or herald shunt malfunction.
RECENT ADVANCES: Intrauterine repair (which remains an experimental procedure) has been shown
to decrease the severity of hindbrain herniation and reduce the incidence of shunt-dependent
hydrocephalus, but does not appear to improve lower extremity function Although intrauterine
meningomyelocele repair may reduce the incidence of shunt-dependent hydrocephalus, even this
group remains at significant risk of developing hydrocephalus
Menongomyelocele with Arnold chiari malformation.
Whenever the hydrocephalus with meningomyele obiveoys shunt placed lead to overdtainage.
Atonic bladder. Detrusor.muscle inactive --> S234 LLESION--> ATONIC BLADDER.
IF LESIONA AT CENTRE WHICH IS AT PONS ( MICTURATION REFLEX).
BTW PONTILE MICTURATION CENTRE AND SPINE LESION LEAD TO SPASTIC BLADDER .
DETRUSOR BLADDER DYSNERGIA. ALSO RESULT FROM.LESION AT THESE ABOVE T1 LEVEL.
CAN U DO.SOMETHING FOR THIS CHILD/
WAHT ADVISE TO MOTHER.?
FIRST DEFINE WHETHER NEXT CHILD ON LOW RISK OR IN HIGH RISK.
IF ANY CHILD IS SUFFERED ALREADY THEN IDENTIFY THE FOLATE DEFFECIENCY IN MOTHER AND TREAT .
0.4 TO 0.5 MG DAILY AND WHEN.CONCEPTION PLANNED START 1MONTH BEFORE 4MG, UPTO 12 WEEK OF
GESTATION..
DEAN SB WORDS.
MAKE ALWAYS
CHECK.LIST.
OBSERVE
COMMENT ON.LEGS. 346
BLADDER
ANAL.SPHINCTER.

BRUI AHOULD BE CONSIDRERED IN A CHILD WITH VAEIN OF GALLEN MALFORMATION. OTHERWISE IF
OBIVEOUS CAUSE IS THERE THEN NO NEED .
MANAGEMENT.
IT IS MULTIDISCIPLINARY APPROACH , ENVOLVE, TREATMENT OF REGURGITATION, BY ANTI REFLUX,

PHYSIOTHERAPY, TREATMENT OF ACUTE PROBLEMS, AND LONG TERM FOLLOW UP.
- GENETIC COINCELLING IN LAST.
FAMILIAL MEGAENCEPHALLY.
A.D
FAMILY HX.
USUALLY UPTO 2 YR THEN IT WOULD BE NORMAL.
HYPOTONIC
347

OBESITY --------------------------------------------------------------------------------------------SHORT CASE.
COMMANDS:
1. This child presented with excessive wt gain for last…… do relevant examination.
2. Parents are concerned about weight of child do GPE & relevant.
Step 1. Intro+ consent + exposure ( proper and adequate with screen)
Step 2. Inspection –stand back for 10 sec and observe—(cushingoid face, distribution of fat , dysmorphism,
squint, nystgmus, polydactly).
Step 3. Ask child to walk –(observe Gait-mypathy/SCFE)and go for Ht + US:LS  then Wt  back examination
for fat pad  do GOWER
Step 4. GPE –(vitals-pulse, B.P, temp), palmer erythema,skin feel for dry coarse/shiny , search for xanthoma
axillary pigmentation take OFC  eye examination for cataract / acuityoral examination –(tonsils),
thyroid examination chest examination for gynaecomastia  abdomen look for striae  SMR  edema.
Step 5. Abdomen for visceromegally.
Step 6. CVS+ RESP examination.
Step 5 –cover with thanks.
Step 6. Offer
 Previous Progressive percentiles for wt and height.

 Fundoscope.
 Any thing u left due to shortage of time.
DESCRIPTION:
EXAMINED …….MY PT CONSCIOUS AND CO-OPERATIVE DURING MY EXAMINATION WITH NO OBIVIOUS

RESPIRATORY DISTRESS/ DYSMORPHISM.
O
His/her pulse rate is ….bpm, R/R is … bpm, B.P is…….mmHg, temp is….. F. his height is ….., wt is ……., OFC
is……., Which are above centile but I want to confirm by plotting on centile chart.
He has truncal obesity with filling of supraclavicular fossa, with thin lean extremities , there is also evidence of
facial plethora , striae over abdomen which are pink in colour, but there is no evidence of cataract, nystgmus,
bruise, palmer erythema, coarse dry skin and axillary pigmentation , goiter , gynaecomastia, any obivius
skeletal deformity.
Abdomen is soft and nontender with no visceromegally ,cardiovascular and respiratory syatem examination is
unremarkable.
348
WHAT IS YOUR DIAGNOSIS?
1. simple obesity –(if all parameters fall –ht & wt >, with no signs of steroid toxicity)
2. cushing –(ht <, with other stigmata+)

3. hypothyroidism –( defend by absence of other clinical features like coarse facial features, (go to thyroid
short case discussion) , or simply we can say yes sir he can be the case of hypothyroidism may be on Rx who
subsided major manifestations).
4. GH deficiency – isolated can be.
HOW WILL U INVESTIGATE?
OBESITY BASELINE
 Lipid profile.
 S.Cholestroll
 S.triglyceride
 LDL
 VLDL
 HDL
 Abdomen USG- for fatty change liver/ gallstone.
 X-ray for osteoporosis and bone age.
 BSR/OGTT.
 LFTS
FOR CUSHING..
 CORTISOL LEVEL
 Serum. crotisol – diurnal level –coz diurnal variation lost in cushing –>both time we get same
level.
 Mid night cortisol level advisable >4.4g/dldiagnostic.
 Salivary cortisol level mid night elevated.
 24 hr urinary cortisol level  elevated.
 A single-dose dexamethasone suppression
 Give dexamethasone 25-30ug/kg at 11 pm  take sample at 8 am next morning  serum
cortisol level
 If level is <5 ug/dl  normal/ if > cushing syndrome.
Cushing syndrome confirmed then we do:
 ACTH stimulation test
 Normal – pituatry is cause
 Suppressed—cortisol secreting adrenal tumor.
 Very high –ectopic ACTH secreting tumour.
 2 –dose dexamethasone suppression test –do find whether pituitary or ectopic.
 30 & 120ug/kg/24 give 4DD for consecutive days.
 pituitary disease—larger dose suppress cortisol
 Ectopic –not suppressed at all.
 Serum T4+TSH level.
 Insulin stress test/ IGF-1 , GHBP level.
 Baseline invx
Management:
 Confirm dx –counceliing of parents

 TREAT UNDERLYING CAUSE :
IF SIMPLE OBESITY
349
 Multidisciplinary approach
 Lifestyle modification.
 Cognitive –behaviour therapy.

 Nutritional adviseMeals should be based on fruits, vegetables, whole grains, lean meat, fish, and
poultry.
 Avoid food with high calorie but low nutrititional value-chocolate.
 Because many obese children are consuming calories greatly in excess of their needs, it is often
impossible to achieve an immediate reduction to the recommended daily calorie level. Instead, a
gradual approach is recommended.
 Any child with 10 yr – he need 2000kcal/day so if he takes more than 35 kcal then reduce calorie by
avoiding beverage and just take water instead/ and avoid snacks (300 estd calories)—do not ask to skip
meals.
 Traffic light diet plan should be introduced.
 Exercise .
 No more than 2 hr/day t.v .
 Bariatric surgery—GUIDELINE RECOMMENDATIONS—(1) surgery be considered only in
children with complete or near-complete skeletal maturity, a BMI ≥40 (2): and a medical complication
resulting from obesity, after they have failed 6 mo of a multidisciplinary weight management program
 Roux-en-Y and the adjustable gastric band.
DISCUSSION:
OBESITY :
 obesity results from an imbalance of caloric intake and energy expenditure.

 Body Mass Index
 Body mass index (BMI) which is an excellent proxy for more direct measurement of body fat.
 BMI = weight in kg/(height in meters)2.
 Adults with a BMI ≥30 meet the criterion for obesity, and those with a BMI 25-30 fall in the
overweight range.
 During childhood, levels of body fat change beginning with high adiposity during infancy.
 Body fat levels decrease for approximately 5.5 yr until the period called adiposity rebound, when body
fat is typically at the lowest level.
 obesity BMI children >2 yr old with a BMI ≥95th percentile meet the criterion for obesity,
 overweight range BMI between the 85th and 95th percentiles .
Risk factors of obesity:
 body habitus.
 Appetite.
 nutritional intake.
 physical activity.
 energy expenditure.
 Environmental factors determine levels of available food- preferences for types of foods, levels of
physical activity, and preferences for types of activities.
350
ENDOCRINE AND GENETIC CAUSES OF OBESITY
DISEASE SYMPTOMS LABORATORY
ENDOCRINE
Cushing syndrome Central obesity, hirsutism, moon face, hypertension Dexamethasone suppression

DISEASE SYMPTOMS LABORATORY
test
Growth hormone deficiency Short stature, slow linear growth Evoked GH response, IGF-1
Nesidioblastosis, pancreatic adenoma, hypoglycemia,
Hyperinsulinism Insulin level
Mauriac syndrome
Short stature, weight gain, fatigue, constipation, cold
Hypothyroidism TSH, FT4
intolerance, myxedema
Short metacarpals, subcutaneous calcifications,
Urine cAMP after synthetic
Pseudohypoparathyroidism dysmorphic facies, mental retardation, short stature,
PTH infusion
hypocalcemia, hyperphosphatemia
GENETIC
Cognitive impairment, retinitis pigmentosa, diabetes
Alstrom syndrome ALMS1 gene
mellitus, hearing loss, hypogonadism, retinal degeneration
Retinitis pigmentosa, renal abnormalities, polydactyly,
Bardet-Biedl syndrome BBS1 gene
hypogonadism
Cognitive impairment, iris coloboma, hypogonadism,
Biemond syndrome
polydactyly
Mutations in the RAB23 gene,
Polydactyly, syndactyly, cranial synostosis, mental
Carpenter syndrome located on chromosome 6 in
retardation
humans
Mid-childhood-onset obesity, short stature, prominent Mutations in the VPS13B gene
Cohen syndrome maxillary incisors, hypotonia, mental retardation, (often called the COH1 gene)
microcephaly, decreased visual activity at locus 8q22
Early-onset obesity, mental retardation, brachycephaly,
Deletion 9q34 Deletion 9q34
synophrys, prognathism, behavior and sleep disturbances
Down syndrome Short stature, dysmorphic facies, mental retardation Trisomy 21
Gene mutation on
ENPP1 gene mutations Insulin resistance, childhood obesity
chromosome 6q
Frohlich syndrome Hypothalamic tumor
Leptin or leptin receptor gene Early-onset severe obesity, infertility (hypogonadotropic
Leptin
deficiency hypogonadism)
Early-onset severe obesity, increased linear growth,
Melanocortin 4 receptor gene hyperphagia, hyperinsulinemia
MC4R mutation
mutation Most common known genetic cause of obesity
Homozygous worse than heterozygous
Neonatal hypotonia, slow infant growth, small hands and Partial deletion of
Prader-Willi Syndrome feet, mental retardation, hypogonadism, hyperphagia chromosome 15 or loss of
leading to severe obesity, paradoxically elevated ghrelin paternally expressed genes
Pro-opiomelanocortin Obesity, red hair, adrenal insufficiency, Loss-of-function mutations of
deficiency hyperproinsulinemia the POMC gene
Ovarian dysgenesis, lymphedema, web neck, short stature,
Turner syndrome XO chromosome
cognitive impairment
OBESITY-ASSOCIATED COMORBIDITIES
DISEASE POSSIBLE SYMPTOMS LABORATORY CRITERIA
CARDIOVASCULAR
Dyslipidemia HDL <40, LDL >130, total cholesterol >200 Fasting total cholesterol, HDL, LDL, triglycerides
351
Serial testing, urinalysis, electrolytes, blood urea
Hypertension SBP >95% for sex, age, height
nitrogen, creatinine
ENDOCRINE
Type 2 diabetes Acanthosis nigrans, polyuria, polydipsia Fasting blood glucose >110, hemoglobin, A1c, insulin

DISEASE POSSIBLE SYMPTOMS LABORATORY CRITERIA
mellitus level, C-peptide, oral glucose tolerance test
Central adiposity, insulin resistance,
Metabolic
dyslipidemia, hypertension, glucose Fasting glucose, LDL and HDL cholesterol
syndrome
intolerance
Polycystic ovary Irregular menses, hirsutism, acne, insulin
Pelvic ultrasound, free testosterone, LH, FSH
syndrome resistance, hyperandrogenemia
GASTROINTESTINAL
Gallbladder disease Abdominal pain, vomiting, jaundice Ultrasound
Nonalcoholic fatty Hepatomegaly, abdominal pain,

liver disease dependent edema, ↑ transaminases AST, ALT, ultrasound, CT, or MRI
(NAFLD) Can progress to fibrosis, cirrhosis
NEUROLOGIC
Pseudotumor
Headaches, vision changes, papilledema Cerebrospinal fluid opening pressure, CT, MRI
cerebri
ORTHOPEDIC
Blount disease (tibia
Severe bowing of tibia, knee pain, limp Knee x-rays
vara)
Musculoskeletal Back pain, joint pain, frequent strains or
X-rays
problems sprains, limp, hip pain, groin pain, leg bowing
Slipped capital Hip pain, knee pain, limp, decreased mobility
Hip x-rays
femoral epiphysis of hip
PSYCHOLOGICAL
Anxiety, depression, low self-esteem, Child Behavior Checklist, Children's Depression
disordered eating, signs of depression, Inventory, Peds QL, Eating Disorder Inventory 2,
Behavioral
worsening school performance, social subjective ratings of stress and depression, Behavior
complications
isolation, problems with bullying or being Assessment System for Children, Pediatric Symptom
bullied Checklist
PULMONARY
Shortness of breath, wheezing, coughing,
Asthma Pulmonary function tests, peak flow
exercise intolerance
Obstructive sleep Snoring, apnea, restless sleep, behavioral Polysomnography, hypoxia, electrolytes (respiratory
apnea problems acidosis with metabolic alkalosis)
Evaluation
 growth chart for weight, height, and BMI trajectories.

 consideration of possible medical causes of obesity.
 and detailed exploration of family eating, nutritional, and activity patterns.
 Examination of the growth chart reveals the severity, duration, and timing of obesity onset.
 Children who are overweight (BMI in the 85th-95th percentile) are less likely to have developed
comorbid conditions than those who are obese (BMI ≥95th percentile).
 Those with a BMI ≥99th percentile are even more likely to have coexisting medical problems.
endocrine causes of obesity  + short stature
 Growth hormone deficiency.

 Hypothyroidism. 352
 Cushing syndrome.
Exploration of family eating and nutritional and activity patterns begins with a description of regular meal and
snack times and family habits for walking, bicycle riding, active recreation, television, computer, and video-

game time. It is useful to request a 24-hour dietary recall with special attention to intake of fruits, vegetables,
and water, as well as high-calorie foods and high-carbohydrate beverages. When possible, evaluation by a
nutritionist is extremely helpful. This information will form the basis for incremental changes in eating
behavior, caloric intake, and physical activity during the intervention.
NORMAL LABORATORY VALUES FOR RECOMMENDED TESTS

LABORATORY TEST NORMAL VALUE
Glucose <110 mg/dL
Insulin <15 mU/L
Hemoglobin A1c <5.7%
AST 2-8 yr <58 U/L
AST 9-15 yr <46 U/L
AST 15-18 yr <35 U/L
ALT <35 U/L
Total cholesterol <170 mg/dL
LDL <110 mg/dL
HDL <35 mg/dL
Triglycerides 2-15 yr <100 mg/dL
Triglycerides 15-19 yr <125 mg/dL
TRAFFIC LIGHT DIET PLAN

FEATURE GREEN LIGHT FOOD YELLOW LIGHT FOODS RED LIGHT FOODS
Low-calorie, high-fiber, low-fat, nutrient- Nutrient-dense, but higher in calories High in calories, sugar, and
Quality
dense and fat fat
Types of Fatty meats, sugar, fried
Fruits, vegetables Lean meats, dairy, starches, grains
food foods
Quantity Unlimited Limited Infrequent or avoided
PROPOSED SUGGESTIONS FOR PREVENTING OBESITY

PREGNANCY
Normalize body mass index before pregnancy.
Do not smoke.
Maintain moderate exercise as tolerated.
In gestational diabetics, provide meticulous glucose control.
POSTPARTUM AND INFANCY

Breast-feeding is preferred for a minimum of 3 mo.
Postpone the introduction of solid foods and sweet liquids.
FAMILIES
Eat meals as a family in a fixed place and time.
353
Do not skip meals, especially breakfast.
No television during meals.
Use small plates, and keep serving dishes away from the table.
Avoid unnecessary sweet or fatty foods and soft drinks.

Remove televisions from children's bedrooms; restrict times for television viewing and video games.
SCHOOLS
Eliminate fundraisers with candy and cookie sales.
Review the contents of vending machines and replace with healthier choices.
Install water fountains.
Educate teachers, especially physical education and science faculty, about basic nutrition and the benefits of
physical activity.
Educate children from preschool through high school on appropriate diet and lifestyle.
Mandate minimum standards for physical education, including 30-45 min of strenuous exercise 2-3 times weekly.
Encourage “the walking schoolbus”: Groups of children walking to school with an adult.
COMMUNITIES
Increase family-friendly exercise and play facilities for children of all ages.
Discourage the use of elevators and moving walkways.
Provide information on how to shop and prepare healthier versions of culture-specific foods.
HEALTH CARE PROVIDERS

Explain the biologic and genetic contributions to obesity.
Give age-appropriate expectations for body weight in children.
Work toward classifying obesity as a disease to promote recognition, reimbursement for care, and willingness and
ability to provide treatment.
INDUSTRY
Mandate age-appropriate nutrition labeling for products aimed at children (e.g., red light/green light foods, with
portion sizes).
Encourage marketing of interactive video games in which children must exercise in order to play.
Use celebrity advertising directed at children for healthful foods to promote breakfast and regular meals.
GOVERNMENT AND REGULATORY AGENCIES

Classify obesity as a legitimate disease.
Find novel ways to fund healthy lifestyle programs, (e.g., with revenues from food and drink taxes).
Subsidize government-sponsored programs to promote the consumption of fresh fruits and vegetables.
Provide financial incentives to industry to develop more healthful products and to educate the consumer on
product content.
Provide financial incentives to schools that initiate innovative physical activity and nutrition programs.
Allow tax deductions for the cost of weight loss and exercise programs.
Provide urban planners with funding to establish bicycle, jogging, and walking paths.
Ban advertising of fast foods directed at preschool children, and restrict advertising to school-aged children.
ANTICIPATORY GUIDANCE: ESTABLISHING HEALTHY EATING HABITS IN CHILDREN

Do not punish a child during mealtimes with regard to eating. The emotional atmosphere of a meal is very
important. Interactions during meals should be pleasant and happy.
Do not use foods as rewards.
Parents, siblings, and peers should model healthy eating, tasting new foods, and eating a well-balanced meal.
Children should be exposed to a wide range of foods, tastes, and textures.
Foods should be offered multiple times. Repeated exposure to initially disliked foods will break down resistance.
Offering a range of foods with low energy density helps children balance energy intake. 354
Restricting access to foods will increase rather than decrease a child's preference for that food.
Forcing a child to eat a certain food will decrease his or her preference for that food. Children's wariness of new
foods is normal and should be expected.

Children tend to be more aware of satiety than adults, so allow children to respond to satiety, and let that dictate
servings. Do not force children to “clean their plate.”
CUSHING SYNDROME:
Prototype : short obese child with cushingoid facies/hypertichosis/hirsuitism+ raised B.P

Adrenal tumor –clinically signs of masculinization+ hirsuitism all over+ pubic hair+voice deep+acne and
enlarged clitoris in girls..
 The face is rounded, with prominent cheeks and a flushed appearance (moon facies).
 Generalized obesity is common in younger children.
 In children with adrenal tumors, signs of abnormal masculinization occur frequently; accordingly, there
may be hirsutism on the face and trunk, pubic hair, acne, deepening of the voice, and enlargement of
the clitoris in girls.
 Growth is impaired, with length falling below the 3rd percentile, except when significant virilization
produces normal or even accelerated growth.
 Hypertension is common and may occasionally lead to heart failure.
 An increased susceptibility to infection may also lead to sepsis.
In older children:
 Obesity +short stature is a common presenting feature.

 Gradual onset of obesity and deceleration or cessation of growth may be the only early manifestations.
 Older children most often have more severe obesity of the face and trunk compared with the
extremities.
 Purplish striae on the hips, abdomen, and thighs are common.
 Pubertal development may be delayed, or amenorrhea may occur in girls past menarche. Weakness,
headache, and emotional lability may be prominent.
 Hypertension and hyperglycemia usually occur.
 hyperglycemia may progress to frank diabetes. Osteoporosis is common and may cause pathologic
fractures.
Rx
 Treatment of underlying cause.

 Central -Transsphenoidal pituitary microsurgery is the treatment of choice in pituitary Cushing
disease
 Adrenal tumor—adrenalectomy—then replacement with steoroid 10mg/m2/day.
 Iatrogenic –remove the offending drug by tapering and adjustment.
355

BRONCHIECTASIS/CYSTIC FIBROSIS-----------------------------------------------------------------------LONG CASE
DISCUSSION:
BRONCHIECTASIS: it is a chronic suppurative lung disease characterized by irreversible abnormal

dilatation and anatomic distortion of the bronchial tree due to obstruction & inflammation
Conditions associated with bronchiectasis include: --(in order of sequence in our setup)
 Infections—pertussis , measles, and tuberculosis (Endo bronchilal),bronchopneumonia.

 Foreign body aspiration.
 Aspiration of gastric contents eg: GERD (in CP),H-type TEF
 C.Fibrosis—developed countries it is common.
 Primary ciliary dyskinesia/immotile cilia synd:/kartagner syndrome( Bronchiectasis+Nasal polyps+situs
inversus or dextrocardia)
 Immune deficiency syndromes (especially humoral immunity/sub IgG
class,hypogammaglobinemia,Hyper IgE syndrome,HIV
 Lobar sequestration (Non functional Mass of normal lung tissue that has blood supply from systemic circulation
ie abd or thoracic & it lacks normal communication with tracheobronchial tree)
Congenital
 William Campbell syndrome—absence of bronchial cartilage.—C.T disorder.

 Marnier Kuhn syndrome –congenital tracheobronchomegally.—C.T disorder.
 Rt middle lobe syndrome --(chronic extrinsic compression of right middle lobe bronchus by hilar
lymph nodes)
 Yellow nail syndrome -- (pleural effusion, lymphedema, discolored nails).
Three basic mechanisms are involved in the pathogenesis of bronchiectasis:
 Obstruction tumor, foreign body, impacted mucus due to poor mucociliary clearance, external
compression, bronchial webs, and atresia.
 InfectionsBordetella pertussis, measles, rubella, togavirus, respiratory syncytial virus, adenovirus,
and Mycobacterium tuberculosis induce chronic inflammation, progressive bronchial wall damage, and
dilatation thus unable to clear secretions & increase amount of bacteria in lung (dean sb Q hw measles
causes bronchiectasis)
 Chronic inflammation similarly contributes to the mechanism by which obstruction leads to
bronchiectasis
The common thread in the pathogenesis of bronchiectasis consists of difficulty clearing secretions and
recurrent infections with a “vicious circle” of infection and inflammation resulting in airway injury and
remodeling.
Bronchiectasis can manifest in any combination of three pathologic forms.
TYPES OF BRONCHIECTASIS AND HRCT FINDINGS:
 Cylindrical bronchiectasis Most common. The bronchial outlines are regular, but there is diffuse
dilatation of the bronchial unit due to destruction of elastic tissue. The bronchial lumen ends abruptly
because of mucous plugging.
 Varicose bronchiectasisthe degree of dilatation is greater, and local constrictions cause an 356
irregularity of outline resembling that of varicose veins. There may also be small sacculations.it is due
to destruction of Muscular coat of bronchial wall.
 Saccular (cystic) bronchiectasisbronchial dilatation progresses and results in ballooning of bronchi
that end in fluid- or mucus-filled sacs due to cartilage destruction of bronchial wallThis is the most
severe form of bronchiectasis.

----------------------------
Localized bronchiectasis :
Upper Lobe ----TB, CF
Right Middle Lobe---TB
Right lower lobe---F.Body , Immunodeficiency ,recurrent Aspiration
Generalized bronchiectasis: C.F, Immunodeficiency
Central bronchiectasis:
CF,William Campbell,Allergic broncho pulmonary aspergillosis (ABPA) (Examiner Q)
Other definations:
 Prebronchiectasis(chronic or recurrent endobronchial infection with nonspecific HRCT changes—

may be reversible);
 HRCT bronchiectasis (clinical symptoms with HRCT evidence of bronchial dilation—may persist,
progress, or improve and resolve);
 Established bronchiectasis (like the previous but with no resolution within 2 yr). Therefore, early
diagnosis and aggressive therapy are important to prevent the development of established
bronchiectasis.
 Cough + production of copious purulent sputum most common. worse in the morning only(dean
sb )
Acute onset –pneumonia
Gradual in onset is TB
Chronic onset –C.fibrosis,immunodeficiency
 Hemoptysis is seen with some frequency.
 Fever can occur with infectious exacerbations.
 Anorexia and poor weight gain may occur as time passes.
Physical examination:
 Typically reveals crackles localized to the affected area+/- but wheezing.

 digital clubbin g.
 In severe cases dyspnea and hypoxemia can occur.
 Pulmonary function studies  obstructive, restrictive, or mixed pattern. Typically, impaired
diffusion capacity is a late finding.
How would u diagnose?
A: sir I would confirm my diagnosis by
1. CXR
2. CT Chest
3. Pulmonary function tests
357
For Cause
I would go for

1. CBC ,ESR
2. Mantox
3. Sputum for C/S
4. Sweat chloride test
5. Barium swallow /videofloroscopy (for recurrent aspirations)
6. Sacharrin test+ nasal mucosal biopsy (for Kartagner syn )
7. Immunoglobulin levels (for Immuno deficienies )
For Complication
8. Echo
--------------
CXR- (Examiner Q)
 Increase size of lung.

 ↑parallel bronchovascular markings (suggests tramtrack appearance or thick bronchial walls)
 Air trapping/hyperinlation
 Loss of lung volume or peribronchial firbrosis we call it honey comb appearance also
 Crowding of bronchi.
 Multiple cystic areas
HRCT- Thin sections—more pulmonary prominence
 tram lines/signet ring appearance .(Normally bronchus & B.atery r of same size when
Bronchus thickness becomes >1.5cm than artery then signet ring appearance ocurrs)
 Varicose (bronchi with “beaded contour”).
 Cystic (cysts in “strings and clusters”).
 Mixed forms.
 The lower lobes are most commonly affected.
 Air trapping.
Q: What is the significance of CT in Bronchiectasis ? Examiner Q
1. confirms diagnosis
2. Type of bronchiectasis
3. Assess disease location (zones)& denotes extent of involvement of lung
4. Lymph node involvement
5. Foreign body
6. Congenital causes
7. underlying disease
Q: Is there any role of VQ scan in progression of disease?
A: VQ scan is ventilation perfusion scan. It shows perfusion or non perfusion areas. If shows
perfusion area of lung <10% then we go for surgery. It has no diagnostic value (NB)
Q: PFT helps in diagnosis or not? 358
A: it shows either obstructive or restrictive or mixed pattern.it indicate severity of disease as

initially there is obstructive pattern in bronchiectasis then restrictive usually late

Complications of bronchiectasis:/ (List the problems of bronchiectasis in ur pt?) ( (Eaminer Q)
1. Recurrent exacerbations
2. Hemoptysis
3. Lung abscess
4. Empyema
5. Cor pulmonale
6. Metastatic brain abscess
7. Halitosis (bad breath)
8. Failure to thrive
--------------------------------------------------------------------------------------------------------------
CYSTIC FIBROSIS
 Inherited multisystem disorder of children and adults characterized by obstruction +

infection of airways and by maldigestion and its consequences.
 Dysfunction of the cystic fibrosis transmembrane conductance regulator protein (CFTR)
 CF in early life exocrine pancreatic insufficiency & major cause of severe chronic lung
disease in children.
 It is also responsible for many cases of salt depletion, nasal polyposis, pansinusitis, rectal
prolapse, pancreatitis, cholelithiasis, and insulin-dependent hyperglycemia.
 CF may manifest as failure to thrive & occasionally, as cirrhosis or other forms of hepatic
dysfunction.
COMPLICATIONS OF CYSTIC FIBROSIS

RESPIRATORY
Bronchiectasis, bronchitis, bronchiolitis, pneumonia
Atelectasis
Hemoptysis
Pneumothorax
Nasal polyps
Sinusitis
Reactive airway disease
Cor pulmonale
Respiratory failure
Mucoid impaction of the bronchi
Allergic bronchopulmonary aspergillosis
GASTROINTESTINAL
Meconium ileus, meconium plug (neonate)
Meconium peritonitis (neonate)
Distal intestinal obstruction syndrome (non-neonatal obstruction)
Rectal prolapsed
Intussusception
Volvulus
Fibrosing colonopathy (strictures)
Appendicitis
Intestinal atresia
359
Pancreatitis
Biliary cirrhosis (portal hypertension: esophageal varices, hypersplenism)
Neonatal obstructive jaundice

Hepatic steatosis
Gastroesophageal reflux
Cholelithiasis
Inguinal hernia
Growth failure (malabsorption)
Vitamin deficiency states (vitamins A, K, E, D)
Insulin deficiency, symptomatic hyperglycemia, diabetes
Malignancy (rare)
OTHER
Infertility
Delayed puberty
Edema-hypoproteinemia
Dehydration–heat exhaustion
Hypertrophic osteoarthropathy-arthritis
Clubbing
Amyloidosis
Diabetes mellitus
Aquagenic palmoplantar keratoderma (skin wrinkling)
GENETICS:
 C.F –A.R –CFTR protein encode –/CFTR is expressed largely in epithelial cells of airways,
the gastrointestinal tract (including the pancreas and biliary system), the sweat glands,
and the genitourinary system.--> It functions as a chloride channel regulator.It involves
chromosome 7
 More than 1932 CFTR polymorphisms grouped into 5 main classes of mutations that affect
protein function are associated with the CF syndrome
 The most prevalent mutation of CFTR is the deletion of a single phenylalanine residue at
amino acid 508 (ΔF508).
 In our Pakistan mutation is S549 / Arg117His?.
ONE PROPOSED CLASSIFICATION OF CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR (CFTR)

MUTATIONS
CLASS EFFECT ON CFTR FUNCTIONAL CFTR PRESENT?

I Reduced/absent synthesis of CFTR No
Block in protein processing & degradation in endoplasmic
II No/substantially reduced (70%)
reticulum/Golgi body
Defective regulation of chloride channel ; CFTR not activated by No (non function CFTR present in
III
adenosine triphosphate or cyclic adenosine monophosphate apical membrane)
IV Reduced chloride transport through CFTR at the apical membrane Yes
V Splicing defect with reduced production of CFTR Yes
 Among mutations 1st three are more severe.
Cultured CF intestinal epithelial cells homozygous for the ΔF508 mutation are 360
unresponsive to the secretory effects of cholera toxin.--> due mutated chloride
channel –no CAMP work.

PATHOGENESIS:
 The membranes of CF epithelial cells are unable to secrete chloride ions in response to
cyclic adenosine monophosphate (cAMP)–mediated signals, and at least in the respiratory
tract, excessive amounts of sodium are absorbed through these membranes Dec water
in tract lumen  thick secrection+.
 Similar pathophysiologic events take place in the pancreatic and biliary ducts (and in the
vas deferens), leading to desiccation of proteinaceous secretions and obstruction. Because
the function of sweat gland duct cells is to absorb rather than secrete chloride, salt is not
retrieved from the isotonic primary sweat as it is transported to the skin surface; chloride
and sodium levels are consequently elevated.
 Airflow obstruction at the level of small airways is the earliest observable physiologic
abnormality of the respiratory system.
 Chronic bronchiolitis and bronchitis are the initial lung manifestations  but after
months to years, structural changes in airway walls produce bronchiolectasis and
bronchiectasis
Common organism causing infections are:
 Airway colonization with

 Staphylococcus aureus.
 Pseudomonas aeruginosa.
 Burkholderia cepacia
 H.influenza
PATHOLOGY
 The earliest pathologic lesion in the lung is that of bronchiolitis (mucous plugging and an
inflammatory response in the walls of the small airways) with time, mucus
accumulation and inflammation extend to the larger airways (bronchitis).
 Goblet cell hyperplasia and submucosal gland hypertrophy become prominent pathologic
findings, which is most likely a response to chronic airway infection. Organisms appear
to be confined to the endobronchial spaceinvasive bacterial infection is not
characteristic.
 With long-standing disease, evidence of airway destruction such as bronchiolar
obliteration, bronchiolectasis, and bronchiectasis becomes prominent.
 Imaging findings:
 Both increased airway wall thickness and luminal cross-sectional area
relatively early in lung disease evaluation.
 Bronchiectatic cysts and emphysematous bullae or subpleural blebs are
frequent with advanced lung disease,
 Upper lobes being most commonly involved.
 These enlarged air spaces may rupture and cause pneumothorax.
 Interstitial disease is not a prominent feature, although areas of fibrosis
appear eventually.
 Bronchial arteries are enlarged and tortuous hemoptysis in bronchiectatic airways.
 Small pulmonary arteriesmedial hypertrophy secondary pulmonary hypertension.
 The paranasal sinuses are uniformly filled with secretions containing inflammatory
products, and the epithelial lining displays hyperplastic and hypertrophied secretory
elements.
 The nasal mucosa may form large or multiple polyps, usually from a base surrounding the
ostia of the maxillary and ethmoidal sinuses.
 The pancreas is usually small, occasionally cystic. 361
 In 85-90% of patients, the lesion progresses to complete or almost
complete disruption of acini and replacement with fibrous tissue and
fat.
 Infrequently, foci of calcification may be seen on radiographs of the
abdomen.

 The islets of Langerhans contain normal appearing β cells, although
they may begin to show architectural disruption by fibrous tissue in the
2nd decade of life.(NB)
 The intestinal tract shows minimal changes.
 Focal biliary cirrhosis:
 secondary to blockage of intrahepatic bile ducts is uncommon in early life, although it is
responsible for occasional cases of prolonged neonatal jaundice.
 symptomatic multilobular biliary cirrhosis that has a distinctive pattern of large irregular
parenchymal nodules and interspersed bands of fibrous tissue.
 Approximately 30-70% of patients have fatty infiltration of the liver, in some cases
despite apparently adequate nutrition.
 The gallbladder may be hypoplastic and filled with mucoid material and often contains
stones.
 Mucus-secreting salivary glands are usually enlarged and display focal plugging and
dilatation of ducts.
 Glands of the uterine cervix are distended with mucus, copious amounts of which
collect in the cervical canal.
 Endocervicitis may be prevalent in teenagers and young women.
 In >95% of males, the body and tail of the epididymis, the vas deferens, and the
seminal vesicles are obliterated or atretic.
CLINICAL MANIFESTATION:
Respiratory Tract
 Cough is the most constant symptom of pulmonary involvement—initially dry then

productive.
 In older patients, the cough is most prominent upon arising in the
morning or after activity.
 Expectorated mucus is usually purulent.
 Recurrent pneumonia.
 Extensive bronchiolitis accompanied by wheezing is a frequent symptom during the
first years of life.
 As lung disease slowly progresses exercise intolerance, shortness of breath, and
failure to gain weight or grow.
 Cor pulmonale, respiratory failure.
 Colonization with B. cepacia and other multidrug-resistant organisms may be
associated with particularly rapid pulmonary deterioration and death.
 The rate of progression of lung disease is the chief determinant of morbidity and
mortality. The course of lung disease is largely independent of genotype. Severe
mutations tend to be associated with more rapid progression.
 A few mutations may substantially or even fully spare the lungs.
 Male gender and exocrine pancreatic sufficiency are also associated with a slower
rate of pulmonary function decline.
 Early physical findings include increased anteroposterior diameter of the chest,
generalized hyperresonance, scattered or localized coarse crackles, and digital
clubbing.
 Expiratory wheezes may be heard, especially in young children.
 Cyanosis is a late sign.
 Common pulmonary complications include atelectasis, hemoptysis, pneumothorax,
and cor pulmonale; these usually appear beyond the 1st decade of life.
 Paranasal sinuses are virtually always opacified radiographically, acute sinusitis is
infrequent.
362
 Nasal obstruction and rhinorrhea are common, caused by inflamed, swollen mucous
membranes or, in some cases, nasal polyposis.
 Nasal polyps are most troublesome between 5 and 20 yr of age.

Intestinal Tract
 In 15-20% of newborn infants with CF, the ileum is completely obstructed by

meconium (meconium ileus).
 The frequency is greater (≈30%) among siblings born subsequent to a child with
meconium ileus .
 Abdominal distention, emesis, and failure to pass meconium appear in the 1st 24-48
hr of life.
 Abdominal radiographs dilated loops of bowel with air-fluid levels and,
frequently, a collection of granular, “ground-glass” material in the lower central
abdomen. Rarely, meconium peritonitis results from intrauterine rupture of the
bowel wall and can be detected radiographically as the presence of peritoneal or
scrotal calcifications.
 Meconium plug syndrome occurs with increased frequency in infants with CF but is
less specific than meconium ileus.
 Ileal obstruction with fecal material (distal intestinal obstruction syndrome [DIOS])
occurs in older patients, causing cramping abdominal pain and abdominal distention.
 maldigestion from exocrine pancreatic insufficiency—(>85%).
 Symptoms include:
 frequent, bulky, greasy stools and failure to gain weight even
when food intake appears to be large.
 Characteristically, stools contain readily visible droplets of fat.
 A protuberant abdomen, decreased muscle mass, poor growth,
and delayed maturation are typical physical signs.
 Excessive flatus may be a problem.
 Virtually all individuals homozygous for ΔF508 have pancreatic insufficiency.
 Less common gastrointestinal manifestations:
 Intussusceptions.
 fecal impaction of the cecum with an asymptomatic right lower
quadrant mass.
 Epigastric pain owing to duodenal inflammation.
 Acid or bile reflux with esophagitis symptoms is common in older
children and adults.
 Subacute appendicitis and periappendiceal abscess have been
encountered.
 rectal prolapse now less frequently as the result of earlier
diagnosis and initiation of pancreatic enzyme replacement
therapy.
 hypoproteinemia with anasarca appears in malnourished infants, especially if
children are fed soy-based preparations.
 Neurologic dysfunction (dementia, peripheral neuropathy) and hemolytic anemia
may occur because of vitamin E deficiency.
 Deficiency of other fat-soluble vitamins is occasionally symptomatic.
Hypoprothrombinemia due to vitamin K deficiency may result in a bleeding
diathesis. Clinical manifestations of other fat-soluble vitamin deficiencies, such as
decreased bone density and night blindness, have been noted. Rickets is rare.
Biliary Tract
 Evidence for liver dysfunction is most often detected in the 1st 15 yr of life.
 Found in up to 30% of individuals.
 Biliary cirrhosis becomes symptomatic in only 5-7% of patients. 363
 Manifestations can include icterus, ascites, hematemesis from esophageal varices,
and evidence of hypersplenism.
 Biliary colic secondary to cholelithiasis may occur in the 2nd decade or later.
 Liver disease occurs independent of genotype but is associated with meconium ileus
and pancreatic insufficiency.

Pancreas
 In addition to exocrine pancreatic insufficiency, evidence for hyperglycemia and

glycosuria, including polyuria and weight loss, may appear, especially in the 2nd
decade of life.
 Eight percent of 11-17 yr old patients and 30% of patients >25 yr of age have CF-
related diabetes.
 Ketoacidosis usually does not occur, but eye, kidney, and other vascular
complications have been noted in patients living ≥10 yr after the onset of
hyperglycemia.
 Recurrent, acute pancreatitis occurs occasionally in individuals who have residual
exocrine pancreatic function and may be the sole manifestation of two CFTR
mutations.
Genitourinary Tract
 Sexual development is often delayed but only by an average of 2 yr.

 More than 95% of males are azoospermic because of failure of development of
wolffian duct structures, but sexual function is generally unimpaired.
 The incidence of inguinal hernia, hydrocele, and undescended testis is higher than
expected.
 Adolescent females may experience secondary amenorrhea, especially with
exacerbations of pulmonary disease.
 Cervicitis and accumulation of tenacious mucus in the cervical canal have been
noted. The female fertility rate is diminished.
 Pregnancy is generally tolerated well by women with good pulmonary function but
may accelerate pulmonary progression in those with moderate or advanced lung
problems.
Sweat Glands:
 Excessive loss of salt in the sweat predisposes young children to salt depletion
episodes, especially during episodes of gastroenteritis and during warm weather.
 These children present with hyponatremic hypochloremic alkalosis. Frequently,
parents notice salt “frosting” of the skin or a salty taste when they kiss the child.
 A few genotypes are associated with normal sweat chloride values.
Q: what is cause of hyponatremic hypochloremic alkalosis in CF pt?
A: b/c of loss of Nacl +water volume through sweat glands there is hypovolumia
there is increased HCO3 absorbtion through renal tubules.
DIAGNOSIS AND ASSESSMENT:
CF –classical/nonclassical
CLASSICAL –clinical evidence of >1 organ system + elevated sweat chloride

364
NON-CLASSICAL –1 system involves or multisystem + normal sweat chloride test.

DIAGNOSTIC CRITERIA FOR CYSTIC FIBROSIS (CF)
Presence of typical clinical features (respiratory, gastrointestinal, or genitourinary)
OR
A history of CF in a sibling
OR
A positive newborn screening test
PLUS
Laboratory evidence for CFTR (CF transmembrane regulator) dysfunction:
Two elevated sweat chloride concentrations obtained on separate days(examiner Q)
OR
Identification of two CF mutations
OR
An abnormal nasal potential difference measurement
Sweat Testing
 using pilocarpine iontophoresis (of 3 ampere current)to collect sweat(gold standard procedure for
sweat chloride tests S/b dean sb ) standard approach to diagnosis of CF.
 An electric current is used to carry pilocarpine into the skin of the forearm and locally stimulate the
sweat glands If an adequate amount of sweat is collected(100mg) the specimens are analyzed for
chloride concentration.
 Testing may be difficult in the 1st 2 wk of life because of LOW SWEAT RATES but is recommended
any time after the 1st 48 hr of life.
 Positive results should be confirmed.
 for a negative result, the test should be repeated if suspicion of the diagnosis remains.
 More than 60 mEq/L of chloride in sweat is diagnostic of CF when 1 or more other criteria are
present.
 Threshold levels of 30-40 mEq/L for infants have been suggested.
 Borderline (or intermediate) values of 40 to 60 mEq/L have been reported in patients of all ages who
have CF with atypical involvement and require further testing.
 Chloride concentrations in sweat are somewhat lower in individuals who retain exocrine pancreatic
function but usually remain within the diagnostic range.
 Pre-requisties of test . No dehydration , no steroid therapy, no electrolyte imbalance.
 CONDITIONS ASSOCIATED WITHFALSE-POSITIVE AND FALSE-NEGATIVE SWEAT
TEST RESULTS
WITH FALSE-POSITIVE RESULTS (examiner Q) dean sb

Eczema (atopic dermatitis)
Ectodermal dysplasia
Malnutrition/failure to thrive/deprivation
Anorexia nervosa
Congenital adrenal hyperplasia
Adrenal insufficiency
Glucose-6-phosphatase deficiency
Mauriac syndrome 365
Fucosidosis
Familial hypoparathyroidism
Hypothyroidism
Nephrogenic diabetes insipidus

Pseudohypoaldosteronism
Klinefelter syndrome
Familial cholestasis syndrome
Autonomic dysfunction
Prostaglandin E infusions
Munchausen syndrome by proxy
WITH FALSE-NEGATIVE RESULTS

Dilution
Malnutrition
Edema
Insufficient sweat quantity
Hyponatremia
Cystic fibrosis transmembrane conductance regulator (CFTR) mutations with preserved sweat duct function
DNA Testing
 Several commercial laboratories test for 30-96 of the most common CFTR mutations.
 This testing identifies ≥90% of individuals who carry 2 CF mutations.
 Some children with typical CF manifestations are found to have 1 or no detectable mutations by this
methodology.
 Some laboratories perform comprehensive mutation analysis screening for all of the >1,500 identified
mutations.
Other Diagnostic Tests
 The finding of increased potential differences across nasal epithelium, the loss of this difference with
topical amiloride application, and the absence of a voltage response to a β-adrenergic agonist have been
used to confirm the diagnosis of CF in patients with equivocal or frankly NORMAL sweat
chloride values.
Pancreatic Function
 Exocrine pancreatic dysfunction is clinically apparent in many patients.

 3-day stool collection (stool fat output >7% of oral fat intake is diagnostic of pancreatic dysfunction)
or direct documentation of enzyme secretion after duodenal intubation and pancreozymin-secretin
stimulation provides a reliable measure but the fat collection is cumbersome and duodenal intubation
is very invasive and rarely performed.
 Elastase-1 activity in a fresh stool sample, is used routinely A simpler test that can be used to screen
pancreatic function, the quantification or severity of steatorrhea.Also VIT E level is used
 Many authorities advocate yearly monitoring with a modified 2-hr oral glucose tolerance test (OGTT)
after 10 yr of age.
 This approach is more sensitive than spot checks of blood and urine glucose levels and glycosylated
hemoglobin levels.
 IMAGING –HRCT
 PULMONARY FUNCTION TEST.

 NEW BORN SCREEN-IRT ( immune reactive trypsin)Level-----NOT AFTER 2
MONTHS (EXAMINER Q) 366

 PRENATAL DIAGNOSIS—MUTATION ANALYSIS by chorionic villous sampling at 8-
10 weeks or Aminocentesis at 16-18 weeks ( NB)

TREATMENT
MANAGEMENT:
o Multidisciplinary approach (A nurse, respiratory therapist, social worker, dietitian, and

psychologist)
o My Aim of Rx is to
Keep Secretion free
Infection free
o For these I would go for
o Inhalation therapy
o Physiotherapy
o Postural drainage
o Antibiotic (oral,IV & inhalation as well )
o Bronchodilators
o Anti inflammatory drugs
o Bronchoscopy & lavage
o Nutritional care
o Prevent & treat complications
o Patient and parent education.
o Psychosocial support
o Surgery
o Single lung transplant/liver transplant(no heart lung transplant now b/c corpulmonale resolves after
lung Transplant)
o Genetic counseling & Antenatal diagnosis
o Vaccination(influenza vaccine yearly)
Q: what are the surgical indications of bronchiectasis?
o Recurrent exacerbations
o Recurrent pneumothorax
o Recurrent pseudomonas infection
o Hemoptysis
o Foreign body not removed by bronch oscopy
o Localized sequestration segment
o FTT
Note: at least 10 lobes are needed for survival so 10 lobes are saved after lobectomy (examiner Q)
Q: what are the indications of lung transplant in pt with CF?
o ↑ Frequency of exacerbations
o Life threatening hemoptysis
o Recurrent & refractory pneumothorax
o Impaired quality of life—Oxygen dependant at home
o FEV1 <30% of predicted
o Persisting type 2 respiratory failure
NOTE: cystic fibrosis does not occur in transplanted lung b/c of normal cl- channels
Follow-up evaluations are scheduled every 1-3 mo.
At each visit: look at parameters:
 Anthropometrics—ht , wt.
 Sputum analysis 367
 PFT,LFTs
 Documentation of disease progression at 6 month –1 yr interval  CXR, PFT, CBC,
vit. E level.
 HRCT at primary and secondary school level can assess the progression of bronchiectasis

NOTE:
THE MOST COMMON PRESENTATION OF THE PATIENT WITH K/C OF CYSTIC FIBROSIS IN EMERGENCY OR
OPD IS THE EXACERBATION OR PULMONARY INFECTION (EXAMINER Q)
SYMPTOMS
Increased frequency and duration of cough
Increased sputum production
Change in appearance C colour) of sputum
Increased shortness of breath
Decreased exercise tolerance
Decreased appetite
Feeling of increased congestion in the chest
SIGNS
Increased respiratory rate
Use of accessory muscles for breathing
Intercostal retractions
Change in results of auscultatory examination of chest
Decline in measures of pulmonary function consistent with the presence of obstructive airway disease
Fever and leukocytosis
Weight loss
New infiltrate on chest radiograph
After admission aim of Rx or we wl moniter for (examiner Q)

o 2 free
o Good sleep
o ↑ oral intake
o Sputum color normal
o ↓ sputum frequency
------------------------------
Because secretions of CF patients are not adequately hydrated, attention in early childhood to oral hydration,
especially during warm weather or with acute gastroenteritis, may minimize complications associated with
impaired mucus clearance. Intravenous therapy for dehydration should be initiated early
COMPLICATIONS OF THERAPY FOR CYSTIC FIBROSIS*

COMPLICATION AGENT
Gastrointestinal bleeding Ibuprofen
Hyperglycemia Corticosteroids (systemic)
Growth retardation Corticosteroids (systemic, inhaled)
Renal dysfunction:
Tubular Aminoglycosides
Interstitial nephritis Semisynthetic penicillins, nonsteroidal anti-inflammatory drugs
Hearing loss, vestibular dysfunction Aminoglycosides
368
Arthritis Quinolones
Hypomagnesemia Aminoglycosides
Hyperuricemia, colonic stricture Pancreatic extracts ( PERT) (very large doses)---NB

COMPLICATION AGENT
Goiter Iodine-containing expectorants
Gynecomastia Spironolactone
Enamel hypoplasia or staining Tetracyclines (used in 1st 8 yr of life)
Pulmonary Therapy
Goal : clear secretions from airways and to control infection.
1. Inhalation Therapy
o Human recombinant DNase (2.5 mg):
 Single daily aerosol dose.
 ↓viscoelasticity of prulent sputum secretions
 Usually NOT given during RTI.

Advantages:
1. Improves pulmonary function.
2. Decrease the number of pulmonary exacerbations.
3. Promotes a sense of well-being in patients who have moderate disease and
purulent secretions.
4. Improvement is sustained for ≥12 mo with continuous therapy.
5. Benefit for those with normal forced expiratory volume in 1 sec (FEV 1) values
or advanced lung disease has also been documented.
 N-acetylcysteine:
is toxic to ciliated epithelium, and its repeated administration should be avoided
 Nebulized hypertonic saline ( 3% ,6%) : hyperosmolar agent draw water into the airway and
rehydrate mucus and the peri ciliary fluid layer, resulting in improved mucociliary clearance. nebulized
2-4 times daily results in increased mucus clearance and improved pulmonary function.
 Aerosolized antibiotics are often used when the airways are colonized with Pseudomonas as part of
daily therapy. ( common examiner Q)
Example: AEROSOLIZED TOBRAMYCIN used as a suppressive therapy
(ON 1 MONTH, OFF 1MONTH)

Dose: 300mg/kg BD
Other inhalation drugs available are Aminoglycoside, colistin, ticarcillin ( examiner Q)
NEW INHALATION THERAPIES:
o Anti protease proteins

o Recombint alpha Anti 1 trypsin
o Recombint human secretary leuko protease inhibitor
2. Airway Clearance Therapy 369
Che st physical therapy (chest percussion combined with postural drainage): induce cough and
chest

vibration +move secretions from smaller airways.
o Chest PT is recommended 1-4 times a day, for 10-20 min depending on the severity of lung
dysfunction. Cough, huffing, or forced expirations are encouraged after each lung segment is
“drained.”
o Vest-type mechanical percussors are also useful.
o Voluntary coughing, repeated forced expiratory maneuvers with and without positive
expiratory pressure, patterned breathing, and use of an array of handheld oscillatory devices
are additional aids to clearance of mucus.
o Routine aerobic exercise
Contraindications of chest physiotherapy: pulmonary hemorrhage, pneumothorax
3. Antibiotic Therapy
 Goal is to reduce the intensity of endobronchial infection and to delay progressive lung
damage.
 Antibiotic treatment varies from intermittent short courses of 1 antibiotic to nearly
continuous treatment with 1 or more antibiotics.
 Dosages for some antibiotics are often 2 to 3 times the amount recommended for minor
infections because patients with CF have proportionately more lean body mass and higher
clearance rates for many antibiotics than other individuals. (examiner Q)
Oral Antibiotic Therapy
Indications :
 Presence of respiratory tract symptoms.

 Identification of pathogenic organisms in respiratory tract cultures.
 Common: S. aureus, nontypable Haemophilus influenzae, P. aeruginosa; B. cepacia and
other gram-negative rods.
 The first 2 can be eradicated from the respiratory tract in CF with use of oral antibiotics, but
Pseudomonas is more difficult to treat b/c produces alginate bio film which protect it from
neutrophil & Antibiotic (examiner Q)
The usual course of therapy is ≥2 wk, and maximal doses are recommended.
 The quinolones are the only broadly effective oral antibiotics for Pseudomonas infection, but
resistance against these agents emerges rapidly.
 Infection with mycoplasmal or chlamydial organisms has been documented, providing a
rationale for the use of macrolides on an empirical basis for flare of symptoms.
 Macrolides may reduce the virulence properties of P. aeruginosa, such as biofilm production,
and contribute anti-inflammatory effects.
 Long-term therapy with azithromycin three times a week has been shown to improve lung
function in patients with chronic P. aeruginosa infection.
Intravenous Antibiotic Therapy
 Although many patients show improvement within 7 days, it is usually advisable to extend the
period of treatment to at least 14 days.
 Permanent intravenous access can be provided for long-term or frequent courses of therapy in
the hospital or at home.
 In general, treatment of Pseudomonas infection requires 2-drug therapy.(NB) A 3rd agent
may be required for optimal coverage of S. aureus or other organisms.
1. Aminoglycosides have a relatively short half-life in many patients with CF. The initial 370
parenteral dose is generally given every 8 hr. After blood levels have been determined, the
total daily dose should be adjusted. Peak levels of 10-15 mg/L are desirable, and trough
levels should be kept at <2 mg/L to minimize the risk of ototoxicity and nephrotoxicity.

Once- or twice-daily aminoglycoside dosing may have advantages over dosing every 8 hr.
Changes in therapy should be guided by lack of improvement and by culture results.
2. Ceftazidime in double dose.
 If patients do not show improvement, complications such as heart failure and reactive airways or
infection with viruses, Aspergillus fumigatus , nontuberculous mycobacteria , or other unusual
organisms should be considered. B. cepacia is the most frequent of a growing list of gram-
negative rods that may be particularly refractory to antimicrobial therapy.
4. Bronchodilator Therapy
 Salbutamol
 Cromolyn sodium
 Ipratropium bromide.
 CF children –Reversible bronchial obstruction. –(frank asthma /ABPA)
Reversible obstruction is defined as improvement of ≥15% in flow rates after inhalation of a

bronchodilator.
5. Anti-Inflammatory Agents
a. Corticosteroids—(ABPA+severe reactive airway disease).
i. Alternate day regime-improve PF and reduce hospital stay.
ii. Including growth retardation, cataracts, and abnormalities of glucose tolerance at a
dose of 2 mg/kg and growth retardation at 1 mg/kg.
b. Inhaled corticosteroids have theoretical appeal, but there are few data documenting their
efficacy and safety; it appears that discontinuing inhaled corticosteroids in patients with CF
had no effect on lung function, antibiotic use, or bronchodilator use.
c. Ibuprofen, given long term—for mild lung disease.
6. Endoscopy and Lavage :
Tracheobronchial suctioning or lavage if atelectasis or mucoid impaction is present.

Bronchopulmonary lavage can be performed by the instillation of saline or a mucolytic agent
through a fiberoptic bronchoscope. Antibiotics (usually gentamicin or tobramycin) can also be
instilled directly at lavage in order to transiently achieve a much higher endobronchial
concentration than can be obtained by using intravenous therapy.
Q: Indication of Bronchoscopy in CF pt? (Examiner Q)
o Mucus plugs
o Atelectasis
o Bleeding
o Foreign body
o Vascular rings
Other Therapies
Expectorants such as iodides and guaifenesin do not effectively assist with the
removal of
secretions from the respiratory tract.

371
Emerging Therapies
o A number of potential therapies are under development, including promising

mutation-specific therapies in clinical trials.

o For class 1 mutations (nonsense or premature stop-codon mutations) that result in a
premature termination of the mRNA that leads to no protein production, PTC124
suppress the termination codon, allowing for read through and partial correction of
the defect in approximately 30% of subjects with CF. Additional studies are under
way to further evaluate PTC124's efficacy.
o “potentiators,” including VX-770 (Vertex Pharmaceuticals, Cambridge, MA), that
activate CFTR mutants (G551D-CFTR) that traffic to the plasma membrane but do
not appropriately activate.
o denufosol and Moli1901 (lancovutide, Lantibio/AOP Orphan Pharmaceuticals AG,
Vienna) are directed at bypassing the primary CFTR defect by regulating alternative
ion channels and normalizing the ion transport properties of affected tissue, thus
correcting the mucociliary abnormality observed in the respiratory tract of the patient
with CF.
o Gene therapy
TREATMENT OF INTESTINAL COMPLICATIONS
 MECONIUM ILEUS
o Adequate hydration.
o NG pass and do suction.
o (Gastrografin) enemas with reflux of contrast material into the ileum not only confirm the
diagnosis but have also resulted in the passage of a meconium plug and clearing of the
obstruction.
o Use of this hypertonic solution requires careful correction of water losses into the bowel.
Children in whom this procedure fails require operative intervention. Children who are
successfully treated generally have a prognosis similar to that of other patients with severe CF
mutations.
o Surgical: Bishop koop procedure.
DISTAL INTESTINAL OBSTRUCTION SYNDROME (MECONIUM ILEUS EQUIVALENT)
o Despite appropriate pancreatic enzyme replacement, 2-5% of patients accumulate fecal

material in the terminal portion of the ileum and in the cecum, which may result in partial or
complete obstruction.
Rx
o High fiber diet+Pancreatic enzyme replacement + stool softener (laxatives) + open lapartomy.
D/D : Intussusception/Volvulous.
 GASTROESOPHAGEAL REFLUX
Because several factors raise intra-abdominal pressure, including cough and obstructed
airways, Supine position during physiotherapy , postural drainage.
Rx
 Dietary, positional, and medication therapies should be considered.

372
 Cholinergic agonists are contraindicated because they trigger mucus secretion and
progressive respiratory difficulty.
 Reduction of stomach acid secretion can help, with proton pump inhibitors being the most
effective agents.
 Fundoplication is a procedure of last resort.

Rectal Prolapse
 Though uncommon, rectal prolapse occurs most often in infants with CF and less
frequently in older children with the disease.
 It is usually related to steatorrhea, malnutrition, and repetitive cough.
Rx
 The prolapsed rectum can usually be replaced manually by continuous gentle pressure
with the patient in the knee-chest position.
 To prevent an immediate recurrence, the buttocks can be taped closed.
 Adequate pancreatic enzyme replacement, decreased fat and roughage in the diet, stool
softener, and control of pulmonary infection result in improvement.
 may require sclerotherapy or surgery.
Hepatobiliary Disease
 Liver function abnormalities associated with biliary cirrhosis can be improved by

treatment with ursodeoxycholic acid.
 Average age of presentation is 10 yr.(NB)
 Portal hypertension with esophageal varices, hypersplenism, or ascites occurs in ≤8%
of children with CF.
 The acute management of bleeding esophageal varices includes nasogastric suction
and cold saline lavage. Sclerotherapy is recommended after an initial hemorrhage. In
the past, significant bleeding has also been treated successfully with portosystemic
shunting. Splenorenal anastomosis has been the most effective treatment. Pronounced
hypersplenism may require splenectomy. Cholelithiasis should prompt surgical
consultation. Obstructive jaundice in newborns with CF needs no specific therapy.
Hepatomegaly with steatosis requires careful attention to nutrition and may respond
to carnitine repletion. End-stage liver disease is an indication for liver transplantation
in children with CF, especially if pulmonary function is good
Pancreatitis
 Pancreatitis can be precipitated by fatty meals, alcohol ingestion, or tetracycline

therapy. Serum amylase and lipase values may remain elevated for long periods.
 Rx –MCT Oil.
Small bowl bacterial overgrowth
 Bacteria in jujenum >105 /ml

 Rx –flush gastrographin via percutanoeus endoscopy gastrotomy.
Fibrosing colonpathy:
 Complication of PERT.
Hyperglycemia
 Onset of hyperglycemia occurs most frequently after the 1st decade.(NB)

373
 Approximately 20% of young adults are treated for hyperglycemia, although the
incidence of CF-related diabetes (CFRD) may be higher.
 Prevalence is greater in females and in ΔF508 homozygotes.
 Ketoacidosis is rarely encountered.

 The pathogenesis includes both impaired insulin secretion and insulin resistance.
 Routine screening consists of an annual modified 2-hr oral glucose tolerance
test after the child reaches age 8-10 yr.
 Glucose intolerance without urine glucose losses is usually not treated.
 Glycosylated hemoglobin levels should be followed at least annually.
 With persistent glycosuria and symptoms, insulin treatment should be instituted.
 Oral hypoglycemic agents may be effective.
 Corticosteroid therapy should be avoided.
 The development of significant hyperglycemia favors acquisition of P.
aeruginosa and B. cepacia in the airways and may adversely affect pulmonary
function. Thus, careful control of blood glucose level is an important goal.
Other Therapy
 Nasal Polyps
o Nasal polyps occur in 15-20% of patients with CF and are most
prevalent in the 2nd decade of life.
Rx  Local corticosteroids and nasal decongestants.
Surgery: indications: 1)completely obstruct the nasal airway 2)

rhinorrhea becomes constant 3) widening of the nasal bridge
 Rhinosinusitis
Opacification of paranasal sinuses is not an indication for intervention.
Rx Antibiotics +/- maxillary sinus aspiration for culture.
 Hemoptysis
CAUSE: bronchial artery rupture, FB, Aneurysm (EXAMINER Q)
 In moderate to severe lung disease.

 No Rx for minor just treat with antibiotic and reassure and followup
 If any hemoptysis >20 ml—admit in hospital
 O2 inhalation
 Vitamin K
 Blood trx –if needed
 Massive hemoptysis >300 ml/24 hr-- blood loss
 Propup
 Stop CPT
 Transfusion therapy.
 i.v antibiotics
 vitamin K and reassure.
If no response
 Bronchial artery embolisation.

 Emergency lobectmy. 374
 Lung transplantation.

PNEUMOTHORAX
 Poor prognostic factor –if occur mean pt may die within 3 yr (75%).
 O2—Chest tube & video thoracostomy
CORPULMONALE/ RHFAILURE
 Poor prognostic –mean survival rate 6 month.

 Rx—nocturnal O2 +diuretics+digoxin+antibiotics + BiPAP –lung transplantation.
ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS:
Presents with Rusty sputum in CF

LABS: ↑serum eosinophills,
↑Serum IgE level
CXR –bronchopulmonary infilterates,bronchial wall thickening (examiner Q)
CT CHEST—central bronchiectasis(examiner Q)
Rx
Antifungal—itraconazole
Steroids for 1-2 weeks then tapper on AD in 4-6 months
NUTRITION (EXAMINER Q)
 High energy diet is recommended –high fat, high protein of more biological value, high calorie).
o Require 120% of normal energy requirement. (Because of infection & breathing +anorexia)
o
o Diet should be liberal contain high intake of variety of foods –rich in fat, sugar, salt, protein
fruits and cereals.
o Breast feeding is desirable for babies with C.F
 MCT oil is also recommended.
 Fat soluble vitamin supplement –ADEK (VIT-ADK given 2-3 time of RDA, while VITAMIN E is
10-15 times of RDA.)
o VITAMIN A –5000 UNITS DAILY.
o VITAMIN D 400 IU DAILY.
o VITAMIN E 100 UNITS DAILY.
o VITAMIN K 10 mg TWICE/WEEK.
o ZINC + IRON supplement.
 Pancreatic enzyme replacement therapy (lipase+ amylase+ protease)
o DOSE: 500-1000 units lipase/kg of diet fat (dose is calculated by lipase b/c of its increase
content)
o Monitored by stool fat out put
o If it does not responds then add PPI,s & H2 blockers
o Complication: colonic stricture+ hyperuricemia
SALT DEPLETION:
 Guideline for recommended amount of salt intake:
 Under 6 month –0.5g/day.
 6-12 month –1g/day
 1-5 yr –2 g/day
 Over 5 yr –3g/day.
ORS can be used as a source of salt.

 Replace salt several times a day in hot climate. 375
 Avoid over dressing.

Hypertrophic pulmonary osteo arthropathy:
In this condition there is elevation of periosteum over disease portions of long bones. it causes bone
pain (all Joints), kyphosis &clubbing
Rx
NSAIDS
Growth:
Growth hormone 3 times a week will improve nutritional outcome
Infertility: (NB)
Males: have absent b/l vasa deferens so spermatozoa are aspirated from head of epididimis then we go
for
ICSI (intra cytoplasmic sperm injections) into oocyte obtained by egg harvesting…
Females: 3 monthly depo provera is used..OCPs usually not
Surgery (NB)
 Minor surgical procedures, including dental work, should be performed with the use of local anesthesia
if possible in children with CF.
 Patients with good or excellent pulmonary status can tolerate general anesthesia without any intensive
pulmonary measures before the procedure. Those with moderate or severe pulmonary infection usually
do better with a 1- to 2-wk course of intensive antibiotic treatment and increased airway clearance
before surgery.
.
PROGNOSIS :
nd
Life expectancy increased to median survival rate 36yr >90% mortality due to lung disease, 2 cirrhosis.
(EXAMINER Q)
Poor prognostic factors are:
 Female pt
 Pancreatic insuffieciency
 Recurrent p. auruginosa under 6 yr.
 Recurrent and refractory pneumothorax
 Poor socioeconic status.
 Recurrent hemoptysis
 Poor pt
 Pneumothorax
 No CF clinic
 ABPA.
EXAMINER Q (BHATTI SB )
Q: Why not a case of chronic Asthma?
1. No suppuration
2. No clubbing 376
3. Symptoms free in B/w where as Bronchiectasis pt are never symptoms free
Q: Why not a case of interstitial lung disease?

1. Clubbing +ve
2. cynosis
3. ↑AP diameter of chest
4. No productive cough (suppuration)
Q: What is pulmonary hemmosiderosis?
Read in nelson respiratory unit
Bronchiectasis +repeated rhinnorea D/D
1. Asthma
2. Immunodeficiency
Bronchiectasis+Recurrent otitis media D/D
1. Asthma
2. Immunodeficiency
Bronchiectasis+slenomegaly D/D
1. Immunodeficiency
2. Disseminated TB
3. Amyloidosis
Q: Clinically what is difference b/w type 1& type 2 respiratory failure?
 Type 1 pt is usually cyanosed &irritable

 Type 2 pts r drowsy,may have fits & ↑BP
Q: WHY UR PT IS EXCESSIVELY SWEATING NOW? DEAN SB
A:
 ↑ work of breathing
 Cardiac failure—corpulmonale
 TB
 Cystic fibrosis
 Hypoglycemia
 thyrotoxicosis
Q: IF UR PT HAS COR PULMONALE WHT SIGNS WILL U LOOK FOR? DEAN SB
 hyperdynamic chest
 Loud P2
 JVP raised
 Hepatomegaly
 Sweating
 Edema
 Cyanosis
377

JIA -------------------------------------------------------------------LONG CASE.
Prototype case:
My patient Ali Raza 8 year age resident of kasur admitted thru Opd with P/C of pain in joints for last
3 month, fever for 2 month, difficulty in walking for last 1 month.
According to patients mother child was in usual state of health 3 month back then he had pain in
joints started from Rt/Lt ankle then Rt/lt knee followed wrist joints in last, involved >5 joints within
course of disease from the onset of pain in joints, symmetrical/asymetrical, non migratory,
associated with morning stiffness in form of restricted painful movement of invovled joint for more
than 1 hour, no hx of nocturnal discmfort/night waking and use of splints/ orhtoses, joint pain
Followed by fever 1 month later, that was documented upto 101-102 0F during course of illness, it
was intermittant, more in evening time, relieve with antipyretics advised by local practisioner/self .
Then 1 month back he/she had sudden/progressively onset of difficulty in walking.
There is hx of poor apetite, wt loss, distrubed sleep after illness aswell.
There is associated hx of effect on activity of daily living (ADL) in form of painful eating/ painful
mastication/ dressing/ writing/ walking/ limitation of sports activity/ social activtiy/ depression.
Hx of delayed puberty/short stature, requirement of GH.
No hx of visual distrubance/ pain in eyes ( 0occular complication uveitis,glaucoma,post cap cataract,

band keratopathy), back pain (enthesitis related arthritis).
No hx of
 preceding URTI,dyspnea, palpitation,abnormal movements. (RF)

 rashes, abdominal pain,chest pain,jaundice,petechae/bruises.(SOJIA, SLE,JDM).
 Photosensetivity, oral ulcers,headache, seizures. (SLE, JDM),
 urinary complaints (reactive arthritis).
 skin/ nail changes (psoriatic arthritis).
 l/motion, bleed P/R. (IBD).
 contact/ tick exposure.
PAST HISTORY:...........................................................................................................
378
……………………………………………………………………………………………………………………………………………………………
……………………………………………………………………………………………………………………………………………………………
……………………………………………………………………………………………………………………………………………………………
……

FAMILY HISTORY: parents are related, and he have …. Brothers and…. Sisters all are healthy . no hx
of arthritis/ psoriasis/IBD in family
VACCINATION HX: He is vaccinated according to EPI schedule and had no further vaccination
SOCIAL HISTORY: he was student of class …. Then he left to study because of illness and limitations
of ADLs are in form of painful eating/ painful mastication/ dressing/ writing/ walking/ limitation of
sports activity/ social activtiy/ depression. His father is ……by occupation and earns sufficient to
manage home, live in their own house/rent.
ON /EXAMINATION :
My patient …..year of age sitting on chair comfortably, co operative during

my examaninatio his vitalls are H.R=…… RR……Temp……and B.P…………his/her anthropometric
measurements are height……… cm, weight………. Kg , which are below 50 th centile for his age.
On GPE he is pale, but no evidence of jaundice, petechae, bruise, edema, oral ulcer,
lymphadenopathy. Oral hygiene is normal,
On systemic musculoskeletal examination: ………………………………………………………………….
DISCUSSION :
JUVENILE IDIOPATHIC ARTHRITIS (JIA)
 American College of Rheumatology (ACR)use term (JRA) and categorizes disease into 3
onset types.
 International League of Associations for Rheumatology (ILAR) using the term juvenile
idiopathic arthritis (JIA) which is inclusive of all subtypes of chronic juvenile arthritis.
 We refer to the ILAR classification criteria; enthesitis-related arthritis and psoriatic JIA
CRITERIA FOR THE CLASSIFICATION OF JUVENILE RHEUMATOID ARTHRITIS

379
Age at onset: <16 yr
Arthritis (swelling or effusion, or the presence of 2 or more of the following signs: limitation of

range of motion, tenderness or pain on motion, increased heat) in ≥1 joints
Duration of disease: ≥6 wk
Onset type defined by type of articular involvement in the 1st 6 mo after onset:
Polyarthritis: ≥5 inflamed joints
Oligoarthritis: ≤4 inflamed joints
Systemic disease: arthritis with rash and a characteristic quotidian fever
Exclusion of other forms of juvenile arthritis
CHARACTERISTICS OF THE AMERICAN COLLEGE OF RHEUMATOLOGY (ACR) AND INTERNATIONAL

LEAGUE OF ASSOCIATIONS FOR RHEUMATOLOGY (ILAR) CLASSIFICATIONS OF CHILDHOOD
CHRONIC ARTHRITIS
PARAMETER ACR (1977) ILAR (1997)
Juvenile rheumatoid
Term Juvenile idiopathic arthritis (JIA)
arthritis (JRA)
Minimum duration ≥6 wk ≥6 wk
Age at onset <16 yr <16 yr
• Oligoarthritis:
A Persistent: <4 joints for

≤4 joints in 1st 6 mo after presentation • Pauciarticular course of disease
B Extended: >4 joints after 6

mo
• Polyarticular rheumatoid
factor–negative
>4 joints in 1st 6 mo after presentation • Polyarticular
• Polyarticular rheumatoid
380
factor–positive
Fever, rash, arthritis • Systemic • Systemic

PARAMETER ACR (1977) ILAR (1997)
• Psoriatic arthritis
• Enthesitis-related arthritis
Exclusion of other • Undifferentiated:

Other categories included
forms
A Fits no other category
B Fits more than one

category
Inclusion of psoriatic arthritis,

inflammatory bowel disease, ankylosing No Yes
spondylitis
INTERNATIONAL LEAGUE OF ASSOCIATIONS FOR RHEUMATOLOGY CLASSIFICATION OF JUVENILE

IDIOPATHIC ARTHRITIS (JIA)
CATEGORY DEFINITION EXCLUSIONS
Arthritis in ≥1 joints with, or

a Psoriasis or a history of psoriasis in
preceded by, fever of at least 2 wk
the patient or a 1st-degree relative.
in duration that is documented to
be daily (“quotidian”*) for at least 3 b Arthritis in an HLA-B27–positive boy
days and accompanied by ≥1 of the beginning after the 6th birthday.
following:
c Ankylosing spondylitis, enthesitis-
1 Evanescent (nonfixed) related arthritis, sacroiliitis with
Systemic-onset
erythematous rash. inflammatory bowel disease, Reiter
JIA
syndrome, or acute anterior uveitis,
2 Generalized lymph node
or a history of one of these disorders
enlargement.
in a 1st-degree relative.
3 Hepatomegaly or splenomegaly
d Presence of immunoglobulin M RF on
or both.
at least 2 occasions at least 3 mo
4 Serositis.[†] apart.
Arthritis affecting 1-4 joints during a, b, c, d (above) 381

Oligoarticular JIA the 1st 6 mo of disease. Two
subcategories are recognized: plus

1 Persistent oligoarthritis— e. Presence of systemic JIA in the

affecting ≤4 joints throughout patient.
the disease course.
2 Extended oligoarthritis—
affecting >4 joints after the 1st 6
mo of disease.
Arthritis affecting ≥5 joints during the

Polyarthritis (RF-
1st 6 mo of disease; a test for RF is a, b, c, d, e
negative)
negative.
Arthritis affecting ≥5 joints during the

Polyarthritis (RF- 1st 6 mo of disease; ≥2 tests for RF at
a, b, c ,e
positive) least 3 mo apart during the 1st 6 mo of
disease are positive.
Arthritis and psoriasis, or arthritis and

b, c, d, e
at least 2 of the following:
1. Dactylitis.[‡]
Psoriatic arthritis
2. Nail pitting[?] and onycholysis.
3. Psoriasis in a 1st-degree relative.
Arthritis and enthesitis,[|] or arthritis or

Enthesitis-related
enthesitis with at least 2 of the a, d, e
arthritis
following:
1 Presence of or a history of sacroiliac

joint tenderness or inflammatory
lumbosacral pain or both.[?]
2 Presence of HLA-B27 antigen.
3 Onset of arthritis in a male > 6 yr

old.
4 Acute (symptomatic) anterior 382

uveitis.
5 History of ankylosing spondylitis,

enthesitis-related arthritis,
sacroiliitis with inflammatory bowel
disease, Reiter syndrome, or acute
anterior uveitis in a 1st-degree
relative.
Arthritis that fulfills criteria in no

Undifferentiated
category or in ≥2 of the above
arthritis
categories.
* 0 0
Quotidian fever is defined as a fever that rises to 39 C once a day and returns to 37 C between fever peaks.
†
Serositis refers to pericarditis, pleuritis, or peritonitis, or some combination of the three.
‡
Dactylitis is swelling of ≥1 digits, usually in an asymmetric distribution, that extends beyond the joint margin.
?
A minimum of 2 pits on any one or more nails at any time.
|
Enthesitis is defined as tenderness at the insertion of a tendon, ligament, joint capsule, or fascia to bone.
?
Inflammatory lumbosacral pain refers to lumbosacral pain at rest with morning stiffness that improves on movement.
THE MAIN FEATURES OF THE SUBTYPES OF JUVENILE IDIOPATHIC ARTHRITIS
PEAK
% OF ALL
AGE OF F: M EXTRA-ARTICULAR LABORATORY
ILAR SUBTYPE JIA ARTHRITIS PATTERN NOTES ON THERAPY
ONSET RATIO FEATURES INVESTIGATIONS
CASES
(YR)
Less responsive to standard

Anemia; WBC ↑↑; ESR ↑↑;
Polyarticular, often affecting Daily fever; treatment with MTX and anti-TNF
SYSTEMIC CRP ↑↑; ferritin ↑;
2-4 1 : 1 <10 knees, wrists, and ankles; also evanescent rash; agents; consider interleukin-1
ARTHRITIS platelets ↑↑ (normal or ↓
fingers, neck, and hips pericarditis; pleuritis receptor antagonist in resistant
in MAS)
cases
ANA POSITIVE IN ≈60%;

Uveitis in ≈30% of other test results usually NSAIDS and intra-articular steroids;
OLIGOARTHRITIS <6 4 : 1 50-60 Knees ++; ankles, fingers +
cases normal; may have mildly ↑ MTX occasionally required
ESR/CRP
POLYARTHRITIS:
383
ANA positive in 40%; RF Standard therapy with MTX and
Symmetric or asymmetric;
RF-negative 6-7 3 : 1 30 Uveitis in ≈10% negative; ESR ↑ or ↑↑; CRP NSAIDs; then, if nonresponsive, anti-
SMALL AND LARGE JOINTS;
↑/normal; mild anemia TNF agents or other biologics
CERVICAL SPINE;

PEAK
% OF ALL
AGE OF F: M EXTRA-ARTICULAR LABORATORY
ILAR SUBTYPE JIA ARTHRITIS PATTERN NOTES ON THERAPY
ONSET RATIO FEATURES INVESTIGATIONS
CASES
(YR)
TEMPOROMANDIBULAR JOINT
Rheumatoid nodules
Aggressive symmetric RF positive; ESR ↑↑; CRP Long-term remission unlikely; early
RF-positive 9-12 9 : 1 <10 in 10%; low-grade
polyarthritis ↑/normal; mild anemia aggressive therapy is warranted
fever
NSAIDs and intra-articular steroids;

Asymmetric arthritis of small Uveitis in 10%; ANA positive in 50%; ESR ↑; second-line agents
Psoriatic arthritis 7-10 2 : 1 <10
or medium-sized joints psoriasis in 50% CRP ↑/normal; mild anemia
used less commonly
NSAIDs and intra-articular

Acute anterior
Predominantly lower limb
uveitis; association steroids; consider
Enthesitis- joints affected; sometimes 80% of patients positive for
9-12 1 : 7 10 with reactive arthritis
related arthritis axial skeleton (but less than in HLA-B27
and inflammatory sulfasalazine as alternative
adult, ankylosing spondylitis)
bowel disease
to MTX
EPIDEMIOLOGY
The worldwide incidence 0.8 to 22.6/100,000 children per year
 Pauciarticular JIA (oligoarthritis) is the most common subtype (50-60%), followed by

polyarticular (30-35%) and systemic-onset (10-20%).
 There is no sex predominance in systemic-onset JIA (SoJIA), but more girls than boys are
affected in both pauciarticular (3 : 1) and polyarticular (5 : 1) JIA.
 The peak age at onset is between 2 and 4 yr for pauciarticular disease.
 Age of onset has a bimodal distribution in polyarthritis, with peaks at 2-4 yr and 10-14 yr.
 SoJIA occurs throughout childhood without a peak.
ETIOLOGY
 The etiology and pathogenesis of JIA is not completely understood.

 2 components: immunogenetic susceptibility and an external trigger. JIA is a complex
genetic trait in which multiple genes may affect disease susceptibility.
 Nongenetic triggers include bacterial and viral infections:
 parvovirus B19.
 Rubella .
 EBV.
 Abnormal reproductive hormone levels. 384
 Joint trauma.
PATHOGENESIS

 JIA is an autoimmune disease associated with alterations in both humoral and cell-mediated
immunity.
 T lymphocytes have a central role release proinflammatory cytokines (e.g., TNF-α, IL-6,
and IL-1)recruit of TH cells .
 Inheritance of specific cytokine alleles may predispose to upregulation of inflammatory
networks resulting in systemic-onset disease or more severe articular disease.
 Systemic-onset JIA may be more accurately classified as an autoinflammatory disorder,. All
these immunologic abnormalities cause inflammatory synovitis, characterized
pathologically by villous hypertrophy and hyperplasia with hyperemia and edema of the
synovial tissue.
 Vascular endothelial hyperplasia is prominent
 Advanced and uncontrolled disease leads to pannus formation and progressive erosion of
articular cartilage and contiguous bone
 Arthritis must be present for a diagnosis of any subtype of JIA to be made.

 Arthritis is defined by intra-articular swelling or the presence of 2 or more of the following
signs:
 limitation in range of motion.
 tenderness or pain on motion.
 Increased heat or erythema.
 Easy fatigability and poor sleep quality may be associated. Involved joints are often swollen,
warm to touch, and painful on movement or palpation with reduced range of motion but
usually are not erythematous
 Arthritis in large joints, especially knees, initially accelerates linear growthaffected limb
longer discrepancy in limb lengths. Continued inflammation stimulates rapid and
premature closure of the growth plate, resulting in shortened bones.(very important)
OLIGOARTHRITIS –HLA DR-8+/ ANA+ 50%.
Most common / 45% of all JIA.
F>>, 1-5 yr (3 yr peak).
35% -chronic uveitis—usually asymptomatic B/L usually can occur unilateralmay lead to
blindness due to band keratopathy, glaucoma, cataract –(synachae form later on which we see thru
torch in short/long case).
Defined as involving ≤4 joints within the first 6 mo of disease onset.
Predominantly large joints of the lower extremities, such as the knees.ankle+ subtalar other are
wrist and elbow. 
385
Arthritis is rarely erosive.
Often only a single joint is involved.

Isolated involvement of upper extremity large joints is less common.
Persistent oligoarticular JIA: those in which disease do not involve more than 4 joints ever / over 6
month.
Extended oligoarticular JIA. disease in more than 4 joints involved over time changes.
It has worse prognosis.  best response to MTX, can be severe and go to adult life (Q).
Involvement of the hip is almost never a presenting sign and suggests a spondyloarthropathy or
nonrheumatologic cause.
REMEMBER ITS EXCLUSION –
1. If psoriasis in pt / family hx of psoriasis.

2. Spondyloarthropathy
3. RF+
The presence of a positive antinuclear antibody (ANA) test result confers increased risk for
asymptomatic anterior uveitis-(usually bilateral )-asymptomatic is more dangerous. requiring
periodic slit-lamp examination
Oligoarticular pt with ANA+ve disease duration ≤4 year and onset of illness @<6 year he is high
risk pt for uveitis & he need 3 mothly slit lamp examination—(same is true for polyarticular).
Same pt if with disease duration >4 yr then-moderate risk 6 monthly checkup.
Same pt with duration >7 yr –low risk  12 monthly checkup.
TREATMENT:
PROGNOSIS GOOD –remission in 5 years with Rx.
POLYARTHRITIS (POLYARTICULAR DISEASE) RF-VE:HLA DR-4+
ANA+ve 25%, 25% of JIA.Uveitis 10%
Characterized by inflammation of ≥5 joints in both upper and lower.
Can involve small/large joints.
Usually asymmetrical. 386
Joint destruction in 10-15%.

When RF+, polyarticular disease resembles the characteristic same presentation like adult
rheumatoid arthritis Rx like adult RA.
POLYARTHRITIS (POLYARTICULAR DISEASE) RF+VE (RF+ on 2 occasions 3 month apart): --no HLA
association- resemble adult RA.
F>>, 5-10% of JIA, late childhood-teens  poor functional outcome >50%.
Symmetrical  progressive course  destroy joints (deformities more).
Metacarpophalangeal joint most commonly involved
Rheumatoid/SC nodules +  EARLY EROSIVE CHANGES.
extensor surfaces of the elbows and over the Achilles tendons.
although unusual if + are associated with a more severe course.
almost exclusively occur in RF-positive individuals.
Micrognathia reflects chronic temporomandibular joint (TMJ) disease.
Cervical spine involvement (C2-3) manifesting as decreased neck extension, occurs with a risk of
atlantoaxial subluxation and neurologic sequelae.
Hip disease may be subtle, with findings of decreased or painful range of motion on exam
TREATMENT: NSAIDs /MTX –oral, s/c,i.m.
SYSTEMIC-ONSET DISEASE (SoJIA)10% of JIA, (ANA &RF –VE) –uveitis –rare.
is characterized by arthritis, fever and prominent visceral involvement, including

hepatosplenomegaly, lymphadenopathy, and serositis (pericarditis).
Characteristic fever, defined as spiking temperatures to ≥39OC, occurs on a daily or twice-daily basis
for at least 2 wk, with a rapid return to normal or subnormal temperatures.
The fever is often present in the evening and is frequently accompanied by a characteristic faint,
erythematous, macular rash.
RASH :
387
DESCRIPTION OF RASHTransient Erythematous (salmon colored linear/circular non-prurititic
macular rash migratory lasting <1 hour Seen in crops over the trunk and proximal extremities
aggravated by superficial trauma / heat.

Koebner phenomenon, a cutaneous hypersensitivity to superficial trauma, is often present. Heat,
such as from a warm bath, also evokes rash.
Fever, rash, hepatosplenomegaly, and lymphadenopathy are present in >70% of affected children.
Some children initially present with only systemic features, but definitive diagnosis requires
presence of arthritis.
Arthritis may affect any number of joints, but the course is classically polyarticular, may be very
destructive, and includes hip, cervical spine, and TMJ involvement.
Polyarticualr arthritis can be a late feature.
Myocarditis – can be but occasionally.
NATURAL EVOLUTION  systemic featurespolyarthritissystemic features regress 

polyarthritis remain+.
PROGNOSIS:
 50% remit in 2-3 years.

 joint destruction-20% .
 death occur due to infection, immunosupression, myocardial involvement and MAS.
 uveitis is rare.
MACROPHAGE ACTIVATION SYNDROME (MAS):
 rare but potentially fatal complication of SoJIA that can occur at anytime during the disease
course.
 It is also referred to as secondary hemophagocytic syndrome or hemophagocytic
lymphohistiocytosis (HLH)
 MAS classically manifests as acute onset of profound anemia associated with
thrombocytopenia or leukopenia with high, spiking fevers, lymphadenopathy, and
hepatosplenomegaly.
 Patients may have purpura and mucosal bleeding, as well as elevated fibrin split product
values and prolonged prothrombin and partial prothromboplastin times.
 The erythrocyte sedimentation rate (ESR) falls because of hypofibrinogenemia and hepatic
dysfunction, a feature useful in distinguishing MAS from a flare of systemic disease.
 The diagnosis is suggested by clinical criteria and is confirmed by bone marrow biopsy
demonstrating hemophagocytosis .
 EMERGENCY TREATMENT with high-dose intravenous methylprednisolone,
cyclosporine, or anakinra may be effective. Severe cases may require therapy similar to that
for primary HLH (Chapter 501).
PRELIMINARY DIAGNOSTIC GUIDELINES FOR MACROPHAGE ACTIVATION SYSTEM (MAS)

COMPLICATING SYSTEMIC JUVENILE IDIOPATHIC ARTHRITIS (JIA) 388
LABORATORY CRITERIA

9
1 Decreased platelet count (≤262 ? 10 /L).
2 Elevations of aspartate aminotransferase (>59 U/L).
9
3 Decreased white blood cell count (≤4.0 ? 10 /L).
4 Hypofibrinogenemia (≤2.5 g/L).
CLINICAL CRITERIA
1 Central nervous system dysfunction (irritability, disorientation, lethargy, headache, seizures, coma).
2 Hemorrhages (purpura, easy bruising, mucosal bleeding).
3 Hepatomegaly (edge of liver ≥3 cm below the costal arch).
HISTOPATHOLOGIC CRITERION
• Evidence of macrophage hemophagocytosis in the bone marrow aspirate
DIAGNOSTIC RULE
• The diagnosis of MAS requires the presence of any 2 or more laboratory criteria or of any 2 or 3 or more
clinical and/or laboratory criteria. A bone marrow aspirate for the demonstration of hemophagocytosis may
be required only in doubtful cases.
RECOMMENDATIONS
• The aforementioned criteria are of value only in patients with active systemic JIA. The thresholds of
laboratory criteria are provided by way of example only.
COMMENTS
1 The clinical criteria are probably more useful as classification criteria than as diagnostic criteria because they often
occur late in the course of MAS and may be, therefore, of limited value for the early suspicion of the syndrome.
2 Other abnormal clinical features in systemic JIA–associated MAS not previously mentioned are: nonremitting high
fever, splenomegaly, generalized lymphadenopathy, and paradoxic improvement of signs and symptoms of
arthritis.
3 Other abnormal laboratory findings in systemic JIA–associated MAS not previously mentioned are: anemia,
erythrocyte sedimentation rate fall, elevated alanine aminotransferase, increased bilirubin, presence of fibrin
degradation products, elevated lactate dehydrogenase, hypertriglyceridemia, low sodium levels, decreased
albumin, and hyperferritinemia.
389
ENTHESITIS RELATED ARTHRITIS:
 ILAR –use this term for most of spondylopathies

 diseases collectively referred to as spondyloarthritides include ankylosing spondylitis (AS),
arthritis associated with inflammatory bowel disease (IBD) and psoriasis, and reactive
arthritis
 ERA constitutes about 10% of JIA.
 Unlike other forms of JIA, spondyloarthritis is most common in older boys. These disorders
are often familial, owing in large part to the influence of HLA-B27.
 Enthesitis, a key feature of the spondyloarthritides, is marked by inflammation where
tendons, ligaments, and joint capsules attach to bone. Enthesitis lesions also exhibit chronic
inflammation, resulting in calcification of ligaments and fusion of joints in advanced disease
such as AS.
 Axial and peripheral joint inflammation and enthesitis cause pain and swelling, localized
tenderness, stiffness, and loss of range of motion. Common extra-articular manifestations
include gastrointestinal inflammation even in the absence of overt IBD and ocular
inflammation, which causes pain, erythema, and photophobia
DEF : Enthesitis-Related Arthritis
Children are classified as having ERA if they have either arthritis and enthesitis or arthritis or
enthesitis, with two of the following additional characteristics:
(1) sacroiliac joint tenderness or inflammatory lumbosacral pain.
(2) the presence of HLA-B27.
(3) age > 6 yr and male sex.
(4) acute anterior uveitis.
(5) a family history of an HLA-B27–associated disease (ERA, sacroiliitis with IBD, reactive arthritis, or
acute anterior uveitis) in a first-degree relative.
Patients excluded from this group:
1)with psoriasis (or a family history of psoriasis in a first-degree relative).
2) ANA +.
3)  RF +.
Many children with ERA go on to eventually have AnkyloSpond, but many do not.
It is not currently possible to determine whose ERA will progress.
Diagnosis above criteria / HLA B27 +. 390
TREATMENT sulphasalazine + NSAIDs (endomethacin) next choice to conside is MTX.

 EXTRA-ARTICULAR MANIFESTATIONS  ACUTE ANTERIOR UVEITIS , AORTITIS, FEVER ,
MUSCLE WEAKNESS.
JUVENILE ANKYLOSING SPONDYLITIS
Defending For JIA—DESCRIPTION  less likely /unlikely he is case of JAS Because it appear usually
in adolescents / young adults , have positive family history & JAS is usually oligoarthritis in which
legs > involved than arms , they have early loss of spinal flexibility , sacroillaiac joint involvement
is a late feature in which pts have back pain , however it is more common in boys. I need HLA B27
which is helful coz ot comes +ve in >90% cases.
 JAS frequently begins with oligoarthritis and enthesitis.

 The arthritis occurs predominantly in the lower extremities and often involves the hips, in
contrast to oligoarticular JIA.
 Also unlike in adult-onset AS, in JAS axial involvement is usually absent until later in the
disease course.
 Enthesitis is particularly common, manifesting as localized and often severe tenderness at
characteristic tendon (as well as ligament, fascia or capsule) insertions around the plantar
surface of the foot, ankle (Achilles), and knee (patella).
EXTRA-ARTICULAR COMPLICATION  Acute iridocyclitis/anterior uveitis 25%. A.R-uncommon
PROGNOSIS
 JASLONG ACTIVITY  LONG DIS. INACTIVITY.

 MOST PATIENT  LONG DISEASE  DISABILITY.
 EARLY HIP INVOLVEMENT  POOR OUTCOME.
 HLA-B27 +  CHRONIC DISEASE
PSORIATIC ARTHRITIS
 girls = boys.
 arthritis can precede psoriasis.
 ½ of pts have rash before arthritis and ½ have after arthritis.
 The most common presentation is asymmetric arthritis involving < 5 joints.
 Both large (knee, ankle) and small (finger, toe) joints can be involved—(Saudage digits),
including distal interphalangeal joints.
 In a child with oligoarthritis or even polyarthritis, the presence of nail pitting , dactylitis,
onycholysis, and/or a family history of psoriasis supports the diagnosis of psoriatic
arthritis.
 The presence of HLA-B27 is not a risk factor for psoriasis, and most patients with psoriatic
arthritis do not have axial involvement. 391
 Uveitis – 10%
 ANA + > common
 HLA B27 < common.
 Arththritis can be erosive.

 However, when HLA-B27 is present, axial arthritis is more common.
IBD-ARTHRITIS.
( Unlikely he is case of arthritis secondary to IBD because these pt have oligoarthritis with
involvement of lower limb joints mainly, they have unexplained anemia as well)
Arthritis can present before IBD manifestation—prof. Tahir masood
In a child with chronic arthritis, the presence of erythema nodosum, pyoderma gangrenosum,
fever, weight loss, or anorexia suggests IBD
Two patterns of arthritis complicate IBD
(1): Polyarthritis affecting large and small joints is most common  reflects the activity of the
intestinal inflammation. / NO spine involvement / HLA B27 –ve.
(2): Arthritis of the axial skeleton including the sacroiliac joints occurs Less frequently, resulting
in AS.—HLA B27 +
 As with psoriatic arthritis, the presence of HLA-B27 is a risk factor for the development of
axial disease.
 The severity of axial involvement is independent of the activity of the gastrointestinal
inflammation.
PROGNOSIS
USUALLY GOOD CONTROLL GIT SYMPTOMS  JOINT CONTROLLED.
LABORATORY FINDINGS:
List of investigations:
 CBC
 ESR may / may not be elevated
 CRPmay/ may not be elevated
 ANA---ve in all if positive I will think possibility of psoriatic arthritis who have 50% +ve.
 RF  -ve
 HLA B27 +ve in >90% in JAS while less frequent in other spondyloarthritis..
 X-RAY SPINE/ HIP JOINTS + PERIPHERAL JOINTS.
 MRI –detect early changes.
Early radiographic changes in the sacroiliac joints include: 392
 Irregular margins and erosions with sclerosis+ Widening of joint space typically starting on
the iliac side of the joint.

Peripheral joints may exhibit:
 periarticular osteoporosis + loss of sharp cortical margins in areas of enthesitis, which may
eventually show erosions or bony spurs.
Squaring of the corners of the vertebral bodies and the classic “bamboo spine and calcification of
ligaments characteristic of advanced AS, develop later.
These findings are rare in early disease, particularly in childhood.
DIAGNOSIS OF SPONDYLOARTHROPATHY
 Older child, boy, oligoarthritis

 JOINTS – Hip , knee, ankle , feet (intertarsal) + enthesitis.
 Loss of normal LUMBER lordosis
 Inability too touch toes.
 Pain on palpating / compressing pelvis.
 RADIOGRAPHICsacroillitis (late presentation).
D/D OF BACK PAIN
 JAS
 SUPPURATIVE ARTHRITIS OF SI JOINT
 OSTEOMYELTIS OF PELVIS/SPINE.
 LEUKEMIA
 EWING SARCOMA.
SYMPTOMS CHARACTERISTIC OF INFLAMMATORY BACK PAIN
Pain at night with morning stiffness
No improvement with rest
Improvement with exercise
Insidious onset
Legg-Calve-Perthes disease (avascular necrosis of the femoral head), slipped capital femoral
epiphysis, and chondrolysis may also manifest as pain over the inguinal ligament and loss of internal
rotation of the hip joint, but without other features of spondyloarthritis, such as involvement of
other entheses and/or joints. Radiography or MRI is critical for distinguishing these conditions.
393
TREATMENT

The aims of therapy for JAS:
 control inflammation.
 minimize pain.
 preserve function, and prevent ankylosis (fusion of adjacent bone.
Rx STEPS:
 NSAIDs.
 I/A steroids.
 MTX
 SULPHALSAZINE FOR JAS
 BIOLOGICAL AGENTS FOR UNRESPONSIVE
 INSOLE SUPPORTIVE
 EXERCISE
 PHYSIOTHERAPY
 MONITORING
NSAIDs—( naproxen (15-20 mg/kg/day), physical therapy, and education.
 mild dsNSAIDs can be helpful when used along with intra-articular corticosteroids (e.g.,
triamcinolone hexacetonide) to control peripheral joint inflammation.
 JASit is typically necessary to add a second-line agent. Sulfasalazine (up to 50 mg/kg/day;
maximum 3 gm/day) or methotrexate (10 mg/m2) may be beneficial for peripheral arthritis
 For adults biologics that inhibit tumor necrosis factor-α (TNF-α) (etanercept, infliximab,
adalimumab) have been efficacious in reducing symptoms and improving function in adults
with AS, and there is evidence that similar responses are seen in children.
 TNF inhibitors have not been shown to halt bony progression in established AS
 Physical therapy and low-impact exercise should be included in the treatment program for
all children with spondyloarthritis.
 Exercise to maintain range of motion in the back, thorax, and affected joints should be
instituted early in the disease course.
 Custom-fitted insoles are particularly useful in management of painful entheses around the
feet.
 use of pillows to position the lower extremities while the child is in bed can be helpful.
MONOARTICULAR ARTHRITIS
 TB  Other favoring points , contact –only dx by synovial biopsy (go to T.B notes for detail).
 TRAUMA
 INFECTION –septic arthritis ( UTI/RTI/GIT infection hx +, acute hx , resolve )
SLE ARHTRITIS
 Jaccouds type – it is periarticular not synovial –remember

 Non-erosive Non deforming .
394
 Can involve both small / large joints.
LYME DISEASE:

Typically previous hx of visit to endemic area where bite by a flea containing spirochete which is
borellia burgdorferi  it leads to early local disease with 14 days which fever, arthritis and myalgia
 then early disseminated disease whitin 1-3 month then after 2 month late stage which mainly
involve joint typically ologoarticular and usually 90% knee is involved along the erythema migrans
(redish large area with central clearing) – dx serology / joint aspirate contain thousand to lac PMN
cells.
REACTIVE ARTHRITIS:
Preceding hx of illness (2-3 weeks before) related to:

 Entric-GIT –salmonella, shigella, c.j, yersenia, giardiasis.
 Genitourinary—chlamydae, E.Coli.
 Other sterile arthritis—ARF, IE.
 May lead to:
 Monoarthritis
 Polyarthritis.
 Enthesitis –sometimes
 Transient usually <6 weeks
 One thing - clamydial/ bacterial  may have potential to become chronic arthritis/
spondyloarthropathy.
VIRUS RELATED ARTHRITIS
 parvovirus
 Rubella - small joints if disease by natural infection then with 7 days it leads while if after
immunixation then it take 10-28 days . // uncommon in children .
 Mumps/varicella  large joints.
 Hep.b viruS
-----------------------------*-----------------------------
ENLIST INVESTIGATIONS FOR JIA .
 R.F –IgM   --poor prognosis –increase chance of systemic features.

 ANA + 50%  inc risk of chronic uveitis
 CBC  NNC anemia, TLC  platelates ----------------( if dec in SOJIA pt think for MAS).
 ESR  ---------------------(if low then favour MAS).
 CRP
 HLA Typing – B27-For ERA-----DR-4 for poly RF-,-----------DR-8 for oligo.
 MRI –joints—detect early changes so that we can treat before clinical apparent.
 X-RAY JOINTS
 Early radiographic changes of arthritis include:
 soft tissue swelling. 395
 Joint space narrowing
 periarticular osteoporosis.
 periosteal new-bone apposition around affected joints.
 Late changes:

 Joint erosions.
 LLdiscrepancy.
 USG Joint for effusion & synovitis.
 Slit lamp examination –iridocyclitis
 Joint aspiration –minimal role
Other workup for MAS
 S.Ferittin level >1000 ng/ML

 ESRdue to hypofibrinogenemia & dec hepatic function.
 LFT
 CBC
 BMA—doubtful cases.
TREATMENT
GOALS;
 Provide analgesia.
 Control inflammation.
 Maintain joint fuction.
 Prevent deformities.
 Treat complications & extra-articular manifestations.
 Ensure optimal nutrition.’
 Rehabilitation.
 Optimal pscycosocial support
 Educate pt & parents.
 Ensure compliance and follow up
 Monitor disease activity.
1. Analgesia
 paracetamol.
 Ice packs for active inflamed joints
 Hot packs for stiff joints
 Morning stiffness –warm baths/hot packs.
 Rest NSAIDs-naproxen , pyroxicam, endomethacin.
2. Control inflammation:
 #1 NSAIDs –naproxen , diclofenac sodium, ibuprofen, indomethacin, piroxicam,
aspirin.
Advantages—dec pain, & stiffness ,  ROM , Anti-inflammatory effect –longer time
Effect –analgesia seen early effect / anti-inflammatory effect occur after 1-3 months.
Newer –COX-2 if gastritis is problem.
 #2. Local steroids – triamcenolone acetate –I/A.
Indication- NSAIDs not responding, contractures , or single joint involvement.
At a time 2 injections can be given – kanacort is trade name .
 #3. DMARDs –MTX, leflunomide, sulfasalazine, etanercept .
396
MTX – 10-20 mg/m2 once/week oral, s/c, I.M. + Folate except on fixed day on which MTX
has to be given. S.E – oral ulcer, hepatotoxicity, B.M suppression.
Effect : take 2-3 month to show effect so steroids given in btw as briging therapy.

PHARMACOLOGIC TREATMENT OF JUVENILE IDIOPATHIC ARTHRITIS (JIA)
TYPICAL
TYPICAL DOSES JIA SUBTYPE SIDE EFFECT(S)
MEDICATIONS
NONSTEROIDAL ANTI-INFLAMMATORY DRUGS
15 mg/kg/day PO Polyarticular
divided bid Gastritis, renal toxicity, liver toxicity,
Naproxen Systemic onset
(maximum dose 500 mg pseudoporphyria
bid) Oligoarticular
40 mg/kg/day PO
Ibuprofen divided tid Same as above Same as above
(maximum dose 800 tid)
0.125 mg/kg PO once

daily
Meloxicam Same as above Same as above
(maximum dose 15 mg
daily)
DISEASE-MODIFYING ANTIRHEUMATIC DRUGS
Polyarticular
0.5-1 mg/kg PO or SC
Systemic onset Nausea, vomiting, oral ulcerations,
weekly
Methotrexate hepatitis, blood count dyscrasias,
(maximum dose 25 Extended or immunosuppression, teratogenicity
mg/week) refractory
oligoarticular
Initial 12.5 mg/kg PO

daily; increase by 10
mg/kg/day
GI upset, allergic reaction,
Sulfasalazine Polyarticular pancytopenia, renal and hepatic
Maintenance: 40-50
toxicity
mg/kg divided bid
(maximum dose 2
g/day)
GI upset, hepatic toxicity, allergic

397
rash, alopecia (reversible),
Leflunomide* 10-20 mg PO daily Polyarticular
teratogenicity (needs washout with
cholestyramine)

TYPICAL
TYPICAL DOSES JIA SUBTYPE SIDE EFFECT(S)
MEDICATIONS
BIOLOGIC AGENTS
Anti–Tumor Necrosis Factor-α
Polyarticular
0.8 mg/kg SC weekly or
0.4 mg/kg SC twice Systemic onset
Immunosuppressant, concern for
Etanercept weekly
Extended or malignancy
(maximum dose 50
mg/wk) refractory
oligoarticular
Infliximab* 3-10 mg/kg IV q 4-8 wk Same as above Same as above
<30 kg: 20 mg SC every

other week
Adalimumab Same as above Same as above
>30 kg: 40 mg SC every
other week
Anti-Cytotoxic T Lymphocyte–Associated Antigen-4 Immunoglobulin
<75 kg: 10 mg/kg/dose

IV q 4 wk
75-100 kg: 750 mg/dose Immunosuppressant; concern for
Abatacept Polyarticular
IV q 4 wk malignancy
>100 kg: 1,000 mg/dose
IV q 4 wk
Anti-CD20
750 mg/m2 IV 2 wk ? 2
Rituximab* (maximum dose 1000 Polyarticular Immunosuppressant
mg)
Interleukin-1 Receptor Antagonist
Anakinra* 1-2 mg/kg SC daily Systemic onset Immunosuppressant
398

SLE ---------------------------------------------------------------------------------------LONG CASE/SHORT CASE.
BIODATA.
P/C CAN BE:
 FEVER*
 RASH*
 ARTHRITIS*
 NEPHRITIS-URINARY COMPLAINTS*.
 MALAR RASH
 LYMPHADENOPATHY
 FATAGUE , MALAISE, WT LOSS**.
*=50% at presentation.
** very common presentation at first time and at flare of disease.
 Neuropsychiatric, GI, pulm, CVS,  uncommon in pediatric SLE.

 Skin , musculoskeletal , blood and renal –common organ affected in pediatric SLE.
Symptoms to ask:
Anorexia, wt loss, fatigue, fever, alopecia malar rash, photosensitivity, oral ulcer,joint pain/swelling,
chest pain, body swelling, palpitation, respiratory distress, headache , alterd beahvoiur, focal deficit,
fits, poor school performance, urinary complaint in form of hematurea, abdominal pain-
serositis/pancreatitis, polyurea,polydydypsia-diabetes, raynaud phenomenon, visual disturbance.
Drug side effects in known case-steroids-fascial swelling, hypertension, poor height, gastric pain,
muscle weakness, bony pains, fractures etc, difficulty in walking –AVN femoral and knee.
AODL
Past hx”:
When , where , presenting complaints that time, initial investigations, (sort out cause that time ask
drug hx like hydralazine, methyldopa, pencillamine, chlorpromazine), no. of hospital admissions,
reasons of admissions , complications during course of disease and how managed?
Management detail:
 Current
 Home trx
 Modification
 Compliance
 Side effects
Family history: 399

Vaccination HX
Nutritional hx’

Birth hx.
Development hx.
Disease impact
Parents concern
Parents knowdge about management , complications & prognosis.
Socioeconomic hx:
EXAMINATION:
DISCUSSION:
 Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by multisystem

inflammation and the presence of circulating autoantibodies directed against self-antigens.
 disproportionately affecting women of reproductive age.
 most commonly involved are the skin, joints, kidneys, blood-forming cells, blood vessels, and central
nervous system.
 Compared with adults, children and adolescents with SLE have more severe disease and more
widespread organ involvement.
ETIOLOGY:
The pathogenesis of SLE remains unknown, but several factors likely influence risk and severity of
disease, including genetics, hormonal milieu, and environmental exposures.
GENETIC PREDISPOSITION TO SLE:
 congenital deficiencies of C1q, C2, and C4.

 family history of SLE or other autoimmune disease.
 HLA-B8, HLA-DR2, and HLA-DR3 occur with increased frequency in SLE.
 Although SLE has a clear genetic component, its occurrence is sporadic in families and
concordance is incomplete.
HORMONAL FACTORS:
 Because SLE preferentially affects women, especially during their reproductive years.
 90% - with SLE are female making gender the strongest risk factor for SLE.
 Estrogens role - studies suggest that estrogen exposure promotes B-cell autoreactivity.
400
ENVIRONMENTAL EXPOSURES:
 Unknown mechanism.

 Viruses (EBV), UV, drugs.
EPIDEMIOLOGY
 Prevalence in children and adolescents (1-6/100,000) is lower than that in adults (20-70/100,000).
 Predominantly affects females, with reported 5 : 1 ratio prior to puberty, 9 : 1 ratio during reproductive
years, and near prepubertal ratios in the postmenopausal period.
 Childhood SLE is rare before 5 yr of age and is usually diagnosed in adolescence.
 Up to 20% of all individuals with SLE are diagnosed prior to age 16 yr.
PATHOLOGY
 Histologic features most suggestive of SLE include findings in the kidney and skin, especially the
discoid rash.
 The finding of diffuse proliferative glomerulonephritis (class IV) significantly increases risk for renal
morbidity.
 Renal biopsies are very helpful to establish the diagnosis of SLE and to stage disease. Immune
complexes are commonly found with “full house” deposition of immunoglobulin and complement.
 The characteristic discoid rash is characterized on biopsy by hyperkeratosis, follicular plugging, and
infiltration of mononuclear cells into the dermal-epidermal junction.
 The histopathology of photosensitive rashes can be nonspecific, but immunofluorescence
examination of both affected and nonaffected skin may reveal deposition of immune complexes
within the dermal-epidermal junction. This finding is called the lupus band test, which is specific
for SLE.
PATHOGENESIS .
 A hallmark of SLE is the generation of autoantibodies directed against self-antigens, particularly

nucleic acids.
 During cell necrosis or apoptosis, the antigens are released.
 SLE skin cells are highly susceptible to damage from ultraviolet light, and the resulting cell demise
results in release of cell contents, including nucleic antigens.
 Individuals with SLE may have markedly increased levels of apoptosis or significantly impaired ability
to clear cell debris, causing prolonged exposure to these nucleic antigens in the bloodstream and ample
opportunity for their recognition by immune cells, leading to production of autoantibodies by B cells.
 Circulating autoantibodies may form immune complexes and deposit in tissues, leading to local
complement activation, initiation of a proinflammatory cascade, and, ultimately, tissue damage.
 Antibodies to double-stranded DNA can form immune complexes, deposit in glomeruli, and initiate
inflammation leading to glomerulonephritis.
 IFN-α production by dendritic cells can be stimulated in vivo by immune complexes. Excess levels of
interferon can promote expression of other proinflammatory cytokines and chemokines, maturation of
monocytes into dendritic dells, promotion of autoreactive B and T cells, and loss of self-tolerance.
Many, but not all, patients with SLE exhibit this interferon signature.
 Both B and T cells demonstrate functional impairments in SLE.
 In active SLE, B-cell populations have impaired tolerance and increased autoreactivity, enhancing B
cells’ ability to produce autoantibodies following exposure to self-antigen.
CLINICAL MANIFESTATIONS 401
 Any organ system can be involved.

 The presentation of SLE in childhood or adolescence differs from that in adults.

 The most common presenting complaints of children with SLE include fever, fatigue, hematologic
abnormalities, arthralgia, and arthritis.
 Renal disease in SLE is often asymptomatic; thus careful monitoring of blood pressure and urinalyses
is critical.
POTENTIAL CLINICAL MANIFESTATIONS OF SYSTEMIC LUPUS ERYTHEMATOSUS

TARGET ORGAN POTENTIAL CLINICAL MANIFESTATIONS
Constitutional Fatigue, anorexia, weight loss, fever, lymphadenopathy
Arthritis, myositis, tendonitis, arthralgias, myalgias, avascular necrosis,
Musculoskeletal
osteoporosis
Malar rash, discoid rash, photosensitive rash, cutaneous vasculitis, livedo
Skin reticularis, periungual capillary abnormalities, Raynaud's phenomenon, alopecia,
oral and nasal ulcers
Renal Hypertension, proteinuria, hematuria, edema, nephrotic syndrome, renal failure
Pericarditis, myocarditis, conduction system abnormalities, Libman-Sacks
Cardiovascular
endocarditis
Seizures, psychosis, cerebritis, stroke, transverse myelitis, depression, cognitive
Neurologic impairment, headaches, pseudotumor, peripheral neuropathy, chorea, optic
neuritis, cranial nerve palsies
Pleuritis, interstitial lung disease, pulmonary hemorrhage, pulmonary
Pulmonary
hypertension, pulmonary embolism
Immune-mediated cytopenias (hemolytic anemia, thrombocytopenia or
Hematologic leukopenia), anemia of chronic inflammation, hypercoaguability,
thrombocytopenic thrombotic microangiopathy
Hepatosplenomegaly, pancreatitis, vasculitis affecting bowel, protein-losing
Gastroenterology
enteropathy
Ocular Retinal vasculitis, scleritis, episcleritis, papilledema
DIAGNOSIS
 Presence of 4 of the 11 American College of Rheumatology 1997 Revised Classification Criteria for
SLE simultaneously or cumulatively establishes the diagnosis of SLE.
 ANA-negative lupus is extremely rare.
 Hypocomplementemia, although common in SLE, is not represented among the classification criteria.
AMERICAN COLLEGE OF RHEUMATOLOGY 1997 REVISED CLASSIFICATION CRITERIA FOR SYSTEMIC

LUPUS ERYTHEMATOSUS*
Malar rash
Discoid rash
Photosensitivity
402
Oral or nasal ulcers
Arthritis:
Nonerosive, affecting 2 or more joints

Serositis:
Pleuritis, pericarditis, peritonitis
Renal manifestations:
Persistent proteinuria or cellular casts
Consistent renal biopsy
Seizure or psychosis
Hematologic manifestations:
Hemolytic anemia
Leukopenia (<4,000 leukocytes/mm3)
Lymphopenia (<1,500 leukocytes/mm3)
Thrombocytopenia (<100,000 thrombocytes/mm3)
Immunologic abnormalities:
Positive anti–double-stranded DNA or anti-Smith antibody test result
False-positive rapid plasma regain RPR test result, positive lupus anticoagulant test
result, or elevated anticardiolipin immunoglobulin (Ig) G or IgM antibody
Positive antinuclear antibody test result
*
The presence of 4/11 criteria establishes the diagnosis of SLE. These criteria were developed for
classification in clinical trials and not for clinical diagnosis.
DIFFERENTIAL DIAGNOSIS
Note: SLE is a clinical diagnosis which do not need DD but if examiner ask then give differentials of:
 MCTD
 SOJIA
SLE can be considered in the differential diagnosis of many clinical scenarios, including unexplained
fevers, joint pain, arthritis, rash, cytopenias, neurologic or cardiopulmonary abnormalities, and
nephritis.
DRUG-INDUCED LUPUS: refers to the presence of SLE manifestations triggered by exposure to

certain medications, including minocycline, many anticonvulsants, sulfonamides, antiarrhythmic
agents, and other drugs .
In individuals prone to SLE, these agents may act as a trigger for true SLE. In others, these agents
provoke a reversible lupus-like syndrome.
How drug induced differ from SLE.
1. Unlike SLE, drug-induced lupus affects males and females equally.

2. An inherited predisposition toward slow acetylation may increase the risk of drug-induced lupus.
3. Circulating antihistone antibodies are often present in drug-induced SLE, and these antibodies are
detected in up to 20% of individuals with SLE.
4. Hepatitis, which is rare in SLE, is more common in drug-induced lupus. 403
5. less likely to demonstrate antibodies to double-stranded DNA, hypocomplementemia, and significant
renal or neurologic disease.
6. Manifestations of drug-induced lupus resolve after withdrawal of the offending medication; complete
recovery may take several months to years.

MEDICATIONS ASSOCIATED WITH DRUG-INDUCED LUPUS
DEFINITE ASSOCIATION
Minocycline, procainamide, hydralazine, isoniazid, penicillamine, diltiazem, interferon-α,
methyldopa, chlorpromazine, etanercept, infliximab, adalimumab
PROBABLE ASSOCIATION
Phenytoin, ethosuximide, carbamazepine, sulfasalazine, amiodarone, quinidine, rifampin,
nitrofurantoin, beta blockers, lithium, captopril, interferon-gamma, hydrochlorothiazide, glyburide,
docetaxel, penicillin, tetracycline, statins, gold, valproate, griseofulvin, gemfibrozil, propylthiouracil
LABORATORY FINDINGS:
LIST OF INVESTIGATIONS:
 ANA
 ANTI-DsDNA.
 ANTI-Smith Antibody test
 Anti-RNP
 Anti-Ro/La Antibody test.
 Compliment levels C3,4 .
 COOMBS TEST (direct)  +ve
 CLOTTING PROFILE-APTT--WITH LUPUS ANTICOAGULANT
 CBC –ANEMIA, LEUKOPENIA, LYMPHOPENIA, THROMBOCYTOPENIA.
 URINE C/E- proteinurea, celluar cast.
 RFTS.
 SKIN BIOPSY—ESP OF DISCOID RASH –FINDINGS ALREADY MENTIONED.
 RENAL BIOPSY—INDICATIONS: 1. Proteinura >0.5 g/day or +++ protein .
 2. gross hematurea/ RBC cast.
 3. every SLE pt –latest recommendation.
 ECG/CXR/ECHO.
 ABDOMINAL USG.
 LFTS..?
 JOINT X-RAY DEPEND UPON INVOLVEMENT.
ANA TEST:
 +ve in 95-99% of individuals with SLE.

 This test has poor specificity for SLE, as up to 20% of healthy individuals also have a positive ANA
test result, making the ANA a poor screening test for SLE.
 ANA titers are not reflective of disease activity; therefore, repeating ANA titers is not helpful in disease
management.
Anti-DsDNA.
 More Specific. 404

 levels correlate with disease activity, particularly nephritis.
Anti-smith antibody

 although found specifically.
 does not correlate with disease activity.
SERUM LEVELS OF TOTAL HEMOLYTIC COMPLEMENT (CH50), C3, AND C4
 typically decreased in active disease and often improve with treatment.

HYPERGAMMAGLOBULINEMIA:
 is a common but nonspecific finding.
INFLAMMATORY MARKERS-ESR/CRP.
 erythrocyte sedimentation rate, are often elevated in active disease.

 C-reactive protein (CRP) correlates less well with disease activity.
AUTOANTIBODIES COMMONLY ASSOCIATED WITH SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)
ANTIBODY CLINICAL ASSOCIATION

Correlates with disease activity, especially nephritis, in some
Anti–double-stranded DNA (60-70%)
with SLE
Anti-Smith antibody 40-50% Specific for the diagnosis of SLE
Increased risk for Raynaud phenomenon and pulmonary
hypertension
Anti-ribonucleoprotein antibody 70-90%
High titer may suggest diagnosis of mixed connective
tissue disorder
Associated with sicca syndrome

May suggest diagnosis of Sjogren syndrome
Increased risk of neonatal lupus in offspring (congenital
Anti-Ro antibody (anti-SSA antibody) 30-40%
heart block)
Anti-La antibody (anti-SSB antibody) 15-20%
May be associated with cutaneous and pulmonary
manifestations of SLE
May be associated with isolated discoid lupus
Antiphospholipid antibodies (including anticardiolipin
Increased risk for venous and arterial thrombotic events
antibodies) 50%
Present in a majority of patients with drug-induced
Antihistone antibodies (15-20%) lupus
May be present in SLE
Antiphospholipid antibodies:
 increase clotting risk.

 found in up to 66% of children and adolescents.
 Antiphospholipid antibodies can be detected by several means, and laboratory features that point to the
presence of these antibodies include:
 Anticardiolipin antibodies. 405
 partial thromboplastin time, dilute Russell viper-venom time) prolonged.
 Circulating lupus anticoagulant (which confirms that a prolonged partial thromboplastin time is not
corrected with mixing studies).

 When an arterial or venous clotting event occurs in the presence of an antiphospholipid antibody,
antiphospholipid antibody syndrome is diagnosed.
 Antiphospholipid antibody syndrome can occur in the context of SLE or independent of SLE
SIMPLE SCREENING TEST :

 ANA
 CBC-HB, TLC, PLT.
 ESR
 RFTS
 URINE C/E.
TREATMENT
Goals of management:
1. Control disease activity-prevetn and suppress disease flare to restore health towards normal.
2. Prevent scaring of organs.
3. Minimize adverse drug effects.
 For all patients, sunscreen and avoidance of prolonged direct sun exposure and other ultraviolet light
may help control disease.
 Hydroxychloroquine: (5-7 mg/kg/day).
 Recommended for all individuals with SLE if tolerated.
 ESPECIAL INDICATION IN MILD DISEASE LIKE rash and mild arthritis,
 prevents SLE flares, improves lipid profiles, and may have a beneficial impact on mortality and renal
outcomes.
Potential toxicities:
 retinal pigmentation.
 Impairing color vision.
 MONITORING: ophthalmology exams every 6-12 mo are recommended.
 NONSTEROIDAL ANTI-INFLAMMATORY AGENTS (NSAIDS) FOR arthralgia and arthritis.
CORTICOSTEROIDS:
Mainstay for treatment of significant manifestations of SLE
SIDE EFFECTS
 Growth disturbance.
 Weight gain.
 Striae.
 Acne.
 Hyperglycemia.
 Hypertension .
 Cataracts.
 Avascular necrosis.
 Osteoporosis.
406
SEVERE DISEASE high doses of intravenous methylprednisolone (e.g., 30 mg/kg/day for 3 days)
or high doses of oral prednisone (1-2 mg/kg/day).

As disease manifestations improve, corticosteroid dosages are gradually tapered, along with
monitoring for evidence of adrenal insufficiency. It often becomes necessary to introduce steroid-
sparing immunosuppressive medications in order to limit cumulative steroid exposure.
 STEROID-SPARING IMMUNOSUPPRESSIVE AGENTS

 Methotrexate.
 Leflunomide.
 Azathioprine.
 Mycophenolate mofetil.
 Cyclophosphamide.
Persistent moderate disease including arthritis, significant cutaneous or hematologic involvement,

and pleural disease.
RxMethotrexate, leflunomide, and azathioprine
severe, potentially life-threatening SLE manifestations, renal, neurologic, and cardiopulmonary

disease
Rx intravenous or oral cyclophosphamideadequate hydration can attenuate the risk of hemorrhagic
cystitis. young girls are at much lower risk of gonadal failure than older women, and the use of
gonadotropin-releasing hormone agonists, such as leuprolide acetate, may help prevent gonadal failure.
LUPOUS NEPHRITIS Rx
azathioprine, mycophenolate mofetil, or cyclophosphamide.

rituximab is an effective treatment for significant glomerulonephritis, this agent has not been studied in
children or in refractory disease.
.
Given the lifelong nature of SLE, care of children and adolescents with this disease also involves
preventive practices.
 Owing to the enhanced risk of atherosclerosis in SLE, attention to cholesterol levels, smoking status,
body mass index, blood pressure, and other cardiovascular risk factors is warranted. Adequate intake of
calcium and vitamin D is necessary to prevent future osteoporosis.
 Infections commonly complicate SLE, so routine immunization is recommended, including annual
influenza vaccination and administration of the 23-valent pneumococcal vaccine.
 Pregnancy can worsen SLE, and obstetric complications are more common in SLE. In addition, many
of the medications used to treat SLE are teratogenic. As a consequence, it is important to counsel
adolescent girls about these risks and appropriate contraceptive options.
COMPLICATIONS
 most common causes of death in individuals with SLE include infection and complications of
glomerulonephritis and neuropsychiatric disease .
 Over the long term, the most common causes of mortality include complications of atherosclerosis and
malignancy.
 The increased risk of premature atherosclerosis in SLE is not explained by traditional risk factors and
is due in part to the chronic immune dysregulation and inflammation associated with SLE.
 Increased malignancy rates may be caused by immune dysregulation and exposure to medications with
carcinogenic potential.
MORBIDITY IN CHILDHOOD LUPUS

Renal Hypertension, dialysis, transplantation 407
Central nervous Organic brain syndrome, seizures, psychosis, neurocognitive
system dysfunction
Cardiovascular Atherosclerosis, myocardial infarction, cardiomyopathy, valvular

disease
Immune Recurrent infection, functional asplenia, malignancy
Musculoskeletal Osteopenia, compression fractures, osteonecrosis
Ocular Cataracts, glaucoma
Endocrine Diabetes, obesity, growth failure, infertility, fetal wastage
PROGNOSIS
 Currently, the 5-year survival rate for pediatric SLE is >90%.

 However, given their long burden of disease, children and adolescents with SLE face a high risk of
future morbidity and mortality from the disease and its complications, especially atherosclerosis and
malignancy .
-------------------------------------*------------
GLOMERULONEPHRITIS ASSOCIATED WITH SYSTEMIC LUPUS ERYTHEMATOSUS
Renal disease in childhood SLE is present in up 80% patients.
Occasionally, renal disease is the only presenting clinical manifestation.
PATHOGENESIS AND PATHOLOGY
 immune complexes.
 Classification of lupus nephritis of the World Health Organization (WHO) is based on a
combination of light microscopy, immunofluorescence, and electron microscopy features
WHO class I nephritis (minimal mesangial lupus nephritis)no histologic abnormalities are
detected on light microscopy but mesangial immune deposits are present on
immunofluorescence or electron microscopy.
WHO class II nephritis (mesangial proliferative nephritis), light microscopy shows both
mesangial hypercellularity and increased matrix along with mesangial deposits containing
immunoglobulin and complement.
WHO class III nephritis Class III nephritis is defined by <50% glomeruli with involvement.
WHO class IV nephritis:  ≥50% glomerular involvement poorer prognosis
 Both iii & iv are interrelated lesions characterized by both mesangial and endocapillary lesions.
 Immune deposits are present in both the mesangium and subendothelial areas.
 A subclassification scheme helps grade severity of the proliferative lesion based on whether the
glomerular lesions are segmental (<50% glomerular tuft involved) or global (≥50% glomerular tuft 408
involved).
 The WHO classification scheme also delineates whether there is a predominance of chronic
disease versus active disease.

 Chronic injury results in glomerular sclerosis and is felt to be the consequence of significant
proliferative disease seen in class III and IV.
 Other signs of active disease include capillary walls that are thickened secondary to
subendothelial deposits (creating the wire-loop lesion), necrosis, and crescent formation.
 WHO class IV nephritis is associated with poorer outcomes but can be successfully treated with
aggressive immunosuppressive therapy.
WHO class V nephritis (membranous lupus nephritis).
 less commonly seen as an isolated lesion and resembles idiopathic membranous nephropathy
with subepithelial immune deposits.
 This lesion is often seen in combination with class III or IV proliferative nephritis, and if the
membranous lesion is present in >50% glomeruli, both classes are noted in designation.
 This classification scheme also identifies cases with combinations of mixed class III, IV, and V
lesions, resulting in more appropriate treatment for such patients.
 Transformation of the histologic lesion from one class to another is common.
 This is more likely to occur among inadequately treated patients and usually results in
progression to a more severe histologic lesion.
CLASS –VI –(ADVANCED SCLEROSING NEPHRITIS)—CKD
The majority of children with SLE are adolescent girls.
MILDER FORMS OF LUPUS NEPHRITIS(all class I-II, some class III) include:
 Hematuria.
 Normal renal function.
 proteinuria <1 g/24 hr.
Some patients with class III and all patients with class IV nephritis have:
 Hematuria .
 Proteinuria.
 Reduced renal function.
 Nephritic syndrome/ or acute renal failure.
 The urinalysis may be normal on rare occasions in patients with proliferative lupus nephritis.
Patients with class V nephritis commonly present with nephrotic syndrome.
DIAGNOSIS:
 ANA,anti-dsdna,urine c/e, Complements.

 Renal biopsy should be performed in all patients with SLE.
TREATMENT 409
 The goal of immunosuppressive therapy in lupus nephritis is producing  clinical and serologic
remission, defined as normalization of anti-DNA antibody, C3, and C4 levels.

 Therapy is initiated in all patients with prednisone at a dose of 1-2 mg/kg/day in divided doses
followed by a slow steroid taper over 4-6 mo beginning 4-6 wk after achieving a serologic
remission.
SEVERE FORMS OF NEPHRITIS (WHO CLASSES III AND IV).
 6 consecutive monthly intravenous infusions of cyclophosphamide at a dose of 500-1,000 mg/m2

followed by additional infusions every 3 mo for 18 mo appears to reduce the risk of progressive renal
dysfunction.
WHO CLASS I OR II LUPUS NEPHRITIS
 Azathioprine at a single daily dose of 1.5-2.0 mg/kg may be used as a steroid-sparing agent in patients
with.
WHO type IV lupus nephritis resistant to conventional immunosuppressive therapies.
 Rituximaba chimeric monoclonal antibody specific for human CD20.
 Autologous stem cell transplantation has been successful in inducing remission in sever treatment
resistant cases.
 Disease can recur after RENAL TRANSPLANTATION but rare.
PROGNOSIS
 Renal survival without the need for dialysis is seen in 80% of patients 10 years after the diagnosis of
SLE nephritis.
 Patients with diffuse proliferative WHO class IV lupus nephritis exhibit the highest risk for progression
to end-stage renal disease..
 Patients require counseling regarding the risk of malignancy or infertility, which may be increased in
those receiving a cumulative dose of >20 g of cyclophosphamide or other immunosuppressant
therapies.
th
Source-nelson 19 edition.
----------------------------------------------------------*-----------------
Neonatal lupus:
 distinct from SLE, is one of the few rheumatic disorders manifesting in the neonate.
Clinical manifestations of neonatal lupus include :
 Characteristic annular or macular rash typically affecting the face (especially the periorbital area),
trunk, and scalp.
 cytopenias and hepatitis. 410
 CARDIAC COMPLICATIONS:
 congenital heart block—feared complicationpermanent.
 Conduction system abnormalities range from prolongation of the PR interval to
complete heart blockin progressive cardiomyopathy (rarely).

 Conduction system abnormalities can be detected in utero beginning at 16 wk of
gestational age.
The noncardiac manifestations of neonatal lupus are usually reversible.
 CUTANEOUS MANIFESTATIONS:
Rash:
 typically appears within the first 6 wk of life after exposure to ultraviolet light.
 lasts 3-4 mo.
 It can be present at birth.
 Neonatal lupus results from the passive transfer of maternal immunoglobulin (Ig) G autoantibodies to
the fetus.
 The vast majority of neonatal lupus cases are associated with maternal anti-Ro (also known as SSA)
and anti-La antibodies (also known as SSB); however other autoantibodies, including anti-
ribonucleoprotein (anti-RNP), have also been reported to cause neonatal lupus.
 <3% of offspring born to mothers with anti-Ro and anti-La antibodies experience congenital heart
block..
HOW TO PREVENT CHILD:both fluorinated corticosteroids and intravenous immunoglobulin have

been used in pregnant women with anti-Ro or anti-La antibodies to prevent occurrence or
progression of fetal cardiac conduction abnormalities.
 Significant conduction system abnormalities after birth are treated with cardiac pacing, and severe
cardiomyopathy may require cardiac transplantation.
 Transient, noncardiac manifestations are conservatively managed, with topical steroids used
occasionally to treat the rash.
 Because maternal autoantibodies gain access to the fetus via the placenta at the 16th wk of
gestation, all pregnant women with circulating anti-Ro or anti-La antibody (or those with a history
of offspring with neonatal lupus or congenital heart block) are monitored by a pediatric cardiologist
with regular fetal electrocardiography from 16 wk of gestation until delivery. If fetal bradycardia is
found unexpectedly during in utero monitoring, screening for maternal anti-Ro and anti-La
antibodies is warranted.
 In contrast to SLE, neonatal lupus is not characterized by ongoing immune dysregulation, although
infants with neonatal lupus may be at some increased risk for development of future autoimmune
disease.
 A mother who has borne a child with congenital heart block due to neonatal lupus has a 15% risk of
recurrence with future pregnancies.
PROGNOSIS:
 With cardiac pacing, children with conduction system disease have an excellent prognosis.
 If the conduction defect is not corrected, affected children may be at risk for exercise intolerance,
arrhythmias, and death.
----------------------------------------*---------------------
411
TREATMENT OF HTN IN SLE PTS:
 Thiazide & beta blockers are first line.

 If proteinurea then add ACEI which is first line in case.
 Second line include CCB and minoxidil.
 HTN is aggravated by steroid trx so change to second line drugs.
TREATMENT OF CVS MANIFESTATIONS:
 Conditions can be- pericardititis, libman sacks endocarditis, premature atheroschlerosis.

 Pericarditis- NSAIDs.
 Libmansacks endocarditis- steroids high dose+, cytotoxics, / surgery.
 Inc TG- use hydroxychloroquine .
PULMONARY.
 Steroids + antibiotic to infection,

 If pulmonary hemorrhage then use I.V steroids And cytotoxics & PPV.
NEUROPSYCHIATRIC DISORDERS:
 Use high dose steroid + cytototoxic drugs.

 Anti-psycotics, anti-depressants, anticonvulsants depend upon condition.
 Anelgesics in headache.
JOINTS:
 Hydroxychloroquine+ MTX & low steroids and NSAIDs are used.

 Advise home exercise and physiotherapy.
SKIN –( Already discussed).
-Raynaud phenomenon – although less common in pediatric than adult SLE.
Avoid cold , cover areas, low dose aspirin, nifedipine, steroids and topical nitroglycerine patch.
HEPATOBILLIARY & GIT
Causes of Abdominal pain in SLE
1. PERITONITIS
2. PANCREATITIS
3. ACUTE ISCHEMIC ENTERITIS
4. PSEUDO-OBSTRUCTION/ PARALYTIC ILLEUS.
 Hepatomegally seen in 40% SLE Pts while spleen++ in 30%.
 LUPOID HEPATITIS Fatty liver changes –(impaired liver synthetic test) it occur due to steroid
use.
ENDOCRINE INVOLVEMENT:
 THYROID—HYPO/HYPER.
 1/3rd of SLE pt hav anti-thyroid antibodies and 1/3rd of these pt develop
hypothyroidism.
 D.M – induced by steroids.
412
 Delayed puberty / ovarian failure –CPA
ANTI-PHOSPHOLIPID ANTIBODIES

 Associated with increase risk of chorea, thrombosis and epilepsy , migraine and avascular necrosis.
 Risk of thrombosis more in adults.
ISSUES OF PREGNANCY:
 OCP cautiously prescribed –risk of induce SLE ,HTN, thrombosis, chronic active hepatitis.
 Combined preparation with low dose estrogen and progesterone are preferable.
 Preferable barrier methods are used.
 Risk to pregnancy more esp when pt on cytotoxic drugs:
 SLE inc risk of miscarriage, neonatal SLE, heart block.
 Male child if treatment plan with cytotoxic drugs then must be informed about sperm bank.
FOLL0W UP MONTIORING OF DISEASE:
 Rx should be properly follow up.

 Follow up for remission & disease activity.
 Disease activity is monitored by:
 Clinical symptoms .
 Anti-DsDNA.
 C3,C4.
 Renal profile.
 ANTI-c1q.
----------------------------------------*------------------------
MIXED CONNECIVE TISSUE DISORDER.
Generalized connective tissue disorder characterized by presence of high titre of anti-U1 RNP in combination
with clinical features commonly seen on SLE , scleroderma, polymyositis.
Overlapping clinical features.
5 major diffuse CT disease according to current classification—SLE,SCLERODERMA, POLYMYOSITIS, JDM,

R.ARTHRITIS./ sjogren syndrome +/-.
Clinical fearures:
 Joint pain/swelling.
 Raunaud phenomenon.
 Sjogren syndrome.
 Muscle inflammation.
 Schlelrodactly.
DX  high titre of speckled pattern ANA (≥1280), Anti-U1 RNP.
PROGNOSIS better than other CT disorder due to decrease renal involvement & better response to steroids. 413
NOTES ……………………………………………………………………………………………………………………………………….

JIA -------------------------------------------------------------------------------------------------SHORT CASE
COMMAND:
1. child presented with joint problems Do locomtor examination of this child.

2. Do knee joint and relevant examination.
3. Do GPE And relevant –rare command.
Steps to consider are:
Inspection  palpation  movement (active first then passive) measurements functional ability
measurements. –(disease complication + look on Rx complication).
Step 1: intro+ consent + exposure –(adequate ).
Step 2: Ask child is he able to walk—(GAIT)—antalgic.
Step 3. Ask to sit on couch and keep hands on side/ over thighs.
Step 4. look –symmetry/swelling/loss of normal countor/ angulation/ deformity/ redness / muscle wasting.
Step 5. Feel  temperature all over joints and compare with normal adjacent area of joints start from hand
to shoulder then knee to ankle.
 Obivious swelling/effusion/tenderness –then take care not to hurt pt over that joint by passive
movement.
Step 6. Start to check ROM –ACTIVE first then PASSIVE. (THROUGHT THAT EXAMINATION LOOK AT CHILD
FACE ASWELL).
Order of ROM –( HandswristelbowshouldersTMJCervical spine lumber spine  hips

ankle  feet (head to head , and head to toe).
Step 7. Hand examination – inspect for rash, pitting, nail pit, digital ulcer, deformity over finger (boutannier/
swan neck), muscle wasting, gottrons papules over PIP&MCP jointsthen palpate each joint for
tenderness and effusion, flex and extend the child fingers while checking for tenosynovitis then check
for active ROM(stand infront of pt and demonstrate same like pt has to do).
1. Make a fist with thumb inside.  observe is it closing fully  then u cover pts fist with your hand
and observe full ROM and tenderness.(
2. Approximate each finger with thumb (counting on digits).+ abduct thumb from index finger
3. Do radial then ulner deviation  look ROM and note … R-20/U-300
4. Make namastay sign (cathaderal hand)- (flexion at wrist) then extension. F-80/E-700
Step 8. Elbow examinationinspection –(rash/S.C nodule) ROM
 1.Flexion (1350)
 2.extension (0-100)
 3.supination—(elbow should be flexed) (900)
 4.pronation. (900)
Step 9: shoulder examination: inspection—then ROM –demonstrate each step.
414
1. Pull your hand above head/ keep both hand behind occiput.—check flexion & abduction.
2. Give yourself hug.-----checking adduction
3. Scratch your back-----checking external rotation.
4. Hide your hand behind back ---internal rotation and extension.

Step 10. Neck examination  cervical spine inspect-palpate and check ROM 
1. Touch chin with chest –flexion at neck (45)

2. Head touch back –extension (50)
3. Touch chin to be in line with shoulder –both sides-----checking rotation.
4. Ear to shoulder –both sides –lateral flexion.
Step 11. Jaw examination.—look for micrognathia, and feel tenderness at TMJ, crepitus or click over TMJ by
asking the patient open and close mouth. Demonstrate for 3 finger for interdental distance.
Step 12. Thoracolumber spine: first inspect child when he is standing then ask to to touch feet—feel for
tenderness over spine , paraspine areas and SI joint and check for kyphosis/scoliosis.  ROM
1. Touch toes –flexion

2. Arching back –extension.
3. Lateral bending both side rt/lt bending.
4. Ask to sit/if already on couch then Lateral rotation rt and left by placing hand over pelvis—it
is at thoracic level entirely.
Step 13. Sacroiliac joint examination  inspection , ROM:
1. Ask child to lye supine then ask to keep leg on opposite knee  this is FABER TEST which
comprise of flexion at hip , abduction , and external rotation.  during this you press down the
medial surface of knee (knee of FABER test side) and keep hand to push down on contralateral
Anterior superior iliac spine  look at face if tender it indicate S1 joint involvement /
inflammation.
2. Perform pelvic work test by criss cross or from each side.
Step 14. Lower limb examination:
 Gait –already done / can be done here

 Stand on each leg –look sacral area for tendelenberg sign.
 Squat –proximal muscle weakness—( optional can be coz child may have active inflammation of
lower limb joints.
Step 15. HIP examination : (DO IN SUPINE POSITION)
 Inspect Muscle bulk, posture

 Palpate for tenderness.
 Measure True leg length ( mark area of ASIS then measure upto medial malleoli)
ROM –
 Take lower limb to flex TO abdomen till 90 0 and DO Internal rotation THEN External
rotation.
 Make straight leg and ask for abduction and adduction—of both legs.
 Turn child to semiprone then check extension.
Step 16. KNEE EXAMINATION : 415
 Inspect quadriceps bulk, redness over joint/ swelling.

 feel –tenderness , temperature, effusion, and enthuses at patella hold its all 3 angles .

 do buldge sign –milking any joint fluid down the lateral aspect of joint  look for buldge medially
then stroking upward on the medial aspect moving any fluid present in suprapatellar bursa.
 Pattelar tap
 Check ROM –flexion and extension
 Knee stability  contraindicated when knee is actively inflamed.
 Check anteroposterior movement at knee joint –flex knee and sit/hold child foot then check for
cruciate ligaments –lachman sign –pull forward –if moved it indicate ruptured anterior cruciate. If
posterior movement then it indicate posterior cruciate ruptured.
 Check lateral mobility –with knee fully extended.—(for medial/lateral ligaments).
 Mc murray sign –click feel for meniscal tear-not routinely performed in our exams no one ask.
STEP 17. ANKLE AND FEET.
 Look –swelling, redness, bulk.

 Feel –tenderness, enthuses.
Check ROM
 Ankle plantarfelxion then dorsiflexion.
 Subtalar –inversion and eversion
 Midtarsal –first stabilize heel /calcaneus with one hand and then move forfoot with other hand –
ABDUCTION and ADDUCTION.
 1st metatarsophalangeal joint –flexion-extension.
STEP 17 DO GPE –special consideration at eye examination with pen torch –pulpillary size, photophopia,
synachae, cataract.
Step 18 cover with thanks .
Offer: slit lamp examination
DESCRIPTION :
I have examined a child who is mentally alert and interactive throught my examination , no apparent
respiratory distress, on his/her locomotor examination he had normal gait however obivious flexion
deformities involving …..digits of rt/lt hand in form of flexion at PIP and extension at DIP most likely boutannier
deformity , normal range of active and passive at all other joints of body & no signs of active inflammation at
any joint of body.
There are no signs of steroid toxicity in form of cushingoid face, rash, hirsuitism/hypertrichosis, strae, proximal
muscle weakness and cervical fat pad.
 want to know anthropometrics of child & check b.p .

 I want to do slit lamp examination of pt.
Impression:
 Polyarticular JIA.
 Can be extended Oligoarticular JIA.
 Investigations 416
 CBC with p.smear
 ANA
 Anti-ccp

 RA factor
 x-ray joints
 USG –if effusion
 MRI- Joints
 Slit lamp eye examination
 Baselines
Management : --( DETAIL IN LONG CASE)
 Establish dx
 Counceliing
 Multidisciplinary approach
 Rx of acute problems
 Medical Rx.
 Surgical Rx.
Prognosis :
417

DOWN SYNDROME ----------------------------------------------------------------------------------------LONG CASE.
BASIC GENETICS:
 Normal Human cells contain a multiple of 23 chromosomes (n = 23).

 A haploid cell (n) has 23 chromosomes (typically in the ovum or sperm).
 If a cell's chromosomes are an exact multiple of 23 (46, 69, 92 in humans), those cells are referred to as
euploid.
 Polyploid cells are euploid cells with more than the normal diploid number of 46 (2n) chromosomes:
3n, 4n.—(common abnormality usually losses)
 Mosaicism is an abnormality defined as the presence of 2 or more cell lines in a single individual.
 Triploid cells are those with 3 haploid sets of chromosomes (3n) and are only viable in a mosaic form.
Triploid infants can be liveborn but do not survive long.
 Triploidy is often the result of fertilization of an egg by 2 sperm (dispermy).
 Abnormal cells that do not contain a multiple of haploid number of chromosomes are termed
aneuploid cells.
 Aneuploidy is the most common and clinically significant type of human chromosome abnormality,
occurring in at least 3-4% of all clinically recognized pregnancies.
 Monosomies occur when only 1, instead of the normal 2, of a given chromosome is present in an
otherwise diploid cell—lethal except in mosaics.
 An exception to this rule is monosomy for the X chromosome (45,X), seen in Turner syndrome; it has
been estimated that the majority of 45,X conceptuses are lost early in pregnancy for as yet unexplained
reasons.
 The most common cause of aneuploidy is nondisjunction, the failure of chromosomes to disjoin
normally during meiosis (see Fig. 76-1). Nondisjunction can occur during meiosis I or II or during
mitosis. After meiotic nondisjunction, the resulting gamete either lacks a chromosome or has 2 copies
instead of 1 normal copy, resulting in a monosomic or trisomic zygote, respectively.
 Trisomy is characterized by the presence of 3 chromosomes, instead of the normal 2, of any particular
chromosome. Trisomy is the most common form of aneuploidy. Trisomy can occur in all cells or it may
be mosaic. Most individuals with trisomy exhibit a consistent and specific phenotype depending on the
chromosome involved.
 FISH is a technique that can be used for rapid diagnosis in the prenatal detection of common fetal
aneuploidies including chromosomes 13, 18, and 21 as well as sex chromosomes .-
DOWN SYNDROME
Trisomy 21 is the most common genetic cause of moderate mental retardation.
The incidence of Down syndrome in live births is approximately 1 in 733.
incidence at conception is more than twice that rate difference due to early pregnancy losses.
Affected individuals are more prone to congenital heart defects (50%) such as atrioventricular septal
defects, ventricular septal defects, isolated secundum atrial septal defects, patent ductus arteriosus,
418
and tetralogy of Fallot.
Congenital and acquired gastrointestinal anomalies and hypothyroidism are common . Other
abnormalities include megakaryoblastic leukemia, immune dysfunction, diabetes mellitus, and

problems with hearing and vision . Alzheimer disease–like dementia is a known complication that
occurs as early as the 4th decade and has an incidence 2-3 times higher than sporadic Alzheimer
disease.
Most males with Down syndrome are sterile, but some females have been able to reproduce, with a
50% chance of having trisomy 21 pregnancies.
Two genes critical region of chromosome 21 may be targets for therapy.
HALLS CRITERIA FOR DIAGNOSIS OF DOWN SYNROME:
1. Hypotonia
2. Poor moro reflex.
3. Flat face
4. Upward slanted palpaberal fissure.
5. Small dysplstic ears.
6. Joint hyperflexibilty.
7. Short neck with redundant skin
8. Short 5th finger with clinodactly
9. Pelvic dysplasia
10. Single transverse palmer crease.
CLINICAL FEATURES OF DOWN SYNDROME IN THE NEONATAL PERIOD
CENTRAL NERVOUS SYSTEM

Hypotonia*
Developmental delay
Poor Moro reflex*
CRANIOFACIAL
Brachycephaly with flat occiput
Flat face*
Upward slanted palpebral fissures*
Epicanthal folds
Speckled irises (Brushfield spots)
Three fontanels
Delayed fontanel closure
Frontal sinus and midfacial hypoplasia
Mild microcephaly
Short hard palate
Small nose, flat nasal bridge
Protruding tongue, open mouth
Small dysplastic ears*
CARDIOVASCULAR
Endocardial Cushing defects
419
Ventricular septal defect
Atrial septal defect
Patent ductus arteriosus

Aberrant subclavian artery
Pulmonary hypertension
MUSCULOSKELETAL
Joint hyperflexibility*
Short neck, redundant skin*
Short metacarpals and phalanges
Short 5th digit with clinodactyly*
Single transverse palmar creases*
Wide gap between 1st and 2nd toes
Pelvic dysplasia*
Short sternum
Two sternal manubrium ossification centers
GASTROINTESTINAL
Duodenal atresia
Annular pancreas
Tracheoesophageal fistula
Hirschsprung disease
Imperforate anus
CUTANEOUS
Cutis marmorta
*
Hall's criteria to aid in diagnosis.
ADDITIONAL FEATURES OF DOWN SYNDROME THAT CAN DEVELOP OR BECOME SYMPTOMATIC

WITH TIME
NEUROPSYCHIATRIC
Developmental delay
Seizures
Autism spectrum disorders
Behavioral disorders (disruptive)
Depression
Alzheimer disease
SENSORY
Congenital or acquired hearing loss
Serous otitis media

420
Refractive errors (myopia)

Congenital or acquired cataracts
Nystagmus
Strabismus
Glaucoma
Blocked tear ducts
CARDIOVASCULAR
Acquired mitral, tricuspid, or aortic valve regurgitation
Endocarditis
MUSCULOSKELETAL
Atlantoaxial instability
Hip dysplasia
Slipped capital femoral epiphyses
Avascular hip necrosis
Recurrent joint dislocations (shoulder, knee, elbow, thumb)
ENDOCRINE
Congenital or acquired hypothyroidism
Diabetes mellitus
Infertility
Obesity
Hyperthyroidism
HEMATOLOGIC
Transient lymphoproliferative syndrome
Acute lymphocytic leukemia
Acute myelogenous leukemia

421
GASTROINTESTINAL

Celiac disease
Delayed tooth eruption
Respiratory
Obstructed sleep apnea
Frequent infections (sinusitis, nasopharyngitis, pneumonia)
CUTANEOUS
Hyperkeratosis
Seborrhea
Xerosis
Perigenital folliculitis
3 universal / consistent findings of pts with down syndrome:
1. Developmental delay
2. Hypotonia
3. Short stature.
HEALTH SUPERVISION FOR CHILDREN WITH DOWN SYNDROME
CONDITION TIME TO SCREEN COMMENT
Birth; by pediatric cardiologist 50% risk of congenital heart

Congenital heart
disease. Increased risk for
disease
Young adult for acquired valve disease pulmonary hypertension
Birth or by 6 mo; by pediatric

Strabismus, cataracts, ophthalmologist Cataracts occur in 15%, refractive
nystagmus errors in 50%
Check vision annually
Birth or by 3 mo with auditory brainstem

Hearing impairment or response or otoacoustic emission testing; check Risk for congenital hearing loss plus
loss hearing q6mo up to 3 yrs if tympanic membrane 50-70% risk of serous otitis media.
is not visualized; annually thereafter 422
Increased risk for Hirschsprung

Constipation Birth
disease

CONDITION TIME TO SCREEN COMMENT
Screen with IgA and tissue

Celiac disease At 2 years or with symptoms
transglutaminase antibodies
Increased risk for neonatal

At birth and in adolescence or if symptoms
Hematologic disease polycythemia (18%), leukemoid
develop
reaction, leukemia (<1%)
Hypothyroidism Birth; repeat at 6-12 mo and annually Congenital (1%) and acquired (5%)
Discuss school placement

At each visit
Growth and options
development
Use Down syndrome growth curves
Proper diet to avoid obesity
Obstructive sleep
Start at ∼1 yr and at each visit Monitor for snoring, restless sleep
apnea
At each visit by history and physical exam
Radiographs at 3-5 years or when planning

Atlantoaxial to participate in contact sports Special Olympics recommendations
subluxation or are to screen for high risk sports,
instability (incidence Radiographs indicated wherever neurologic e.g., diving, swimming, contact
10-30%) symptoms are present even if transient (neck sports
pain, torticollis, gait disturbances, weakness)
Many are asymptomatic
Menstruation and contraception

Gynecologic care Adolescent girls
issues
Recurrent infections When present Check IgG subclass and IgA levels
Depression, anxiety, obsessive

compulsive disorder,
schizophrenia seem in 10-17%
Psychiatric, behavioral
At each visit
disorders Autism spectrum disorder in 5-
10%
Early-onset Alzheimer disease
423
The life expectancy for children with Down syndrome is reduced and is approximately 50 to 55 yr.

This same study reported increased risk of adult deaths due to congenital heart disease, seizures,
and leukemi
This risk of having a child with trisomy 21 is highest in women who conceive at >35 yr of age.
Even though younger women have a lower risk, they represent half of all mothers with babies with
Down syndrome because of their higher overall birth rate.
 All women should be offered screening for Down syndrome in their 2nd trimester:
 4 maternal serum tests:--(QUAD SCREEN)
 (free β-human chorionic gonadotropin (β-hCG), unconjugated estriol, inhibin, and α-
fetoprotein).
 it can detect up to 80% of Down syndrome pregnancies compared to 70% in the triple
screen.
 Both tests have a 5% false-positive rate.
method of screening during the 1st trimester:
 fetal nuchal translucency (NT) thickness that can be done alone or in conjunction with:
 maternal serum β-Hcg.
 pregnancy-associated plasma protein-A (PAPP-A).
note: NT alone can detect ≤70% of Down syndrome pregnancies, but with β-hCG and PAPP-A, the
detection goes up to 87%.
If both 1st and 2nd trimester screens are combined using NT and biochemical profiles (integrated
screen), the detection rate goes up to 95%.
If only 1st trimester quad screening is done,  α-fetoprotein (MSAFP, which is decreased in
affected pregnancies) is recommended as a 2nd trimester follow-up.
Detection of fetal DNA in maternal plasma may also be diagnostic.
In approximately 95% of the cases of Down syndrome there are 3 copies of chromosome 21. The
origin of the supernumerary chromosome 21 is maternal in 97% of the cases as a result of errors in
meiosis.
Meiotic non-dysjunction The majority of these occur in maternal meiosis I (95%).
Mosiac1%  some cells having 46 chromosome.
translocation 4% hat involves chromosome 21.
The majority of translocations in Down syndrome are fusions at the centromere between
chromosomes 13, 14, 15, 21, and 22 known as Robertsonian translocations.
424
The translocations can be de novo or inherited.
Chromosome analysis is indicated in every person suspected of having Down syndrome.

If a translocation is identified  parental chromosome studies must be performed to determine
whether 1 of the parents is a translocation carrier, which carries a high recurrence risk for having
another affected child. That parent might also have other family members at risk.
Translocation (21;21) carriers have a 100% recurrence risk for a chromosomally abnormal child.
Robertsonian translocations, such as t(14;21), have a 5-7% recurrence risk when transmitted by
females.
425

ACUTE LEUKEMIA ----------------------------------------------------------------LONG CASE
Biodata
Presenting complaints can be
 Pallor
 Petechae, bruise,bleed.
 Fever.
 Bone pains/ bacheache.
 Petechae, bruise,bleed.
 Abdominal distension.
 Abdominal.pain.
 Lymphadenopathy/swelling
 Fits,CVA, altered sensorium.
 Testicular swelling.
Hopc
Details of PC.
Ask Hx of
Most likely differentials. (ASK FROM MOTHER / RELATIVE WHAT DR. TOLD U IS THAT BLOOD CA
OR LYMPH NODE CA).
exposure to hakeem medication, radiation, chemicals, drugs, viral illnes and maternal age.
Anorexia , wt loss, fatigue, night sweats, glandular swelling, abdominal pain, distention, loose
motion, constipation, vomiting.
Petechae, bruise, bleed, joint pain, oral ulcer,hair loss.
Cough , respiratory distress, dysphagia, stridor, ( mediastinal mass) T cell leukemia.
Gingival hyperplasia, subcutaneous nodules(AML).
426
Complication of disease:
Body swelling , palpitation , oligourea/ anurea, respiratory distress (TLS).

Hadache , fits, altered sensorium, weakness, or focal neurological deficit.
( indicators of CNS involvement). Hx of scrotal swelling.
For relapse : hx of fever, wt loss, bone pains, petecahe, bruise, bleed + CNS + scrotal ( as above).
For febrile neutropenia: oral ulcer, prolong unresponsive fever,
Complication of treatment
Hematurea, jaundice, ( MTX), nausea, Anorexia, vomiting, rash , alopecia, growth, hearing
impairment, cataract, spasticity, altered behavior (intrathecal MTX = leukoencephalopathy).
Management detail (key procedures: BMA, CSF, IT MTX, iradiations,prophylaxis)
He diagnosed at........., where he presented with complaints of ........., which were for .... Duration
before admission, he investigated with help of blood , radioimaging X Ray, CT , and ultrasound, BMA
, CSF analysis for which pts mother actually don't know their interpretation, treated with injectable
medications of .... Name, and intrathecal MTX, and transfused with PCV , ... Time and no Hx of
transfusion related reaction, he uses barrier in form of mask and proper hand wash , takes
prophylaxis . During the course of ilness he had improvement of symptoms.
Parents are related as first cousin and had ..... Brothers and .... Sisters all are normal , no Hx of
similar problem, contact.
Developmentally normal child student of .... Class.
Vaccinated child according to EPI schedule no xtra vaccine has been given.
Nutritionally he is talking this ......... With total calorie intake of......... No dietary restrictions has been
advised so for.
Parents have poor/ fair knowledge regarding disease its treatment,complication, course and
prognosis. However they are advised for BMT option.
Disease have significant impact on child health, schooling and pscycological impact, parents and Sibs. 427
Parents are concerned about……. issues of child.

Father is .... By occupation earning ...... , however social support is +, live in their own / rented house,
....no. Of rooms and proper sanitation.
On examination:
Q: WHY LYMPHOMA?
A: typical age of NHL lymphoma is after 5-19 yr with sudden onset of painless rapidly progressive
lymphadenopathy with no B.M involvement in form of peteche, bruise, bleed hx , and no
visceromegally on examination goes more in favor of lymphoma how ever late stage and
presentation can present like ALL so definitive diagnosis require tissue bx .
I WILL STANDARIZE THE PATIENT BEFORE STARTING CHEMOTHERAPY, IF IT IS HIGH RISK THEN I WILL
ADD DAUNORUBICIN & CNS INJECTIONS WILL BE PROLONG, I WILL KEEP ON CHEMOTHERAPY IN
MALE FOR 2.5 YR TO 3 YEAR WHILE IN FEMALE IT IS 2 YR, BY START WITH INDUCTION REMISSION,
CONSOLIDASTION, INTERM MAINTAINANCE, WHILE DELAYED INTENSIFICATION FOR HIGH RISK TO
MAINTAIN REMISSION AND FINALLY MAINTAINCE . KEEP FOLLOW UP OF MY PT AFTER EVEN
REMISSION THROUGHT LIFE FOR ORGANOMEGALLY, TESTES RELAPSE, S/E OF DRUGS.
Q: what are rapid early responser?
A: On day 8 bone marrow response +, decrease organomegally, and counts become normal.
Q: What is clinical difference between AML & ALL?
A: AML have s/c skin nodules also called blue berry muffins, gum hypertrophy (M4 , M5)
,proptosis & chloromas, more CNS symptoms and DIC (M3).
Q: What are chloromas?
A: chloromas are the also called granulocytic sarcoma which are localized masses of leukemoid
cells located in retroorbital , skin and epidural it coincide with M2 stage (t8:24).
Q: do we use old FAB classification in leukemia?
A: No now immunophenotyping is used.
Q: is it rule to pt hav TLS ever with tumor? 428
A: No TLS can occur with / without tumor.

Q: What are metabolic derangements of TLS?/
A: increase K+, uric acid, PO4 , RFTs, but only Ca+ decreases.
Q: Tumors associated with increase risk of TLS?
A: ALL, lymphoma, solid tumors.
Q: what is standard risk?
A: All pts apart from high risk are so called standard risk.
Q: leukemic pt with onset of headache & vomiting what does it signify?
A: Pt may have developed CNS disease/ relapse, meningitis, ICB, or may be drug side effect.
Q: Variants of leukemia?
A: Aplastic leukemia, Aleukemic leukemia, MD anemia.
Q: how will u differentiate histologically AML & ALL?
A: ALL is PAS +, While AML is sudan black +, peroxidase +, auer rod cells + in blast cells.
Q: what are predictors of relapse?
A: Gene translocation, poor early response, minimal residual disease M1= <5% Blast cells, M2=
5-25% blast cells, M3=>25% blast cells.
Q: good response to treatment is seen in which subtypes of lymphoma?
A: Lymphocyte predominance amd mixed cellularity.
DISCUSSION:
LEUKEMIA: group of malignant disease in which the genetic abnormalities in hematopoietic cells
give rise to an unregulated clonal proliferation of cells either due to increase rate of
proliferation or dec rate of apoptosis. 5000 new cases/yr
Epidemiology:
 Leukemias are common malignat neoplasm about 41 % of all malignancies in children <15 yr 429
of age.
 ALL-77%.

 AML-11%.
 CML-2-3%.
 JCML-1-2%.
 More common in boys.
 Peak incidence of 2-6 yr
 Identical twin –if twin 1 diagnosed during 1st yr of life then risk to second twin is >70%, while
if one among twin diagnosed later 5-7 yr the other would have risk twice than general
population regardless of zygotisy.
ETIOLOGY:
 Unknown mostly.
 Genetic factors(bloom, AT, SCID, down syndrome, turner, NF-1)
 Environmental factors (radiation, chemical exp, drugs
 Infections (EBV).
FAB (French,American, british) CLASSIFICATION:
L1= small lymphoblast+ little cytoplasm (good response to chemo) most common.
L2= large lymphoblast+ more cytoplasm pleomorphic lymhoblas).
L3= Cytoplasmic vacuoles, tiny strippled nuclear chromatin (burkitt leukemia).
PROGNOSTIC FACTORS:
GOOD
1. Low initial WBC count <50.

2. Female
3. 1-10 yr age
4. <4 weeks to remission.
5. Translocation 12:21,trisomy 4,10.
6. Hyperdyploidy
7. Minimal residual disease.
8. Pre-B ALL.
BAD 430
1. High initial WBC count >50.

2. male

3. <1 & >10 yr age
4. >4 weeks to remission.
5. Translocation 2:11, & 9:22.
6. Hypodyploidy
7. Large B ALL.
8. CNS involvement.
INVESTIGATIONS :
 CBC with peripheral smear & blast cells.

 BMA/BX look for Morphology, flow cytometry, immunophenotyping &
cytogenic analysis.
 CXR for any medistinal mass for T Cell derived ALL.
 CSF Examination for CNS disease, staging & prognosic importane.
 S.ca, PO4, ALK.PO4,Uric acid, RFTs ,S/E, for TLS.
 Baseline ECG, ECHO before start of chemotherapy.
CHEMOTHERAPY
MODIFIED UK-10 PROTOCOL FOR ALL.
CALCULATE THE RISK OF PATIENT THEN DECIDE PROTOCOL ACCORDINGLY.
PRE-CHEMO PROTOCOL
1. REMISSION INDUCTION
2. CONSOLIDATION
3. INTERIM MAINTAINANCE
4. DELAYED INTENSIFIACTION
5. MAINTAINCE.
PRE-CHEMO PROTOCOL-Prephase
Started 1 week before chemo—admit pt.
Protocol to avoid from TLS.
If pt develop TLS then remember PD as An option apart from medical measures.
 I.V FLUIDS – if TLC < 50,000 – 2L/m2/day.

 50,000 – 3 L/m2/day.
 Tablet allopurinol (zyloric) 10 mg/kg/day for 10 days.
431
 Co-trimoxazole (septran) 10 mg/kg/day .
 Syp-citralka / soda bicarb injection in i.v fluids.—keep urine PH6-7 coz inc PH lead to inc PO4.
 Steroids ( tablet deltacortil)

 Advise for hygienic measure , mask over face, minimal visitors and avoid street /bazari food,
& consult with dr even for mild illness/infection.
 Rasburicase is also another drug tried along with allopurinol.
 TLS can develop without starting Tx in ALL with high TLC n other solid tumours.
REMISSION INDUCTION: (PV-MD)—28 DAYS Rx
 Prednisolone—60mg/kg/day for 21 days then tapper over 7 day +mucaine.

 Vincristine—1.5mg/m2/dose i.v 4 doses weekly interval (inj=1mg/2mg)
 Daunorubicin—25mg/m2/dose 4 doses every weekly (i.v infusion 100 ml in 1 hr)
 Methotrexate—10 mg <5 yr / 12.5 mg >5 yr (inj = 50 mg). 3 doses I/T @2wk interval.
 L-asparaginase (leunase) 9 injections (doses) on AD starting from 3rd day of induction with
dose of 6000 units/m2 /dose (inj=5000 units)., S/C.
 BMA 0, 8, 29/28 Days of treatment.
 BMA on 29 day of induction is of prognostic significance.
 If BMA on 29 is not showing remission then prolong induction with 2 weeks more by
adding steroids + vincristine + daunorubicin.
REMISSION: defined as < 5% blast in bone marrow & return of neutrophil and platelete count to
normal level in 4-5 wk of trx. It may be complete =<5%, partial 5-25%, no response= >25%.
CONSOLIDATION: (MS-CC) ---- (4-6 Week Rx).
 Cyclophosphamide. (1200mg/m2/dose –3 doses @ 2weekly interval i.v infusion in N/S. (INJ-

500mg/1G).
Note: normal saline drip must continue 6-8 hrs after cyclophosphamide to irrigate bladder
/Mesna and prevent mucosal damage by causing h.cystitis.
 Methotrexate—same like remission induction but given 2 doses/2wk/IT.
 Cytosar (Cytarabine) 100mg/m2/day OD/BD i.v bolus for 4 days every wk for 4 weeks. (inj-
100mg).
 Septran: syp – alternate days.
Note : keep eye on monitoring of ANC –AIM to keep between 1000-2000.
INTERIM MAINTAINANCE: ( PV-6MM)
From completion of consolidation till 20 weeks starting chemo.
Prednisolone: Same dose for 1st 5 days with vincristine every month. 432
Vincristine: 1.5mg/m2/dose i.v bolus monthly.

MTX: 20 mg/m2 PO once a week (fixed day with Sunday along with folic acid for week except
Sunday) tab 2.5/10 mg.
6MP: 70 mg/kg/day PO/Daily . tab=50 mg.
DELAYED INTENSIFICATION: (PV-MD)—5 weeks Rx.
For High risk to maintain remsission.
Prednisolone (same dose +mucaine).
Vincristine inj same dose, total 3 inj.weekly for 3 wks.

3 weeks
MTX inj : same dose weekly total 2 injections I/T.
Daunorubicin inj: same dose 2 injections /weekly.
Plus: (2 week trx with following)
INJ –MTX 300 mg/m2 i.v infusion in 50 ml N/S over 24 hr × wkly
Along with :
Leucovorin (folinic acid) = 10 mg/m2 i.v infusion in 50 ml N/S over ½ hr ×6hrly for 2-3 days.
MAINTAINANCE—(PV-6MM=same drugs like for interm maintainance) for 24 MONTHS.
 Keep TLC Btw 3000-4000.

 Continue septran AD for throughout maintenance.
 If tlc drops then reduce dose of oral MTX and 6MP by 10%.
 Keep monitoring TLC if count fall by <1500 then stop chemo.
 PLT <75 ---STOP
 TLC<750 ---STOP
 Adhere to rules of barrier nursing, observe for infection, use of GCSF if required.
 When count stabilize add drug one by one starting with MTX then 6 MP.
SIDE EFFECTS OF DRUGS:
VINCRISTINE:
 Peripheral neuropathy.------------Sensory/motor/ mix.* dean sb Q. 433

 Phlebitis
 Constipation.

 Hairloss
 Nausea.
 Vomiting.
 SIADH.
DAUNORUBICIN:
 Cardiac toxicity.
 Diarrhea
 Sorethroat.
 Abdominal pain.
 Allergy.
METHOTREXATE:
 BM suppression.
 Stomatitis.
 Hepatitis.
 Osteopenia.
 Intrathecal –leukoencephalopathy/leukodystrophy.
L-ASPARAGINASE:
 Pancreatitis
 Hyperglycemia.
CYCLOPHOSPHAMIDE:
 Hemorrhagic cystitis.
 Pulm. Fibrosis.
 Malignancy of bladder
 Infertility.
CYTOSAR
 Nausea
 Vomiting.
 BM suppression.
 Conjuctivitis.
6MP
 B.M suppression. 434

 Hepatic necrosis.
 Mucositis.

RELAPSE:
B.M= 15-20%. MOST DANGEROUS. Rx-intensive chemo which not used previously then BMT.
CNS: (20%) raised ICP, CN palsy, Dx-leukemia/blast cells in CSF, Rx-chemo+craniospinal irradiation+
IT chemo.
TESTES: 1-2%. Painless swelling of one or Both testes Dx- biopsy of testes . Rx- chemo + local
irradiation.-survival rate good.
PROGNOSIS: >80% survival rate @ 5 yr from Dx.
TUMOR INDEX CALCULATION is depend on parameters
 peripheral blast cells.

 Liver size .
 Spleen.
 TLC count.
RISK STRATIFICATION
1. STANDARD RISK.
2. MODERATE RISK.
3. HIGH RISK >1.2 – radiotherapy added.
Patients with Ph+ ALL, who have developed resistance to other therapies, can now be treated with
the newly approved drug ponatinib.
Immunohistochemistry
 A negative myeloperoxidase (MPO) stain and a positive and terminal deoxynucleotidyl
transferase (TdT) is the hallmark of the diagnosis of most cases of acute lymphoblastic
leukemia (ALL).
 However, positive confirmation of lymphoid (and not myeloid) lineage should be sought by
flow cytometric demonstration of lymphoid antigens, such as CD3 (T-lineage ALL) or CD19
(B-lineage ALL), in order to avoid confusion with some types of myeloid leukemia (eg, M0),
which also stain negative with myeloperoxidase.
Flow Cytometry and Cytogenetics

 Although more than 95% of cases of the L1 or L2 subtype of acute lymphoblastic leukemia
(ALL) are positive for Terminal deoxynucleotidyl transferase (TdT), TdT is not specific for ALL;
TdT is absent in L3 (mature B-cell) ALL. However, TdT helps to distinguish ALL from 435
malignancies of more mature lymphocytes (ie, non-Hodgkin lymphoma [NHL]).

 In cases of acute leukemia that are myeloperoxidase (MPO) negative, and TdT positive, the
distinction between acute myelogenous leukemia (AML) and ALL is made based on the
analysis of flow cytometry results.
 Patients with AML demonstrate myeloid markers such as CD33, whereas patients with ALL
demonstrate lymphoid markers.
DESCRIPTION OF MANAGEMENT:
After confirming my diagnosis I will council the parents regarding the disease, its course,
complication, treatment and prognosis , will manage the supportive measures by stabilizing the pt
by correcting anema with PCV , thrombocytopenia with platelate transfusion, empirical antibiotics
to treat infection then according to C/S, i will take the hygienic measures for pt, barrier nursing and
advise for face mask & minimal exposure to infections, nutritional rehabilitation, vaccination &
start pre-chemo protocol , and SPECIFIC will treat with chemotherapy & involve multidisciplinary
approach by involving myself, oncologist, nutritionist, pharmacist , nursing help and social support
with pscycotherapist. I will do follow up of my patient and ensure compliance & psychosocial
support.
BONE MARROW TRANSPLANTATION:
It is the re-constitution of hematopoietic system by transfer of the pleuripotent cells (stem cells)
from the bone marrow. This usually require prior ab;aation of pts own marrow by intensive chemo
or radiotherapy.
TYPES OF CELLS:
 B.M.
 Cord blood.
 Peripheral blood stem cells.
SOURCES:
 Autologous (pts own stem cells).

 Allologous:
o Identical Twin (syngenic).
o Related.
o Unrelated.
436
 CORD BLOOD:
ADVANTAGE:

 Few cells/ kg needed.
 Large no. of cells in cord blood compared to B.M.
 Cord blood cells are in highly proliferative state.
 Short time to process.
 Less chance of GVHD.
DISADVANTAGE:
 Only one chance to engraft with cord blood, while BMT can be repeated if once fail.
 Delayed engraftment of neutrophils (24 days). While 10-14 days for marrow & 7-12 days for
PBSC.
 Theoretical chance of transmission of acquired disease.
INDICATIONS OF BMT:
NON-MALIGNANT:
 Adrenoleukodystrophy.
 Metachromatic leukodystrophy.
 Hurler syndrome.
 Osteopetrosis.
 SCID/ WAS
 Pure red cell aplasia, Sickle cell, thalesmia , aplastic anemia, fanconi anemia.
MALIGNANT:
 ALL, AML, CML, JCML, MDS, HD/NHD.


DONOR IDENTIFICATION:
 HLA matching is required:

Class i HLA – HLA –A, HLA-B, HLA-C.
Class ii HLA – HLA-DR, HLA DP, HLA-DQ. (Memo= HLA-D then PQR).
 Required 6/6 match = HLA-A, HLA-B, HLA-DR (Each have 2 allele).

 If 3/6 match = haplotypic donor.
 If donor and recipient are not 6/6 then mismatch.
FACTORS CONSIDERATION OF DONOR: 437
 Younger is better
 CMV –ve have good outcome.

 Female to male tx is less favorable.
 Body wt appropriate.
TRANSPLANT PROCESS:
1. Conditioning (-10 days prior to infusion).

2. Stem cell infusion = 0 day
3. Neutropenic phase – 2 week
4. Engraftment phase - + 15 – 30 days
5. Post-engraftment.
CONDITIONING:
 -10 Days prior to infusion.

Purpose:
 Eliminate malignancy.
 Prevent rejection of new stem clls.
 Create space for new cells.
Regime: total body irradiation + cyclophosphamide or / busulphan + cyclophosphamide.
 ATG may be added to prevent rejection of graft.
STEM CELL PROCESSING & INFUSION:
 In this stem cells are taken from donor after harvesting and then passed from a machine
which deplete the T Cells to decrease the chance of GVHD.
 Infusion of cells via CVP like B.Tx.
NEUTROPENIC PHASE:
 Last 2-4 wk in which no effective immune system

 Poor healing.
 Supportive care with empirical antibiotic needed.
 HSV may get reactivate.
 Endogenous flora like , skin, GUT organism .
 Hospital acquired infection esp fungal infection.
 Fever occur.
438
ENGRAFTMENT STAGE:

 Cells go to B/M and start producing normal cells.
 Several weeks take
 Fever subsides and resolution of mucositis.
 Chance of GVHD & veno occlusive disease.
POST-ENGRAFTMENT PHASE:
 Months to yrs.
 Weaning off of immunosuppression.
 Management of chronic GVHD.
 Re-immunization after 1 year of transplant with DT (then check titre after 1 mnth), IPV &
yearly influenza.
 If protecton titre obtained from Tetanus vaccine proceed with Hib , pneumococcal and Hep-
B.
 MMR after 2 year.
 Note : if patient immunized successfully with above vaccine then off immunosupressants for
6 months & no chronic GVHS present.
OUTCOME IS IMPROVED BY:
1. Good supportive care

2. Antibiotic regime
3. HLA matching.
PROGNOSIS:
NON MALIGNANT:
 Matched sibling donor 70-90%.

 Unrelated 30-65%.
MALIGNANT: ALL/AML-
 Related donor – 55-68%.

 Unrelated donor - 25-50%.
SUITABILITY:
 < 55 Yr age of recipient.

 Healthy.
 HLA matched donor & recipient. 439
 1 in 4 chance of having HLA match sibling.

 Allogenic tx – close HLA matching .

OBTAINING A GRAFT:
1). B.M – Illiac crest – puncture under GA
2). PERPHERAL stem cell transplant : stem cells are mobilized by single agent chemo or
hematopoietic growth factor like GMCSF . when WBC increase after 7-12 days then individual is
connected to T cell separator machine –blood is drawn off , spun and centrifuge , stem cells
harvested & remaining blood returned to pt ( it takes 2-4 hr).
3). AUTOLOGOUS TRANSPLANT:
 Recipient whIle in “remission” undergoes B.M/ peripheral stem cell harvest .

 Stem cells are processed, frozen in liquid nitrogen .
 Recipient starts conditioning –1 day after end of conditioning stem cell product is thawed &
infused i.v.
COMPLICATIONS:
AUTOLOGUS:
 Residual cancer cells can cause relapse.

 Conditioning toxicity (infertility, malignancy).
 Infection in cytopenic state.
ALLOGENIC:
 Marrow rejection.
 GVHD.
 Infection.
 Acute regime related toxicity ( veno-occlusive disease, pneumonitis).
GRAFT VERSUS HOST DISEASE (GVHD).
Major cause of morbidity and mortality after allogenic HSCT .
Engraftment of immunocompitent donor lymphocytes (T) in an immunocompromised host with T

cell activation against HOST MHC antigen and attack entirely body called GVHD.
this involve skin , GIT, liver. 440
ACUTE GVHD:
 Develop 2-5 week post transplantation. (<100 day after BMT).

 Erythematous maculopapular rash.
 Anorexia , vomiting, diarrhea.
 INCREASE billirubin, ALT ,AST, ALP,
DIAGNOSIS:
 SKIN , liver , GIT Bx.

PROGNOSIS:
GRADE 1—good – usually no trx required.
GRADE II- moderate – severe disease – trx required usually.
GRADE III- severe multiorgan disease.
GRADE-IV- life threatening.
CHRONIC GVHD:
 Develop / persist > 3 month after transplant (>100 days aftr transplant).
 incidence: 25%.
Increase risk in :
 Matched unrelated donor.

 Peripheral blood as stem source.
 Oldr donor/ recipient.
 Female for male recipient.
 Dx of malignancy ans use of TBI as a part of prep regime.
If only skin and liver involved –favourable prognosis.
Extensive multiorgan disease –poor prognosis.
TREATMENT : single agent prdnisolone or CSA.
+ ANTIBIOTICS AND SEPTRAN
1-3 YR OF IMMUNOSUPPRESION.
PROPHYLAXIS OF GVHD:
441
Post transplant immunosuppressive drugs e.g: cyclosporine or tacrolimus, or combination of MTX ,
prdnisolone, MMF
OR

Remove T lymphocyte from graft.
Despite prophylaxis: 30% Develop GVHD after BMT from matched sib.
While 60% from the unrated donor.
INCREASE RISK OF GVHD:
Malignant disease.
Older donor/ recipient.
Unmanipulated allograft
Prophylaxis with only one drug.
TREATMENT OF GVHD:
Steroids.
ATG
Monoclonal antibodies.
Extracorporal photopharesis.
Clinical Staging and Grading of Graft Versus Host Disease (GVHD)
STAGE SKIN LIVER INTESTINAL TRACT
+ Maculopapular rash <25% of body surface Bilirubin 2–3 >500 mL diarrhea/day

mg/dL
++ Maculopapular rash 25%–50% of body Bilirubin 3–6 >1,000 mL diarrhea/day

surface mg/dL
+++ Generalized erythroderma Bilirubin 6–15 >1,500 mL diarrhea/day

mg/dL
++++ Generalized erythroderma with bullous Bilirubin >15 Severe abdominal pain with
formation and desquamation mg/dL or without ileus 442

GVHD SKIN LIVER INTESTINAL TRACT DECREASE IN CLINICAL
GRADE STAGE STAGE STAGE PERFORMANCE
I + to ++ 0 0 None
II + to +++ + + Mild
III ++ to +++ ++ to ++++ ++ to +++ Marked
IV ++ to ++++ ++ to ++++ ++ to ++++ Extreme
MISCELLANEOUS FACTS ABOUT ALL.
 Cyclophoshamide should be given in morning bacuse in morning more use of water which
lead to decrease risk of hemorrhagic cystitis.
 Amphotericin B is broadspectrum antifungal and covers both candidial and asparagilus but
fluconazol cover asparagilus & only cover candida.
 We do BMA on day 8 after induction start to decide for prophylactic cranial radiation if M1
(<5% blast ) that is RER rapid early response –no need for cranial irradiation.If M3 (>25%) it is
slow early response SER. then treat as high risk –go for cranial radiation and extend
treatment induction.
 BMA on 29 day if M1&2 then CNS INTENSIFICATION, while M3 Then off study.
 BMA 43 DAY indicated for M1&2 On day 29 –if M1 then continue treatment with induction if
M2,3 then off study.
 In peripheral smear if a single blast cell it favour to ALL because when bone marrow have
25% blast cells then it appears in peripheral blood, but if peripheral smear reveal >25% blast
cells then it confirm then we can do direct immunochemistry with certain cell markers.
443

INFLAMMATORY BOWEL DISEASE ----------------------------------------------------------LONG CASE.
2 distinctive disorders of idiopathic chronic intestinal inflammation:
1. Crohn disease
2. Ulcerative colitis.
3. Indeterminate colitis, represents ∼10% of pediatric patients. –(mixed picture of
CD & UC)
 A bimodal distribution has been shown with an early onset at 10-20 yr of age and
a 2nd, smaller peak at 50-80 yr of age.
 IBD may begin as early as the 1st yr of life, and an increased incidence among young
children has been observed since the turn of the century.
 Children with early-onset IBD are more likely to have colonic involvement.
 In developed countries, these disorders are the major causes of chronic intestinal
inflammation in children beyond the 1st few yr of life.
Genetic + Abnormal mucosal immune response and environmental influences are involved in the
pathogenesis of IBD.
 The risk of IBD in family members of an affected person has been reported in the range of 7-
30%;
 A child whose parents both have IBD has a >35% chance of acquiring the disorder.
 Relatives of a patient with ulcerative colitis have a greater risk of acquiring ulcerative colitis than
Crohn disease, whereas relatives of a patient with Crohn disease have a greater risk of acquiring this
disorder; the 2 diseases can occur in the same family.
 The risk of occurrence of IBD among relatives of patients with Crohn disease is somewhat
greater than for patients with ulcerative colitis.
 Both twins will be affected if they are monozygotic rather than dizygotic.
 The concordance rate in twins is higher in Crohn disease (36%) than in ulcerative
colitis (16%).
GENETIC DISORDERS THAT HAVE BEEN ASSOCIATED WITH IBD:
 Turner syndrome.
 Glycogen storage disease type Ib.
 Immunodeficiency disorders.
 In 2001 the first IBD gene, NOD2.
 A perinuclear antineutrophil antibody (pANCA) is found in ∼70% of patients with
ulcerative colitis compared with <20% of those with Crohn disease. (UP=ULCERATIVE
=PANCA))
 55% Crohn disease are positive for anti-Saccharomyces cerevisiae (ASCA) antibody.
 Additional markers for crohns disease including:
444
 Antibody to Escherichia coli outer membrane porin (anti-OmpC).
 Anti-flagellin (anti-CBir1) antibodies

Environmental factors:
 Cigarette smoking is a risk factor for Crohn disease but paradoxically protects
against ulcerative colitis.
An abnormality in intestinal mucosal immunoregulation may be of primary importance in

the pathogenesis of IBDMediators of inflammation (cytokines, arachidonic acid
metabolites, reactive oxygen metabolites, growth factors) are involved, leading to tissue
destruction and remodeling with fibrosis. Most therapies are aimed at interfering with these
mediators.
Extraintestinal manifestations:
 more commonly with Crohn disease than with ulcerative colitis.

 Growth retardation is seen in 15-40% of children with Crohn disease at diagnosis.
 joint, skin, eye, mouth, and hepatobiliary involvement tend to be associated with
colitis, whether ulcerative or Crohn.
Manifestations which correlate with disease activity are:
1. peripheral arthritis.
2. Erythema nodosum.
3. Anemia.
manifeastations with no corealtion with disease activity:
1. sclerosing cholangitis.
2. ankylosing spondylitis.
3. Sacroiliitis.
Activity of pyoderma gangrenosum correlates less well with activity of the bowel disease,
Arthritis occurs in 3 patterns: (common examiner Q)
1. Migratory peripheral arthritis involving primarily large joints.

2. Ankylosing spondylitis.
3. Sacroiliitis.
The peripheral arthritis of IBD  nondestructive.
Ankylosing spondylitis—Appear in 3rd decade-mostly in UC pts with HLA-B27+.
S/S :
445
 low back pain.
 Morning stiffness.
 Back, hips, shoulders, and sacroiliac joints are typically affected.

 Isolated sacroiliitis is usually asymptomatic.
Among the skin manifestationserythema nodosum is most common.
 Patients with erythema nodosum or pyoderma gangrenosum have a high likelihood of

having arthritis as well.
 Glomerulonephritis, uveitis, and a hypercoagulable state are other rare manifestations
that occur in childhood.
 Cerebral thromboembolic disease has been described in children with IBD.
COMPARISON OF CROHN DISEASE AND ULCERATIVE COLITIS

FEATURE CROHN DISEASE ULCERATIVE COLITIS
Rectal bleeding Sometimes Common
Diarrhea, mucus, pus Variable Common
Abdominal pain Common Variable
Abdominal mass Common Not present
Growth failure Common Variable
Perianal disease Common Rare
Rectal involvement Occasional Universal
Pyoderma gangrenosum Rare Present
Erythema nodosum Common Less common
Mouth ulceration Common Rare
Thrombosis Less common Present
Colonic disease 50-75% 100%
Ileal disease Common None except backwash ileitis
Stomach-esophageal disease More common Chronic gastritis can be seen
Strictures Common Rare
Fissures Common Rare
Fistulas Common Rare
Toxic megacolon None Present
Sclerosing cholangitis Less common Present
Risk for cancer Increased Greatly increased
Discontinuous (skip) lesions Common Not present
Transmural involvement Common Unusual
Crypt abscesses Less common Common
Granulomas Common None
Linear ulcerations(FLASK) Uncommon Common 446

EXTRAINTESTINAL COMPLICATIONS OF INFLAMMATORY BOWEL
DISEASE
MUSCULOSKELETAL
Peripheral arthritis
Rheumatoid arthritis
Sacroiliitis
Ankylosing spondylitis
Digital clubbing and hypertrophic osteoarthropathy
Periosteitis
Osteoporosis, osteomalacia
Recurrent multifocal osteomyelitis
SKIN AND MUCOUS MEMBRANES
Oral lesions
Cheilitis
Apthous stomatitis, glossitis
DERMATOLOGIC
Erythema nodosum
Pyoderma gangrenosum
Metastatic Crohn disease
Psoriasis
Perianal skin tags
Polyarteritis nodosa
OCULAR
Conjunctivitis
Uveitis, iritis
Episcleritis
Scleritis
Retrobulbar neuritis
Chorioretinitis with retinal detachment
Crohn keratopathy
Posterior segment abnormalities
Retinal vascular disease
BRONCHOPULMONARY
Chronic bronchitis with bronchiectasis
Chronic bronchitis with neutrophilic infiltrates
Fibrosing alveolitis
Pulmonary vasculitis
Small airway disease and bronchiolitis obliterans
Eosinophilic lung disease 447
Granulomatous lung disease
CARDIAC
Pleuropericarditis

Cardiomyopathy
Endocarditis
Myocarditis
MALNUTRITION
Decreased intake of food
• IBD
• Dietary restriction
Malabsorption
• IBD
• Bowel resection
• Bile salt depletion
• Bacterial overgrowth
Intestinal losses
• Electrolytes
• Minerals
• Nutrients
Increased caloric needs
• Inflammation
• Fever
HEMATOLOGIC
Anemia: iron deficiency (blood loss)
Vitamin B12 (ileal disease or resection, bacterial overgrowth, folate deficiency)
Anemia of chronic inflammation
Anaphylactoid purpura (Crohn disease)
Hyposplenism
Autoimmune hemolytic anemia
Coagulation abnormalities
Increased activation of coagulation factors

Activated fibrinolysis
Anticardiolipin antibody
Increased risk of arterial and venous thrombosis with cerebrovascular stroke, myocardial
infarction, peripheral arterial, and venous occlusions
RENAL AND GENITOURINARY

Metabolic
448
• Urinary crystal formation (nephrolithiasis, uric acid, oxylate)
Hypokalemic nephropathy
Glomerulitis

Membranonephritis
Renal amyloidosis, nephrotic syndrome
PANCREATITIS
Secondary to medications (sulfasalazine, 6-mercaptopurine, azathioprine, parenteral nutrition)
Ampullary Crohn disease
Granulomatous pancreatitis
Decreased pancreatic exocrine function
Sclerosing cholangitis with pancreatitis
HEPATOBILIARY
PSC
Fatty infiltration of the liver
Cholelithiasis
Autoimmune hepatitis
ENDOCRINE AND METABOLIC
Growth failure, delayed sexual maturation
Thyroiditis
Osteoporosis, osteomalacia
NEUROLOGIC
Peripheral neuropathy
Meningitis
Vestibular dysfunction
Pseudotumor cerebri
CROHN DISEASE (REGIONAL ENTERITIS, REGIONAL ILEITIS, GRANULOMATOUS COLITIS)
 Crohn disease, an idiopathic, chronic inflammatory disorder of the bowel, involves

any region of the alimentary tract from the mouth to the anus.
 The inflammatory processeccentric and segmental  often with skip areas.
 inflammation in ulcerative colitis is limited to the mucosa (except in toxic
megacolon),
 Crohn disease  transmural.
 pediatric Crohn disease more extensive involvement of intestine than adults.
 At initial presentation, >50% of patients have disease that involves ileum and colon
(ileocolitis).
 20% have exclusively colonic disease.
 Upper GI involvement (esophagus, stomach, duodenum) is seen in up to 30% of
children.
 Isolated small bowel disease < in children than adults. 449
 Bimodal age distribution: with the 1st peak beginning in the teenage years. The
incidence of Crohn disease has been increasing, whereas that of ulcerative colitis
has been stable.

 the reported incidence of pediatric Crohn disease is 4.56/100,000 and the pediatric
prevalence is 43/100,000.—(USA)
 inflammatory, stricturing, or penetrating.

 small bowel disease  obstructive pattern (most commonly with right lower
quadrant pain) characterized by fibrostenosis.
 Colonic disease  Inflammatory symptoms (infectious)(diarrhea, bleeding,
cramping).
 Systemic signs and symptoms are more common in Crohn disease than in
ulcerative colitis. Fever, malaise, and easy fatigability are common.
 Growth failure with delayed bone maturation and delayed sexual development can
precede other symptoms by 1 or 2 yr >>in CD .
 Children can present with growth failure as the only manifestation of Crohn disease.
 Causes of growth failure in CD:
 Inadequate caloric intake.
 Malabsorption.
 Chronic inflammation on bone metabolism and appetite.
 Use of corticosteroids during treatment.
 Primary or secondary amenorrhea and pubertal delay are common.
 Perianal disease is common (tags, fistula, abscess).
 Gastric or duodenal involvement  recurrent vomiting and epigastric pain.
 Partial small bowel obstruction, usually secondary to narrowing of the bowel
lumen from inflammation or stricture, can cause symptoms of cramping abdominal
pain (especially with meals), borborygmus, and intermittent abdominal distention.
 Stricture should be suspected  if the child notes relief of symptoms in association
with a sudden sensation of gurgling of intestinal contents through a localized region
of the abdomen.
Penetrating disease  fistula formation
 Enteroenteric or enterocolonic fistulas.

 Enterovesical fistulaurinary infection, pneumaturia, or fecaluria.
 Enterovaginal fistulasoriginate from the rectum  cause feculent vaginal
drainage, and are difficult to manage.
 Enterocutaneous fistulas  often are caused by prior surgical anastomoses with
leakage
Intra-abdominal abscess  fever and pain .

450
Splenic abscess+/-.
Anorectal abscesses often originate immediately above the anus at the crypts of Morgagni.

perianal fistulas  Purulent drainage
Perianal abscess usually painful
Psoas abscess secondary to intestinal fistula can present as hip pain, decreased hip
extension (psoas sign), and fever.
Extraintestinal manifestations :
more commonly with Crohn disease than with ulcerative colitis.
Especially associated with Crohn disease include:
 Oral aphthous ulcers.

 Peripheral arthritis.
 Erythema nodosum.
 Digital clubbing.
 EpiscleritiS.
 renal stones (uric acid, oxalate), and gallstones.
The peripheral arthritis is nondeforming.
 The occurrence of extraintestinal manifestations usually correlates with the presence of colitis.
 Extensive involvement of small bowel, especially in association with surgical resection, can lead to
short bowel syndrome.
 Complications of terminal ileal dysfunction or resection include bile acid malabsorption with
secondary diarrhea and vitamin B12 malabsorption—(MEAGALOBLASTIC ANEMIA)
 Chronic steatorrhea can lead to oxaluria with secondary renal stones.
 The risk of cholelithiasis is also increased secondary to bile acid depletion.
DIFFERENTIAL DIAGNOSIS
1. infectious enteropathies (Most common)

2. Yersinia  can cause many of the radiologic and endoscopic findings in the distal small bowel that are
seen in Crohn disease.
3. Bacterial dysentery  are more likely to be mistaken for ulcerative colitis than for Crohn disease.
4. Celiac disease and Giardia infection have been noted to produce a Crohn-like presentation
including diarrhea, weight loss, and protein-losing enteropathy.
5. GI tuberculosis  mimic Crohn disease.
6. Foreign-body perforation of the bowel  (toothpick) can mimic a localized region with Crohn
disease. Small bowel lymphoma can mimic Crohn disease but tends to be associated with nodular
filling defects of the bowel without ulceration or narrowing of the lumen. 451
7. Recurrent functional abdominal paincan mimic the pain of small bowel Crohn disease.
8. Lymphoid nodular hyperplasia of the terminal ileum (a normal finding) may be mistaken for Crohn
ileitis.

9. periappendiceal abscess  Right lower quadrant pain or mass with fever can be the result of. This
entity is occasionally associated with diarrhea as well.
10.
Growth hormone deficiency, gluten-sensitive enteropathy (celiac disease), Turner syndrome, or
anorexia nervosa Growth failure may be the only manifestation of Crohn disease; other disorders such
as must be considered.
11. JIA In case If arthritis precedes the bowel manifestations.
12. Leukemia  can manifest with abdominal pain in association with an abnormal blood cell count and
might initially be mistaken for Crohn disease.
13. Chronic granulomatous disease of childhood can cause inflammatory changes in the bowel as well as
perianal disease Antral narrowing in this disorder may be mistaken for a stricture secondary to Crohn
disease.
DIFFERENTIAL DIAGNOSIS OF PRESENTING SYMPTOMS OF CROHN DISEASE

PRIMARY PRESENTING SYMPTOM DIAGNOSTIC CONSIDERATIONS
Right lower quadrant abdominal Appendicitis, infection (e.g., Campylobacter, Yersinia spp.), lymphoma,
pain, with or without mass intussusception, mesenteric adenitis, Meckel diverticulum, ovarian cyst
Chronic periumbilical or epigastric
Irritable bowel syndrome, constipation, lactose intolerance, peptic disease
abdominal pain
Rectal bleeding, no diarrhea Fissure, polyp, Meckel diverticulum, rectal ulcer syndrome
Infection, hemolytic-uremic syndrome, Henoch-Schonlein purpura,
Bloody diarrhea
ischemic bowel, radiation colitis
Irritable bowel syndrome, lactose intolerance, giardiasis, Cryptosporidium
Watery diarrhea
infection, sorbitol, laxatives
Perirectal disease Fissure, hemorrhoid (rare), streptococcal infection, condyloma (rare)
Growth delay Endocrinopathy
Anorexia, weight loss Anorexia nervosa
Arthritis Collagen vascular disease, infection
Liver abnormalities Chronic hepatitis
DIAGNOSIS
 At the onset, symptoms may be subtle (growth retardation, abdominal pain alone); this explains why
the diagnosis might not be made until 1 or 2 years after the start of symptoms.
 The diagnosis of Crohn disease depends on finding typical clinical features of the disorder (history,
physical examination, laboratory studies, and endoscopic or radiologic findings), ruling out specific
entities that mimic Crohn disease, and demonstrating chronicity.
 The history can include any combination of abdominal pain (especially right lower quadrant), diarrhea,
vomiting, anorexia, weight loss, growth retardation, and extraintestinal manifestations.
 Only 25% initially have the triad of diarrhea, weight loss, and abdominal pain. Most do not have
diarrhea, and only 25% have GI bleeding.
 Children with Crohn disease often appear chronically ill.
 They commonly have weight loss and growth failure, and they are often malnourished.
 The earliest of sign of growth failure is decreased height velocity, which can be present in up to
88% of prepubertal patients with Crohn disease and typically precedes symptoms.
 Children with Crohn disease often appear pale, with decreased energy level and poor appetite; the latter 452
finding sometimes results from an association between meals and abdominal pain or diarrhea.
ON EXAMINATION:

 abdominal tenderness -- diffuse or localized to the right lower quadrant.
 A tender mass or fullness may be palpable in the right lower quadrant.
 Perianal disease, when present, may be characteristic.
 Large anal skin tags (1-3 cm diameter) or perianal fistulas with purulent drainage suggest Crohn
disease.
 Digital clubbing, findings of arthritis, and skin manifestations may be present.
INVESTIGATIONS:
CBC  anemia--iron deficiency/Megalo. /WBC mild /N Plt count.
ESR  elevated, may be normal.
Serum albumin level  --( small bowel inflammation or protein-losing enteropathy)
STOOL C.E = Fecal calprotectin or lactoferrin is often elevated.
Anti–Saccharomyces cerevisiae antibodies.
Antibody to Escherichia coli outer membrane porin (anti-OmpC), and anti-flagellin (anti-CBir1)
antibodies are associated with Crohn's disease.
ABDOMINAL –XRAY –thumb printing on colon wall /partial intestinal obstruction.
BARIUM CONTRAST STUDIES:
small bowel follow-through  aphthous ulceration and thickened, nodular folds as well as
narrowing or stricturing of the lumen. Linear ulcers can give a cobblestone appearance to the
mucosal surface, fistulas between bowel (enteroenteric or enterocolonic), sinus tracts, and strictures
SMALL BOWEL ULTRASOUND
ENDOSCOPYThe small and large bowel and the upper GI tract .
Esophagogastroduodenoscopy and ileocolonoscopy should be performed to properly assess the

upper GI tract, terminal ileum, and entire colon.
Findings on colonoscopy:
 patchy, nonspecific inflammatory changes (erythema, friability, loss of vascular pattern), aphthous
ulcers, linear ulcers, nodularity, and strictures.
Findings on biopsy:
 may be only nonspecific chronic inflammatory changes.

 Noncaseating granulomas similar to those of sarcoidosis are the most characteristic histologic
findings, although often they are not present.
 Transmural inflammation is also characteristic but can be identified only in surgical specimens.
453
CT AND MR ENTEROGRAPHY –wall thickening and abscess/fistula.
VIDEO CAPSULE ENDOSCOPY has revealed evidence of small bowel mucosal lesions in some patients
with normal radiologic evaluation.

TREATMENT
Crohn disease cannot be cured by medical or surgical therapy.
The aim of treatment is to relieve symptoms and prevent complications of chronic inflammation
(anemia, growth failure), prevent relapse, minimize corticosteroid exposure, and, if possible,
effect mucosal healing.
MEDICAL RX:
INDUCTION:
1st line
 Exclusive enteral nutrition—elemental diet.

 Polymeric diet –(pediasure/ensure)
 Probiotic and TPN.
Give by mouth / NG –problem is compliance because elemental diet take 4-6 week for complete
remsission and child can’t stay away from food for such a long period of time.
IN MILD TO MODRATE DISEASE:
 5-ASA –(active ingredient –enteric coated –PH protective/ and sustained release. S/E -
Nephrotoxic
 Sulfasalazine –(sulfapyridine linked to 5ASA) –S/E : rash/BM Supression.
 Mesalazine (50-100mg/kg/day) –oral/enema.
2nd line therapy: --(for moderate to severe)
 Corticosteroids (budesonode—released in small intestine and has fewer side effects than
prednisolon)
 Oral/enema.
 INFLIXIMAB
Given on 0,2,6 wks then maintain remsiison if given every 8-12 weeks.
Give TPN in hospital or at home or elemental diet.
FOR MILD TERMINAL ILEAL DISEASE OR MILD CROHN DISEASE OF THE COLON
(WITHOUT COMPLICATION)
 initial trial of mesalamine (50-100 mg/kg/day, maximum 3-4 g) may be attempted.

 5 ASA. 454
 Rectal preparations are used for distal colonic inflammation.
(WITH COMPLICATION) /perianal disease

 metronidazole (10-20 mg/kg/day)
 Corticosteroids continue to be a mainstay of therapy for acute exacerbations of pediatric Crohn
disease because they effectively suppress acute inflammation, rapidly relieving symptoms.
EXTENSIVE OR SEVERE SMALL BOWEL OR COLONIC DISEASE:
 corticosteroids (prednisone, 1-2 mg/kg/day, maximum 40-60 mg).
The goal is to taper dosing as soon as the disease becomes quiescent.
There is no role for continuing corticosteroids as maintenance therapy because, in addition to

their side effects, tolerance develops and steroids have not been shown to change disease
course or promote healing of mucosa.
 controlled ileal-release formulation of budesonide  a corticosteroid with local anti-inflammatory

activity on the bowel mucosa and with high hepatic first-pass metabolism, is also used for mild to
moderate ileal or ileocecal disease.
Budesonide appears to be more effective than mesalamine in the treatment of active

ileocolonic disease but is less effective than prednisone.
BEST TO PREFER IMMUNOMODULATORS AZA /6-MP, WHEN STEROIDS MORE SIDE EFFECTS COZ IT
HAS LESS SYSTEMIC EFECTS.
azathioprine (2.0-2.5 mg/kg/day) or 6-mercaptopurine (1.0-1.5 mg/kg/day) may be effective in

some children who have a poor response to prednisone or who are steroid dependent.
Because a beneficial effect of these drugs can be delayed for 3-6 mo after starting therapy, they
are not helpful acutely. (SHOW EFFECT AFTER 3-6 MONTH).
Methotrexate is another immunomodulator that is effective in the treatment of active Crohn's

disease  improve height velocity in the 1st year of administration.
 Advantages MTX : include once-weekly dosing by either subcutaneous or oral route (10 mg weekly
for 20-29 kg, 15 mg weekly for 30-39 kg, 20 mg weekly for 40-49 kg, 25 mg weekly for >50 kg) and a
more-rapid onset of action (6-8 wk) than azathioprine or 6-mercaptopurine.
 Folic acid is usually administered concomitantly to decrease medication side effects. The
immunomodulators are effective for the treatment of perianal fistulas.
FOR MAINTAINANCE OF REMISSION:
Immunomodulators are fist line of choice for this maintance
 6-MP
 AZATHIOPRINE. 455
 INFLIXIMAB The onset of action of infliximab is quite rapid and it is initially given as 3
infusions over a 6 wk period (0, 2, and 6 wk) then every 2-3 monthly.
 Dose: 5mg/kg i.v
 Indications:

 Presence of stricture.
 Fistula formation.
 Perianal abscess.
 No response to 5-ASA.
 Duration of action – 4-8 wk.
 S.E:
 infusion reactions.
 increased incidence of infections (especially reactivation of latent
tuberculosis).
 increased risk of lymphoma.
 (leukocytoclastic vasculitis).
 Anti-body to infliximab –then poor response & more allergic reactions.
Pre-requisty: A purified protein derivative (PPD) test for tuberculosis should be done before
starting infliximab.
Contra-indication : Active or latent intra-abdominal infection (abscess) is a contraindication

to infliximab therapy.
 ADALIMUMAB  subcutaneously administered, fully humanized monocloncal antibody against

TNF-α, has also been shown to be effective for the treatment of chronically active moderate to severe
EXCLUSIVE ENTERAL NUTRITIONAL THERAPY is an effective primary as well as adjunctive

treatment.
 The enteral nutritional approach (elemental or polymeric diets) is as rapid in onset of response and as
effective as the other treatments. Pediatric studies have suggested similar efficacy to prednisone for
improvement in clinical symptoms, but enteral nutritional therapy is superior to steroids for
actual healing of mucosa.
 Because elemental diets are relatively unpalatable, they are administered via a nasogastric or
gastrostomy infusion, usually overnight.
The advantages of elemental diet:
 free of side effects.

 avoids the problems associated with corticosteroid therapy.
 addresses the nutritional rehabilitation.
 Children can participate in normal daytime activities.
disadvantage of this approach:
 patients are not able to eat a regular diet because they are receiving all of their calories from formula.
perianal and colon disease does not respond well.
 For children with growth failure, this approach may be ideal, however.
.
456
The continuous administration of nocturnal nasogastric feedings for chronic malnutrition and growth
failure has been effective with a much lower risk of complications than parenteral

hyperalimentation. The efficacy of probiotics and omega-3 fatty acids in the treatment of Crohn
disease is controversial.
SURGERY
 Surgery is the treatment of choice for localized disease of small bowel or colon that is unresponsive to
medical treatment, bowel perforation, fibrosed stricture with symptomatic partial small bowel
obstruction, and intractable bleeding
 Recurrence rate after bowel resection is high (>50% by 5 yr); the risk of requiring additional surgery
increases with each operation.
 Complications of surgery: fistula or stricture, anastomotic leak, postoperative partial small bowel
obstruction secondary to adhesions, and short bowel syndrome.
 Perianal abscess often requires drainage unless it drains spontaneously.
 In general, perianal fistulas should be managed by a combined medical and surgical approach.
 symptomatic perianal fistula can require fistulotomy.
 Postoperative medical therapy with agents such as mesalamine, metronidazole, azathioprine,
and, more recently, infliximab, is often given to decrease the likelihood of postoperative
recurrence.
PROGNOSIS
 Crohn disease is a chronic disorder that is associated with high morbidity but low mortality.
 Symptoms tend to recur despite treatment .
 Weight loss and growth failure can usually be improved with treatment and attention to nutritional
needs.
 Up to 15% of patients with early growth retardation secondary to Crohn disease have a permanent
decrease in linear growth. Osteopenia is particularly common in those with chronic poor nutrition and
frequent exposure to high doses of corticosteroids.
 Some of the extraintestinal manifestations can, in themselves, be major causes of morbidity, including
sclerosing cholangitis, chronic active hepatitis, pyoderma gangrenosum, and ankylosing spondylitis.
 Despite these complications, most children with Crohn disease lead active, full lives with intermittent
flare-up in symptoms.
NEW ADVANCES IN CHRONS DISEASE:
 Bone marrow ablation and stem cell transplantation

 New biologic agents—ABETACEPT, VISILUMAB.
DRUG TRADE NAME AVAILABILITY:
 Mesalazine = ascol 400 mg.

 Sulfasalazine = salazyopyrine =500 mg.
457
ULCERATIVE COLITIS

 idiopathic chronic inflammatory disorder, is localized to the colon and spares the upper gastrointestinal
(GI) tract.
 Disease usually begins in the rectum and extends proximally for a variable distance.
 Ulcerative proctitis localized to the rectum / 30% proximal spread –less systemic manifestations /
less responsive to treatment
 Pancolitis entire colon / 50-80%  extensive colitis
 adults more commonly have distal disease.
 The incidence of ulcerative colitis  remained relatively constant, in contrast to an increase in Crohn
disease.
 The prevalence of ulcerative colitis in northern European countries and the United States varies from
100 to 200/100,000 population.
 Men are slightly more likely to acquire ulcerative colitis than are women; the reverse is true for Crohn
disease.
 Blood, mucus, and pus in the stool as well as diarrhea are the typical presentation of ulcerative
colitis. Constipation in proctitis.
 Tenesmus, urgency, cramping abdominal pain (especially with bowel movements), and nocturnal
bowel movements are common.
FULMINANT COLITIS is defined as any child with following:
 Fever.
 Severe anemia.
 Hypoalbuminemia.
 Leukocytosis.
 5 bloody stool/ day for 5 days.
Symptoms beyond 2 week duration often prove to be secondary to IBD , otherwisw may be transient
infectious colitis.
 Anorexia, weight loss, and growth failure may be present, although these complications are more
typical of Crohn disease.
Extraintestinal manifestations that tend to occur more commonly with ulcerative colitis than with
Crohn disease include:
 Pyoderma gangrenosum.
 Sclerosing cholangitis.
 Chronic active hepatitis.
 Ankylosing spondylitis.
 Iron deficiency can result from chronic blood loss as well as decreased intake.
 Folate deficiency is unusual but may be accentuated in children treated with sulfasalazine, which
interferes with folate absorption.
 Chronic inflammation and the elaboration of a variety of inflammatory cytokines can interfere with
erythropoiesis and result in the anemia of chronic disease.
 Secondary amenorrhea is common during periods of active disease. 458
 The clinical course of ulcerative colitis is marked by remission and relapse, often without apparent
explanation.
 After treatment of initial symptoms, ∼5% of children with ulcerative colitis have a prolonged remission
(>3 yr).

 About 25% of children presenting with severe ulcerative colitis require colectomy within 5 yr of
diagnosis, compared with only 5% of those presenting with mild disease.
 It is important to consider the possibility of enteric infection with recurrent symptoms; these infections
can mimic a flare-up or actually provoke a recurrence.
 The use of nonsteroidal anti-inflammatory drugs is considered by some to predispose to exacerbation.
 risk of colon cancer begins to increase after 8-10 yr of disease and can then increase by 0.5-1% per yr.
 it is recommended that patients who have had ulcerative colitis for >10 yr be screened with
colonoscopy and biopsies every 1-2 yr.
Classification according to severity.

 MILD UC
o Gradual onset of frequent diarrhea <4 stool/day.
 MODERATER UC:
o More frequent rectal bleeding.
 SEVER UC:
o >6-10 Bloody diarrhea /day with severe anemia.
D/D:
1. Infectious colitis.—(TB abdomen)

2. Allergic colitis.
3. Crohn colitis. –(In early stage it present same like UC but on follow up with time pt develop small
intestine manifestations.)
4. In the setting of antibiotic use, pseudomembranous colitis secondary to Clostridium difficile should
be considered.
5. Cytomegalovirus infection: (can mimic ulcerative colitis or be associated with an exacerbation of
existing disease)
6. Henoch-Schonlein purpura :--(can manifest as abdominal pain and bloody stools, it is not usually
associated with colitis)
7. Behcet disease:
8. radiation proctitis.
9. viral colitis in immunocompromised patients.
10. ischemic colitis.
11. In infancy although rare UC  CPMA –transient/ rsolve with removal of offending agent/ with hx of
atopy and wheezing+.
12. Hirschsprung disease can produce an enterocolitis before or within months after surgical
correction; this is unlikely to be confused with ulcerative colitis.
NOTE: Every child with a new diagnosis of ulcerative colitis should have stool cultured for enteric
pathogens, stool evaluation for ova and parasites, and perhaps serologic studies for amebae.
INFECTIOUS AGENTS MIMICKING INFLAMMATORY BOWEL DISEASE
AGENT MANIFESTATIONS DIAGNOSIS COMMENTS

459
BACTERIAL

Campylobacter Acute diarrhea, fever, fecal blood, Common in adolescents,

Culture
jejuni and leukocytes may relapse
Acute → chronic diarrhea, right

lower quadrant pain, mesenteric
Common in adolescents
Yersinia adenitis- pseudoappendicitis,
Culture as FUO, weight loss,
enterocolitica fecal blood, and leukocytes
abdominal pain
Extraintestinal manifestations,
mimics Crohn disease
Postantibiotic onset, watery →

Clostridium bloody diarrhea, May be nosocomial
Cytotoxin assay
difficile pseudomembrane on Toxic megacolon possible
sigmoidoscopy
Escherichia coli Colitis, fecal blood, abdominal Hemolytic-uremic

Culture and typing
O157:H7 pain syndrome
Watery → bloody diarrhea, food

Salmonella borne, fecal leukocytes, fever, Culture Usually acute
pain, cramps
Watery → bloody diarrhea, fecal

Shigella Culture Dysentery symptoms
leukocytes, fever, pain, cramps
Edwardsiella
Bloody diarrhea, cramps Culture Ulceration on endoscopy
tarda
May be chronic
Aeromonas
Cramps, diarrhea, fecal blood Culture Contaminated drinking
hydrophila
water
Plesiomonas Diarrhea, cramps Culture Shellfish source
Rarely bovine, now

Culture, PPD,
Tuberculosis Mycobacterium tuberculosis Can mimic Crohn disease
biopsy
Ileocecal area, fistula formation
PARASITES
Trophozoite in 460
Entamoeba Acute bloody diarrhea and liver stool, colonic Travel to endemic area
histolytica abscess, colic mucosal flask
ulceration,

serologic tests
Foul-smelling, watery diarrhea, “Owl”-like

cramps, flatulence, weight loss; trophozoite and
Giardia lamblia no colonic involvement cysts in stool; rarely May be chronic
duodenal
NO BLOOD STOOLS intubation
AIDS-ASSOCIATED ENTEROPATHY
Mucosal findings not like

Cryptosporidium Chronic diarrhea, weight loss Stool microscopy
IBD
Isospora belli As in Cryptosporidium Tropical location
Colonic ulceration, pain, bloody More common when on

Cytomegalovirus Culture, biopsy
diarrhea immunosuppressive
DIAGNOSIS
One should be hesitant to make a diagnosis of ulcerative colitis in a child who has experienced
symptoms for <2-3 wk until infection has been excluded.
 CBC:
o Anemia-(MCH/AOCD)
o Elevated TLC –more severe fulminant colitis.
 ESR –raised
 CRP- raised
 S.ALBUMIN --low
 STOOL EXAMINATION: cyst/ ova/trophozoites,occult blood, leukocytes,culture for organisms, and
fecal calprotectin level.
 BARIUM CONTRAST STUDY –enema –helpful for chronic but un complicated disease, neither for
acute.
o Contraindication : toxic megacolon.
Features in late colitis:
o Colon shortened
o Reduced in diameter
o Dilatation of terminal ileum—(backwash ileitis).
 ENDOSCOPY—COLONOSCOPY  erythema, edema, loss of vascular pattern, granularity, and
friability. There may be a “cutoff” demarcating the margin between inflammation and normal colon, or 461
the entire colon may be involved.
CONTRAINDICATION OF COLONOSCOPY FULMINAT COLITIS coz risk of toxic
megacolon/perforation.

 ENDOSCOPIC TISSUE BIOPSY  cryptitis, crypt abscesses, separation of crypts by inflammatory
cells, foci of acute inflammatory cells, edema, mucus depletion, and branching of crypts. The last
finding is not seen in infectious colitis.
 PLAIN RADIOGRAPHS OF THE ABDOMEN  loss of haustral markings in an air-filled colon or
marked dilation with toxic megacolon. With severe colitisthe colon may become dilated; a diameter
of >6 cm, determined radiographically, in an adult suggests toxic megacolon
 pANCA
TREATMENT
Counceling
Supportive
Specific :
 A medical cure for ulcerative colitis is not available.

 treatment is aimed at controlling symptoms and reducing the risk of recurrence, with a secondary goal
of minimizing steroid exposure.
 About 20-30% of patients with ulcerative colitis have spontaneous improvement in symptoms.
INDUCTION REMISSION:
MILD DISEASE
 5-ASA
 Topical
 Oral
 Rctal enema/suppository—enema is given 50-100 ml retained for 1-1 ½ hr.
 Combination –(ideal)
MODERATE DISEASE:
 Systemic corticosteroids –few months.

 Aminosalicylic acid may be used
 Combination of 5ASA & Corticosteroids.
 Methylprednisolone pulses.
SEVERE DISEASE:
 Cyclosporine –rescue medication for severe colitis—response in 2-3 weeks.

 Advise bowel rest and start on TPN.
TOXIC MEGACOLON:
 Bowel rest –start TPN.

 Methylprednisolone pulses.
462
MAINTANILNCE REMSISSION:
 Corticosteroids
 Immunomodulators

 6-MP
 Azathioprine.
 Biological agent—Infliximab.
SURGERY:
Total abdominal colectomy with end ileostomy –removal of colon and rectum –cure intestinal
symptons but not extra intestinal manifestations .
Indications:
 Massive GIT hemorrhage

 Intestinal perforation
 Fulminant colitis
 Toxic megacolon
 No steroid response after 7-10 days.
Treatment of proctitis:
 Steroid –hydrocortisone enema

 5-ASA Oral / rectal—Suppository/enema.
 Probiotics.
Probiotics –
 best for maintiance of remission in UC

 Prevent pouchitis –a surgery complication
Disadvantage: Can’t induce remission.
Children with moderate to severe pancolitis or colitis that is unresponsive to 5-ASA therapy:
 oral corticosteroids prednisone  1-2 mg/kg/24 hr (40-60 mg maximum dose) OD Dose.

 With severe colitis, the dose can be divided twice daily and can be given intravenously.
 Steroids are considered an effective medication for acute flares.
 azathioprine (2.0-2.5 mg/kg/day) or 6-mercaptopurine (1-1.5 mg/kg/day).
 Cyclosporine, which has been associated with improvement in some children with severe or fulminant
colitis, is rarely used owing to high side-effect profile, the inability of this medication to change the
natural history of disease, and increasing use of infliximab TNF blocking agents are associated with
an increased risk of infection (particularly tuberculosis) and malignancies (lymphoma, leukemia).
463

DERMATOMYOSITIS --------------------------------------------long case/ short case.
Old case/ new case.
Presenting complaints of pt can be:
 Generalized Weakness of body.

 Difficulty in walking.
 Discharging cheesy Skin infections.
 Rash .
 Complications of taken treatment ( steroids ).
Hopc :
Clear in hx reason of current admission
Systemic review:
Most likely differentials of presenting complaints:
Questions For DMS.
Hx of characteristic rash above lid, thick nodules of knuckles, difficuly in rising up from sitting/lying
down , difficulty in climbing stairs, difficulty in combing, weakness more proximal / distal, is he able
to so routine work with hand, musle tenderness,Photosenserivity, dyspnea, dysphagia, drooling,
nasal regurgitation, hyponasality, polyurea, polydypsia , hyperpigmentation (metabolic syndrome),
preceding hx of URTI-(1/3RD Cases +), any hx of discoloured urine (myoglobinurea), visual
disturbance (retinopathy, cataract), mood swings, depression,
Questions for DMD.
Age of onset, course of weakness, progression, any calf hypertrophy sign, body swelling, respiratoy
distress, body sweliing, proximal muscle weakness questions, change in gait/ posture.
Questions for SLE.
Photosensitivity, malar rash –spare nasiolabial fold, hair loss, alopecia, urinary complaint , abdominal
pain, respiratory distress, altered sensorium, oral ulcer joint pain/ swelling.
Questions for Myasthenia Gravis:
Diurnal weakness, ptosis, diplopia.
Questions for scleroderma.
Tight thick skin, any color change in reference to raynaud phenomenon, contractures.
Questions for Mixed connective tissue –(very important and close differential to make if systemic
464
symptoms are along).
Past hx –when, where diagnosed, how managed, what invx & treatment given, follow up regular,
compliance tilldate.

 Investigations: Enzymes, muscle/ skin biopsy, MRI-xray- calf muscle, EMG/NCS.
 no. of admissions—(relapse/remissions)
 reasons of admissions—and determine patterns of illness like monocyclic/chronic polycyclic..
 development of comlicstions and their management , Change in treatment plan.
Management detail:
Current Rx and home Rx—their responses and S.E.
 Steroids –( when started oral/i.v, dose then tapering/ not, duration , any montoux test /CXR done before
associated side effects).
 Methotrexate –( when started, duration, oral/s/c, dose , who inject, any monitoring with LFTs- 3
monthly, any side effect observed?)
Questions regarding Complication of disease.
Questions regarding complication of treatment:
Current status, AODL—(eating, walking, speech, assistance required?, home modification

required?
Parents knowledge, concern.
Disease impact on child-schooling, sibs and parents.
Nutritional hx, vaccination Hx.
Birth hx—development hx.
Family hx: similar problem or any other autoimmune disease in family.
Socioeconomic hx.
EXAMINATION:
 Same approach as for all long cases.

 Locomotor system examination (Active first then passive).
 Gower sign.
DISCUSSION:
JUVENILE DERMATOMYOSITIS (JDM): 465
 Most common inflammatory myositis in children, distinguished by proximal muscle weakness and a
characteristic rash.

ETIOLOGY
 Multifactorial.
 Genetic predisposition.
HLA alleles such as B8, DRB1*0301, DQA1*0501, and DQA1*0301 have been associated with
increased susceptibility to JDM in selected populations. Maternal microchimerism Persistent
maternal cells have been found in blood and tissue samples of children with JDM these maternal
cells are positive for HLA-DQA1*0501, which may assist with transfer or persistence of chimeric
cells.
 Unknown environmental trigger.
 Geographic and seasonal clustering
 history of infection in the 3 mo prior to disease onset is commonly reported;
 Constitutional signs and upper respiratory symptoms predominate, but one third of
patients report preceding gastrointestinal (GI) symptoms. Group A streptococcus,
upper respiratory infections, GI infections, coxsackievirus B, toxoplasma,
enteroviruses, parvovirus B19 But these infectious serology comes negative .
Epidemiology
 The incidence of JDM is approximately 3 cases/1 million children/yr without racial predilection. Peak
age of onset is between 4 and 10 yr.
 There is a second peak of dermatomyositis onset in late adulthood (45-64 yr).
 ratio of girls to boys with JDM is 2 : 1.
PATHOGENESIS
Type I interferons may be important in the pathogenesis of juvenile dermatomyositis. Interferon

upregulates genes critical in immunoregulation and major histocompatibility class (MHC) class I
expression, activates natural killer (NK) cells, and supports dendritic cell maturation.
Upregulation of gene products controlled by type I interferons occurs in patients with

dermatomyositis, potentially correlating with disease activity and holding promise as clinical
biomarkers.
It appears that children with genetic susceptibility to JDM (HLA-DQA1*0501, HLA-DRB*0301) may
have prolonged exposure to maternal chimeric cells and/or an unknown environmental trigger. Once
triggeredinflammatory cascade with type I interferon response leads to upregulation of MHC class
I expression and maturation of dendritic cells.
Overexpression of MHC class I upregulates adhesion molecules, which influence migration of

lymphocytesinflammatory infiltration of muscle In an autoregulatory feedback loop, muscle
inflammation increases the type I interferon response, regenerating the cycle of inflammation.
CELLS INVOLVED IN CASCADE: 466
 NK cells (CD56).
 T-cell subsets (CD4, CD8, Th17).
 monocytes/macrophages (CD14).

MARKERS OF VASCULAR INFLAMMATION-(VIVA Q) elevated in patients with JDM who have
active inflammation.
1. Neopterin.
2. Interferon-inducible protein 10 (IP-10),.
3. Monocyte chemoattractant protein (MCP).
4. Myxovirus resistance protein (MxA).
5. Von Willebrand factor products.
 Children with JDM present with either rash, insidious onset of weakness, or both.
 Fevers, dysphagia or dysphonia, arthritis, muscle tenderness, and fatigue are also commonly reported at
diagnosis.
RASH:
 first symptom in 50% of cases.

 Concomitant with weakness (25%).
 Characteristic heliotrope rash—(blue-violet discoloration of the eyelids that may be associated with
periorbital edema.
 Classic Gottron papules:are bright pink or pale, shiny, thickened or atrophic plaques over the
proximal interphalangeal joints and distal interphalangeal joints and occasionally on the knees,
elbows, small joints of the toes, and ankle malleoli.
 The rash of JDM is sometimes mistaken for eczema or psoriasis.
 mechanic's hands: Rarely, a thickened erythematous and scaly rash develops in children over the
palms and soles along the flexor tendons. associated with anti-Jo-1 antibodies.
-------
 Facial erythema crossing the nasolabial folds is also commonin contrast to the malar rash without
nasolabial involvement typical of systemic lupus erythematosus.
 “shawl sign.”
 often extreme photosensitivity to ultraviolet light exposure with generalized
erythema in sun-exposed areas.
 If seen over the chest and neck, this erythema is known as the Erythema is also
commonly seen over the knees and elbows.
 Evidence of small vessel inflammation  visible in the nail folds and gums as individual capillary
loops that are thickened, tortuous, or absent.
 Telangiectasias may be visible to the naked eye but are more easily visualized under capillaroscopy
or with use a magnifier such as an ophthalmoscope.
 Cutaneous ulcers on toes, fingers, axillae, or epicanthal folds. Severe vascular inflammation.
WEAKNESS:
 insidious and difficult to differentiate from fatigue at onset.

 It is typically symmetric, affecting proximal muscles such as the neck flexors, shoulder girdle,
and hip flexors.
 difficulty climbing stairs, combing hair, and getting out of bed.
 Esophageal and respiratory muscles are also affected, resulting in aspiration or respiratory
467
failure.
 Dysphonia or nasal speech
 Dysphagia
 Gastroesophageal reflux.

 Respiratory muscle weakness do not manifest typical symptoms of impending respiratory
failure with increased work of breathing, instead demonstrating hypercarbia rather than
hypoxemia.
Examination 
 Inability to perform a sit-up, head lag in a child after infancy.

 Gower sign (use of hands on thighs to stand from a sitting position).
 Muscle tenderness as a result of muscle inflammation (1/2 cases).
 Palatal elevation with gag
 Respiratory muscle weakness can be a medical emergency and lead to respiratory failure.
 LIPODYSTROPHY AND CALCINOSIS: Associated with longstanding or undertreated disease.
Calcinosis :
 Dystrophic deposition of calcium phosphate, hydroxyapatite, or fluoroapatite crystals occurs

in subcutaneous plaques or nodules, resulting in painful ulceration of the skin with extrusion
of crystals or calcific liquid.
 Calcinosis is reported in up to 40% of children with JDM.
 In rare instances, an “exoskeleton” of calcium deposition forms, greatly limiting mobility.
Lipodystrophy :
 May be generalized or localized.

 Results in progressive loss of subcutaneous and visceral fat, typically over the face and
upper body.
 May be associated with a metabolic syndrome similar to polycystic ovarian syndrome with
insulin resistance, hirsutism, acanthosis, hypertriglyceridemia, and abnormal glucose
tolerance. Lipodystrophy.
 severe JDM Rarely, vasculitis of the GI tract develops in children with crampy
abdominal pain, pancreatitis, GI bleeding, and potential for intestinal perforation or
infarction.
 Involvement of the cardiac muscle  pericarditis, myocarditis, and conduction
defectspresent with CCF.
 An association with malignancy at disease onset is observed in adults with dermatomyositis
but very rarely in children.
DIAGNOSIS
 Diagnosis of dermatomyositis requires the presence of characteristic rash as well as at least three signs
of muscle inflammation and weaknes.
 developed in 1975 predate the use of MRI and have not been validated in children.
468
DIAGNOSTIC CRITERIA FOR JUVENILE DERMATOMYOSITIS
Heliotrope rash of the eyelids
Classic rash
Gottron papules

Plus three of the following:
Symmetric
Weakness
Proximal
Creatine kinase
Aspartate aminotransferase
Muscle enzyme elevation (≥1)
Lactate dehydrogenase
Aldolase
Myopathy
Electromyographic changes
Denervation
Necrosis
Muscle biopsy
Inflammation
EMGsigns of myopathy and denervation (increased fibrillations, and sharp waves) as well as
muscle fiber necrosis (decreased action potential amplitude and duration).
Nerve conduction studies are typically normal unless severe muscle necrosis and atrophy are
present.
Muscle biopsy
typically indicated when diagnosis is in doubt or for grading disease severity.
Biopsy findings:
 Focal necrosis.
 Phagocytosis of muscle fibers.
 Fiber regeneration.
 Endomysial proliferation.
 Inflammatory cell infiltrates
 Vasculitis.
 Tubuloreticular m inclusion bodies within endothelial cells.
 Findings of lymphoid structures and vasculopathy may portend more severe disease.
AMYOPATHIC JDM.
 Children present with classic rash but no apparent muscle weakness or inflammation
 It is unclear whether these children have isolated skin disease or mild undetected muscle
inflammation,
 risking progression to more severe muscle involvement with long-term sequelae such as
calcinosis and lipodystrophy if untreated.
469
DIFFERENTIAL DIAGNOSIS: depends on the presenting symptoms.

 weakness without rash or atypical disease, other causes of myopathy should be
considered.
 Polymyositis.
 Infection-related myositis (influenza A and B, coxsackievirus B, and other viral illnesses).
Muscular dystrophies (Duchenne and Becker as well as others).
 Myasthenia gravis.
 Guillain-Barre syndrome.
 Endocrinopathies--(hyperthyroidism, hypothyroidism, Cushing syndrome, Addison disease,
parathyroid disorders).
 Mitochondrial myopathies, and metabolic disorders (glycogen and lipid storage diseases).
 Infections associated with prominent muscular symptoms include trichinosis, Bartonella
infection, toxoplasmosis, and staphylococcal pyomyositis.
 Myositis in children may also be associated with vaccinations, drugs, growth hormone, and
graft versus host disease.
The rash of JDM 
 Eczema.
 Psoriasis.
 Malar rash from systemic lupus erythematosus.
 Capillary telangiectasias from Raynaud phenomenon, and other rheumatic diseases.
Muscle inflammation is also seen in children with systemic lupus erythematosus, juvenile idiopathic
arthritis, mixed connective tissue disease, inflammatory bowel disease, and anti-neutrophil
cytoplasmic antibody (ANCA)–positive vasculitides.
LABORATORY FINDINGS
SERUM MUSCLE ENZYME ANALYSISmuscle-derived enzymes.
 Creatine kinase [CK].

 Aldolase.
 AST, ALT.
 Lactate dehydrogenase
Not all enzyme levels rise with inflammation in a specific individual;
ALT is most commonly elevated on initial presentation, whereas the CK level may be normal.
CBC –(anemia of chronic illness) ESR  is often normal, and the
RHEUMATOID FACTOR TEST typically negative.
ANTINUCLEAR ANTIBODY (ANA) +ve in >80%.

470
ANTIBODIES TO SSA, SSB, SM, RIBONUCLEOPROTEIN (RNP), AND DOUBLE-STRANDED DNAare
generally negative.

anti-Jo-1, anti-Mi-2, and other MSAs positive test results for may portend more significant
disease
Antibodies to Pm/Scl identify a small, distinct subgroup of myopathies with a protracted disease
course, often complicated by pulmonary interstitial fibrosis and/or cardiac involvement.
Note: Unlike in adults with JDM, presence of myositis-specific autoantibodies (MSAs) is rare in
children;.
MRI using T2-weighted images and fat suppression
Helpful in dx and management.
Identifies active sites of disease, reducing sampling error and increasing the sensitivity of muscle
biopsy and electromyography, results of which are nondiagnostic in 20% of instances if the
procedures are not directed by MRI.
Extensive rash and abnormal MRI findings may be found despite normal serum levels of muscle-
derived enzymes.
MUSCLE BIOPSY often demonstrates evidence of disease activity and chronicity that is not suspected
from the levels of the serum enzymes alone.
CONTRAST SWALLOW STUDY palatal dysfunction and risk of aspiration.
PULMONARY FUNCTION TESTING detects a restrictive defect consistent with respiratory

weakness and reduced diffusion capacity of carbon monoxide (DLCO) from alveolar fibrosis
associated with other connective tissue diseases.
SIMPLE CALF X-RAY / CXRCalcinosis is seen easily on radiographs, along the fascial planes and
within muscles.
ECG,CXR,ECHOmyocardial even rare complication.
TREATMENT
It is multidisciplinary approach.
Rx of acute problem & GOAL of Rx will be control of inflammation, restore mucle strength by
regular exercise and physiotherapy , maintain functional abilities, prevent end treat complications
minimize treatment side effects and [arental education regarding disease. I will maintain
remission by steroids oral initially then tapering after clinical response then DMARDs like MTX
with cover of folic acid , adequate nutrition, proper skin care & monitoring of disease
complication & ensure proper compliance & follow up.
No evidence-based guidelines for optimal treatment of JDM currently exist.
 Intravenous gammaglobulin is frequently used as an adjunct for treatment of severe disease.
 Corticosteroids are the mainstay of treatment. 471
CLINICALLY STABLE CHILD WITHOUT WEAKNESS:
 prednisone ( 2 mg/kg/day)

 without GI Involvement —oral
 with GI Involvement— (i.v )coz dec absorption.
SEVERE CASES WITH WEAKNESS—(RESPIRATORY OR OROPHARYNGEAL).
 NG pass.
 high-dose pulse methylprednisolone: (30 mg/kg/day for 3 days, maximum dose 1 g/day) with
ongoing weekly or monthly IV dosing along with daily oral corticosteroids as needed.
 Corticosteroid dosage is slowly tapered over a period of 12-24 mo, after indicators of inflammation
(muscle enzymes) normalize and strength improves.
 Methotrexate Weekly oral, intravenous, or subcutaneous (0.5-1 mg/kg or 15-20 mg/m2, max 25
mg) is commonly used as a steroid-sparing agent in JDM.
 Concomitant use of methotrexate halves the cumulative dosage of steroids needed for disease
control.
S/E of MTX:-
 Immunosuppression.
 Blood count dyscrasias.
 Chemical hepatitis.
 Pulmonary toxicityfibrosis, alveolitis.
 nausea/vomiting, and teratogenicity.
Folic acid is typically given with methotrexate starting at a dose of 1 mg daily to reduce toxicity and
side effects of folate inhibition (oral ulcers, nausea, and anemia).
No live-virus vaccination, although inactivated influenza vaccination is recommended yearly.
SKIN FINDINGS Rx:
1 AVOID SUN EXPOSURE and apply high–sun protection factor (SPF) sunscreen daily:
advised in all children with JDM should even in winter and on cloudy days.
2 Hydroxychloroquine: as a secondary disease-modifying agent to reduce rash and maintain

remission. 4 - 6 mg/kg/day orally in either tablet or liquid form. Ophthalmologic follow-up 1 to
2 times per year to monitor for rare retinal toxicity GI intolerance, and skin/hair discoloration.
3 Cyclosporin + IVIG second line Rx.
CALCINOSIS :
1 CCB-nifedipine
2 Colchicine
3 Aluminum OH+ MgSO4.
4 Surgical removal + diltiazem  usually not recommended due to sinus formations.
5 472
SEVERE UNRESPONSIVE DISEASE:
 IVIG.

 MMF
 Cyclosporine and cyclophosphamide.
 NEW DRUGS-RITUXIMAB, INFLIXIMAB.
 Children with pharyngeal weakness:
 nasogastric or gastrostomy feedings
 GI vasculitis require full bowel rest.
 severe respiratory weaknessrare

 ventilator therapy / even tracheostomy
 Physical therapy and occupational therapy:

Integral parts of the treatment program.
 passive stretching early in the disease course then for direct reconditioning of muscles to regain
strength and range of motion once active inflammation has resolved.
 Vitamin D and calcium supplements: are indicated for all children undergoing long-term
corticosteroid therapy, in an attempt to reduce osteopenia and osteoporosis from medication.
 Bed rest is not indicated, because weight bearing improves bone density and prevents contractures.
 Social work and psychology services
COMPLICATIONS
Complication of disease & treatment.
RESPO:
 aspiration pneumonia and respiratory failure
 occasionally require nasogastric feeding and mechanical ventilation until weakness
improves.
 GITCrampy abdominal pain and occult GI bleeding may indicate bowel wall vasculitis and
lead to ischemia, GI bleeding, and perforation.
 Surgery should be avoided if possible, because the GI vasculitis is diffuse and not
easily amenable to surgical intervention.
 Contrast-enhanced CT may show dilation or thickening of the bowel wall,
intraluminal air, or evidence of bowel necrosis.
 CNS due to vasculitisseizures/organic psychosis—rarely brainstem infarction.
 EYE  retinopathy exudates-cotton wool spots, optic atrophy.
 RENAL  RF –due to myoglobinurea.
 Raynaud phenomenon.
 Cardio: involvement by JDM is rare but includes arrhythmias.
 Pathologic calcifications:
 may be related 1. severity of disease 2. prolonged delay to treatment 3. potentially
to genetic polymorphisms of TNF-α-308.
 Calcium deposits tend to form in subcutaneous tissue and along muscleSome
ulcerate through the skin and drain a soft calcific liquid, and others manifest as hard
nodules along extensor surfaces or embedded along muscle. Draining lesions serve
 nidus for cellulitis or osteomyelitis. Nodules cause skin inflammation that may
mimic cellulitis. Spontaneous regression of calcium deposits may occur, but there is
no evidence-based recommendation for treatment of calcinosis.
 Lipodystrophy:
 in 10-40% of patients / at upper trunk.
 Fat atrophy may be generalized, partial, or local.
 Lipodystrophy has been associated with insulin resistance, acanthosis nigricans,
dyslipidemia, hypertension, and menstrual irregularity, similar to features seen in
polycystic ovarian disease or metabolic syndrome X. 473
TREATMET RELATED COMPLICATIONS:

Prolonged corticosteroid therapy:
 Gastic ulceration
 cessation of linear growth.
 weight gainDue to increase appetitie.
 Hirsutism .
 Adrenal suppression.
 Immunosuppression.
 Striae.
 Cushingoid fat deposition.
 Mood changes.
 Osteoporosis.
 Cataracts.
 Avascular necrosis and steroid myopathy.
 PREVENTION OF STEROID S/E :low-salt, low-fat diet with adequate vitamin D and
calcium supplementation.
MTX (already mentioned).
PROGNOSIS
 The mortality rate in JDM 1%.

 period of active symptoms has decreased from about 3.5 years to <1.5 years with more aggressive
immunosuppressive therapy; the vascular, skin, and muscle symptoms of children with JDM generally
respond well to therapy.
 At 7 years of follow-up, 75% of patients have little to no residual disability, but 25% continue to have
chronic weakness and 40% have chronic rash.
 Up to one third may need long-term medications to control their disease.
 Children with JDM appear able to repair inflammatory damage to vasculature and muscle.
 Prior to the advent of corticosteroids, one third of patients spontaneously improved, one third had a
chronic, lingering course, and one third died from the disease.
 Corticosteroids have altered the course of disease, lowering morbidity and mortality.
Methotrexate decreases the length of treatment with corticosteroids, thereby reducing
morbidity from steroid toxicity
FACTS ABOUT JDM:
 Gottron’s and haliotropes are pathognomics.

 Gotrrons can be seen at knee, elbow , malleoli apart from knuckles.
 Heliotropes are purplish violatious which are actually capillary telangectasia cross nasiolabial fold.
 SLE rash spare nasolabial fold.
 Muscle bx findings simple to remember are atrophy necrosisfibre regenerationchronic
inflammatory infiltrate involving blood vessels.
 MRI muscle is used for sample site aid in management plan looks at depth of involvement.
 MRI findings of imflammed muscles: T2- increased signal whilt T1-normal. 474
 JDM involve arterioles and capillaries.
 Ask /Look for signs of diffuse vasculitis like oral ulcers, telangectasias, digital ulcerations GIT
ulceration-bleed, vasomotor instability.
 Fluctuation in pulse/B.P-vasomtor instability.

 HLA-DQA1*0501 found in 86-92% cases.
 ALPHA-TNF is immunomodulator and pro-inflammatory cytokine—INFLIXIMAB /RITUXIMAB
TRIALS.
 TNF-308 polymorphism is associated with 1.) prolong disease course till 3 yr and more chances of
complications and calcification. 2). Thrombospondin-1 which ia antiangiogenic lead to more chances
of capillary occlusion.
 Maternal microcherism is detected in CD4,&8 cells + muscle + skin biopsy.
 Severe disease—present with anasarca and skin ulceration
 Hypernasality of voice , arthritis can be a presenting features associated in 20-50%.
 Calcinosis is due to release of calcium from damaged cells which hav mitochondria.
 Calcification after drainage and regression will leave a pitted scar.
 Calcifications disturb organ function and may lead to limited mobility.
 Both rash & muscle manifestations worsen with sun exposure.
 This is muscle weakness in a child leading to bulbar like manifestions- nasal regurgitation etc.
 Impaired speech is due to soft palate involvement.
 We offer fundoscopy for eye complications related as discussed earlier.
 Do eye examination for cataract & glaucoma like complications sec to steroids if hx +.
 Juvenile polymyositis is identical to JDM but no rash at all
 Amyopathic JDM is rash with no muscle involvement.
JDM pt can be classified based on course of ds.
1. Monocyclic: full recovery without relapse.

2. Chronic polycyclic: chronic relapsing course.
3. Chronic continuous disease ---( persistent disease even pt on maintenance Rx).
4. Ulcerative.
OUT COME MEASUREMENT TOOLS:
Accurate and reliable developed internationally.
3 commonly used are:
1. CHAQ score –(childhood health assessment Questionnaire score.

2. MMT score --(manual muscle testing score)-it assess the muscle strength of seven proximal and 5
distal muscle group bilaterally it predict the disease activity.
3. CMAS—( Childhood myositis assess,emt score).
Oral steroids are best to give in morning to avoid impact on growth
Treatment summary of JDM.
 Avoid sun exposure in all pts at any stage and use of SPF.
 Oral steroids 475
 IV methylprednisolone.
 hydroxychloroquine
 Alternatives if steroids side effect/non-responsive/severe disease:
 MTX + f.acid
 Cyclosporine

 Axathioprine.
 CYP.
 IVIG.
 Plasmapharesis.
 Tacrolimus.
MTX SHOWS ITS EFFECT WITHIN 6-8 weeks OF START HOWEVER CAN TAKE 12 WEEKS AS LONG
AS.
RECENTLY MTX IS USED AS 1ST LINE STEROID SPARING DRUG.
Cyclophosphamide is best to use in pt with sever disease with vasculitis predominance like skin and
GIT ulceration and interstitial lung disease.
AZATHIOPRINE –
Effect show after 3-6 after initiating therapy.
Second line
Complete / partial remission in 70% cases.
CYCLOSPORIN:
S/EHTN HIRSUITISM/HYPERTRICHOSIS, HYPERPLASIA GINGIVAL, NEPHROTOXICITY, SECONDARY

MALIGNANCIES.
POOR PROGNOSTIC FACTORS OF JDM:
1. Sevre disease—vascultis + anasarca/ complications like calcifications, ILD, dysphagia.

2. Myositis specific antibodies.
3. Delayed Rx.
CAUSES OF OSTEOPOROSIS IN A JDM PT.
1. Dec nutrition
2. Steroids
3. Dec muscle bulk and mobility.
4. Deposition of resorbed bone in calcinosis.
5. Dec GIT absorption of Ca.
Periungal capillary count act as a prognostic indicator if count <3 / mm it is more likely to be
associated with relapse if treatment early withdrawn.
ARHTHRITIS IN JDM IT IS TRANSIENT AND NON EROSIVE USUALLY INVOLVE ELBOW . KNEE ,
WRIST , PROXIMAL IP JOINT AND ARTHRITIS IS RAPID RESPNSIVE TO THERAPY.
BEST DIFFERENTIALS TO OFFER IN EXAM ARE:--(Changeable depend upon scenario). 476

1. SLE
2. SCLERODERMA
3. MCTD

4. INFECTION RELATED MYOSITIS.
YONGER THAN 5 YR CHILDREN ARE PRONE TO CALCINOSIS MORE.
RELAPSE IS CALLED WHEN PERIUNGAL CAPPILARY COUNT IS >3/mm SEEN WITH NAIL FOLD
CAPILLAROSCOPE OR MAGNYFYING GLASS.
GROWING PAINS aged 3 to 10 yr who have a history of episodic pain that occurs at night after
increased daytime physical activity and that is relieved by rubbing but who have no limp or
complaints in the morning . There is often a positive family history for growing pains.
NOTES:
477

SCLERODERMA -------------------------------------------------/ SHORT CASE/ LONG CASE.
COMMAND:
1. DO GPE & RELEVANT EXAMINATION.

2. DO LOCOMOTOR EXAMINATION OF THIS PT.
Step 1: intro+ consent + exposure.
Step 2: inspection—stand back ( 5 sec).
Step 3. Do all GPE steps if command is GPE .
Step 4. If pt had thick tight skin then do relevant examination
FOR TISSUE LESION: (SITE , SYMETRICAL/ASYMETRICAL SIZE, SHAPE, SURAFCE, UNDERLYING

TISSUE, PIGMENTED/NOT, WAXY/, TENDER, EXTENT.
Go for JIA maneuvers.
Check CVS examination—(pulmonary HTN).
Abdomen examination
Offer: whatever u suspect.
DESCRIPTION:
Examined a child who is conscious , co-operative during my examination with no obvious respiratory
distress , he/she had pulse rate of …….bpm, respiratory rate of…..bpm, afebrile to touch with B.P
of…….mmHg , height is……….cm , wt is…..kg which are at 3rd centile for his/her age but I need confirm
by plotting on centile chart.
He had fixed flexion deformities of both hand involving ……………….., with evidence of tight thick
indurated shiny skin involving hands & facial region , with schlerodactly & Boutonniere deformity
(PIP flexion with DIP hyperextension) of………..gidits., & multiple well defined hypo pigmented
ulcerative areas which are non-oozing adherent to skin on extensor surfaces more at…………………..,
most likely calcified areas,
Mouth opening is limited
Ther is no active sign of inflammation in other joints.
No evidence of pallor, jaundice, clubbing, nail pitting/ induration, Digital pit ulcers, telangectasia,
rash, petechae, scalp lesion, edema, lymphadenopathy, BCG scar is seen, oral hygiene is good , eyes
& jvp are normal. 478
No evidence of proximal myopathy / signs of steroids toxicity in form of cushingoid face,
dorsocervical fat pad, striae.

Abdominal, CVS (for P.H) ,& pulmonary examination is normal.
Offer: depend upon findings.
DIFFERENTIALS:
MIXED CT DISORDER.
SCLERODERMA
DERMATOMYOSITIS.
INVESTIGATIONS:
SPECIFIC:
 ANA.
 anti-SSc.
 Anti-Scl-70 antibody (anti-topoisomerase I).
 CXR/HRCT if facility available--(pulmonary involvement).
 MRI—soft tissue-- (calcification).
 Skin biopsy.
 PFT –(assess pulmonary function if systemic sclerosis suspected).
SUPPORTIVE:
 CBC + ESR  –( anemia, leukocytosis).

 S.Ca+.
 LFTs.
 ECG,echo.
MANAGEMENT:
Establish diagnosis
Councelling of parents regarding disease its complication, course and management prognosis &
treatment options.
If it proves to be case of scleroderma then I will………
Treatment of acute problems
Supportive:
479
 Nutritional care.
 Analgesia .
 Local care of lesion.

 Physical & occupational therapy.
Specific:
 Cold avoidance if raynaud phenomenon +.

 Superficial morphea topical corticosteroids & advise for UV rays.
 LSMTX+steroids.
 I will start treatment regime with 3 month any one of following whichever is favourable:
 High dose of i.v corticosteroids (30 mg/kg to max dose 1000 mg )fo 3 consecutive days a month.
 High dose oral corticosteroids (0.5-2 mg/kg/day).
Plus
Inj- MTX –S/C – weekly (0.5-1 mg/kg max 25 mg).
Alternate option for skin manifestaion: MMF

PULMONARY INVOLVEMENT IF +  cyclophosphamide—(treat pulmonary alveolitis/prevent
fibrosis).
RENAL INVOLVEMENT  ACEI.
RAYNAUD PHENOMENON Avoid cold expodure by educate pt, wearing stockings , gloves.
If sever enough then I will start pharmacologic treatment in form of CCB-Nifedipine with dose of 2.5-
10 mg daily, other option I would consider for losartan, prazosin, bosentan &sildinafil /GTN patch.
PGE1 Reserved for sevre cases.
DISCUSSION:
JUVENILE SCLERODERMA FIBROSIS IN SKIN-DERMIS.
TYPES:
1. LOCALIZED SCLERODERMA—(MORPHEA)—(limited to skin). –(more common in pediatrics)

2. SYSTEMIC SCLEROSIS (SSc) –(Organ involvement).
ETIOLOGY :
Unknown really but may be due to combination of some vasculopathy, autoimmunity, fibrosis.
Triggering factors include: trauma , infection, michrocherism –(GVHD like reaction from persistant
maternal cells)  all these leas to increase expression of adhesion molecules molecules which
attract platelletes and inflammatory mediators which lead to raynaud phenomenon & pulmonary
HTN.
Macrophage+ other fibroblast cells  increase amount of collagen synthesis

fibrosissubsequently lipoatrophy, dermal fibrosis & loss of sweat glands & hair follicle. Late stage
dermis replaced by compact collagen fibres.
AUTOIMMUNITYmost important.
Disease+  ANA+ in 42%, anti-histone AB (47%), RF +, antiphospholipid antibodies+.
CLASSIFICATION: 480
LOCALIZED SCLERODERMA—(MORPHEA)--(classified on basis of distribution & depth of

involvement).

 PLAQUE MORPHEA—(well circumscribed area of induration , central waxy, surrounded by
violacious halo)-it is unilateral
 GENERALIZED—( dermis+ mainly, confluence of plaque morphea / ≥3 lesions /B/L usually
 BULLOUS—(just a bulla with any subtype of morphea).
 LINEAR—(extend thru dermis, S/C tisse, muscle, underlying bone, more likely unilateral.
 Limbs/trunk ≥1 linear extremities/trunk, flexion contracture, LLdiscrepancy+/-
 En Coup de sabre: sclap&/face, --CNS inv +/-seizures/ headache.
 Parry Romberg syndrome: hemifascial atropy.
DEEP MORPHEA: deep layers (panniculus, fascia, muscle, > B/L.
 SUBCUTANEOUS MORPHEA.—(panniculus/sc tissue. / plague is hyperpigmented & symmetric).

 ESINOPHILIC FACITIS fascia typical of extremities/ orange peel appearance + blood
eosinophilia.
 MORPHEA PROFUNDA
 DISABELLING PANSCLEROTIC MORPHEA OF CHILDHOOD—(generalized full thickness
involving skin on trunk , face, extremities while spare finger tips & toe.
SYSTEMIC SCLEROSIS
 DIFFUSE: --(most common type in childhood---symmetric thick+ hardening of skin (sclerosis) with
fibrous and degenerative changes of viscera)
 LIMITED—(rare in childhood –previous name was CREST syndrome, C=calcinosis cutis, R=raynaud
phenomenon, E=esophageal dysfunction, S= sclerodactly, T=Telangectasia
EPIDEMOIOLOGY :
 1 case in 1 lac population/ localized more common/ LS:SSc ratio is 10:1, / plaque and linear subtype
more common, no gender variation in freq < 8 yr.
CLINICAL FEATURES:
LOCALIZED SCLERODERMA:
 Insidious onset , manifestation according to subtype

 Initial usual lesion is area of erythema or a bluish hue around an area of waxy induration.
 Subtle Erythema may be only manifestation.
 Early edema/erythema followed by indurated hypopigmented/hyperpigmented atrophic lesions.
 Linear morphea can present with entire limb involvement, may present with arthalgia, synovitis,
flexion contractures.
 Limb length discrepancy due to growth impairment because of involvement of muscle/bone.
 En-coup de sabre seizures, learning problems, ipsilateral uveitis.
 Extracutaneous manifestations (25%) arthritis (47%)/ CNS invl.
481
SYSTEMIC SCLERODERMA:
 Insidious onset.
 Remission & exacerbation go /remission or chronic disability death.

SKIN  EARLY PHASE: edema starts from dorsum of hand & fingers spread proximally
includes facedec in edema  induration & fibrosis of skin result in loss of subcutaneous
fat , sweat glands & hair folliclesLATE PHASE: shiny & waxy skin .
 FLEXION CONTRACTURES develop at elbow, knee, hip with associated sondary MUSCLE
ATROPHY & MUSCLE WEAKNESS.
 FACE small oral stoma with dec mouth aperture.
 Skin ulceration + s/c calcifications (pressure points like elbow/knee).
 Sclerodactyly: due to severe raynaud phenomenon it lead to ulceration of fingertips with loss of tissue
pulp & tapered fingers.
 Acro-osteolysis resorption of distal tuft of distal phalanges.
 Salt & pepper appearance hyperpigmented postinflammatory changes surrounded by atrophic
depigmentation give appearance.
PULMONARY INVOLVEMENT: > common visceral manifestation.
 Arterial+ interstitial involvement –(alveolitis)

 Pulmonary HTN poor prognostic sign.
 May be--------------(asymptomatic/ exercise intolerance, dyspnea at rest, Right heart failure.
 PFT  VC & DLCO.
 CXR-Less helpful.
 HRCT-nodules, honey combing, mediastinal adenopathy.
 BAL Eosinophilia+neutrophilia.
GIT: --(25%).
 dysphagia.
 Esophageal and intestinal dysmotality.
 Reflux.
 Gastroparesis.
 Bacterial overgrowth.
 Pseudo obstruction.
RENAL SYTEM:  HTN /RENAL CRISIS-(RARE).
CARDIAC: arrhythmias , ventricular hypertrophy, dec cardiac function.
Note: Mortality is most due to cardiopulmonary disease.
RAYNAUD PHENOMENON:
 most frequent initial symptom of systemic schlerosis. Present in 70%.

 Begins in adolescents –symetric + absence of gangrene /necrosis & no underlying rheumatic ds at all
 Usually it occur before other manifestations./Burning, tingling sensation.
 Phenomenon is so named because of triphasic sequence of blanching (pallor---it is result of initial
arterial vasoconstriction)) cyanosis (due to venous stasis)  erythema (reflex vasodilation)of digits.
(PC-E).
482
Sites: distal finger tips, thumb, ears, nose tip.
Aggravating factors: cold, emotional stress, chemical exposure like polyvinyl.

Relieving factors: warming + medic
D/D ACROCYANOSIS—(painless bluish discol. Vasospastic disorder aftr cold exp), CHILBLAINS—
(episodic colour change with sever cold exposure & nodules formed can be seen in SLE).
Raynaud disease: when this phenomenon occur with any underlying rheumatic disease so called.
Causes :
Isolated raynaud phenomenon
Occupational raynaud = =
 Cold injury.
 Chemicals
Secondary raynaud phenomenon
 S.Sclerosis
 MCTD
 SLE
 DMS
 INFECTIONS—(HEP-C)
 HYPOTHYROID
 CARCINOID.
 DRUG INDUCED—(anti-migraine, beta blockers, bleomycin, interferon,ergotamines.
DIAGNOSIS:
ACR/ELAR criteria for classification of juvenile systemic sclerosis. (major must 2 of 20 minor )
MAJOR CRITERIA (REQUIRED)
 Proximal skin sclerosis / induration of skin.
MINOR CRITERIA
 Cutaneous: sclerodactly.
 Peripheral vascular: raynaud phenomenon, capillary nailfold abnormalities (telangectasia), digital pit
ulcers.
 GIT- Dysphagia/GERD.
 Cardiac—arythemia , heart failure.
 RENAL – new onset HTN, crisis.
 Respiratory : fibrosis on HRCT , pulm HTN.
 NEUROLOGIC: Carpal tunnel / neuropathy.
 MSKELETAL: arthritis/ myositis/ tendon friction, rub.
 SEROLOGY – anti-Scl-70, anti fibrillin, anti-Ssc.
483
DIFFERENTIAL DIAGNOSIS:

1. PSEUDOSCLERODERMA- group of diseases with Patchy or diffuse cutaneous fibrosis with no
other manifestations like scleroderma-e.g PKU, idiopathic.
2. SLEREDEMA: Transient self limited after febrile illness usually streptococcal./over neck, shoulders.
3. MCTD.
4. DERMATOMYOSITIS.
INVESTIGATIONS:
 CBC +ESR
 CXR/ECG/ECHO.
 HRCT-LUNGS
 CT/MRI BRAIN -EXTENT
 PFT –DLCO
 S. ALDOLASE
 ANA
 Scl-70
 Anti-Ssc.
 ANTI-PM.Scl.
 Skin biopsy
 + other workup for differentials.
TREATMENT –(ABOVE WRITTEN).
 Muti-disciplinary approach.
 Supportive
 Specific / STEROIDS+/- UV RAYS/ MMF/CYP.
 Occupational therapy.
 Follow up.
PROGNOSIS:
 LOCALIZED3-4 YR GET SOFTENING OF SKIN RESOLVE.

 LOCALIZED LINEAR & DEEP  SIGNIFICANT MORBIDITY+ DISFIGURMENT+
DISABILITY.
 SYSTEMIC –VARIABLE PROGNOSIS DEPEND UPON ORGAN INVOLV:
 OVERALL GOOD SURVIVAL OF SYSTEMIC COMPARED TO ADULT TYPE
 15 YR SURVVAL UPTO 75-80% CASES.
MOST DEATH DUE TO CARDIAC FAILURE
484

SHORT CASE ( BILLIARY ATRESIA)
COMMAND:
5 MONTH BABY PRSENTED WITH JAUNDICE AND PROGRESSIVE ABDOMINAL DISTENTION DO GPE
AND RELEVANT/ DO RELEVANT EXAMINATION / DO ABDOMEN AND RELEVANT.
STEP 1. Intro + consent + adequate exposure.
STEP 2. Inspection (5 sec)  click the 3 possibilies in your mind.
STEP 3. If child calm  look for cardiac examination and visceromegally/ otherwise start with GPE
protocol (pallor, nails, clubbing?, pulse , skin colour, dry , coarse and itching marks in >8 month baby,
Xantoma, bulk of muscle , s/c tissue, rash ,petechae, bruise, bleed ( signs of micronutrient+
macronutrient defeciencies)  OFC  eye examination ( jaundice + pallor +cataract + subconjuctival
hemorrhage)edema.
STEP 4. Abdominal examination.
STEP 5. Check for stool colour.
STEP 6. Offer fundus examination + anthropometrics .
DESCRIPTION:
1. Sir I have examined ……………, 5 month , conscious and comfortable/co-operative

during my examination with obvious jaundice while no respiratory distress/
dysmorphism.
2. His pulse rate is 120 bpm normal in volume and character , B.P is……..mmHg, afebrile to
touch with respiratory rate of …….bpm.
3. OFC is …..cm which is apparently below 2 SD for his age and gender and corresponding with
the OFC Of …. Month, need to plot on centile chart, Ht is…… and Wt is ……..kg, I would
like to plot on centile charts.
4. He is with jaundice while no evidence of pallor , clubbing, petechae, bruise, bleed, wrist
widening or rachitic rosary, cataract, dry coarse skin, lymphadenopathy , edema or signs of
micro /macronutrient defeciency.
5. his BCG scar seen with normal oral examination however no dentination seen.
6. Abdomen is distended with prominent veins and central slit shaped umbilicus moving with
respiration however no scar , direction of flow of venous blood is away from umbilicus, it is
nontender, I have appreciated his liver that is 4cm Below right CM, nontender, firm in
consistency ,regular margins, with total span of …. Cm, upper border is at….. ICS. While left
lobe of liver is not palpable. SPLEEN is 4cm below left costal margin firm in consistency
notch is palpable. There is no evidence of other visceromegally , there is evidence of free 485
fluid in abdominal cavity in form of shifting dullness, all hernia orifices are intact , genitalia
and back is normal. His pamer is……color.

7. Other systemic examination including cardiovascular, neurological and pulmonary
examination is unremarkable.
8. Sir I want to do fundoscopy of child . (cataract/chorioretinitis/hemorhage) and formal
developmental assessment.
A: Sir based on my clinical evaluation he is the case of neonatal cholestasis most likely sec to TORCH
infection/ neonatal hepatitis.
Q: any other differential in your mind?
A: yes he can be the case of billiary atresia.
Q: why TORCH is your first differential why not biliary atresia?
A: Sir as I have appreciated his OFC which is below standard and hepatosplenomegally, and
developmentall age of….
Q: why not cholestsis sec to hypothyroidism?
A: Unlikely he / she is the case of hypothyroidism because they have obivious coarse facial
feature with enlarge protruding tongue, dry coarse skin, hoarse cry, wide open posterior
fontanelle, umbilical hernia, bradycardia, hypotonia, moreover my pt is with firm liver, free
fluid, spleen and ascites and clay coloured stool.
Q: why did u auscultate heart?
A: coz I considered TORCH as my differential in which cong. Rubella is associated with

pulmonary artery stenosis and PDA.
Q: how will u investige?
A: sir i will investigate my pt by LFTs for S.Billurubin total , direct and indirect fraction , ALT,AST and
ALK. PO4, GGT. And hepatic synthetic functions with PT and INR , s.albumin. S.Cholestroll level (incr),
CBC for HB and differentials,bsr
TORCH titre, HIDA scan, liver biopsy.
Stool complete examination for fat globules and malabsorbtive features, urine for reducing
substance to rule out the possibility of galactosemia.
Fasting Abdominal ultrasound for gall bladdaer , liver ecotexture and Tc sign.
486
Q: Can this child be a case of PFIC?
A: Yes can be the case of PFIC they are FTT,with portal HTN, and jaundice , but absence of thick
rough dry skin , signs of rickts and intense itching marks make the PFIC my differential on down list.

Q: which is severe form of PFIC?
A: Byler disease that is type 1 pfic.
Q:How u differentiate types of pfic?

A: GGT level higher in type 3 , while lower in 1&2.
Q: How u differentiate between pfic and allagile syndrome>?
A: typical syndromic features and absence of bile duct paucity.
Q: what is BRIC type 1?
A: It is a form of intrahepatic cholestasis and pfic 1 class due to same gene BUT different mutation
like missense and split mutation for F1C1,which is characterized by the recurrent bouts of
cholestasis, jaundice, and severe pruritus lasting from 2 wk to 6 mo; it can last up to 5 yr.
Q: how will u differentiate between BRIC and pfic1?
A: clinically as described above and BRIC type I have normal cholesterol and γ-glutamyl
transpeptidase levels.
Q: What is PFIC2?
A: is similar to PFIC 1 but is present in non-Amish families (Middle Eastern European). The disease
results from defects in the canalicular ATP-dependent bile acid transporter BSEP (ABCB11). The
progressive liver disease results from accumul ation of bile acids secondary to reduction in
canalicular bile acid secretion.
Q: What is BRIC2”
A: TYPE OF PFIC TYPE 2characterized by recurrent bouts of cholestasis associated with cholelithiasis
and watery diarrhea.
Q: How will u differentiate between biliary atresia and ideopatic neonatal hepatitis?
A:
characteristics Biliary atresia Idiopathic neonatal

hepatitis
familial incidence unlikely to recur within ≈20%,
the same family
Birth wt relation no Neonatal hepatitis
appears to be more
common in premature or
small for gestational age
infants.
Colour of stool Persistently acholic patients with severe 487
stools suggest biliary idiopathic neonatal
obstruction (biliary hepatitis may have a
atresia). transient severe
impairment of bile

excretion.
On examination abnormal size or less common with
liver consistency in patients neonatal hepatitis.
Abdominal associated anomalies No associated
ultrasound abdominal polysplenia abnormalities.
and vascular
malformations.
gallbladder is either not
visualized or a micro-
gallbladder.
Ultrasonographic Present absent
triangular cord (TC)
sign
HIDA Scan Normal uptake no Dec/ late uptake while
excretion. excretion normal.
biopsy ductular proliferation, hepatocellular disease,
the presence of bile with distortion of lobular
plugs, and portal or architecture, marked
perilobular edema and infiltration with
fibrosis, with the basic inflammatory cells, and
hepatic lobular focal hepatocellular
architecture intact. necrosis
Q: HOW WILL YOU MANAGE?
A: After confirming/ establishing my dx I will councell the parents regarding disease ,

complication, course , treatment option and its prognosis , I will treat the acute problems of
pt by correction and treatment of hypoglycwmia , hypothermia, electrolyte imbalance and
treatment of infection, I will start nutritional rehab with dietary formula or supplements
containing medium-chain triglycerides, vitamin ADEK supplement with their RDA, and water
soluble vitamins with twice the normal dose, Ca,PO4 and Zinc supplement, as they have
problem with retension of bile salts so I will start choleretic ursodeoxycholic acid 15–20
mg/kg/day, treatment of portal hypertension with measures to control bleed and start of
spironolactone for ascites, I will prepare my pt for kasai procedure although well before 3
month but can help in late some time and definitely my plan would be prepare for liver
transplantation.
Q: which are membrane bound enzymes?
A: ALP+GGT So not leak out of cell in hepatic damage while increase in obstruction.
Q: If u r working in emergency n u receive pt with billiary atresia what single inv u wll do?
A: PT and INR.
Q: What is difference between cholestyramine and ursodeoxycholeic acid? 488
A: cholestyramine is bile salt binding resin which impede absorption excretion in stool while
ursofalk is choleretic  enhance excretion in stool.

Q: What is difference between pheno and ursofalk in treatment of pruritis?
A: Phenonon bile salt choleretic/ ursofalk  bile salt choleretic.
Q: How will you differentiate between I/H & E/H cholestasis?
A: I/H Preterm/SGA+Appear ill + early hepatospleno +variable colour stool.
E/HFull term appear well, late hepatosplenomegaly , hav complete cholestasis/acholic

stools.
Q: at what age child develop itching reflex?
A: 8-9 Month.
Q: If u see a pt with jaundice + liver+ clay coloured stool that is typically suggestive of biliary
atresia what possible reason could b?
A: Pt may have fetal form of biliary atresia which is associated with asplenia / may hav
polyspenia, and think for possible heterotaxy and dextrocardia situs inversus as well.
Q: What are the complications of neonatal cholestasis?
A: CLD, Malnutrition,FTT, short stature, bleeding,sepsis.
Q: what is prognosis of neonatal cholestasis?
A: 80%  recover with no fibrosis
20%  fibrosis/cirrhosis/PFIC.
Q: Prognosis of pt with biliary atresia?
A: KASAI procedure if done with 6-8 week  good if not then usually die with 2 yr.
Q: What are the treatment options for pruritis?
A: Cholestyramineursodeoxycholeic acid( helpful if little bit paucity intact anti histamine

rifampicin  phenol  UV light  no response then exclude cirrhosis if no then go for
partial external biliary diversion.
Q; what is partial external biliary diversion?
A: technique involves resecting a segment of intestine to be used as a biliary conduit. One end
of the conduit is attached to the gallbladder and the other end is brought out to the skin,
forming a stoma. The main drawback of the procedure is the lifelong need to use an ostomy
bag.
Q: What are the syndromes associated with cholestasis? 489
A: Allagile, zellweger, trisomies.

Miscellaneous Facts about cholestasis :
- Greenish tinge cholestatic jaundice.

- Peripheral stigmata of CLD Spider nevi + bruise + bleed + caput medusa +palmer
erythema + scratch marks.
- Ultrasound if bile duct dilated cholangiogram / not visualize HIDA scan.
- Ca 25-100 mg/kg/day…………PO4=25-50 Mg/kg/day………..Zinc 1mg/kg/day.
- Porta hepatis  where portal vein and hepatic artery enter liver and hepatic duct exist.
- Kasai Suzuki procedure is for EHBApalliative procedure just a bridge to prevent from
liver fibrosis/ damage till liver transplantation  removal of fibrosed biliary treeform
Roux-en-Y anastomosis bile drainage ./ complications= recurrent cholangitis,cirrhosis,
portal htn.
- SUGGEST BILIARY OBSTRUCTION ALK PO4+ GGT+ 5’ Neuclotidase.
- Progressive obstructive cholangiopathy synonym of biliary atresia.
- E/H CHOLESTASISB.A+Choledochal cyst+ bile duct stenosis+ bile plug syndrome.
- EYE EXAMINATION FOR  cataract (galactosemia + TORCH, xerosis, clouding, bitot.
- Indian hepatic surgeon said they don’t do liver transplantation once ascites develop in
bill. Atresia pt, it is poor prognostic sign.
-
490

ABMBIGOUS GENITALIA ---------------------------------( SHORT CASE ) OVERVIRILIZED FEMALE—
(XX-DSD).
Commands:
1. Parents are concerned about gender Do GPE & Relevant.

2. Do genitalia examination.
3. Simple GPE can come in exam. Just examiner ask in last about what about genitalia of pt (that
candidate usually offer in last/miss).
Step 1. Intro + consent + exposure.
Step 2. Inspection –( well thriving/poorly thriving/hyperpigmentation) wear on gloves
Step 3. SPL ( Press with hand on side of phallus and measure-note it).
Step 4. Palpate for gonads in labioscrotal fold
Step 5. Take lubricant on hand then palpate with 4 fingers over inguinal region then press upto
scrotal area—( this step in case we can’t hav gonads in LS fold.
Step 6. Measure Gonads size –make approximately like 1ml, 2ml –( don’t mention it as 1ml/2ml until
u measure thru orchidometer ).
Step 7. Search for / count urethral opening and look for any hypospadiasis.—(is it on ventral
surface/dorsal surface/root /shaft/tip ).
Step 8. (remove gloves and start GPE  vitals-pulse, B.P,eye examination for (aniridia),
pigmentation, hydrartion status, edema.
Step 9. Quick abdominal examination for any mass (adrenal/ (WAGR)/deny drash, bechwithweidman
syndrome).
Step 10. Offer
 Anthropometrics
 And thing which u left due to shortage of time
DESCRIPTION:
491
ABMBIGOUS GENITALIA ---------------------------------( SHORT CASE ) OVERVIRILIZED FEMALE-
(XX-DSD)

I have examined pt conscious , cooperative throught my examination with no obv.dysmorphism,
respiratory distress.
Genitalia examination show
FUSED/ BIFID LABIOSCROTAL FOLD WITH NO/ RUGAE FORMATION.
PHALUS STRECH LENGH IS........
SINGLE / DOUBLE OPENING at the level of…base/ shaft/root/.
GONADS ARE NOT PALPABLE IN ANY REGION .
Pulse rate is ………..bpm.
Resp.rate is………....bpm.
Afebrile to touch………
B.P is…………………….(raised in 17-hydroxylase deficiency)
There is no evidence of pallor, dehydration ,hyperpigmentation, any asymmetry of limb-(WAGR) , &

normal eye examination-(aniridia) in my child.
Abdomen is soft & nontender with no evidence of visceromegally.
IMPRESSION:
DIAGNOSIS: (DON’T SAY HE/SHE).
Iam considering my pt is the case of XX DSD (FEMALE pseudohermaphroidism/OVERvirilized female)

most likely secondary to:
4. CAH-21-hdroxylase deffeciency/ 11-B Hydroxylase deff.

5. MATERNAL tumours—ovarian –gonadoblastoma/ adrenal.—(although rarely maternal androgen
producing tumor like ovarian tumors and adenomas—which also produce virilization in mother like
acne, hirsuitism , deep voice, increase androgen levels)
6. May be maternal hormonal/ drug therapy – I need to probe detailed hx of maternal medication in my
pts antenatal period. –(drugs which usually are used for threatened abortion)
Why CAH first –coz it is most common cause of genital ambiguity , moreover the expgenous causes
are also which need to ask in detail hx.
492
Can this child be a male with bilateral cryptochordism?

Yes can be , but they have single urethral opening at tip, however can be at base—hypospadiasis , I
will confirm by abdominal USG for undesended if any/ internal mullarian structures
How will u investigate ?
Karyotyping
USG- abdomen –internal genitalia.
Serum 17 hydroxyprogesterone level –elevated
BSR
S.E
ABGs.
S.DHT.
S.Testosterone, corisol, aldosterone.
DHEA.
HCG stimulation test.
Enzyme assay –
How will u manage?
After confirming my dx I will councel the parents regarding disease, complication course and
management, & establishing the gender of pt. I will treat the acute problems of pt with correction of
hypoglycemia, dehydration and electrolyte imbalance. & treatment of underlying condition, sex of
rearing decided on basis of karyptyping and USG of internal structure. & surgical trx. I will do genetic
counceling and ensure proper compliance and follow up.
493

CONSOLIDATION----------------------------------------------------------------------------SHORT CASE.
CHEST EXAMINATION & RELEVANT.
Step 1: intro + consent + exposure adequate.
Step 2: inspection (foot end then side sit down and look around chest/  shape/asymmetry /chest
movement/scar/buldge.
Step 3: count R.R.
Step 4: palpate apex beat and locate.
Step 5: trachea position.
Step 6: chest expansion/movement.
Step 7: vocal fremitus
Step 8: mark area of cardiac and liver by percussion.
Step 9: Percussion
Step 10: Auscultation: first normal breath sounds then vocal resonance.
Step 11: back examination with same sequence.
Step 12: GPE : pulse,Clubbing, BCG scar, lymph node+ throat + nose examination.
Step 13: offer anthropometrics and name age of pt.
DESCRIPTION:
My patient……………conscious, co operative during my examination with no obvious respiratory

distress, pink in room air, with R.R …..bpm,
There is no obvious chest deformity, scar, prominent veins, he has abdominothoracic type of
movement.
Trachea is central, Apex beat is at.......IC Space medial to medclavicular point, normal in character. 494

no tenderness on superficial palpation. My findings are confined to right hemithorax ,decreased
chest expansion,increased vocal fremitus, dull percussion note. bronchial breathing and increased
vocal resonance on right lower side of chest. Back is normal in shape with no visxible deformity .
His/her pulse rate is…….bpm, There is no evidence of clubbing, cyanosis, lymphadenopathy.BCG scar
is seen, throat is normal with no evidence of congestion.
I want to know anthropometrics of child.
D/D OF CONSOLIDATION:
 Collapse with patent bronchus. (vs pull of trachea indeed).
A: He is the case of rt sided consolidation most likelt sec to pneumonia.
Q: Why sec to pneumonia?
A: Because pneumonia is common illness & currently he is febrile, with good built & no
lymphadenopathy. BCG scar is seen which makes less possible consideration to T.B however
the possibility of T.B can not be ruled out need to ask detailed hx, contact tracing &
supportive and diagnostic investigations.
Q: Any other differentials?
A: I considered the possibility of collapse with patent bronchi.
Q: what could be the cuprit organism at this age?
A: as he is > 5 yr of age child so strep. Pneumonae is most common to be involved.
Q: how would u investigate?
A: I Will investigate by doing CXR AP/lateral View, CBC with ESR, blood C/S. mantoux test,
sputum analysis.
Q: How will u manage?
Q: after establishing my diagnosis I will councell the parents regarding the disease, 495
complications, course and treatment options and prognosis , I will treat the acute problems
of my pt with monitoring of TPR, & vitals, antipyretics , empirical antibiotics with B.pencillin

& gentamycin then according to C/S report, will look for adequate treatment response with
followup CXR .
D/D
- RT SIDE CONSOLIDATION MOST PROBABLY SECONDARY TO POST-PNEUMONIA.
-MAY BE SECONDRY TO COLLAPSE CONSOLIDATION ON RT SIDE.
WHY NOT PLEURAL EFFUSION ?.
SIR IF IT WOULD HAV BEEN A CASE OF PLEURAL EFFUSION THEN HE SHOULD HAVE DECREASED
VOCAL RESONANCE AND STONY DULL PERCUSSION NOTE, AND TRACHEA SHIFTED TO OPPOSITE
SITE.
WHAT COULD BE THE OTHER DIFFERENTIAL??
BRONCHIECTASIS..CAN BE BUT THEY ARE USUALY WITH CLUBBIBG AND EMACIATED IF CAUSE
CONSIDERED TO BE TUBERCULOSIS. BUT NEEDS TO EVALUATION BY DETAIL HX OF OTHER CAUSES AS
WELL LIKE T.B, POST PERTUSIS, AND CYSTIC FIBROSIS.
DISCUSSION:
Bronchial breathing can be :
 Tubular. High pitched—seen in pneumonic consolidation, collapsed lung with patent bronchus and
above level of pleural effusion.
 Cavernous.--low pitched
 Amorphic.—low pitched with high tone.
VOCAL RESONANCE:
Types :
 Bronchophony: voice sounds appear to be heard near the earpiece of stethoscope & words are
unclear . seen in consolidation, collapse with patent bronchus, and above level of pleural effusion.
 Aegophony : To use egophony during an exam, ask the patient to say 'e' as you auscultate over the 496
chest wall. Over normal lung areas, you will here the same 'e' tones. Over consolidated tissue, the 'e'
sound changes to a nasal quality 'a' (aaaaay), like a goat's bleating. The sound will often become
louder over consolidated tissue. Observed above level of pleural effusion and pneumothorax.

 Whispering pectoriloquy: if bronchophony is extreme even a whisper can be heard , clearly thru
stethoscope as like directly into examiners ear and is called whispering pectoriloquy. It is heard in
consolidation and large cavity communicating with bronchus.
TRACHEA POSITION:
CENTRAL
 Pneumonia.
 Asthma
 Empyema.
 Bronchiectasis
OPPOSITE SIDE.
 Pleural effusion.
 Pneumothorax.
 SOL(tumor).
SAME SIDE.
 Collapse.
 Fibrosis
DIFFERENCE BETWEEN EMPYEMA & PARAPNEUMONIC EFFUSION.
EMPYEMA
 PH<7.2
 Pleural fluid effusion sugar <40.
 LDH >1000 iu/L.
PARAPNEUMONIC EFFUSION.
 PH>7.2
 Pleural fluid effusion sugar >60.
 LDH <1000 iu/L.
IMPORTANT: T.B present with more common as exudates but also present transudative which is
allergic manifestation.
PATHOLOGICAL STAGES OF DEVELOPMENT OF PNEUMONIA:
STAGE OF CONGESION. Fine crackles.

497
STAGE OF RED HEPATIZATION. Tubular type of bronchial breathing
STAGE OF GRAY HEPATIZATION. Tubular type of bronchial breathing

STAGE OF RESOLUTION. Coarse crackles.
Types of fluids:
Four types of fluids can accumulate in the pleural space:
 Serous fluid (hydrothorax)

 Blood (hemothorax)
 Chyle (chylothorax)
 Pus (pyothorax or empyema)
Conditions associated with transudative pleural effusions:[17]
 Congestive Heart Failure (CHF)

 Hepatic cirrhosis
 Hypoproteinemia
 Nephrotic syndrome
Conditions associated with exudative pleural effusion.
 Infection
 Tuberculosis
 Autoimmune disorders
 Malignancy
 Trauma
 Pulmonary infarction
 Pulmonary embolism
 Pancreatitis
 Ruptured esophagus ( or Boerhaave's syndrome)
 Rheumatoid Pleurisy
 Drug-induced Lupu
Transudate Exudate
Main causes Increased hydrostatic Inflammation
pressure,
Decreased colloid
osmotic pressure
Appearance Clear[1] Cloudy[1]
Specific gravity < 1.012 > 1.020
Protein content < 25 g/L > 29 g/L[2]
fluid protein < 0.5 > 0.5[3]
serum protein
Difference of > 1.2 g/dL < 1.2 g/dL[4]
albumin content
with blood albumin
fluid LDH < 0.6 or < ⅔ > 0.6[2] or > ⅔[3]
upper limit for serum 498
[2]
Cholesterol content < 45 mg/dL > 45 mg/dL

Repeated effusions may require chemical (talc, bleomycin, tetracycline/doxycycline), or surgical
pleurodesis, in which the two pleural surfaces are scarred to each other so that no fluid can
accumulate between them. This is a surgical procedure that involves inserting a chest tube, then
either mechanically abrading the pleura or inserting the chemicals to induce a scar.
499

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Long/Short Cases

Dr Muhammad Qasim Memon

DR MUHAMMAD QASIM MEMON

1. Chronic Liver Disease 04

. | Dr Muhammad Qasim Memon

28. JIA 378

. | Dr Muhammad Qasim Memon

Presenting complaints of patient can be:

. | Dr Muhammad Qasim Memon

. | Dr Muhammad Qasim Memon

QUESTIONS REGARDING DIFFERATIALS:

. | Dr Muhammad Qasim Memon

 QUESTIONS REGARDING COMPLICATIONS OF DS:

. | Dr Muhammad Qasim Memon

Check list for examination of CLD pt.

Same protocol of examination ht , wt.

GPE  abdominal  chest  CVS Neurological examination Musculoskeletal.

LONG CASE PROTOTYPE:

For these compliant they went to

. | Dr Muhammad Qasim Memon

No hx suggestive of Complications of treatment in form of ………(SLE, Nephrotic syndrome, good

Cirrhosis histologicaly definition:

1. Diffuse hepatocyte injury & regeneration

Micro-nodular -- <3 mm –Wilson disease, metabolic.

Macronodular -- >3 mm –hepatitis B,C, drugs.

Post necrotic –wilson, autoimmune, hepatitis, galactosemia,

Biliary cirrhosis –biliary atresia, choledocal cyst, C.F.

. | Dr Muhammad Qasim Memon

Features of the Hepatotropic Viruses

HAV HBV HCV HDV HEV HGV[*] TTV[**]

Virology RNA DNA RNA RNA RNA RNA DNA

Incubation 15– 60– 14– 21– 21– ? ?

Parenteral Rare Yes Yes Yes No Yes Yes

Fecal-oral Yes No No No Yes Possible Possible

Sexual No Yes Yes Yes No Yes Possible

Perinatal No Yes Rare Yes No Yes Yes

Chronic No Yes Yes Yes No Yes Yes

Fulminant Rare Yes Rare Yes Yes No No

COMMON BIOCHEMICAL PROFILES IN THE ACUTE INFECTIOUS PHASE.

cytopathic injury to the hepatocytesALT/AST. 10

 little prognostic value. bilirubin level normalize first , AST/ALT levels

. | Dr Muhammad Qasim Memon

INCUBATION PERIOD: mean for HAV is ≈3 wk

. | Dr Muhammad Qasim Memon

 acute hepatitis only. Often, this is an anicteric illness-DD-acute gastroenteritis.

 Hypoplastic/ aplastic anemia.

anti-HAV (IgG) is usually detected within 8 wk of symptoms onset, and is measured as

 There is no specific treatment for hepatitis A.

. | Dr Muhammad Qasim Memon

The use of Ig >2 wk after exposure is not indicated. Ig is not routinely

≤2 wk since exposure Ig 0.02 mL/kg and HAV vaccine if >1 yr and

>2 wk since exposure No prophylaxis. Consider HAV vaccine if >1

HBV has 8 genotypes (A-H).

. | Dr Muhammad Qasim Memon

 HBsAg is inconsistently recovered in human milk of infected mothers.

 predominantly non-cytopathogenic virus that causes injury mostly by immune-mediated processes.

. | Dr Muhammad Qasim Memon

 Many acute cases of HBV infection in children are asymptomatic.

Chronic HBV infection has 3 identified phases: 15

1. Immune tolerant –(mosr pts, no effective therapy at this yet developed)

. | Dr Muhammad Qasim Memon

Core antigen mutation –HbeAg in negative while HBV-DNA is posetive.

. | Dr Muhammad Qasim Memon