1

Some Pediatric Postgraduate Lecture Notes

No Topic Page
1 Kawasaki disease 2
2 Localization of neurological lesion in general 5
3 Clinical clues to melingering 7
4 Neurology: points to remember 8
5 Mucopolysaccharidoses 9
6 Spinal Muscular Atrophies 12
7 Muscle biopsy 16
8 EMG 18
9 Nerve conduction studies (ENMG) 22
10 Hypoxia-ischemia in neonate (HIE) 23
11 Pediatric non traumatic coma 28
12 Refractory chf in children 34
13 Sexual maturation/sexual development 37
14 Disorders of sex development (dsd) /evaluation of ambiguous genitalia 39
15 Congenital adrenal hyperplasia 45
16 Spasmus nutans 53
17 Role of peripheral smear in diagnosing difficult clinical situations in pediatrics 56
18 Bone marrow transplant 60
19 Blood component therapy 62
20 Neurodegenerative disorders of childhood 63
2 st
21 Pre And Post Ductal O Saturation For CHD Screening Of 1 Day Of NB 67
22 Bleeding disorders in children 67
23 Status asthmaticus or acute severe asthma in children 74
24 Pneumothorax 75
25 Croup (acute laryngotracheobronchitis) 77
26 Acute epiglotitis 78
27 Shock 79
28 Anaphylaxis 85
29 Kerosene poisoning 87
30 Systemic hypertension 87
31 CCF 90
32 Status epilepticus 94
33 Acute renal failure 96
34 Scorpion sting 101
35 Snake envonomation 102
36 Forien body aspiration 103
37 Pediatric burns 104
38 Congenital infections in neonates / vertical transmission / mother to child or perinatal 106
39 Newer antiseptic drugs for children 114
40 Bleeding neonate 120
41 Bronchial Asthma 125
42 Status Asthmaticus 130
43 Clubbing 132
44 Respiratory Failure 133
45 Mechanical Ventilation 137
46 ECMO 141
47 Apparent Life Threatening Event 143
48 SIDS 145
49 SLE 146




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KAWASAKI DISEASE
INTRODUCTION
1. Synonyms: mucocutaneous lymph node syndrome; infantile polyarteritis nodosa.
2. Highest incidence occurring in Asian children more in Japanese.
3. KD is a vasculitis with a predilection for the coronary arteries. Approximately 20-25% of untreated
children develop coronary artery abnormalities (CAA) including aneurysms, whereas <5% of children
treated with intravenous gammaglobulin (IVIG) develop CAA.
4. KD is the leading cause of acquired heart disease in children in most developed countries, including
the United States and Japan.
ETIOLOGY:
1. The cause remains unknown
2. Infection: epidemiologic and following clinical features support an infectious origin
a. Fever, rash, enanthem, conjunctival injection, and cervical lymphadenopathy.
b. Infrequent occurrence of the illness in infants younger than 3 mo, likely due to maternal
antibodies
c. Less common in adults likely due to prior exposures with subsequent immunity.
d. Points against infectious origin:
i. No multiple cases present at the same time within a family or daycare center
ii. No single infectious etiologic agent has been successfully identified so far.
3. Genetic role:
a. Asian children more affected
b. Siblings are affected
c. Significant associations between polymorphisms in the ITPKC gene, a T-cell regulator, with
increased susceptibility to KD
EPIDEMIOLOGY
1. Age: < 5 year; mean age 3 year
2. Sex: More in boys
3. Risk factors: young age, male gender andAsian and Pacific Islander race and Hispanic ethnicity
PATHOLOGY
1. Kd is a vasculitis that predominantly affects the medium-size arteries.
2. The coronary arteries are the most commonly involved, although other arteries, such as the popliteal
and brachial arteries, can also develop dilation.
3. 3-phase process of arteriopathy:
st st
a. 1 phase is a neutrophilic necrotizing arteritis occurring in the 1 2 wk of illness that begins
in the endothelium and moves through the coronary wall. Saccular aneurysms may form
from this arteritis.
nd
b. 2 phase is a subacute/chronic vasculitis driven by lymphocytes, plasma cells, and
eosinophils, which may last weeks to years and results in fusiform aneurysms..
rd
c. 3 pahse: the vessels affected by the subacute/chronic vasculitis then develop smooth
muscle cell myofibroblasts, which cause progressive stenosis. Thrombi may form in the
lumen and obstruct blood flow
CLINICAL MANIFESTATIONS
1. Fever high unremitting, and unresponsive to antibiotics. The duration of fever without treatment is
generally 1-2 wk, but may persist for 3-4 wk.
2. 5 clinical criteria of KD :
a. Fever at least for 5 days
b. Bilateral nonexudative conjunctival injection with limbal sparing;
c. Erythema of the oral and pharyngeal mucosa with strawberry tongue and red, cracked lips;
d. Edema and erythema of the hands and feet; rash of various forms (maculopapular, erythema
multiforme, or scarlatiniform)
e. Nonsuppurative cervical lymphadenopathy, usually unilateral, with node size >1.5 cm
 3

3. Other features:
a. Perineal desquamation
b. Periungual desquamation of the fingers and toes and may progress to involve the entire
hand and foot
c. Gastrointestinal symptoms (vomiting, diarrhea, or abdominal pain)
d. Respiratory symptom (rhinorrhea or cough)
e. Significant irritability
f. Mild hepatitis,
g. Hydrops of the gallbladder,
h. Urethritis and meatitis with sterile pyuria,
i. Arthritis.
j. Indurative edema of the hands
CARDIAC INVOLVEMENT
a. Myocarditis
b. Cardiogenic shock (KD shock syndrome),
c. Pericarditis with effusion
d. Mitral regurgitation
e. CAA develops in up to 25% of untreated patients in the 2nd to 3rd wk of illness. Giant coronary artery
aneurysms (classic definition of >8 mm internal diameter) pose the greatest risk for rupture,
thrombosis or stenosis, and myocardial infarction
f. Axillary, popliteal, iliac, or other arteries may also become dilated, which manifest as a localized
pulsating mass.
g. Variant form of KD: Occasionally KD initially presents with only fever and lymphadenopathy (node-
first KD).
SKIN LESIONS: Rash in a patient with Kawasaki disease. Rashes can be diffuse maculopapular eruptions, or
they may resemble a scarlatiniform or erythema multiforme–like rash.
3 PHASES OF ILLNESS:
a. Febrile phase 1-2 week
b. Sub acute phase 3 weeks
a. Desquamation,
b. Thrombocytosis,
c. The development of CAA
d. Sudden death
c. The convalescent phase: (ESR) returns to normal 6-8 wks. after the onset of illness.
LABORATORY AND RADIOLOGY FINDINGS
a. The leukocyte count is elevated, with a predominance of neutrophils and immature forms.
b. Normocytic, normochromic anemia
c. The platelet count is generally normal in the 1st wk of illness and rapidly increases by
1,000,000/mm3.
d. An elevated ESR and/or C-reactive protein
e. Sterile pyuria, mild elevations of the hepatic transaminases, hyperbilirubinemia, and cerebrospinal
fluid pleocytosis may also be present.
ECHOCARDIGRAPHY:
a. Two-dimensional echocardiography:
a. lack of normal tapering of the vessels is typical. Moreover,
b. coronary artery dimensions may be increased in the 1st 5 wk after presentation.
c. Aneurysms have been defined with use of absolute dimensions by the Japanese Ministry of
Health and are classified as small (<5 mm internal diameter), medium (5-8 mm internal
diameter), or giant (>8 mm internal diameter).
b. Periodic evaluation for preventive cardiology counseling is warranted, and some experts recommend
cardiologic follow-up every 5 yr.
DIAGNOSIS
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a. Complete KD: presence of fever for at least 4 days and at least 4 of 5 of the other principal
characteristics
b. Incomplete KD: patients have persistent fever but fewer than 4 of the 5 characteristics plus laboratory
and echocardiographic findings
DIFFERENTIAL DIAGNOSIS:
a. VIRAL INFECTIONS
a. Adenovirus
b. Enterovirus
c. Measles
d. Epstein-Barr virus
e. Cytomegalovirus
b. BACTERIAL INFECTIONS
a. Scarlet fever
b. Rocky Mountain spotted fever
c. Leptospirosis
d. Bacterial cervical lymphadenitis
e. Meningococcemia
c. RHEUMATOLOGIC DISEASE
a. Systemic-onset juvenile idiopathic arthritis
b. Behçet disease
d. OTHER
a. Toxic shock syndromes
b. Staphylococcal scalded skin syndrome
c. Drug hypersensitivity reactions
d. Stevens-Johnson syndrome
TREATMENT
a. ACUTE STAGE
a. Intravenous immunoglobulin 2 g/kg over 10-12 hr
b. Aspirin 80-100 mg/kg/day divided every 6 hr orally until patient is afebrile for at least 48 hr
b. CONVALESCENT STAGE
a. Aspirin 3-5 mg/kg once daily orally until 6-8 wk after illness onset if normal coronary findings
throughout course
c. LONG-TERM THERAPY FOR PATIENTS WITH CORONARY ABNORMALITIES
a. Aspirin 3-5 mg/kg once daily orally
b. Clopidogrel 1 mg/kg/day (maximum: 75 mg/day)
c. Most experts add warfarin or low-molecular-weight heparin for those patients at particularly
high risk of thrombosis
d. ACUTE CORONARY THROMBOSIS
a. Prompt fibrinolytic therapy with tissue plasminogen activator or other thrombolytic agent
under supervision of a pediatric cardiologist
PROGNOSIS
a. The vast majority of patients with KD return to normal health, as timely treatment reduces the risk of
coronary aneurysms to less than 5%.
b. Giant aneurysms are less likely to regress to normal lumen diameter and are most likely to lead to
thrombosis or stenosis.
c. Coronary artery bypass grafting may be required if myocardial perfusion is significantly impaired; it is
best accomplished with the use of arterial grafts, which grow with the child and are more likely than
venous grafts to remain patent over the long-term.
d. Heart transplantation has been required in rare cases
e. Reassuring data suggest that the standardized mortality ratio among adults in Japan who had KD in
childhood without aneurysms is indistinguishable from that of the general population

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LOCALIZATION OF NEUROLOGICAL LESION IN GENERAL:

1. Is the lesion inside or outside the central nervous system? : The following symptoms are seen only if there
is a lesion in the CNS , there will be:
a. Aphasia
b. Homonymous hemianopia
c. Alternating hemiplegia: Cranial nerve signs on one side of the body and sensorimotor deficits on
the other side of the body.
d. Sign of Babinski
e. Spasticity
f. MLF syndrome (If a lesion in the medial longitudinal fasciculus, the eye on the affected side
cannot adduct during horizontal gaze, but adducts during convergence.
2. If the lesion is in the CNS, neurological examination is to focus on five “levels” of the CNS, which are the
brain, the brainstem, the spinal cord, the peripheral nerves, and the muscles. If the lesion is above the
level of the cord, is it in the brainstem (subtentorial) or is it in the forebrain (supratentorial = cerebral
hemisphere, thalamus and hypothalamus)?
a. Brain (hemispheres):
(a) Alteration of thought processes or consciousness, dysphasia/aphasia, neglect i.e
individuals with right-sided brain damage often fail to be aware of objects to their left,
demonstrating neglect of leftward items.
(b) Seizures and involuntary movements.
(c) When motor and sensory deficits are present, they occur on the contralateral side.
(d) Cerebral cortex:
1. Frontal lobe:
a. Incontinence
b. Impaired smell
c. Contralateral hemiparesis
d. Frontal release signs
2. Parietal (dominant):
a. Dysphasia
b. Acalculia
c. Dyslexia
d. Apraxia
e. Agnosia - Inability to recognise familiar objects, e.g. faces.
3. Parietal non dominant
a. Neglect of contralateral side
b. Spatial disorientation
4. Temporal
a. Receptive aphasia
b. Dyslexia
c. Impaired verbal memory
5. Occipital
a. Cortical blindness
b. Brainstem:
(a) General:
1. Ipsilateral Cranial nerve signs
2. Contralateral hemiplegia and hemisensory loss
3. Diplopia, vertigo, dysarthria, dysphagia, disequilibrium
(b) If the lesion is in the brainstem, is it in the medulla, pons, or midbrain?
1. Medulla: bulbar palsy
2. Pons:
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a. CN 6 or 7 palsy
b. Horizontal gaze palsy or INO
c. Unilateral facial numbness from CN 5
d. Unilateral deafness
3. Midbrain:
a. CN III: ptosis, dilated pupil,
b. eye down and out
c. vertical gaze palsy
c. Signs pointing to a lesion of the spinal cord include:
(a) Atrophy of muscles innervated by the spinal nerves;
(b) "fasciculations" and "fibrillations."
(c) Well-demarcated “level”– sensory or motor. Normal function above and below the
level.
(d) Sensory dissociation – decreased pain on one side and decreased vibration and
position on the other side;
d. Peripheral nerves:
(a) Poly neuropathy:
1. Sensory , motor or sensory motor involvement.
2. Distal symmetric, stocking-glove distribution; it evenly affects the lower
extremities before the upper extremities and progresses symmetrically from
distal to proximal areas.
(b) Dorsal nerve roots:
1. Irritative lesions of a dorsal root result in radicular pain or root pain,
2. May be associated with paresthesias in the area involved
3. Hypo- or areflexia occurs in the muscle subserved by the affected spinal root.
(c) Ventral nerve roots:
1. Weakness and atrophy in the myotomal distribution of the affected root.
2. Fasciculations may be evident in the affected muscle
3. Absent reflexes in the affected muscles
(d) Peripheral nerves
1. Mononeuropaty:
a. Los of sensation in the area of distribution
b. Muscle paralysis, atrophy and wasting
2. Mononeuropathy multiplex
a. More than one nerve in time and space
3. Plexus lesions
a. Mixed nerve and root distribution
e. Neuromuscular junction:
(a) No atrophy
(b) Normal or reduced tone
(c) Weakness: patchy i.e. doesn’t conform to an anatomic structure, fluctuation with time
& exercise i.e. fatigability
(d) Normal or depressed reflexes
(e) No sensory changes
(f) Fatigability of weakness or facilitation of power. Weakness that gets worse or better
with muscle exertion.
f. Muscular: Myopathy
(a) Muscle may be normal, wasted or pseudohypertrophied, depending on the disease
and time of presentation
(b) Weakness, usually more proximal than distal
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(c) Usually proximal rather than distal weakness, but there are distal myopathies. Also,
some myopathies are restricted to certain muscle groups e.g. ocular and pharygeal
muscles
(d) Usually symmetric weakness
(e) Pure motor weakness without sensory signs
(f) Tendon reflexes are usually preseved until late in the disease. They may be depressed
later on in the disease. Normal abdominal and plantar reflexes
(g) Make an attempt to characterize which muscle groups are affected: upper limb
shoulders girdle (deltoids, rotator cuff), lower limb girdle (gluteal, quadreceps), distal
muscles (finger flexors, peroneal muscles), occular muscles, pharyngeal muscles,
diaphgram or heart.
(h) Bowel and bladder sphincters are usually spared.

CLINICAL CLUES TO MELINGERING

1. Pseudoparalysis :
a. Drop test: Arm paresis Hold paretic hand above face and drop it over the face. If hand misses
face, paresis is nonorganic
b. Hoover test for Leg paresis: Cup heels and have patient press down with paretic limb. Then have
patient raise opposite limb. True paresis if no difference in downward pressure at heels
c. Adductor sign: Leg paresis Ask patient to abduct paretic leg to resistance. In true paresis,
opposite leg should abduct.
2. Pseudosensory syndromes:
a. Tuning fork test: Vibratory loss on one half of the skull, sternum or pelvis is thought to be
physiologically impossible because of bone conduction. The presence of vibratory loss over these
surfaces suggests a pseudosensory syndrome.
b. Bowlus and Currier test: In this test, the patient's arms are extended and crossed with thumbs
down and palms facing together. The fingers are then interlocked and the hands rotated
downward, inward and up in front of the chest. The fingertips end up on the same side of the
body as their respective arms. The thumbs are not interlocked so that they lie on the side
opposite the fingers. With true sensory impairment, a patient can quickly identify fingers with
normal and abnormal sensation when rapid sharp tactile stimuli are applied. Patients with
pseudosensory deficits confuse the lateralization, causing them to make many mistakes
identifying digits when sharp stimuli are applied to them.
c. Yes-no test: When testing the sensation of touch, have patients close their eyes and give “yes”
responses when they perceive they are being touched and “no” responses when they perceive
that they do not feel a touch. A repeated “no” response when a supposedly numb limb is touched
favors a pseudosensory syndrome.
d. Big toe. Patients with pseudosensory syndromes may erroneously identify the position of the big
toe 100 percent of the time. In contrast, a rate of at least 50 percent accuracy would be
anticipated with an organic lesion based purely on chance.
3. Pseudoseizure
a. Closed eyes during seizures
b. Resisted eyelid opening
c. No lateral tongue biting
d. Dystonic posturing (including opisthotonos)
e. No postictal confusion
f. Pelvic forward thrusting
g. Geotropic eye movements
h. Normal “ictal” EEG
i. Normal serum prolactin level
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4. Pseudocoma
a. semipurposeful avoiding movements; normal pupils, corneal reflexes, plantar reflexes and
sphincters
b. Normal caloric-provoked nystagmus
5. Pseudoblindness: Normal pupils and OKN
6. Hysterical aphonia:
a. Pressured whispering
b. Normal cough
c. Normal laryngoscopy

Neurology: Points to remember

a. Spinal nerves
a. 31 pairs
b. 8 cervical
c. 12 thoracic
d. 5 lumbar
e. 5 sacral
f. 1 coccygeal
b. vertebral exit
a. C1-C7 exit via intervertebral foramina above corresponding vertebra
b. all other nerves exit via intervertebral foramina below corresponding vertebra
c. Spinal cord termination: adults spinal cord ends at L1-L2 and becomes cauda equine ;subarachnoid space
extends to lower border of S2
d. Pneumonics:

Vertebral Level Sensory Area Way to Remember
T4 Chest at level of nipple T4 at teat pore
T7 Chest at level of xiphoid process T7 at bottom of sternum
T10 Abdomen at level of umbilicus T10 at belly button
L1 Abdomen at inguinal ligament L1 for IL
L4 Lower extremity at patella L4 on all fours

e. Deep Tendon Reflexes Toot values

Ankle reflex Sacral 1 primarily
Knee reflex Lumbar 2, 3, 4
Supinator (brachioradialis) reflex Cervical 5, 6
Biceps reflex Cervical 5, 6
Triceps reflex Cervical 6, 7

f. Cranial Reflexes
Reflex Function Afferent limb Efferent limb
Pupillary Pupillary constriction CN II CN III
Corneal Blink reflex in response to corneal touch CN V1 CN VII
Lacrimation Tearing in response to corneal touch CN V1 CN VII
Jaw Jerk Jaw closure when muscles are stretched CN V3 CN V3
Gag Pharyngeal muscle contraction when pharynx is CN IX CN IX, X
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touched

g. Cutaneous Stimulation Reflexes
a. Pneumonic: we stand on S1 (plantar), kneel on L3 (knee jerk) and sit on S3 (anal reflex)

Abdominal reflexes —upper Thoracic 8, 9, 10
—lower Thoracic 10, 11, 12
Plantar responses Lumbar 5, Sacral 1
Anal reflex Sacral 2, 3, 4


MUCOPOLYSACCHARIDOSES

1. Mucopolysaccharidoses are hereditary, progressive diseases caused by mutations of genes
coding for lysosomal enzymes needed to degrade glycosaminoglycans (acid
mucopolysaccharides), a long-chain complex carbohydrate composed of:
1. Uronic acids
2. Amino sugars
3. Neutral sugars
2. The major GAGs are:
i. Chondroitin -4- sulfate } mesenchymal abnormalities
ii. Chondroitin -6- sulfate }
iii. Dermatan sulfate }
iv. Keratan sulfate }
v. Heparan sulfate – mental deficiency
vi. Hyaluronan
3. GAGs are a Major constituents of the ground substance of connective tissue, as well as nuclear and
cell membranes. These substances are synthesized and, with the exception of hyaluronan, linked to
proteins to form proteoglycans, major constituents of the ground substance of connective tissue, of
nuclear and cell membranes. Degradation of proteoglycans starts with the proteolytic removal of the
protein core followed by the stepwise degradation of the glycosaminoglycan moiety. Failure of this
degradation because of absent or grossly reduced activity of mutated lysosomal enzymes results in
the intralysosomal accumulation of glycosaminoglycan fragments
2. Distended lysosomes accumulate in the cell, interfere with cell function, and lead to a characteristic
pattern of clinical, radiologic, and biochemical abnormalities
3. Mutations of the gene encoding L-iduronidase may result in severe Hurler disease with early death or
in mild Scheie disease manifesting only with limited joint mobility, mild skeletal abnormalities, and
corneal opacities.
4. Mucopolysaccharidoses are autosomal recessive disorders, with the exception of Hunter disease,
which is X-linked recessive.
5. Their overall frequency is between 3.5/100,000 and 4.5/100,000. The most common subtype is MPS-
III, followed by MPS-I and MPS-II.
6. The most common subtype is Sanfilippo disease (MPS-III) followed by Hurler disease ( MPS-I ) and
Hunter disease (MPS II

DEFECTIVE
TYPE EPONYM ENZYME MAIN CLINICAL FEATURES
I-H Hurler α-L-iduronidase Severe Hurler phenotype, mental deficiency, corneal
clouding, death usually before age 14 years
 10

DEFECTIVE
TYPE EPONYM ENZYME MAIN CLINICAL FEATURES
II Hunter- Iduronate sulfate Severe course similar to I-H but clear corneas. Mild
X-linked sulfatase course: less pronounced features, mild mental
recessive deficiency

III-A Sanfilippo A Heparan-S- Behavioral problems, sleeping disorder, aggression,

sulfamidase progressive dementia, mild dysmorphism, coarse hair,
clear corneas, survival to adulthood possible

IV-A Morquio A N-ac- Short-trunk dwarfism, fine corneal opacities,

galactosamine-6- characteristic bone dysplasia; final height <125 cm
sulfate sulfatase

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS
1. Clinical suspicion of a MPS justifies a skeletal survey. Radiographs of chest, spine, pelvis and
hands may show early signs of dysostosis multiplex (vertebral dysplasia, J sella etc)
2. The next diagnostic step is to assay the urinary excretion of GAG. Semiquantitative spot tests are
quick and inexpensive but subject to both false-positive and false-negative results. Quantitative
analysis of single GAG by various methods, or of oligosaccharides by tandem mass spectrometry,
is preferable and reveals type-specific profiles.
3. Morquio disease is often missed in urinary assays but can reliably be diagnosed in serum using
monoclonal antibodies to keratan sulfate.
4. Any individual who is suspected of an MPS disorder based on clinical features, radiographic
results, or urinary GAG screening tests should have a definitive diagnosis established by enzyme
assay. Serum, leukocytes, or cultured fibroblasts are used as the tissue source for measuring
lysosomal enzymes
5. Prenatal diagnosis is available for all MPSs and is carried out on cultured cells from amniotic fluid
or chorionic villus biopsy. Measurement of GAGs in amniotic fluid is unreliable.
6. Carrier testing in Hunter syndrome, an X-linked disorder, requires analysis of IDS gene once the
specific mutation or chromosome arrangement in the family under consideration is known.
7. Prenatal molecular analysis must be offered in a male fetus of a proven female carrier of the IDS
gene. His risk to be affected is 50%. It is very small, but not zero, in a female fetus as a result of
skewed maternal X-chromosome inactivation.
8. Molecular analysis in patients with other enzymatically proven mucopolysaccharidoses or in
known carriers is costly and usually not required. MPSs I, II, and VI are candidates for neonatal
blood spot screening by tandem mass spectrometry allowing early diagnosis and enzyme
replacement therapy.
9. Mucolipidoses and oligosaccharidoses manifest with the same clinical and radiographic features
as mucopolysaccharidoses. In these conditionsthe urinary excretion of GAGs is not elevated.
10. Hurler-like facial features, joint contractures, dysostosis multiplex and elevated urinary GAG
excretion differentiate the mucopolysaccharidoses from congenital disorders of glycosylation and
other neurodegenerative and dwarfing conditions.

MUCOPOLYSACCHARIDOSIS I
Hurler Disease.
1. Genetics:
1. MPS I is caused by mutations of the gene encoding α-L-iduronidase.
2. Clinical features:
1. Diagnosis is usually made between 6 and 24 mo of age
2. Hepatosplenomegaly,
3. Coarse facial features,
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4. Corneal clouding, glaucoma, and retinal degeneration
5. Large tongue,
6. Prominent forehead,
7. Joint stiffness,
8. Short stature,
9. Skeletal dysplasia.
10. Acute cardiomyopathy has been found in some infants <1 yr of age.
11. Most patients have recurrent upper respiratory tract and ear infections, noisy breathing,
and persistent copious nasal discharge.
12. Valvular heart disease with incompetence, notably of the mitral and aortic valves,
regularly develops, as does coronary artery narrowing.
13. Obstructive airway disease, notably during sleep, may necessitate tracheotomy.
Obstructive airway disease, respiratory infection, and cardiac complications are the
common causes of death.
14. developmental delay,
15. combined conductive and neurosensory hearing loss,
16. Progressive ventricular enlargement with increased intracranial pressure caused by
communicating hydrocephalus also occurs.
3. Radiographs:
1. Skull: Enlarged skull, J-shaped sella; Macrocephaly develops, with thickened calvarium,
Premature closure of lambdoid and sagittal sutures, Shallow orbits, Abnormal spacing of
teeth with dentigerous cysts.
2. Thorax: Short, thick clavicles and oar- or paddle-shaped ribs
3. Spine: Notched (inferiorly beaked) vertebrae, gibbus formation
4. Pelvis: small, flared iliac wings
5. Long bones: Enlarged, coarsely trabeculated diaphyses of the long bones with irregular
metaphyses and epiphyses.
6. Hands: Brachydactyly, widening of metacarpals with proximal pointing, irregular carpal
bones
MUCOPOLYSACCHARIDOSIS II.
Hunter disease (MPS II):
1. It is an X-linked disorder caused by the deficiency of iduronate 2-sulfatase (IDS).
2. Hunter disease manifests almost exclusively in males; it has been observed in a few females and
this is explained by skewed inactivation of the X chromosome carrying the normal gene.
3. Patients with severe MPS II have features similar to those of Hurler disease
4. There is no corneal clouding.
5. Coarse facial features, short stature, dysostosis multiplex, joint stiffness, and mental retardation
manifest between 2 and 4 yr of age.
6. Grouped skin papules are present in some patients.
7. Extensive Mongolian spots have been observed in African and Asian patients since birth and may
be an early marker of the disease.
8. Gastrointestinal storage may produce chronic diarrhea.
9. Communicating hydrocephalus and spastic paraplegia may develop due to thickened meninges.
10. In severely affected patients, extensive, slowly progressive neurologic involvement precedes
death, which usually occurs between 10 and 15 yr of age.
11. Airway involvement, valvular cardiac disease, hearing impairment, carpal tunnel syndrome, and
joint stiffness are common and can result in significant loss of function in both the mild and
severe forms.
MUCOPOLYSACCHARIDOSIS III
Sanfilippo disease (MPS III):
1. This makes up a genetically heterogeneous but clinically similar group of 4 recognized types.
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2. Patients with Sanfilippo disease are characterized by slowly progressive, severe CNS involvement
with mild somatic disease. Such disproportionate involvement of the CNS is unique to MPS III.
3. Onset of clinical features usually occurs between 2 and 6 yr in a child who previously appeared
normal.
4. Presenting features include delayed development, hyperactivity with aggressive behavior, coarse
hair, hirsutism, sleep disorders, and mild hepatosplenomegaly. Delays in diagnosis of MPS III are
common due to the mild physical features, hyperactivity, and slowly progressive neurologic
disease. Severe neurologic deterioration occurs in most patients by 6–10 yr of age, accompanied
by rapid deterioration of social and adaptive skills.
5. Severe behavior problems such as sleep disturbance, uncontrolled hyperactivity, temper
tantrums, destructive behavior, and physical aggression are common.
6. Profound mental retardation and behavior problems often occur in patients with normal physical
strength, making management particularly difficult.

MUCOPOLYSACCHARIDOSIS IV.
1.
Morquio disease (MPS IV) is caused by a deficiency of N-acetylgalactosamine-6-sulfatase (MPS
IV-A) or of β-galactosidase (MPS IV-B).
2. Both result in the defective degradation of keratan sulfate.
3. Both types of Morquio disease are characterized by short-trunk dwarfism, fine corneal deposits, a
skeletal dysplasia that is distinct from other mucopolysaccharidoses, and preservation of
intelligence.
TREATMENT
1. Bone marrow transplantation from related or unrelated donors or cord blood transplantation results
in significant clinical improvement of somatic disease in MPS I, II, and VI.
2. Enzyme replacement using recombinant enzymes is approved for patients with MPS I, MPS II, and
MPS VI. It reduces organomegaly, ameliorates rate of growth and joint mobility, and reduces the
number of episodes of sleep apnea and urinary GAG excretion. The enzymes do not cross the blood-
brain barrier and do not prevent deterioration of neurocognitive involvement.
Prevention:
Primary prevention is through genetic counseling and tertiary prevention is to avoid or treat
complications

Spinal Muscular Atrophies
Introduction:
1. The term neuromuscular disease: refers to disorders of the motor unit and excludes influences on
muscular function from the brain, such as spasticity. The motor unit has 4 components: a motor neuron
in the brainstem or ventral horn of the spinal cord; its axon, which together with other axons forms the
peripheral nerve; the neuromuscular junction; and all muscle fibers innervated by a single motor neuron.
2. These neuromuscular diseases may be genetically determined, congenital or acquired, acute or chronic,
and progressive or static.
3. Gen.Features:
a. Polyhydramnios
b. Diminished fetal movement
c. light for gestational age
d. Hypotonia, hyporeflexia and weekness and wasting
e. Fasciculations and fibrillations
f. Funnel shaped thorax
g. Undescended testes.
h. Delay in motor mile stones
4. Spinal muscular atrophies (SMAs)
a. Degenerative diseases of motor neurons that begin in fetal life and continue to be progressive in
 13

infancy and childhood.
b. Reinnervation from an adjacent motor unit forming giant motor units
c. Atrophy of muscle fibers
d. Motor neurons that are spared:
i. cranial nerves III, IV, and VI to extraocular muscles,
ii. striated muscle of the urethral and anal sphincters,
iii. Upper motor neurons
e. Autonomic motor neurons of both the sympathetic and parasympathetic systems are not
spared, but usually do not show clinical manifestations; may involve the detrusor muscle of the
urinary bladder or the smooth muscle urethral and anal sphincters
5. SMA is classified clinically into:
a. A severe infantile form: Werdnig-Hoffmann disease or SMA type 1
b. A late infantile and more slowly progressive form: Dubowitz disease: SMA type 2
c. A more chronic or juvenile form: Kugelberg-Welander disease, or SMA type 3.
d. A severe fetal form: SMA type 0
a. Some patients are transitional between types 1 and 2 or between types 2 and 3 in terms of
clinical function.
6. Variants: severe neonatal anterior horn cell disease with normal SMA1 gene
a. Fazio-Londe disease, is a progressive bulbar palsy resulting from motor neuron degeneration
b. SMA with respiratory distress type 1 (SMARD1)
c. Pontocerebellar hypoplasia type 1
d. X-linked infantile SMA with bone fractures (Arthrogryposis is common)
e. Congenital SMA with predominant lower limb involvement
GENETICS
1. Most cases are inherited as an autosomal recessive trait.
2. The incidence of SMA is 10-15 in 100,000 live births, affecting all ethnic groups; it is the second most
common neuromuscular disease, following Duchenne muscular dystrophy.
3. The genetic locus for all 3 of the common forms of SMA is on chromosome 5, a deletion at the 5q11-q13
locus, indicating that they are variants of the same disease rather than different diseases.
4. Neuropathologically it appears to be a pathologic continuation of a process of programmed cell death
(apoptosis) that is normal in embryonic life. A surplus of motor neuroblasts and other neurons is
generated from primitive neuroectoderm, but only about half survive and mature to become neurons;
the excess cells have a limited life cycle and degenerate. If the process that arrests physiologic cell death
fails to intervene by a certain stage, neuronal death can continue in late fetal life and postnatally.
5. The survivor motor neuron gene (SMN):
a. SMN arrests apoptosis of motor neuroblasts.
b. The SMN1 gene provides instructions for making the survival motor neuron (SMN) protein. The
SMN protein is found throughout the body, with high levels in the spinal cord. This protein is
particularly important for the maintenance of motor neurons in the spinal cord and the
brainstem.
c. The SMN protein helps to assemble the cellular machinery needed to process pre-mRNA.
d. Research findings indicate that the SMN protein is also important for the development of
specialized outgrowths from nerve cells called dendrites and axons. Dendrites and axons are
required for the transmission of impulses between nerves and from nerves to muscles.
e. A small amount of SMN protein is produced from a gene similar to SMN1 called SMN2.
The SMN2gene provides instructions for making several versions of the SMN protein, but only
one version is functional; the other versions are smaller and easily broken down.
f. No of SMN2 copies will decide severity. One copy in SMA I; 2 copies in II; 3 copies in III
CLINICAL MANIFESTATIONS
1. SMA I:
a. The cardinal features of SMA type 1 are severe hypotonia; generalized weakness; thin muscle
mass; absent tendon stretch reflexes; involvement of the tongue, face, and jaw muscles; and
 14

sparing of extraocular muscles and sphincters.
b. Diaphragmatic involvement is late.
c. Infants who are symptomatic at birth can have respiratory distress and are unable to feed.
Congenital contractures, ranging from simple clubfoot to generalized arthrogryposis, occur in
approximately 10% of severely involved neonates. Infants lie flaccid with little movement,
unable to overcome gravity. They lack head control.
d. More than 65% of children die by 2 yr of age, and many die early in infancy.
2.
SMA II:
a. In type 2 SMA, affected infants are usually able to suck and swallow, and respiration is adequate
in early infancy. These children show progressive weakness, but many survive into the school
years or beyond, although confined to an electric wheelchair and severely handicapped.
b. Nasal speech and problems with deglutition develop later. Scoliosis becomes a major
complication in many patients with long survival.
c. Gastroesophageal reflux may lead to malnutrition or to aspiration with acute airway obstruction
or pneumonia.
3. Type III:
a. Kugelberg-Welander disease is the mildest SMA (type 3), and patients can appear normal in
infancy.
b. The progressive weakness is proximal in distribution, particularly involving shoulder girdle
muscles. Patients are ambulatory. Symptoms of bulbar muscle weakness are rare.
c. Approximately 25% of patients with this form of SMA have muscular hypertrophy rather than
atrophy, and it may easily be confused with a muscular dystrophy.
d. Longevity can extend well into middle adult life.
4. Fasciculations are a specific clinical sign of denervation of muscle; may be masked by a thick pad of
subcutaneous fat. Fasciculations are best observed in the tongue, where almost no subcutaneous
connective tissue separates the muscular layer from the epithelium. If the intrinsic lingual muscles are
contracted, such as in crying or when the tongue protrudes, fasciculations are more difficult to see than
when the tongue is relaxed.
5. Cramps and myalgias of appendicular and axial muscles are common
6. The outstretched fingers of children with SMA often show a characteristic tremor owing to fasciculations
and weakness. It should not be confused with a cerebellar tremor.
7. The heart is not involved in SMA. Intelligence is normal, and children often appear brighter than their
normal peers because the effort they cannot put into physical activities is redirected to intellectual
development
8. Progressive deterioration of ambulation and the high risk of falling and fracturing long bones or the pelvis
eventually require use of a wheelchair;
9. Progressive scoliosis is another serious complication and may have a further adverse effect on
respiration.
LABORATORY FINDINGS
1. The serum creatine kinase level may be normal but more commonly is mildly elevated in the hundreds. A
creatine kinase level of several thousand is rare.
2. The chest x-ray in early-onset disease demonstrates thin ribs.
3. Results of motor nerve conduction studies are normal, except for mild slowing in terminal stages of the
disease, an important feature distinguishing SMA from peripheral neuropathy. EMG shows fibrillation
potentials and other signs of denervation of muscle.
4. A secondary mitochondrial DNA depletion is sometimes demonstrated in the muscle biopsy of infants
with SMA.
5. The molecular genetic test of the SMN gene provides definite confirmation of the diagnosis.
DIAGNOSIS
1. The simplest, most definitive diagnostic test is a molecular genetic marker in blood for the SMN gene.
2. Muscle biopsy:
a. Common to all forms of muscular dystrophies are muscle fibre necrosis, regenerative activity,
 15

replacement by interstitial fibrosis and adipose tissue (
b. The muscle biopsy in infancy reveals a characteristic pattern of perinatal denervation that is
unlike that of mature muscle. Groups of giant type I fibers are mixed with fascicles of severely
atrophic fibers of both histochemical types. Scattered immature myofibers resembling myotubes
also are demonstrated. In juvenile SMA, the pattern may be more similar to adult muscle that
has undergone many cycles of denervation and reinnervation.
3. EMG:
a. The denervated muscle fiber becomes progressively more mechanically irritable. Therefore,
there will be “increased insertional activity.”
b. Muscle fibers also become chemically sensitive to their microenvironment and their membranes
can also become unstable enough to produce spontaneously activity. This appear as fibrillation
potentials and positive sharp waves.
c. Reinnervation of muscle is an ongoing process, occurring whenever a muscle is partially
denervated. This process typically involves the development of sprouts from adjacent,
unaffected motor nerve fibers that ultimately contact at least some of the denervated muscle
fibers. These motor units become significantly larger both in amplitude and duration, since the
needle is likely to be recording from more muscle fibers in this clump. Also, the MUPs often
become more irregular (termed “polyphasic”)
4. Sural nerve biopsy is now performed only occasionally, but shows mild sensory neuropathic changes, and
sensory nerve conduction velocity may be slowed; hypertrophy of unmyelinated axons also is seen.
5. At autopsy, mild degenerative changes are seen in sensory neurons of dorsal root ganglia and in
somatosensory nuclei of the thalamus, but these alterations are not perceived clinically as sensory loss or
paresthesias. The most pronounced neuropathologic lesions are the extensive neuronal degeneration
and gliosis in the ventral horns of the spinal cord and brainstem motor nuclei, especially the hypoglossal
nucleus.
TREATMENT
1. No medical treatment is able to delay the progression. Supportive therapy includes orthopedic care with
particular attention to scoliosis and joint contractures, mild physiotherapy, and mechanical aids for
assisting the child to eat and to be as functionally independent as possible. Most children learn to use a
computer keyboard with great skill but cannot use a pencil easily. Valproic acid is sometimes
administered because it increases SMN2 protein, and gabapentin and oral phenylbutyrate also may slow
the progression, but these treatments do not alter the course in all patients. A benefit of antioxidants is
unproved. Gene replacement and protein replacement therapies remain theoretical and experimental.
Potential therapeutic geneticstrategies in SMA include upregulation of SMN2 gene expression,
preventing exon 7 skipping of SMN2 transcripts and improving the stability of the protein lacking the
amino acid sequence encoded by exon 7.
Other Motor Neuron Diseases
2. Motor neuron diseases other than SMA are rare in children. Poliomyelitis used to be a major cause of
chronic disability, but with the routine use of polio vaccine, this viral infection is now rare (see Chapter
249).
3. Other enteroviruses, such as coxsackievirus and echovirus, or the live polio vaccine virus can also cause
an acute infection of motor neurons with symptoms and signs similar to poliomyelitis, although usually
milder. Specific polymerase chain reaction tests and viral cultures of cerebrospinal fluid are diagnostic.
Motor neuron infection with the West Nile virus also occurs.
4. A juvenile form of amyotrophic lateral sclerosis is rare. Upper and lower motor neuron loss is evident
clinically, unlike in SMA. The course is progressive and ultimately fatal.
5. Pena-Shokeir and Marden-Walker syndromes are progressive motor neuron degenerations associated
with severe arthrogryposis and congenital anomalies of many organ systems.
6. Pontocerebellar hypoplasias are progressive degenerative diseases of the central nervous system that
begin in fetal life; type 1 also involves motor neuron degeneration resembling an SMA, but the SMN gene
on chromosome 5 is normal.
7. Motor neurons become involved in several metabolic diseases of the nervous system, such as
 16

gangliosidosis (Tay-Sachs disease), ceroid lipofuscinosis (Batten disease), and glycogenosis II (Pompe
disease), but the signs of denervation may be minor or obscured by the more prominent involvement of
other parts of the central nervous system or of muscle

MUSCLE BIOPSY

1. MUSCLE Biopsy is most useful for the diagnosis of:
a. Inflammatory myopathies
b. Certain muscular dystrophies for which the structural abnormality is known but genetic testing is
not readily available
c. Mitochondrial cytopathies
d. Metabolic myopathies.
e. Neuromuscular disorders that can be confIrmed by electrophysiology, e.g. myasthenia gravis and
related syndromes,
f. Motor neurone disease.
g. Muscular dystrophies (such as Becker’s and Duchenne muscular dystrophies)
facioscapulohumeral dystrophy and myotonic dystrophy) and
h. Spinal muscular atrophy
2. The usefulness of a muscle biopsy depends on consideration of all the following four criteria: •
appropriateness of the test;
a. Choice of muscle;
b. Biopsy technique;
c. Histopathology performed
3. CHOICE OF MUSCLE
a. use the same muscle for every biopsy as there are variations in ‘normal’ between different
muscles
b. Biceps brachialis in the upper limb and vastus lateralis in the lower limb are most frequently
chosen
c. The chosen muscle must be involved in the process (weak) but not severely so. Using the British
Medical Research Council Scale, a power of 4/5 is desirable.
d. The muscle site must be free from trauma, iatrogenic or otherwise. This includes previous biopsy
and recent intra muscular injection or insertion of EMG needles.
e. If the disease is focal or distal, extensor carpi radialis or tibialis anterior may be used,
f. Consider cosmetic issues. A biopsy scar is more discrete on the thigh than upper limb. Likewise
biopsy of facial muscle should be avoided.
g. Consider functional issues. Biopsy should be of large muscles in a limb, small muscles in the hand
with important function should be avoided.
h. Beware of muscle affected by a second pathological process, such as a radiculopathy, which may
confuse interpretation of the biopsy.
BIOPSY TECHNIQUE
a. Muscle biopsy requires written, informed consent.
b. The pathologist requires detailed clinical information so that the specimen is processed and
interpreted in a way that maximizes diagnostic information.
c. The biopsy is best performed in an operating theatre, by direct visualization and under sterile
conditions
d. The biopsy is taken with the muscle fiber fascicles running longitudinally.
e. The fresh specimens are transported immediately for freezing (histochemical and biochemical
analysis) and fixing (electron microscopy) as required.
Staining
1. Histochemical staining
a. Hematoxylin and eosin: evaluation of general architecture of the muscle and variation in the
 17

morphology of individual fibers
b. Oil Red O: a fat-soluble dye used to demonstrate triglycerides and lipids in frozen sections
c. Periodic acid Schiff (PAS): to demonstrate muscle glycogen, mucin and some basement
membranes
d. Van Gieson’ s stain: to differentiate collagen from connective tissue.
2. Enzyme Histochemistry:
a. Oxidative enzymes:
i. The dehydrogenases, the adenosine triphosphatases and enzymes associated with
the glycolytic pathway, such as phosphorylases, are enzymes used for muscle fiber
integrity
ii. Nicotinamide adenine dinucleotide (NADH) is an oxidative enzyme staining
procedure that reveals myofibrillar architecture, mitochondria, and target fibers. It
may also differentiate between Type I and Type II fibers.
b. Hydrolytic enzymes such as galactosidase and phosphorylase, which are found in mammalian
muscle fibers, are useful in the diagnosis of glycogen-storage disorders.
3. Immunohistochemical Staining:
a. It uses antigen– antibody interaction, visualized by fluorescent, enzymatic, or another
marker, to localize specific antigens in tissue sections; identifies the presence, absence,
abnormal accumulation, or maldistribution of certain proteins in neuromuscular disorders.
b. Antibodies against dystrophin can be used to diagnose Duchenne muscular dystrophy
and Becker-type muscular dystrophy.
c. Antibodies against merosin can be used to diagnose congenital muscular
dystrophy.
Normal structure
1. Skeletal muscle is made up of muscle fibers, polygonalvand uniform in size. They bundle into groups
called fascicles.
2. Individual muscle fibers are syncytia, formed by embryonic fusion of many myoblasts or later,
myosatellite cells. Each muscle fiber contains many nuclei, peripherally positioned immediately
adjacent to the sarcolemmal membrane.
3. In cross-section, individual myofibers appear polygonal except in the infant when round fibers are
normal.
4. Muscle contains slow-twitch type I fibres and fast-twitch type II fibres, which can be identified by
enzyme histochemistry.
5. Muscle types and subtypes can be determined by incubating frozen muscle sections at various pH of
adenosine triphosphatase enzyme
6. Normally, Type I and Type II fibers are distributed randomly throughout a muscle fascicle in a mosaic
pattern. If the normal mosaic pattern is disturbed, it may result in grouping of I & II called “fiber-type
grouping,” a phenomenon usually associated with chronic denervation and reinnervation
Abnormal patterns
1. There are two major characteristic myopathologic patterns of neuromuscular disease:
a. Neurogenic, resulting from diseases of the innervating neuron; and
b. Myopathic due to intrinsic diseases of the muscle fiber that can be inherited or acquired,
including the muscular dystrophies, congenital, inflammatory, metabolic and toxic
myopathies.
2. Neurogenic pattern:
a. The earliest structural change in neurogenic atrophy seen on muscle biopsy is the loss of the
polygonal shape of the muscle fiber.
b. A pattern of scattered, atrophic muscle fibers involving both types I and II fibers is another
early finding.
c. The atrophic fibers become small and angulated.
d. If re-innervation occurs then, fiber-type grouping will be evident with ATPase staining and
the normal patchwork pattern will no longer be evident. Instead, groups of similar fiber-
 18

types will lie adjacent to one another. This phenomenon occurs after denervation followed
by reinnervation, when a single remaining near-by motor neuron sprouts and re-innervates
multiple atrophied muscle fibers, altering the fiber-type to reflect the metabolic signature of
the re-innervating motor neuron.
e. Nuclear bags, which appear as clumps of nuclei encircled by the remaining sarcolemmal
membrane;
f. Target or targetoid fibers that are best observed with NADH-TR staining. Target fibers are
characterized by the presence of three zones, each with varying stain intensity, within the
cell. The pale central zone results from reduced oxidative enzymatic activity, disorganized
myofibrils, and a paucity of mitochondria. The central zone is encircled by a darkly stained
zone, that is enriched with mitochondria and has increased enzymatic activity. The third zone
stains normally, and is at the periphery of the myofiber. Target fibers are most commonly
type I muscle fibers.
3. Myopathic Changes
a. Myopathic changes observed on biopsy often include both a common underlying pattern of
muscle disease with superimposed disease-specific structural alterations.
b. Early features: in the disease may cause
i. Focal myofiber damage in mitochodrial disorders,
ii. Segmental damage in the dystrophies, or
iii. Multifocal damage in the inflammatory myopathies
c. Other features include
i. Fiber size variation with both atrophied and hypertrophied muscle fibers.
ii. The atrophied fibers are often rounded, as opposed to the sharply angulated
atrophic fibers observed in neurogenic atrophy.
iii. The hypertrophied fibers, as they enlarge, may eventually divide into two fibers and
are referred to as split fibers
iv. Old damage can be identified by the increase of internalized nuclei which are
common in many myopathies.
v. Ragged red fibers are common in mitochondrial disease

EMG
1. The Motor Unit: The smallest functional unit of the muscular contraction process is called a Motor Unit. It
consists of spinal alpha motor neuron, the multiple branches of its axon, and the muscle fibers that
innervates it. The term units outlines the behavior, that all muscle fibers of a given motor unit act “as one”
within the innervation process.

2. Neurons have a negative concentration gradient most of the time, meaning there are more positively
charged ions (Na+) outside than inside the cell (K +). This regular state of a negative concentration
gradient is called resting membrane potential. A potential is a distribution of charge across the cell
 19

membrane, measured in millivolts (mV). Negative concentration in resting membrane is approximately -70
mV.
+
3. During a stimulus Na gate opens and Na enters the cell reducing the negative membrane potential from -
70 to +30. This is called depolarization. Backward flow of Ka+ restoring the resting potential is called
repolarization. Repolarization may go more than -70 mV and this is called hyperpolarization
4. The change in the membrane voltage from -70 mV at rest to +30 mV at the end of depolarization is 100-
mV change and this change is called the action potential as it spreads along the muscle fiber in both
directions.
5. The electrical changes generated by activity of the MU can be acquired and amplified by electrodes
located in muscle mass and these changes can be recorded and edited using electromyographic (EMG)
devices. The changes generated by a MU is the motor unit action potential (MUAP).

6. Parameters of the motor unit potential:
a. Amplitude, duration, and number of phases may be measured
b. Normal: 2 mV in amplitude, and have a duration of 10–5 ms with 3–4 phases
c. In chronic partial denervation where intramuscular sprouting and re-innervation has occurred,
amplitudes may be as high as 10– 20 mV and durations 20–30 ms.
d. In primary muscle disease, motor unit potentials are small and of short duration; typical values
would be 0.5 mV and 5–10 ms.
e. Polyphasicity can be seen in a wide number of situations, but muscle disease and the early stages
of re-innervation is the most common.
7. EMG is recorded when the muscle is
a. at rest,
b. during a weak contraction and
c. during a strong contraction.
8. With the muscle at rest, spontaneous activity is assessed. In a healthy muscle there is only a brief burst of
EMG signal when the needle is moved within the muscle. This is called insertional activity.
9. Following an axonal injury, several forms of pathological spontaneous activity may be found.
a. Fibrillation potentials (fibs) and positive sharp waves (psw) are seen 14-21 days following an
axonal nerve lesion. They usually persist for 6-12 month, although some spontaneous activity
may persist for many years.

b. Complex repetitive discharges and myokymic discharges are sometimes seen in chronic lesions.
10. The morphology of motor unit action potentials (MUAPs) is analysed during a weak voluntary contraction
(MUAP analysis). Several MUAPs should be recorded within a muscle and amplitude, duration, number of
phases and turns are the most important parameters analysed.
11. In f axonal nerve lesions, the following MUAP changes are typically seen:
a. low-amplitude polyphasic potentials indicate early re-innervation following a (sub)total nerve
lesion,
 20

b. polyphasic normal or high amplitude MUAPs are seen in subacute neurogenic lesions after partial
nerve damage and during later stages of re-innervation.
c. Satellite potentials are the electric footprint of collateral sprouting.
d. MUAPs of high amplitude and long duration indicate a chronic neurogenic lesion without ongoing
re-innervation.
A) normal motor unit action potential (MUAP)

B) MUAP in a chronic lesion; note that the amplification is different and the amplitude of the MUAP is
app. 10-times that of the normal MUAP.

C) low-amplitude polyphasic MUAP in early reinnervation following a (sub)total nerve damage;

D) polyphasic MUAP of normal amplitude in subacute neurogenic lesion or re-innervation at a later
stage

E) MUAP with several satellite potentials indicating collateral sprouting.

 21

12. In the next step motor unit recruitment and interference pattern can be analysed.
a. Recuitment is the successive activation of the additional motor units with increasing strength of
voluntary muscle contraction. Reduced recruitment is seen in nerve lesions. To differentiate this
from central weakness the firing frequency of motor units (MU) is used.
b. Firing frequency: During muscle contraction, to increase force you either fire more rapidly or
recruit more units. Firing rate in normal muscle between 4 to 12 hz before second unit begins to
fire. In peripheral nerve lesions the firing frequency is higher (>20/s) than in central lesions
(about 10/s).
c. Interference pattern: A normal muscle has a full interference pattern. i.e. during a maximal
voluntary muscle contraction of a healthy individual, a "full" or "complete" interference pattern
is present; a less dense interference pattern indicates loss of MU. A less dense, high amplitude
interference patter is seen in chronic nerve lesions.
13. Myopathy:
a. Number of functioning muscle fibers decreased—units smaller, shorter duration.
b. Abnormal firing causes polyphasia
c. Acute: short duration, small amplitude units with normal or early recruitment
d. Chronic: (some denervation often occurs) longduration, high amplitude MUAPS can be seen
(often with short-duration, small units)
e. Recruitment is still normal or early until end stage

MYOPATHY EMG: Small amplitude, brief, polyphasic action potentials

Denervation EMG

1. The denervated muscle fiber becomes progressively more mechanically irritable. Therefore,
there will be “increased insertional activity.”
2. Muscle fibers also become chemically sensitive to their microenvironment and their membranes
can also become unstable enough to produce spontaneously activity. This appear as fibrillation
potentials and positive sharp waves.
3. Reinnervation of muscle is an ongoing process, occurring whenever a muscle is partially
denervated. This process typically involves the development of sprouts from adjacent,
unaffected motor nerve fibers that ultimately contact at least some of the denervated muscle
fibers. These motor units become significantly larger both in amplitude and duration, since the
 22

needle is likely to be recording from more muscle fibers in this clump. Also, the MUPs often
become more irregular (termed “polyphasic”)
Nerve conduction studies (ENMG)

1. The basic idea of NCSs is electrical excitation of all thick fibres in the peripheral nerve, and recording
response at some distance either from the nerve itself (mixed nerve or sensory nerve action potential
- SNAP) or from the innervating muscle (compound muscle action potential – CMAP).
2. Responses are then quantitatively described using NCS parameters:
a. Latency (ms) measures time delay between the electrical stimulus and beginning of the
response.
b. Amplitude (mV or µV) measures voltage difference between the baseline and the peak of
response.
c. Area (msmV or msµV) surface between the baseline and the response curve, and provides
similar information as amplitude.
d. Conduction velocity (m/s) can be calculated by dividing distance by latency (difference).
3. During motor NCSs fix “active” electrode (E1) on muscle motor point, and “reference” electrode (E2)
on a distal bone. Typically 8 cm proximal to the middle of “active” electrode stimulate the nerve using
“supramaximal” nerve stimuli (i.e., stimulus strength evoking maximum amplitude CMAP increased by
20%). Distance should be measured along the anatomic course of the studied nerve (e.g., median
nerve at the wrist).
4. During sensory NCSs measure 14 cm distance along the anatomic course of the nerve. We can then
stimulate the nerve either proximally and record distally (antidromic study) or stimulate distally and
record proximally (orthodromic study).
5. These studies are performed by passing a small, controlled electric current along the nerve and
measuring how long it takes for the current to travel along the nerve. Electrodes are placed on the
hands/ arms or feet/legs. Electrical pulses are passed through the skin and recordings are made of
the signals further along the nerve
6. Nerve conduction studies are helpful in the diagnosis of motor, sensory, radiculopathis and
neuropathies.
7. In neuropathy, conduction is often slowed, and the response pattern may show a dispersion of
potentials due to unequal involvement of myelinated and unmyelinated axons. However, when
neuropathies affect only small umyelinated or thinly myelinated fibers (or when weakness is due to a
muscle disorder), results are typically normal.
8. A nerve can be repeatedly stimulated to evaluate the neuromuscular junction for fatigability; eg, a
progressive decremental response occurs in myasthenia gravis.





HYPOXIA-ISCHEMIA IN NEONATE (HIE)
Definitions and criteria:
Hypoxemia refers to decreased arterial concentration of oxygen. Hypoxia refers to a decreased
oxygenation to cells or organs. Ischemia refers to blood flow to cells or organs that is insufficient to
maintain their normal function.
Asphyxia ( Greek "a stopping of the pulse")
A gold standard definition of birth asphyxia does not exist. Better term is perinatal asphyxia since
asphyxia may occur in utero, at birth or in the postnatal period.
1. WHO definition: “failure to initiate and sustain breathing at birth”
5. Definition by Apgar criteria:
 23

a. It could be defined as moderate asphyxia as slow gasping or an Apgar score of 4-6 at 1
minute of age.
b. Severe asphyxia was defined as no breathing or an Apgar score of 0-3 at 1 minute of age.
6. AAP & ACOG criteria
1. Fetal acidosis (Ph. <7.0),
th
2. A 5 min Apgar score of 0-3,
3. Encephalopathy (altered tone, depressed level of consciousness, seizures),
4. Multi organ dysfunction.
Etiology of asphyxia
Antenatal:
1. Inadequate oxygenation of maternal blood from hypoventilation during anesthesia, cyanotic
heart disease, respiratory failure, or carbon monoxide poisoning;
2. Low maternal blood pressure from acute blood loss, spinal anesthesia, or compression of the
vena cava and aorta by the gravid uterus;
3. Inadequate relaxation of the uterus to permit placental filling as a result of uterine tetany
caused by the administration of excessive oxytocin;
4. Premature separation of the placenta;
5. Impedance to the circulation of blood through the umbilical cord as a result of compression
or knotting of the cord;
6. Placental insufficiency from toxaemia or postmaturity.
7. Prolonged labour due to CPD
After birth:
1. Failure of oxygenation as a result of severe forms of cyanotic congenital heart disease or
severe pulmonary disease;
2. Severe anemia (severe hemorrhage, hemolytic disease);
3. Shock severe enough to interfere with the transport of oxygen to vital organs from
overwhelming sepsis, massive blood loss, and intracranial or adrenal hemorrhage.
Pathophysiology
The pathophysiology in HIE consists of multiple phases:
1. Changes in the vasculature.
a. Loss in auto-regulation and the development of cerebral blood flow being dependent on
systemic arterial pressure
b. A decrease in systemic arterial blood pressure increases the risk for tissue acidosis and
ischemic brain injury
2. Primary energy failure:
a. Due to loss of oxygen, cellular energy metabolism shifts to a dependency upon anaerobic
metabolism.
3. Anaerobic metabolism leads to depletion of adenosine triphosphate and increased levels of
a. Lactate and Inorganic phosphates.
b. Excitatory and toxic amino acids, glutamate,
c. Intracellular sodium and calcium producing tissue swelling and cerebral edema.
d. Free radicals and nitric oxide leading to mitochondrial dysfunction.
e. Mitochondrial dysfunction signals pathways of apoptotic or necrotic cell death. Apoptotic
cell death is believed to occur when energy supplies are not completely exhausted, while
necrotic cell death occurs when energy supplies are no longer available.
4. A second energy failure occurs 6–48 h after hypoxia ischemia. The second energy failure phase also
results in the detrimental release of excitatory neurotransmitters and free radicals as well as
depletion of high phosphate reserves, but differs from the primary energy failure phase since it is
independent of cerebral acidosis.
5. A third phase where cytokines and other detrimental factors of chronic inflammation leading to
further damage has recently been proposed i.e. impairment or alteration of axonal growth,
neurogenesis, and synaptogenesis.
 24

6. Blood-brain barrier (BBB) cerebral spinal fluid (CSF) albumin levels were 5 times higher in infants with
HIE when compared with controls indicating increase in permeability of the BBB leading to infiltration
of neutrophils and monocytes from the systemic compartment.
7. Some findings suggest that angiogenesis is activated after acute insult in the neonatal brain. In the
adult brain, angiogenesis is a key repair mechanism after a hypoxic ischemic event. Angiogenesis can
be activated to enhance brain repair after HIE in newborns are essential to creating viable strategies
on how to improve functional and structural recovery after injury It has also been shown that
angiogenesis could be induced by the transplantation of CD34+ cells from umbilical cord blood and
that this improvement is beneficial suggesting that the neovascularization mechanisms are essential
for survival and may be a potential therapeutic approach.
8. Neuronal loss is a prime feature of HIE. Neurogenesis is an endogenous repair mechanisms after
brain injuries that may restore function. Velthoven et al. demonstrated that bone marrow derived
mesenchymal stem cells treatment after HIE was able to increase neurogenesis and formation of new
oligodendrocytes,
9. Autophagy is a lysosomal pathway for intracellular degradation of macromolecules and organelles
and plays an important role in maintaining cellular survival and homeostasis. There are some
experiments that describe pharmacological inhibition of autophagy being neuroprotective, while
others have shown that the autophagic machinery precipitates a peculiar form of cell death (known
as autosis) that contributes to the aetiology of other types of acute brain damage in neonatal
asphyxia. The possibility of using pharmacological modulators (activators or inhibitors) of autophagy
for neuroprotection is a current research question. Increase in AMP promotes autophagy by
stimulating the ability of serine/threonine kinase 11 (STK11; also known as LKB1). Shortage in amino
acids triggers autophagy as it results in the inactivation of mechanistic target of rapamycin complex 1
(MTORC1). Lithium was able to inhibit post-ischemic autophagy after 72 h. Taurine limits autophagy
initiation by stimulating MTORC1 activity.
Pathology:
1. Neuronal loss
2. Cerebrovascular hemorrhage esp. intraventricular
3. Term infants demonstrate neuronal necrosis of the cortex (later, cortical atrophy) and parasagittal
ischemic injury.
4. Preterm infants demonstrate PVL (later, spastic diplegia), status marmoratus of the basal ganglia, and
IVH.
5. Term more often than preterm infants have focal or multifocal cortical infarcts that manifest clinically
as focal seizures and hemiplegia.
6. Pulmonary arteriole smooth muscle hyperplasia may develop, which predisposes the infant to
pulmonary hypertension
7. Congestion and petechiae are seen in the pericardium, pleura, thymus, heart, adrenals, and
meninges.
8. If fetal distress produces gasping, the amniotic fluid contents (meconium, squames, lanugo) are
aspirated into the trachea or lungs.
Clinical presentation
1. Antinatal: intrauterine growth restriction
2. Perinatal:
1. Fetal bradycardia
2. Decline in beat-to-beat variability
3. Variable or late (type II) deceleration
4. Fetal scalp blood pH <7.20
5. Meconium stained liquor and aspiration.
3. Immediate NB period
1. At birth, affected infants may be depressed and may fail to breathe spontaneously.
2. During the ensuing hours, they may remain hypotonic or change from a hypotonic to a
hypertonic state
 25

3. Pallor, cyanosis, apnea, a slow heart rate, and unresponsiveness to stimulation are also signs
of HIE.
4. Cerebral edema may develop during the next 24 hr and result in profound brainstem
depression. During this time, seizure activity may occur.
5. Seizures in asphyxiated newborns may also be due to hypocalcemia, hypoglycemia, or
infection
6. CNS dysfunction, heart failure and cardiogenic shock, persistent pulmonary hypertension,
respiratory distress syndrome, gastrointestinal perforation, hematuria, and acute tubular
necrosis are associated with perinatal asphyxia secondary to inadequate perfusion
4. Multi organ involvement:
Hypoxic-ischemic encephalopathy, infarction, intracranial
CNS
hemorrhage, seizures, cerebral edema, hypotonia, hypertonia
Myocardial ischemia, poor contractility, cardiac stun, tricuspid
CVS
insufficiency, hypotension
Pulmonary hypertension, pulmonary hemorrhage, respiratory
R.S
distress syndrome - MAS
Renal Acute tubular or cortical necrosis
Adrenal Adrenal hemorrhage
Gastrointestinal Perforation, ulceration with hemorrhage, necrosis
Inappropriate secretion of antidiuretic hormone, hyponatremia,
Metabolic
hypoglycemia, hypocalcemia, myoglobinuria
Integument Subcutaneous fat necrosis
Hematology Disseminated intravascular coagulation
Diagnosis:
1. Computed tomography (CT) scan.
1. Focal hemorrhagic lesions,
2. Diffuse cortical injury, and damage to the basal ganglia;
3. Bilateral, diffuse hypodensity reflects marked cortical neuronal injury, with associated
edema
4. CT has limited ability to identify cortical injury during the 1st few days of life.
2. Ultrasonography:
1. It is the preferred modality in evaluation of the preterm infant.
2. intraventricular hemorrhage
3. Necrosis of basal ganglia and thalamus.
4. Periventricular white matter injury.
3. Magnetic resonance imaging (MRI):
1. Identifies regions of hypoxia and ischemia
4. Evoked electrical potentials (auditory, visual)
5. Amplitude-integrated electroencephalography (aEEG) may help to determine which infants are at
highest risk for long-term brain injury. A single-channel tracing is generated from 2 electrodes
placed in the biparietal area. A filter is used to filter and attenuate the signal between 2 Hz and
15 Hz. This technique is simple to perform and correlates with standard EEG. It has good
reliability, a positive predictive value of 85%, and a negative predictive value of 91-96% for
infants who will have adverse neurodevelopmental outcome.
Sarnat and Sarnat stages of HIE:
SIGNS STAGE 1 STAGE 2 STAGE 3
1. Level of consciousness Hyperalert Lethargic Stuporous, coma
2. Muscle tone Normal Hypotonic Flaccid
3. Posture Normal Flexion Decerebrate
4. Tendon reflexes/clonus Hyperactive Hyperactive Absent
5. Myoclonus Present Present Absent
 26

6. Pupils Mydriasis Miosis Unequal, poor light reflex
7. Seizures None Common Decerebration
8. Outcome Good Variable Death, severe deficits
Treatment
1. Immediate resuscitation.
a. Ventilation.
b. Oxygenation
c. Perfusion.
d. Correct metabolic acidosis
2. Maintain a normal serum glucose level (~75-100 mg/dL) to provide adequate substrate for brain
metabolism.
3. Avoid hyperglycemia to prevent hyperosmolality
Control of seizures
1. Phenobarbital for 2 months. High-dose phenobarbital (20 mg/kg) reduced the incidence of
seizures and improved neurologic outcome at 3 years in term asphyxiated newborns; additional
doses of 5-10 mg/kg (up to 40-50 mg/kg total) may be needed.
2. Phenytoin (20 mg/kg loading dose) or lorazepam (0.1 mg/kg) may be needed for refractory
seizures.
Prevention of cerebral edema
1. Avoidance of fluid overload; moderate fluid restriction (eg, 60 mL/kg). If cerebral edema is
severe, further restriction of fluid intake to 50 mL/kg is imposed.
2. Observe the infant for SIADH.
3. Glucocorticoids and osmotic agents like manitol are not recommended.
Neuroprotective agents:
1. There is some clinical evidence that highdose prophylactic phenobarbital may decrease
neurodevelopmental impairment in infants with HIE.
2. Magnesium has an inhibitory effect on glutamate receptors and Ca2+ channels during hypoxia.
3. Prevention of free radical formation:
1. Xanthine oxidase inhibitor.
2. Allopurinol
4. Resuscitation with room air. In a trial room air-resuscitated infants recovered more quickly than
neonates resuscitated with 100% oxygen who manifest biochemical changes indicative of
prolonged oxidative stress at 4 weeks of age
5. Osteopontin (OPN) is a mutifunctional glycoprotein decreased infarct volume and improved
neurological outcomes 7 weeks after HIE injury
6. Immunomodulatory effects of interferon beta (IFNβ) as seen in an inflammatory environment
such as multiple sclerosis (MS) will also have a therapeutic effect in the neonatal HIE model
7. c-Jun N-terminal kinases (JNKs): JNKs play a role in regulation of apoptosis; Reductions in early
neuronal damage [98]; Reduced inflammation and inhibition of apoptotic neuronal loss.
8. Melatonin: Antioxidant, anti-inflammatory, and anti-apoptotic properties; Protect the brain
independently or in concert with therapeutic hypothermia; Reducing oxidative stress and
improved survival with favorable neurodevelopmental outcome at 6 months of age in
combination with hypothermia.
9. Erythropoietin (EPO): Associated with anti-inflammatory, anti-excitotoxic, anti-oxidative, and
anti-apoptotic properties; Vasogenic and pro-angiogenic functions; Hypoxia-inducible-factor-1
mediates increase in EPO expression
10. Xenon: May trigger neurodegeneration in the developing brain. Thus, the safety of a newborn
injured brain is not expected; Neuroprotective in adult rats in transient brain ischemia; Limited
protection when given alone but protection for up to 30 days when given in combination with
hypothermia (neonatal rodents)
11. Topiramate (TPM): AMPA and Kainate receptors inhibition; Blockade of Na channels, high
voltage-activated calcium currents, carbonic anhydrase isoenzymes and mitochondrial
 27

permeability transition pore; TPM in concert with melatonin decreases infarcted volume and
apoptosis in neonatal HI rat model; Pretreatment significantly reduced the brain damage and
subsequent cognitive impairments
12. Cord blood: Rich with hematopoietic stem cells [127–131] and neurotrophic factors acting on the
following: Immunomodulation, reduction of immune cell infiltration, and the potential to
increase neurogenesis and an angiogenesis
13. Systemic or selective cerebral hypothermia
1. Selective Head cooling for 72 hours starting within 6 hours of birth, with the rectal
temperature maintained at 34.5 0c.
2. Whole body cooling to 33.5 o C for 72 hours. Systemic hypothermia may result in more
uniform cooling of the brain and deeper CNS structures
3. Decrease the rate of apoptosis
4. Suppresses production of glutamate, free radicals, NO, and lactate.
5. Prevent s the decline in high-energy phosphates like Phosphocreatine and adenosine
triphosphate
6. Downregulate the secondary mediators cytokines,
7. Reduce seizures.
8. Most effective when implemented within 6 hr of the event.
9. Hyperthermia has been found to be associated with impaired neurodevelopment.

COMPLICATIONS OF BIRTH ASPHYXIA (Short notes)
Immediate:
1. Hypoxic ischemic encephalopathy- seizures
2. Persistent pulmonary hypertension
3. Myocardial dysfunction
4. Acute renal tubular necrosis
5. Necrotizing enterocolitis
6. Adrenal hemorrhage with adrenal insufficiency
7. Disseminated intravascular coagulation
8. Metabolic derangements:
a. Hypocalcemia
b. Hypoglycemia
c. Metabolic acidosis
d. hyperkalemia
9. Intracranial hemorrhage
10. Stress ulcer stomach
Delayed:
1. Cerebral palsy
2. Mental retardation
3. Epilepsy
4. Autism
5. Attention deficit hyperactive disorder
6. Dyslexia
7. Short stature (pituitary dysfunction)
8. Hydrocephalus (intracranial hemorrhage)
9. Microcephaly
PROGNOSIS
1. Poor prognosis:
1. Infants with initial cord or initial blood pH <6.7 have a 90% risk for death or severe
neurodevelopmental impairment at 18 mo of age.
2. Infants with Apgar scores of 0-3 at 5 min, high base deficit (>20-25 mmol/L),
 28

3. Decerebrate posture, and lack of spontaneous activity
4. Flaccid coma, apnea, absent oculocephalic reflexes, and refractory seizures,
5. low Apgar score at 20 min, absence of spontaneous respirations at 20 min of age, and
persistence of abnormal neurologic signs at 2 wk of age
6. Stage 2 and 3 encephalopathy
7. MRI and EEG abnormalities
8. Microcephaly and poor head growth during the 1st year
2. Better prognosis:
1. Normal MRI and EEG findings
Brain death after neonatal HIE
1. Coma unresponsive to pain, auditory, or visual stimulation;
2. Apnea with pco2 rising from 40 to over 60 mm hg without ventilatory support;
3. Absent brainstem reflexes (pupil, oculocephalic, oculovestibular, corneal, gag, sucking).
4. These findings must occur in the absence of hypothermia, hypotension, and elevated levels
of depressant drugs (phenobarbital).
5. An absence of cerebral blood flow on radionuclide scans and no electrical activity on EEG

Pediatric Non Traumatic Coma
Altered levels of consciousness
1. Syncope: acute reduction of blood flow to the brain with transient loss of consciousness the patient
recovers fully.
2. Seizure: transient loss of conciousness due to disruption in brain electrical activity
3. Stupor: The patient can be awakened only by vigorous physical stimulation.
4. Vegetative state: complete unawareness of the self and the environment with variable preservation
of brainstem functions
5. Brain death is defined as the permanent absence of all brain functions
6. Locked in syndrome (Psuedocoma): Patient is conscious but are unable to speak or move with
preserved eye movements and blinking
7. Coma
1. Coma is defined as the total absence of arousal, and awareness of the self and surroundings
that last at least 1 hour
2. Comatose patients have no eye opening and no sleep wake cycles
3. To differentiate from syncope or concussion, coma must last for at least 1 h.
4. A GCS of less than 8 is considered an alternate definition of coma.
5. Coma is a symptom, not a diagnosis.
Physiology
1. Arousal: is dependent on the reticular activating system (RAS) a network of neurons in the brainstem
with projections to the thalamus, hypothalamus and cortex.
2. Awareness:
1. Awareness is mediated by the cerebral cortex in widely distributed neuronal networks.
2. Awareness is the product of cortical function that resides within both hemispheres and
then projects down to the thalamus for motor and sensory functions.
Two main causes of coma
1. Lesion in both cerebral cortex: mass, vascular, metabolic, toxin etc
2. Brain stem lesions affecting the reticular activating systems
Major etiological factors
1. Substrate (glucose)needed for energy
2. Adequate blood flow to deliver these substrates,
3. Maintenance of normal body temperature,
4. Serum concentrations of metabolic wastes (ammonia)
5. Exogenous toxins
 29

6. CNS infection
7. Seizure with abnormal neuronal activity
8. Electrolyte imbalance
Coma scales
1. Glasgow Coma Scale (GCS). 1974, Graham Teasdale and Bryan Jennett: standardized bedside tool to
quantify arousal and awareness; has tree components assessing eye opening and verbal and motor
responses.
2. The Pediatric Glasgow Coma Scale is a modified sclae for children
3. Glasgow-Lie`ge Scale (GLS), combines the GCS with five brain stem reflexes (i.e., fronto-orbicular,
oculocephalic, pupillary, and oculocardiac reflexes). Used for patients under intubation or ventilation
4. Full Outline of UnResponsiveness (FOUR)
1. Eye response
2. Motor response (eg. asking the patient to make a fist or a ‘thumbs-up’, or ‘V-for-victory’ sign)
3. Brain stem reflexes
4. Respiratory function

GCS score
1. The minimum score is a 3 which indicates deep coma or a brain-dead state.
2. The maximum is 15 which indicates a fully awake patient
3. (the original maximum was 14, but the score has since been modified)
Clinical categorization of coma
1. Coma with focal signs
2. Coma with meningeal irritation
3. Coma without focal signs and without meningeal irritation
4. Overlapping conditions
Coma with focal signs
1. Intracranial hemorrhage
2. Stroke: arterial ischemic or sinovenous thrombosis
3. Tumors
 30

4. Focal infections-brain abscess
5. Post seizure state: Todd’s paralysis
6. Acute disseminated encephalomyelitis
Coma with meningeal irritation
1. Meningitis
2. Encephalitis
3. Subarachnoid hemorrhage
Coma without focal signs and without meningeal irritation
1. Hypoxia-Ischemia:
1. Cardiac failure
2. Respiratory failure
3. Shock,
4. Near drowning
2. Metabolic disorders:
1. Hypoglycemia,
2. Acidosis (e.g. Organic acidemias, diabetic keto-acidosis)
3. Hyperammonemia (e.g. Hepatic encephalopathy, urea cycle disorders, valproic acid
encephalopathy, disorders of fatty acid metabolism, Reye syndrome) Uremia,
3. Fluid and Electrolyte disturbances (dehydration, hyponatremia, hypernatremia)
4. Systemic Infections: Bacterial: gram-negative sepsis, meningitis, toxic shock syndrome, cat-scratch
disease, Shigella encephalopathy, Enteric encephalopathy
5. Post infectious disorders: Acute necrotizing encephalopathy,
6. ADEM, Hemorrhagic shock and encephalopathy syndrome
7. Post immunization encephalopathy: Whole cell pertussis vaccine,
8. Semple Rabies vaccine
9. Drugs and toxins
10. Cerebral malaria
11. Rickettsial: Lyme disease, Rocky mountain spotted fever
12. Hypertensive encephalopathy
13. Post seizure states
14. Non-convulsive status epilepticus
15. Post migraine
Evaluation of the Comatose Child
1. Coma is a medical and neurological emergency
2. The evaluation (clinical as well as investigations) and treatment have to proceedsimultaneously
Stabilization
1. Children with Glasgow Coma Score less than 8 should preferably be intubated; mechanical ventilation
should be provided in case the breathing efforts are not adequate.
2. Appropriate oxygenation should be ensured.
Vascular access
1. (20 mL/kg- Normal saline) for shock
2. IV glucose for hyoglycemia
3. Anticonvulsant (inj Lorazepam, 0.1 mg/kg followed by phenytoin
4. loading 20 mg/kg for seizures
5. Correct Acid base and electrolyte abnormalities
6. Maintain normothermia
7. Blood Samples drawn for blood glucose, S. Electrolytes, Arterial Blood gas, lactate, CBC with platelets,
MP slide/RDT, LFT, KFT, Blood culture, urine sugar and ketones)
Cerebral herniation and ICT
Features
1. GCS < 8
2. Asymmetric pupils,
 31

3. Absent doll’s eye movements
4. Tonic posturing,
5. Papilledema,
6. Hypertension with bradycardia,
7. Abnormal respiratory pattern.
Management:
1. Give 20%mannitol or 3% NS (if patient in shock),
2. Intubate & short term hyperventilation (paco2:30-35mmhg):
History
1. Presence of fever:
1. Sepsis,
2. Meningitis,
3. Encephalitis), but other disorders in
4. Acute disseminated encephalomyelitis,
5. Reye’s syndrome,
6. Mitochondrial and other inborn errors of metabolism.
2. History of trauma, drug/toxin exposure, dog bite, seizures,
3. Past medical illnesses,
4. Family history
Examination
Vital Signs
1. Fever:
1. Infection
2. Heat stroke
3. Abnormality of hypothalamic temperature regulatory mechanisms.
2. Tachycardia:
1. Hypovolemic or
2. Septic shock,
3. Heart failure or
4. Arrhythmias.
3. Bradycardia:
1. Ict
2. Myocarditis,
3. Hypoxia,
4. Sepsis,
5. Toxins
4. Tachypnea with respiratory distress
1. pneumonia,
2. Pneumothorax,
3. Empyema
4. Asthma.
5. Quiet tachypnea
1. Diabetic ketoacidosis,
2. Uremia,
6. Hypertension
1. Hypertensive encephalopathy
2. Increased intracranial pressure
3. Stroke;
4. Poisonings (e.g. Ethylene glycol).
7. Hypotension
1. sepsis,
2. cardiac dysfunction
 32

3. toxic ingestion,
4. adrenal insufficiency
8. CVS examination:
1. congenital or
2. rheumatic heart disease
3. Endocarditis àintracranial abscess dissemination.
9. Abdominal examination:
1. Hepatosplenomegaly
1. Hepatitis
2. Liver failure
10. Signs
1. Pallor: Cerebral malaria, Intracranial bleed, Hemolytic uremic syndrome
2. Icterus: Hepatic encephalopathy, leptospirosis, complicated malaria
3. Rashes: Meningococcemia, Dengue, Measles, Rickettsial diseases, Arboviral diseases like JE
4. Petechiae: Dengue, Meningococcemia, Hemorrhagic fevers
5. Head and scalp hematomas: Traumatic/non-accidental injury
6. Dysmorphism, Neurocutaneous markers: Possibility of seizures
7. Abnormal Odour of exhaled breath: Diabetic ketoacidosis, hepatic coma
11. Neurological Examination
1. Level of Consciousness: Pediatric GCS
2. Unilateral pupillary dilatation: oculomotor nerve compression from ipsilateral uncal
herniation
3. Doll’s eye (oculo vestibular) corneal, cough and gag reflexes: brainstem function.
4. Conjugate lateral deviation of the eyes:
1. Ipsilateral hemisphere lesion, a
2. contralateral hemisphere seizure focus,
3. damage involving the contralateral pontine horizontal gaze center
5. Lateralgaze palsy: central herniation with compression of bilateral sixth nerves.
6. Tonic upward gaze: bilateral hemispheric damage.
7. Motor Response
1. Focal deficits: post ictal todd’s palsy or structural abnormality
2. posturing: decerebrate or decorticate
3. Tonic-clonicmovements: seizures.
4. Myoclonic jerks: anoxic and hepatic encephalopathy.
5. Dystonias: japanese b encephalitis, tubercular meningitis, inborn errors of
metabolism or metoclopramide toxicity.
6. Neck rigidity: meningitis, tonsillar herniation or craniocervical trauma.
7. The kernig’s and brudzinski’s signs: more reliable signs of meningeal irritation
8. Clinical recognition of herniation syndromes
Basic Investigations
1. Blood glucose: hyper/ hypoglycemia
2. TLC: infection
3. Electrolytes: sodium, potassium, calcium, magnesium
4. Renal and liver function tests,
5. Arterial blood gas analysis and lactate.
6. Urine should also be reducing sugars and ketones.
7. Blood and urine cultures
8. Peripheral smear and rapid diagnostic test for malaria
9. CT:
1. for intracranial hemorrhage, cranial trauma, stroke, herniation and cerebral edema.
2. A contrast CT for meningeal enhancement: menigitis, brain abscess or neurocysticercosis.
3. A normal CT does not rule out ICT
 33

10. LP:
1. Rule out contraindications
2. Cell count, glucose, protein, Gram stain, Ziehl-Neelsen stain, bacterial culture, viral
polymerase chain reaction for Herpes Simplex virus,
3. Latex agglutination test, and additional cultures guided by clinical suspicion (fungal or
tubercular).
Second-Line Investigations
1. Blood ammonia, hyperammonemia maybe caused by some inborn errors of metabolism, reye’s
syndrome, liver failure or valproate toxicity.
2. Urine and blood samples for amino and organic acid disorders,
3. Free fatty acid and carnitine levels
Magnetic Resonance Imaging (MRI)
1. MRI with Magnetic resonance Angiography for stroke.
2. Frontotemporal pathology in herpes simplex
3. Encephalitis,
4. Thalamic involvement in japanese B encephalitis,
5. Demyelination in ADEM, or acute necrotizing encephalopathy
6. MRI is also useful for prognostication.
Electroencephalogram (EEG)
1. Diffuse theta and delta activity, absence of faster frequencies in encephalopathies.
2. Epileptiform activity: absence or complex partial status;
3. Triphasic waves: hepatic or uremic encephalopathy;
4. Periodic lateralizing epileptiform discharges: herpes encephalitis
Other Investigations
1. A urine toxicology screen: for clinical suspicion of poisoning.
2. Unexplained coma: thyroid
3. Function tests and thyroid antibodies (for hashimoto encephalopathy)
4. Work-up for central nervous system vasculitis
Management
1. Stabilization of vitals: airway, breathing and circulation
2. ICT: hyperventilation, mannitol / 3% saline
3. Mannitol is administered as an initial bolus of 0.25–1 g/kg followed by 0.25–0.5 g/kg boluses
repeated every 2– 6 h as per requirement.
4. Hypertonic saline is administered as a continuous infusion at 0.1 to 1.0 ml/kg/h, to target a serum
sodium level of 145–155 meq/L.
5. Treat hypoglycemia with intravenous dextrose: 2 ml/kg 10% d, then 6–8 mg/kg/min infusion.
6. Seizures
1. Lorazepam 0.1 mg/kg, followed by phenytoin loading (20 mg/kg).
2. Non convulsive status epilepticus (NCSE) maybe seen in comatose children, andshould be looked
for in all children with unexplained encephalopathy.
3. Maintain normothermia.
4. Correct acid base and electrolyte abnormalities
5. Treatment of infections:
1. Broad spectrum antibiotics (ceftriaxone, vancomycin)
2. If viral encephalitis is likely, then samples for PCR for herpessimplex virus
should be sent and acyclovir should be started.
3. Antimalarials (quinine/artesunate) should be started if there is a clinical
suspicion of cerebral malaria.
6. Antidotes:
a. Naloxone (0.1 mg/kg) for opiate poisoning.
b. Flumazenil is useful for benzodiazepine overdosage.
7. Steroids:
 34

c. acute disseminated encephalomyelitis,
d. meningococcemia with shock,
e. enteric encephalopathy,
f. tubercular meningitis, and pyogenic meningitis.
8. Diabetic ketoacidosis, hepatic encephalopathy, uremia or hyperammonemia, should treated
appropriately.
9. Sick children with acute febril encephalopathy, empirical therapy with antibiotics, acyclovir and
antimalarial agents should be started while the results of investigations are awaited
10. Prognosis
1. Prolonged coma after a hypoxic-ischemic insult carries a poor prognosis
2. Most children surviving infectious encephalopathies
3. Have a comparatively better outcomes, often surviving with Mild or moderate difficulties
only.
4. Outcome has been shown to be worse for patients who were younger, had a lower GCS
score on presentation, or had absent brainstem reflexes, worse motor responses,
hypothermia, or hypotension

Refractory CHF in children
Definition:
Refractory CHF is defined in patients who are symptomatic at rest due to worsened heart failure, or
repeated exacerbations of heart failure, despite treatment with optimal "triple" therapy. Optimal
triple therapy includes diuretics, digitalis glycosides, and angiotensin-converting enzyme (ACE)
inhibitors, or the combination of hydralazine and nitrates.
According to the latest classification proposed by the ACC/AHA,3 this corresponds to stage D heart
failure.
CHF classifications:
1. NYHA Functional Classification of CHF
NYHA Class Patients with Cardiac Disease (Description of HF Related Symptoms)
Patients with cardiac disease but without resulting in limitation of
Class I (Mild) physical activity. Ordinary physical activity does not cause undue fatigue,
palpitation, dyspnea, or anginal pain.
Patients with cardiac disease resulting in slight limitation of physical
Class II (Mild) activity. They are comfortable at rest. Ordinary physical activity results in
fatigue, palpitation, dyspnea, or anginal pain
Patients with cardiac disease resulting in marked limitation of physical
Class III (Moderate) activity. They are comfortable at rest. Less than ordinary activity causes
fatigue, palpitation, dyspnea, or anginal pain.
Patients with cardiac disease resulting in the inability to carry on any
physical activity without discomfort. Symptoms of heart failure or the
Class IV (Severe)
anginal syndrome may be present even at rest. If any physical activity is
undertaken, discomfort is increased.
American Heart Association Heart Failure Stages
Stage A: Presence of heart failure risk factors but no heart disease and no symptoms
Stage B: Heart disease is present but there are no symptoms (structural changes in heart before
symptoms occur)
Stage C: Structural heart disease is present AND symptoms have occurred
Stage D: Presence of advanced heart disease with continued heart failure symptoms requiring
aggressive medical therapy
Ross classification of heart failure in infants
 35

Class I: No limitations or symptoms
Class II: Mild tachypnea or diaphoresis during feeding in infants. Dyspnea on exertion in older
children. No growth failure
Class III: Marked tachypnea or diaphoresis during feeds or exertion Prolonged feeding times
Growth failure
Class IV: Symptoms at rest with tachypnea, retractions, grunting or diaphoresis
Pathophysiology:
1. Complex pathophysiological mechanisms are active in CHF, and they include neuro humoral
perturbations, such as activation of the renin-angiotensin system. This activation induces sodium
retention in the kidney, leading to plasma volume expansion, increased left ventricular preload,
increased myocardial wall stress, and exacerbation of systolic failure.
2. Loop diuretics further stimulate the renin-angiotensin system. This additional stimulation contributes
to peripheral vasoconstriction, increased afterload, and, ultimately, diminished cardiac output.
Signs of refractory CCF
1. The signs of decompensated CHF include new weight gain and peripheral edema, gallop, jugular
venous distention greater than baseline and increased P2 due to increased pulmonary artery
pressures. Patients with refractory CHF should be admitted to the intensive care unit (lCU) for
aggressive hemodynamic monitoring and therapy.
2. Hemodynamic: left ventricular ejection fraction less than 20%, low cardiac output, arterial
hypotension, sinusal tachycardia, and kidney failure.
3. Biochemical: high values of norepinephrine and natriuretic peptides, and hyponatremia.
4. Electrophysiological: presence of potentially serious arrhythmias.
Evaluation
a) Searching for potentially treatable and reversible factors;
b) Correct characterization of the symptoms;
c) Defining the hemodynamic profile with a view to designing treatment.
Search for Potentially Treatable Factors:
a) Anemia, pulmonary embolism and infections are usual causes of decompensation.
b) Common viral infections frequently cause persistence of symptoms of decompensated HF for several
weeks after the resolution of the viral picture.
c) Thyroid dysfunction is a cause of decompensation and should be ruled out,
d) Atrial fibrillation is involved in 25%-50% of patients with refractory HF.
e) Obesity increases the risk of developing HF
Characterization of the Symptoms
a) Symptoms of advanced or refractory HF are the result of 2 pathophysiological mechanisms,
congestion and low output, and either can predominate in a given patient.
b) In relation to lung or systemic congestion, HF symptoms are due to elevated left or right filling
pressures, respectively. The former causes exertional dyspnea, orthopnea, cough with decubitus, or
dyspnea with minimal effort or at rest. The latter causes edema, ascites, anorexia, easy satiety, under
nutrition, and discomfort when the patient tries to stoop or bend the spine.
c) Symptoms attributable to low heart output are sometimes less specific, such as asthenia, lack of
energy, easy fatigue and depression, and/or irritability related to the impossibility of carrying out
normal activity. As a consequence of a low cerebral perfusion, there can also be changes in nocturnal
sleep patterns, drowsiness, or concentration difficulties.
Definition of the Hemodynamic Profile
a) Low perfusion
a. Low pulse
b. Pulsus alternans
c. Cold extremities
d. Drowsiness
b) Systemic / lung congestion
a. Orthopnea
 36

b. Elevated JVP
c. Edema
d. Ascites
Management:
1. Pharmacological management:
a. Nesiritide: It is a recombinant form of the endogenous type B natriuretic peptide that has
recently been approved. It acts as an arterial and venous vasodilator, increases natriuresis
and suppresses the activation of the renin-angiotensin-aldosterone and adrenergic systems.
b. Antidiuretic hormone arginine vasopressin (AVP) antagonists are currently under study.
c. Phosphodiesterase Inhibitors. The phosphodiesterase inhibitors (PDE-I) (e.g., amrinone,
milrinone, enoximone, piroximone) inhibit phosphodiesterase isoform III in cardiac and
vascular tissues. PDE-I effectively reduce pulmonary vascular resistance and improve the
hemodynamic consequences of postcapilbry pulmonary hypertension. PDE-I also improve
blood flow to the extremities
d. positive inotropic drugs are capable of increasing systolic volume, both the classical ones
(dobutamine, dopamine, milrinone, adrenaline, norepinephrine) are useful for cardiogenic
shock
2. Ultrafiltration
Extracorporeal ultra filtration removes intravascular fluid, resulting in a compensatoy movement of fl
uid from the interstitial compartment.
Ultra filtration may restore responsiveness to loop diuretics and decrease proinflammatory cytokine l
evels
3. Mechanical circulatory support
a. Counter pulsation devices (intra aortic balloon pump and non invasive counter pulsation)
Mechanism: Removing a certain blood volume from the femoral artery during
systole and replacing this volume rapidly during diastole
b. Cardiopulmonary assist device
It provides full cardiopulmonary support (including hemodynamic support and oxygenation
of venous blood) analogous to that provided by bypass during cardiac surgery.
Disadvantage:Limited use outside the cardiac catheterization laboratory
c. Left ventricular devices: Intermediate left ventricular assist devices can provide temporary
support until other replacement therapy. Used in patients with chronic HF who have a poor
long-term prognosis
d. Long-term left ventricular devices: Permanent mechanical assistance ("destination therapy")
in selected patients who are not cardiac transplant candidates
4. Surgery
a. Surgical approaches to end-stage HF under active investigation. Reconstructive cardiac
surgery, cardiomyoplasty, and mitral valve repair
b. Cardiac transplantation.

SEXUAL MATURATION
1. Generally, adolescence begins at age 11–12 years and ends between ages 18 and 21. Most teenagers complete
puberty by age 16–18 years;
2. Most girls enter puberty at age 9 or 10 years, reach menarche on average at 12 1/2, and achieve full fertility by
age 15 or 16. Boys begin pubertal development somewhat later than girls, at age 11 or 12 years, produce
sperm (spermarche) and have their first ejaculation on average at age 13 or 14, and achieve full fertility at
approximately age 16.
3. Puberty consists of a series of predictable events. The staging system is published by Marshall and Tanner and
the sequence of changes, commonly referred to as "Tanner stages".
4. Sexual maturity rating (SMR) includes stage of pubic hair growth, penis and testis development in boys, and
breast maturation in girls.
 37


CLASSIFICATION OF SEX MATURITY STATES IN BOYS
SMR PUBIC HAIR PENIS TESTES
STAGE
1 None Preadolescent Preadolescent
2 Scanty, long, slightly pigmented Minimal change/ Enlarged scrotum,
enlargement pink, texture altered
3 Darker, starting to curl, small amount Lengthens Larger

4 Resembles adult type, but less quantity; coarse, curly Larger; glans and Larger, scrotum Dark
Breadth increase in
size
5 Adult distribution, spread to medial surface of thighs Adult size Adult size


CLASSIFICATION OF SEXUAL MATURITY STATES IN GIRLS
STAGE PUBIC HAIR BREASTS
1 Preadolescent Preadolescent
2 Sparse, lightly pigmented, straight, medial border Breast and papilla elevated as small mound;
of labia diameter of areola increased
3 Darker, beginning to curl, increased amount Breast and areola enlarged, no
contour separation
4 Coarse, curly, abundant, but less than in adult Areola and papilla form secondary
mound
5 Adult feminine triangle, spread to medial Mature, nipple projects, areola part
surface of thighs of general breast contour

SEXUAL DEVELOPMENT
Components of reproductive system:
1. Sex chromosomes
2. Gonads
3. Internal genitalia
4. External genitalia

sex Chromosomes Gonad Internal genitalia External genitalia
Male XY Testis Wolffian (Epididymis, Vas deferens) Penis, scrotum
Female XX Ovary Mullerian (Uterus, Fallopian tube) Clitoris, vulva
 38


Sex development can be divided into two sequential processes:
1. Sex determination – refers to the undifferentiated gonads that commit to developing into either
testes or ovaries
2. Sex differentiation – i.e. gonadal hormones act on the internal and external genitalia resulting in
differentiation into male and female
3. All fetuses develop with a female blueprint. Conversion female into male fetus is done by Y
chromosome. In the absence of Y chromosome, the bipotential gonad will develop into an ovary
aided by the expression of other ovary-specific genes
4. The TESTES are essential for male sexual differentiation, but the ovaries are NOT necessary for female
differentiation
5. The genetic sex of the embryo is established at with the inheritance of an X or Y chromosome from
the father
6. The Y chromosome, through the testis-determining gene Sry, acts dominantly to trigger
differentiation of testes from the indifferent gonads that would otherwise develop as ovaries
7. If Sry gene is translocated to X chromosome in the father an XX offspring can develop into male
phenotype. Similarly if Sry gene undergoes deletion in the father, an XY offspring can develop into
female phenotype.
Gonads:
1. There are 3 different cell lineages of bipotential fate present in the gonads
2. The supporting cell lineage will give rise to Sertoli cells in the testis and follicle cells in the ovary.
3. The steroidogenic cell lineage produces the sexual hormones that will contribute to the development
of the secondary sexual characteristics of the embryo. In the male these are the Leydig cells in the
female the Theca cells.
4. The connective cell lineage will contribute to the formation of the organ as a whole
Male differentiation:
1. Sertoli cells secrete anti-Mullerian hormone (AMH) &Leyding cells secrete testosterone.
2. Testosterone secretion is stimulated by placental human chorionic gonadotropin (hCG), which peaks
at 8-12 wk. In the latter half of pregnancy, lower levels of testosterone are maintained by luteinizing
hormone (LH) secreted by the fetal pituitary.
3. AMH causes the regression of the Mullerian structures that would otherwise develop into the
Fallopian tubes, uterus, cervix and the upper third of the vagina in the female
4. Testosterone stimulates the Wolffian ducts will develop into male internal genitalia: – Epididymis –
vas deferens – vesicula seminalis
5. The development of external male genitalia is dependent on the conversion of testosterone to
dihydrotestosterone (DHT) by the enzyme 5a-reductase
6. Under the influence of DHT, the genital tubercle will form the penis, the urethral folds will form the
urethra & the genital folds form the scrotum
7. DHT is also produced via an alternative biosynthetic pathway from androstanediol, and this pathway
must be intact for normal and complete prenatal virilization to occur. A functional androgen receptor,
produced by an X-linked gene, is required for testosterone and DHT to induce these androgen effects.
Female differentiation:
1. A chromosome complement of 46,XX will lead to the development of ovaries. Both the long and short
arms of the X chromosome contain genes for normal ovarian development.
2. DAX1, SOX3 and Wnt4 are the three candidate genes currently known to suppress testicular
differentiation. DAX1 and SOX3 inhibit SF1 and SOX9, preventing Sertoli cell differentiation, favoring
granulosa cell development.
3. In female fetuses, Wolffian structures regress in the absence of testosterone and Mullerian ducts
persist in the absence of AMH.
4. Wnt4 arrests the Leydig cell precursors and induces development of Mullerian ducts into fallopian
tubes, uterus, cervix and upper third of vagina.
5. FOXL2 helps in follicular development in the ovary and in suppression of somatic testis formation in
 39

genetic females.
6. Female sexual development does not depend on the presence of ovaries or hormones. The lack of
testosterone will lead to a clitoris, urethra, the rest of the vagina and the labia for the female.

DISORDERS OF SEX DEVELOPMENT (DSD)
1. DEFINITION OF DSDs : (DSDs) are defined as conditions involving the following elements:
a. Congenital development of ambiguous genitalia (e.g., 46,XX virilizing congenital adrenal
hyperplasia; clitoromegaly; micropenis)
b. Congenital disjunction of internal and external sex anatomy (e.g., Complete Androgen
Insensitivity Syndrome; 5-alpha reductase deficiency)
c. Incomplete development of sex anatomy (e.g., vaginal agenesis; gonadal agenesis)
d. Sex chromosome anomalies (e.g., Turner Syndrome; Klinefelter Syndrome; sex chromosome
mosaicism)
e. Disorders of gonadal development (e.g., ovotestes)
2. DSD conditions usually present with:
a. Atypical genitalia in the newborn period or as
b. Delayed puberty in an adolescent.
3. DSDs include anomalies of
a. The sex chromosomes,
b. The gonads,
c. The reproductive ducts (internal genitalia)
d. The external genitalia.
4. The current system for the classification of DSD was introduced in the Chicago Consensus in 2005. There
are three broad groups:
a. Sex chromosome DSD,
b. 46,XX DSD, and
c. 46,XY DSD
5. 46,XX DSD: (formerly known as female pseudohermaphroditism)
a. Androgen Exposure
i. Fetal/Fetoplacental Source
1. 21-Hydroxylase (P450c21 or CYP21) deficiency
2. 11β-Hydroxylase (P450c11 or CYP11B1) deficiency
3. 3β-Hydroxysteroid dehydrogenase II (3β-HSD II) deficiency
4. Cytochrome P450 oxidoreductase (POR)
5. Aromatase (P450arom or CYP19) deficiency
6. Glucocorticoid receptor gene mutation
ii. Maternal Source
1. Virilizing ovarian tumor
2. Virilizing adrenal tumor
3. Androgenic drugs
b. Disorder of Ovarian Development
i. XX gonadal dysgenesis
ii. Testicular DSD (SRY+, SOX9 duplication)
c. Undetermined Origin
i. Associated with genitourinary and gastrointestinal tract defects
6. 46,XY DSD (formerly known as male pseudohermaphroditism)
a. Defects in Testicular Development
a. Denys-Drash syndrome (mutation in WT1 gene)
b. WAGR syndrome (Wilms tumor, aniridia, genitourinary malformation, retardation)
c. Deletion of 11p13
d. Campomelic syndrome (autosomal gene at 17q24.3-q25.1) and SOX9 mutation
 40

e. XY pure gonadal dysgenesis (Swyer syndrome)
f. Mutation in SRY gene
g. XY gonadal agenesis
h. Unknown cause
b. Deficiency of Testicular Hormones
a. Leydig cell aplasia
b. Mutation in LH receptor
c. Lipoid adrenal hyperplasia (P450scc or CYP11A1) deficiency; mutation in StAR
(steroidogenic acute regulatory protein)
d. 3β-HSD II deficiency
e. 17-Hydroxylase/17,20-lyase (P450c17 or CYP17) deficiency
f. Persistent müllerian duct syndrome because of antimüllerian hormone gene mutations
or receptor defects for antimüllerian hormone
c. Defect in Androgen Action
a. Dihydrotestosterone deficiency because of 5α-reductase II mutations or
AKR1C2/AKR1C4 mutations
b. Androgen receptor defects:
i. Complete androgen insensitivity syndrome
ii. Partial androgen insensitivity syndrome (Reifenstein and other syndromes)
c. Smith-Lemli-Opitz syndrome (defect in conversion of 7-dehydrocholesterol to
cholesterol, DHCR7)
7. Ovotesticular DSD
a. XX
b. XY
c. XX/XY chimeras
8. Sex Chromosome DSD
a. 45,X (Turner syndrome and variants)
b. 47,XXY (Klinefelter syndrome and variants)
c. 45,X/46,XY (mixed gonadal dysgenesis, sometimes a cause of ovotesticular DSD)
d. 46,XX/46,XY (chimeric, sometimes a cause of ovotesticular DSD)

Evaluation of Ambiguous genitalia
1. Definition. Ambiguous genitalia are present when the sex of an infant is not readily apparent after
examination of the external genitalia.
2. Incidence.
a. Congenital adrenal hyperplasia is often considered the most common cause with anincidence
quoted from 1 in 14,000 to 1 in 28,000, followed by androgen insensitivity and mixed gonadal
dysgenesis.
b. Hypospadias has a frequency of about 1 in 300 births, but only a minority of these patients has a
disorder of sex development
3. Embryology.
a. The early fetus, regardless of the genetic sex (XX or XY), is bipotential and can undergo either
male or female differentiation. The innate tendency of the embryo is to differentiate along
female lines.
b. Development of the gonads.
i. Gonadal development occurs during the embryonic period (the third through the
seventh to eighth weeks of gestation).
ii. Testicular differentiation. Gonadal differentiation is determined by the absence or
presence of the Y chromosome. If the Y chromosome (more specifically, the sex-
determining region of the Y or SRY gene) is present, the gonads differentiate as testes.
The testes then produce and release testosterone, which is converted to
 41

dihydrotestosterone (DHT) in the target organ cells by 5α-reductase. DHT induces
male differentiation of the external genitalia. The testes descend behind the
peritoneum and normally reach the scrotum by the eighth or ninth month.
iii. Ovarian differentiation. In the female fetus, where the Y chromosome/SRY gene is
absent, the gonads form ovaries (even in 45,X Turner syndrome, histologically normal
ovaries are present at birth). As ovaries do not produce testosterone, female
differentiation proceeds. Two X chromosomes are needed for differentiation of the
primordial follicle. If part or all of the second X chromosome is missing, ovarian
development fails, resulting in atrophic, whitish, streaky gonads by 1–2 years of age.
c. Development of external genitalia.
i. This part of sexual differentiation occurs in the fetal period, beginning in the seventh
week of gestation, and proceeds up to the 14th week
ii. Normal male. At ~9 weeks postconceptional age, in the presence of systemic
androgens (especially DHT), masculinization begins with lengthening of the anogenital
distance. The urogenital and labioscrotal folds fuse in the midline (beginning caudally
and progressing anteriorly), leading to the formation of the scrotum and the penis.
iii. Normal female. In the female fetus, the anogenital distance does not increase. The
urogenital and labioscrotal folds do not fuse and instead differentiate into the labia
majora and minora. The urogenital sinus divides into the urethra and the vagina.
4. Pathophysiology
a. Virilization of female infants (female pseudohermaphroditism).
i. Many belong to this group. They have a 46,XX karyotype, are SRY negative, and have
exclusively ovarian tissue.
ii. The degree of masculinization of the female infant depends on the potency of the
androgenic exposure.
iii. The most common cause of excess fetal androgens congenital adrenal hyperplasia
(CAH) and excessive production of adrenal androgens (dehydroepiandrosterone and
androstenedione) and testosterone.
iv. Most common is 21-hydroxylase deficiency, which causes adrenal hyperplasia, and
excessive production of adrenal androgens (dehydroepiandrosterone and
androstenedione) and testosterone. Two forms of CAH:
1. Classic:
a. a simple virilizing form – cortisol deficiency
b. a salt-losing form – aldosterone deficiency
2. Non classic: mild and delayed onset
v. 11-Hydroxylase enzyme deficiency is less common and associated with salt retention,
volume expansion, and hypertension.
vi. Other, less common causes.
1. Virilizing maternal or fetal tumors
2. Maternal androgen ingestion or topical use.
b. Inadequate virilization of male infants (male pseudohermaphroditism).
i. This condition is caused by:
1. Inadequate androgen production or
2. Incomplete end-organ response to androgen.
ii. These patients have a 46,XY karyotype and exclusively testicular tissue.
iii. Decreased androgen production:
1. 3β-HSD II deficiency
2. 17-Hydroxylase/17,20-lyase (P450c17 or CYP17) deficiency
3. Deficiency of Müllerian-inhibiting substance
4. Testicular unresponsiveness to human chorionic gonadotropin (hCG) and
luteinizing hormone (LH); and
5. Anorchia (absent testes caused by loss of vascular supply to the testis during
 42

fetal life).
iv. Decreased end-organ response to androgen:
1. Defect in the androgen receptor
2. Unknown defect with normal receptors.
v. 5α-Reductase deficiency. Results in failure of the external genitalia to undergo male
differentiation because of the lack of DHT
c. Disorders of gonadal differentiation
i. True hermaphroditism. The presence of both a testis and an ovary (or ovotestes) in
the same individual is a rare cause of ambiguous genitalia. Most individuals with true
hermaphroditism have a 46,XX karyotype, but mosaics of 46,XX/45,X/46,XY/multiple
X/multiple Y have all been reported. The appearance of the genitalia is variable;
fertility is poor.
ii. Gonadal dysgenesis
1. Pure gonadal dysgenesis. Characterized by the presence of a streak gonad
bilaterally (complete gonadal dysgenesis) or unilaterally (partial gonadal
dysgenesis).
2. Mixed gonadal dysgenesis. Characterized by the presence of a unilateral
functioning testis and a contralateral streak gonad. All patients have a Y
chromosome and some degree of virilization of the external genitalia. Mixed
gonadal dysgenesis is associated with a high incidence of gonadal malignancy in
mid to late childhood.
d. Chromosome abnormalities, syndromes, and associations.
i. In general, chromosomal abnormalities do not usually lead to genital abnormalities.
However, disruption of normal sex development has been reported occasionally in
trisomies 13 and 18, triploidy, and a number of other chromosomal anomalies.
ii. Single-gene disorders and syndromes such as Smith-Lemli-Opitz syndrome, Rieger
syndrome, CHARGE syndrome (coloboma, heart defects, choanal atresia, retarded
growth and development, genital abnormalities, and ear anomalies),
iii. Camptomelic dysplasia, and others can also be associated with external sexual
ambiguity
iv. VATER/VACTERL (vertebral, anal, tracheal, esophageal, renal dysplasia/vertebral
defects, anal atresia, cardiac malformations, tracheoesophageal fistula, renal
dysplasia, and limb abnormalities) association can include abnormally developed
genitalia.
VI. Clinical presentation.
a. History.
a. Family history of early neonatal deaths (a death in early infancy accompanied by
vomiting and dehydration may be secondary to CAH),
b. Consanguinity of the parents (increased risk for autosomal recessive disorders), and
female relatives with amenorrhea and infertility (male pseudohermaphroditism or
chromosomal anomalies)
c. Ingestion or topical use of drugs during pregnancy (particularly androgens or
progestational agents).
b. Physical examination
a. General examination.
i. dysmorphic features (syndromes and chromosomal abnormalities),
ii. hypertension or hypotension, areolar hyperpigmentation, and signs of
dehydration (as signs of CAH).
b. Genitalia. Gonads: The number, size, and symmetry of gonads should be evaluated.
Palpable gonads below the inguinal canal are usually testes. Ovaries are not found in
scrotal folds or in the inguinal region. However, the testes may be intra-abdominal.
c. Phallus length: Measured from the pubic ramus to the tip of the glands, a stretched
 43

penile length in a full-term infant should be ≥2.0 cm.
d. Urethral meatus: Look for hypospadias (usually accompanied by chordee).
e. Labioscrotal folds: Findings can range from unfused labia majora, variable degrees of
posterior fusion, and bifid scrotum to fully fused, normal-appearing scrotum. The
presence of a vaginal opening or urogenital sinus should be determined. A rectal
examination, to determine presence of a uterus, may be considered.
VII. Diagnosis
A. Laboratory studies
1. Initial evaluation. An important test in the initial evaluation is the chromosome analysis. Most
cytogenetic laboratories can now provide preliminary results of a karyotype in a few days.
Fluorescent in situ hybridization techniques (FISH) allow even faster determination of the sex
chromosome status; X- and Y-specific probes are available.
2. Buccal smears are unreliable and therefore obsolete. The remainder of the diagnostic evaluation
depends on the sex chromosome status.
3. Blood for basic biochemical studies can be obtained at the same time as the karyotype, including
17-hydroxyprogesterone (17-OHP), testosterone, dihydrotestosterone, sodium, and potassium
levels.
4. Normal 46, XX karyotype. This finding implies virilization of a genetic female and is caused by
excessive maternal or fetal androgen. If the mother is not virilized, the infant almost always has
virilizing adrenal hyperplasia. To confirm the diagnosis, measure the following:
a. 17-hydroxyprogesterone (17-OHP). This is the precursor to the enzyme defect in 21-
hydroxylase and 11-hydroxylase enzyme deficiency. In infants with either defect, the
serum or plasma level of 17-OHP will be 100–1000 times the normal infant level.
b. Daily serum measurements of sodium and potassium. Infants with 21-hydroxylase
enzyme deficiency usually have relative or absolute aldosterone deficiency and begin to
demonstrate hyperkalemia at days 3–5 and hyponatremia 1–2 days later. If
hyperkalemia becomes clinically significant before the 17-OHP result is available,
empirical treatment with intravenous saline, cortisol, and fludrocortisone may be
needed.
c. Serum testosterone. About 3% of infants with ambiguous genitalia are true
hermaphrodites, and most have a 46,XX karyotype. If the 17-OHP is not elevated and
there is no maternal virilization, a high testosterone level suggests hermaphroditism or
fetal testosterone-producing tumor.
5. Normal 46,XY karyotype.
a. Testosterone (T) and dihydrotestosterone (DHT). These hormone levels should be
measurable and are higher in newborns than later in childhood. In the male
pseudohermaphrodite, testosterone is low in any defect in testosterone production. The
T-to-DHT ratio should be between 5:1 and 20:1 when expressed in similar units. A high
T-to-DHT ratio suggests 5α-reductase deficiency.
b. Androstenedione levels are measured to diagnose 17-ketosteroid reductase deficiency.
c. LH and follicle-stimulating hormone (FSH). These hormones are also higher in infancy
than they are in childhood. A diagnosis of gonadotropin deficiency is suspected if these
values are low in a reliable assay but can be confirmed in infancy only if there are other
pituitary hormone deficits. Note that growth hormone and ACTH deficiency are
manifested in the newborn period as hypoglycemia. In primary gonadal defects and
some androgen-resistant states, LH and FSH are elevated.
d. hCG stimulation test. hCG is administered to stimulate gonadal steroid production when
testosterone values are low (as in gonadotropin deficiency or a defect in testosterone
synthesis). A rise in the testosterone level confirms the presence of Leydig cells and, by
implication, testicular tissue. In patients with 5α-reductase deficiency, the basal T-to-
DHT ratio may be normal but elevated after hCG stimulation.
e. Assessment of pituitary function. If gonadotropin deficiency due to impairment of
 44

pituitary function is suspected (eg, microphallus/micropenis combined with
hypoglycemia), thyroid function tests, growth hormone levels, ACTH stimulation test,
and imaging studies of the pituitary gland may be indicated.
6. Abnormal karyotype. Mixed gonadal dysgenesis with a dysplastic gonad may be present in infants
with abnormal karyotype and abnormal genitalia. Hormone studies are unlikely to be revealing in
this scenario. These techniques may allow detection of SRY gene material in 46,XX phenotypic
males and be useful in determining whether Y material is present in a 45,X individual, placing the
patient at risk for gonadoblastoma.
B. Radiographic studies
1. Ultrasonography to evaluate adrenal and pelvic structures. Although a uterus is sometimes
palpable on rectal examination shortly after birth (because of enlargement in response to
maternal estrogen), ultrasonography seems less invasive. The presence and localization of gonads
may also be clarified by ultrasonography. Adrenal ultrasonography is sufficiently sensitive to
determine adrenal abnormalities in the majority of patients with untreated adrenal hyperplasia.
2. Contrast studies to outline the internal anatomy (sinography, urethrography,
vesicocystoureterography, and intravenous urography) may be indicated in complex cases and
before reconstructive surgery.
3. Magnetic resonance imaging (MRI) has been used to evaluate patients with disorders of sex
development but, at least in the neonatal period, sensitivity may only be marginally improved
over ultrasound.
VIII. Management
1. General considerations. It is very important to protect the privacy of child and parents while
diagnostic studies are in progress. A multidisciplinary team should assist the patient and family
throughout the diagnostic process and beyond.
2. Once a diagnosis has been established, gender should be assigned and a team of specialists
should supervise medical treatment (steroid replacement, gonadal removal, reconstructive
surgery, etc.) and treatment of psychosocial aspects.
3. Circumcision should be delayed in any infant with a DSD until completion of multidisciplinary
evaluation and gender assignment.
4. Medical management in the neonatal period and early infancy
a. Congenital adrenal hyperplasia.
i. Glucocorticoid therapy. Should be initiated as soon as possible. Maintenance
cortisol replacement therapy is often given orally. Hydrocortisone is the oral
preparation of choice. (See Chapter 148.) Initial doses usually range from 10
to 20 mg/m2/d given as 3 divided doses and often require adjustments for
growth and during periods of stress. Alternatively, intramuscular cortisone
acetate is sometimes used in children <6 months of age out of concern that
oral hydrocortisone may be absorbed erratically in these infants.
ii. Mineralocorticoid therapy. Fludrocortisone acetate at a dose of 0.05–0.1 mg
daily (given orally) is often used. Unlike hydrocortisone, the dose of
fludrocortisone does not change with increase of body size or during stress.
Some endocrinologists also recommend sodium supplementation (1–5
mEq/kg/d).
5. Incompletely virilized genetic male. Treatment with depo-testosterone might be considered by
the team of specialists depending on the results of the diagnostic evaluation.
IX. Prognosis, gender assignment, long-term care.
It is now believed that prenatal and early exposure of the brain to androgens, if present, influences gender-
specific behavioral patterns and sexual identity in addition to the external appearance of the genitalia or their
future function.

CONGENITAL ADRENAL HYPERPLASIA
 45

1. Synonyms: Adrenogenital syndrome; CAH
2. A group of autosomal recessive disorders resulting from the deficiency of one of the enzymes required for
cortisol synthesis in the adrenal cortex.
a. Cortisol deficiency increases secretion of corticotrophin (ACTH), which, in turn, leads to
adrenocortical hyperplasia and overproduction of intermediate metabolites.
b. In most cases, adrenal hyperplasia also involves a deficiency in aldosterone, which results in mild
to severe loss of body sodium.
c. In some, it also involves overproduction of adrenal androgens, which, in affected females, results
in prenatal virilization with an ambiguous /male external genitalia at birth.
3. Types:
a. 21-hydroxylase deficiency accounts for the vast majority of cases (90%),
b. 11-hydroxylase (5%),
c. cholesterol desmolase,
d. 17-hydroxylase
e. 3-hydroxysteroid dehydrogenase

21- OH DEFICIENCY
1. Classic 21-hydroxylase deficiency occurs in approximately 1 in 15,000 - 20,000 births
1. More than 90% of CAH cases are caused by 21-hydroxylase deficiency. This P450 enzyme hydroxylates
as follows:
a. progesterone à11-deoxycorticosteroneà aldosterone
b. 17-hydroxyprogesterone à11-deoxycortisolà cortisol
2. More than 90% of mutations causing 21-hydroxylase deficiencies are recombination between CYP21
and CYP21P.
3. Accumulation of 17-hydroxyprogesterone leads to high levels of androstenedione that are converted
outside the adrenal gland to testosterone. This problem begins in 8-10 wk of gestation and leads to
abnormal genital development in females
4. 21-hydroxylase deficiency can be divided into classic deficiency with and without salt wasting (cortisol
and aldosterone deficiencies) and non-classic type.
a. Classic
i. Virilizing syndrome- affected females are virilized in utero and present at birth with
cliteromegaly, labial fusion, and normal internal organs. This is the most common cause
of ambiguous genitalia in females.
 46

ii. Salt losing > 75% of 21-OH deficiency have salt losing because there is inadequate
production of aldosterone. These neonates will fail to gain weight, vomit, have
hyponatremia and hyperkalemia, hypoglycemia and be acidotic. They may appear septic.
b. Non-Classic- will often present later on in childhood with signs and symptoms of androgen
excess.
Affected female infant:
1. Enlargement of the clitoris and by partial or complete labial fusion.
2. The vagina usually has a common opening with the urethra (urogenital sinus).
3. The clitoris may be so enlarged that it resembles a penis; because the urethra opens below this organ,
some affected females may be mistakenly presumed to be males with hypospadias and
cryptorchidism.
4. The severity of virilization is usually greatest in females with the salt-losing form of 21-hydroxylase
deficiencies.
5. The internal genital organs are normal, because affected females have normal ovaries and not testes
and thus do not secrete antimüllerian hormone.
Behavior problems:
1. Prenatal exposure of the brain to high levels of androgens may influence subsequent sexually
dimorphic behaviors in affected females.
2. Girls may demonstrate aggressive play behavior, tend to be interested in masculine toys such as cars
and trucks, and often show decreased interest in playing with dolls.
3. Women may have decreased interest in maternal roles. There is an increased frequency of
homosexuality in affected females.
4. Nonetheless, most function heterosexually and do not have gender identity confusion or dysphoria. It
is unusual for affected females to assign themselves a male role except in some with the severest
degree of virilization.
Untreated female children:
a. The clitoris may become further enlarged in affected females.
b. Although the internal genital structures are female, breast development and menstruation may
not occur unless the excessive production of androgens is suppressed by adequate treatment.
Male infant:
1. Male infants appear normal at birth. Thus, the diagnosis may not be made in boys until signs of
adrenal insufficiency develop.
2. Because patients with this condition can deteriorate quickly, infant boys are more likely to die
than infant girls. For this reason, all 50 American states and many countries have instituted
newborn screening for this condition.
Untreated male children
1. Child may have rapid somatic growth and accelerated skeletal maturation. Thus, affected patients are
tall in childhood but premature closure of the epiphyses causes growth to stop relatively early, and
adult stature is stunted.
2. Muscular development may be excessive. Pubic and axillary hair may appear, and acne and a deep
voice may develop.
3. The penis, scrotum, and prostate may become enlarged in affected boys; however, the testes are
usually prepubertal in size so that they appear relatively small in contrast to the enlarged penis.
4. Occasionally, ectopic adrenocortical cells in the testes of patients become hyperplastic similarly to the
adrenal glands, producing testicular adrenal rest tumors.
Nonclassic forms:
1. Similar but usually milder signs of androgen excess may occur in non classic 21-hydroxylase
deficiency. In this attenuated form, cortisol and aldosterone levels are normal and affected females
have normal genitals at birth.
2. Males and females may present with precocious pubarche and early development of pubic and
axillary hair.
3. Hirsutism, acne, menstrual disorders, and infertility may develop later in life, but many females and
 47

males are completely asymptomatic.
Adrenomedullary Dysfunction
1. Development of the adrenal medulla requires exposure to the extremely high cortisol levels normally
present within the adrenal gland. Thus patients with classic CAH have abnormal adrenomedullary
function.
2. They may have blunted epinephrine responses, decreased blood glucose, and lower heart rates with
exercise.
3. Ability to exercise is unimpaired and the clinical significance of these findings is uncertain.
LABORATORY FINDINGS
1. Salt-losing disease: hyponatremia, hyperkalemia, metabolic acidosis, and, often, hypoglycemia;
abnormalities can take 10-14 days or longer to develop after birth.
2. Blood levels of 17-hydroxyprogesterone are markedly elevated. However, levels of this hormone are
high during the 1st 2-3 days of life even in unaffected infants and especially if they are sick or
premature.
3. Blood levels of cortisol are low in patients with the salt-losing type of disease. They are often normal
in patients with simple virilizing disease but inappropriately low in relation to the ACTH and 17-
hydroxyprogesterone levels.
4. In addition to 17-hydroxyprogesterone, levels of androstenedione and testosterone are elevated in
affected females;
5. Testosterone is not elevated in affected males, because normal infant males have high testosterone
levels compared with those seen later in childhood.
6. Levels of urinary 17-ketosteroids and pregnanetriol are elevated but are now rarely used clinically
because blood samples are easier to obtain than 24 hr urine collections.
7. ACTH levels are elevated but have no diagnostic utility over 17-hydroxyprogesterone levels. Plasma
levels of renin are elevated, and serum aldosterone is inappropriately low for the renin level.
8. Diagnosis of 21-hydroxylase deficiency is most reliably established by measuring 17-
hydroxyprogesterone before and 30 or 60 min after an intravenous bolus of 0.125-0.25 mg of
cosyntropin (ACTH 1-24). Nomograms exist that readily distinguish normals and patients with
nonclassic and classic 21-hydroxylase deficiency.
9. Genotyping is clinically available and may help confirm the diagnosis, but it is expensive.
10. Prenatal diagnosis of 21-hydroxylase is possible late in the 1st trimester by analysis of DNA obtained
by chorionic villus sampling or during the 2nd trimester by amniocentesis.
NEWBORN SCREENING
1. Because 21-hydroxylase deficiency is often undiagnosed in affected males until they have severe
adrenal insufficiency, newborn screening is mandatory.
2. These programs analyze 17-hydroxyprogesterone levels in dried blood obtained by heelstick and
absorbed on filter paper cards; the same cards are screened in parallel for other congenital
conditions, such as hypothyroidism and phenylketonuria.
3. The nonclassic form of the disease is not reliably detected by newborn screening.
4. The main difficulty with current newborn screening programs is that to reliably detect all affected
infants, the cutoff 17-hydroxyprogesterone levels for recalls are set so low that there is a very high
frequency of false-positive results
TREATMENT
Glucocorticoid Replacement
1. Cortisol deficiency is treated with glucocorticoids. 15-20 mg/m2/24 hr of hydrocortisone daily
administered orally in 3 divided doses.
2. Double or triple doses are indicated during periods of stress, such as infection or surgery.
Glucocorticoid treatment must be continued indefinitely in all patients with classic 21-hydroxylase
deficiency but may not be necessary in patients with nonclassic disease unless signs of androgen
excess are present. Therapy must be individualized.
Monitoring:
1. Growth: crossing to higher height percentiles may suggest under treatment, whereas loss of height
 48

percentiles often indicates overtreatment with glucocorticoids. Overtreatment is also suggested by
excessive weight gain.
2. Pubertal development should be monitored by periodic examination
3. Skeletal maturation is evaluated by serial radiographs of the hand and wrist for bone age.
4. 17-hydroxyprogesterone and androstenedione, should be measured early in the morning
5. Menarche may be delayed in girls with suboptimal control.
6. Children with simple virilizing disease true precocious puberty may be treated with a gonadotropin
hormone–releasing hormone analog such as leuprolide . Males with 21-hydroxylase deficiency who
have had inadequate corticosteroid therapy may develop testicular adrenal rest tumors, which usually
regress with increased steroid dosage. Testicular MRI, ultrasonography, and color flow Doppler
examination help define the character and extent of disease.
Mineralocorticoid Replacement
1. Patients with salt-wasting disease require mineralocorticoid replacement with fludrocortisone.
Infants 0.1-0.3 mg daily in 2 divided doses with sodium supplementation (sodium chloride, 8 mmol
/kg) in addition to the mineralocorticoid. Older infants and children: 0.05-0.1 mg daily of
fludrocortisone
2. Therapy is evaluated by monitoring of vital signs; tachycardia and hypertension are signs of
overtreatment with mineralocorticoids.
3. Serum electrolytes should be measured frequently in early infancy as therapy is adjusted. Plasma
renin activity is a useful way to determine adequacy of therapy; it should be maintained in or near the
normal range but not suppressed.
Surgical Management of Ambiguous Genitals
1. Virilized females usually undergo surgery between 2-6 mo of age. The clitoris is reduced in size, with
partial excision of the corporal bodies and preservation of the neurovascular bundle; however,
moderate clitoromegaly may become much less noticeable even without surgery as the patient
grows.
2. Vaginoplasty and correction of the urogenital sinus usually are performed at the time of clitoral
surgery; revision in adolescence is often necessary.
3. Female sexual dysfunction increases in frequency and severity in those with the most significant
degrees of genital virilization and with the degree of enzymatic impairment (prenatal androgen
exposure) caused by each patient’s mutations.
Sex assignment:
1. Confused gender identity is not common with CAH; it occurs mostly in females with the salt-wasting
form of the disease and the greatest degree of virilization.
2. Educate the patient, family, and others about how to deal with the intersex condition.
3. They propose that surgery should be delayed until the patient decides on what, if any, correction
should be performed.
4. Severely virilized genotypic (XX) females raised as males have generally functioned well in the male
gender as adults.
5. Adrenalectomy (with hormone replacement) may be an alternative to standard medical hormone
replacement therapy, but patients treated in this way may be more susceptible to acute adrenal
insufficiency.
Prenatal Treatment
1. Mothers with pregnancies at risk are given dexamethasone, a steroid that readily crosses the
placenta, in an amount of 20 μg/kg prepregnancy maternal weight daily in 2 or 3 divided doses. This
suppresses secretion of steroids by the fetal adrenal, including secretion of adrenal androgens.
2. If started by 6 wk of gestation, it ameliorates virilization of the external to determine the sex and
genotype of the fetus; therapy is continued only if the fetus is an affected female.
3. Chorionic villus biopsy is then performed to determine the sex and genotype of the fetus; therapy is
continued only if the fetus is an affected female.
4. Maternal side effects of prenatal treatment have included edema, excessive weight gain,
hypertension, glucose intolerance, cushingoid facial features, and severe striae.
 49


11β-Hydroxylase Deficiency
ETIOLOGY
1. Deficiency of 11β-hydroxylase is caused by a mutation in the CYP11B1 gene.
2. Because 11-deoxycortisol is not converted to cortisol, levels of corticotropin are high.
3. Precursors particularly 11-deoxycortisol and deoxycorticosterone—accumulate and are shunted into
androgen biosynthesis
4. Aldosterone synthase is generally unaffected in this disorder.
5. This disorder presents in a classic, severe form and very rarely in a nonclassic, milder form.
Clinical features:
1. Patients may not manifest signs of adrenal insufficiency such as hypotension, hypoglycemia,
hyponatremia, and hyperkalemia. Hypertension may occur as a consequence of elevated levels of
deoxycorticosterone.
2. All signs and symptoms of androgen excess that are found in 21-hydroxylase deficiency may also
occur in 11β-hydroxylase deficiency.
Lab:
3. Plasma levels of 11-deoxycortisol and deoxycorticosterone are elevated.
4. Because deoxycorticosterone and metabolites have mineralocorticoid activity, plasma renin activity is
suppressed. Consequently,
5. aldosterone levels are low even though the ability to synthesize aldosterone is intact.
6. Hypokalemic alkalosis occasionally occurs.
TREATMENT
1. Patients are treated with hydrocortisone in doses similar to those used for 21-hydroxylase deficiency.
2. Mineralocorticoid replacement is sometimes transiently required in infancy

3β-Hydroxysteroid Dehydrogenase Deficiency
Etiology:
1. Deficiency of 3β-hydroxysteroid dehydrogenase (3β-HSD) occurs in fewer than 2% of patients with
adrenal hyperplasia.
2. This enzyme is required for conversion of Δ5 steroids (pregnenolone, 17-hydroxypregnenolone,
dehydroepiandrosterone [DHEA]) to Δ4 steroids (progesterone, 17-hydroxyprogesterone, and
androstenedione).
3. The deficiency of the enzyme results in decreased synthesis of cortisol, aldosterone, and
androstenedione but increased secretion of DHEA.
4. Mutations in the HSD3B2 leads to 3β-HSD deficiency.
CLINICAL MANIFESTATIONS
1. Because cortisol and aldosterone are not synthesized in patients with the classic form of the disease,
infants are prone to salt-wasting crises.
2. Because androstenedione and testosterone are not synthesized, boys are incompletely virilized.
Varying degrees of hypospadias may occur, with or without bifid scrotum or cryptorchidism.
3. Because DHEA levels are elevated and this hormone is a weak androgen, girls are mildly virilized, with
slight to moderate clitoral enlargement.
4. Postnatally, continued excessive DHEA secretion can cause precocious adrenarche.
5. During adolescence and adulthood, hirsutism, irregular menses, and polycystic ovarian disease occur
in females.
6. Males manifest variable degrees of hypogonadism, although appropriate male secondary sexual
development may occur.
LABORATORY FINDINGS
1. The hallmark of this disorder is the marked elevation of the Δ5 steroids (such as 17-
hydroxypregnenolone and DHEA) preceding the enzymatic block.
2. Patients may also have elevated levels of 17- hydroxyprogesterone because of the extraadrenal 3β-
 50

HSD activity that occurs in peripheral tissues; these patients may be mistaken for patients with 21-
hydroxylase deficiency.
3. The ratio of 17- hydroxypregnenolone : 17-hydroxyprogesterone is markedly elevated in 3β-HSD
deficiency, in contrast to the decreased ratio in 21-hydroxylase deficiency.
4. Plasma renin activity is elevated in the salt-wasting form.
DIFFERENTIAL DIAGNOSIS
1. Children with premature adrenarche;
2. Modest elevations in DHEA in pre teenage children or women usually represent a normal variant.
TREATMENT
1. Glucocorticoid and mineralocorticoid replacement with hydrocortisone and fludrocortisone,
respectively, as in 21- hydroxylase deficiency.
2. Incompletely virilized genetic males may benefit from several injections of 25 mg every 4 wk of a
depot form of testosterone early in infancy to increase the size of the phallus. They may also require
testosterone replacement at puberty.

17-HYDROXYLASE DEFICIENCY / 17,20 LYASE DEFICIENCY
Etiology:
1. Less than 1% of CAH
2. 17-hydroxylase converts pregnenolone to 17-hydroxypregnenolone and progesterone to 17-
hydroxyprogesterone
3. 17,20-lyase reaction converts 17-hydroxypregnenolone to DHEA and, to a lesser extent, 17-
hydroxyprogesterone to Δ4-androstenedione. DHEA and androstenedione are steroid precursors of
testosterone and estrogen
4. The enzyme is expressed in both the adrenal cortex and the gonads and is encoded by a gene on
chromosome 10q24.3. Most mutations affect both the hydroxylase and lyase activities, but rare
mutations can affect either activity alone.
5. Mutations in genes other than CYP17 can have the same phenotype as 17,20-lyase deficiency (i.e.,
deficient androgen synthesis with normal cortisol synthesis).
CLINICAL MANIFESTATIONS
1. Patients with 17-hydroxylase deficiency cannot synthesize cortisol, but their ability to synthesize
corticosterone is intact. Because corticosterone is an active glucocorticoid, patients do not develop
adrenal insufficiency.
2. Deoxycorticosterone, the immediate precursor of corticosterone, is synthesized in excess. This can
cause hypertension, hypokalemia, and suppression of renin and aldosterone secretion, as occurs in
11β-hydroxylase deficiency.
3. In contrast to 11β-hydroxylase deficiency, patients with 17-hydroxylase deficiency are unable to
synthesize sex hormones. Affected males are incompletely virilized and present as phenotypic
females (but gonads are usually palpable in the inguinal region or the labia) or with sexual ambiguity.
4. Affected females usually present with failure of sexual development at the expected time of puberty.
17-Hydroxylase deficiency in females must be considered in the differential diagnosis of primary
hypogonadism.
5. Levels of deoxycorticosterone are elevated and renin and aldosterone are consequently suppressed.
6. Cortisol and sex steroids are unresponsive to stimulation with ACTH and human chorionic
gonadotropin, respectively.
7. Patients with isolated 17,20-lyase deficiency have deficient androgen synthesis with normal cortisol
synthesis, and therefore do not become hypertensive.
TREATMENT
1. Patients with 17-hydroxylase deficiency require cortisol replacement to suppress secretion of
deoxycorticosterone and thus control hypertension. Additional antihypertensive medication may be
required.
2. Females require estrogen replacement at puberty.
 51

3. Genetic males may require either estrogen or androgen supplementation depending on the sex of
rearing. Because of the possibility of malignant transformation of abdominal testes with androgen
insensitivity syndrome, genetic males with severe 17-hydroxylase deficiency being reared as females
require gonadectomy at or before adolescence.

Lipoid Adrenal Hyperplasia
ETIOLOGY
1. Lipoid adrenal hyperplasia is a rare disorder, most frequently found in Japanese persons. Patients
with this disorder exhibit marked accumulation of cholesterol and lipids in the adrenal cortex and
gonads, associated with severe impairment of all steroidogenesis.
2. Lipoid adrenal hyperplasia is usually caused by mutations in the gene for steroidogenic acute
regulatory protein (StAR), a mitochondrial protein that promotes the movement of cholesterol from
the outer to the inner mitochondrial membrane.
CLINICAL MANIFESTATIONS
1. Patients with lipoid adrenal hyperplasia are unable to synthesize any adrenal steroids. Thus, affected
infants are likely to be confused with those with adrenal hypoplasia congenita.
2. Salt-losing manifestations are typical, and many infants die in early infancy.
3. Genetic males are unable to synthesize androgens and thus are phenotypically female but with
gonads palpable in the labia majora or inguinal areas.
4. Genetic females appear normal at birth and may undergo feminization at puberty with menstrual
bleeding. They too, progress to hypergonadotropic hypogonadism when accumulated cholesterol kills
granulosa (i.e., steroid synthesizing) cells in the ovary.
LABORATORY FINDINGS
1. Adrenal and gonadal steroid hormone levels are low in lipoid adrenal hyperplasia, with a decreased or
absent response to stimulation (ACTH, human chorionic gonadotropin).
2. Plasma renin levels are increased.
3. Imaging studies of the adrenal gland demonstrating massive adrenal enlargement in the newborn
help establish the diagnosis of lipoid adrenal hyperplasia.
TREATMENT
1. Patients require glucocorticoid and mineralocorticoid replacement.
2. Genetic males are usually assigned a female sex of rearing; thus both genetic males and females
require estrogen replacement at the expected age of puberty.

Deficiency of P450 Oxidoreductase (Antley-Bixler Syndrome)
ETIOLOGY, PATHOGENESIS, AND CLINICAL MANIFESTATIONS
1. P450 oxidoreductase (POR, gene located on chromosome 7q11.3) is required for the activity of all
microsomal cytochrome P450 enzymes including the adrenal enzymes CYP17 and CYP21. Thus,
complete POR deficiency abolishes all microsomal P450 activity. This is embryonically lethal in mice
and presumably in humans as well.
2. Patients with mutations that decrease but do not abolish POR activity have partial deficiencies of 17-
hydroxylase and 21-hydroxylase activities in the adrenals.
3. Deficiency of 17-hydroxylase leads to incomplete masculinization in males; 21-hydroxylase deficiency
may lead to virilization in females. Additionally, aromatase (CYP19) activity in the placenta is
decreased, leading to unopposed action of androgens produced by the fetal adrenal.
4. This exacerbates virilization of female fetuses and may virilize the mother of an affected fetus as well.
5. Because many other P450 enzymes are affected, patients often (but not invariably) have other
congenital anomalies collectively referred to as Antley-Bixler syndrome. These include
craniosynostosis; brachycephaly; frontal bossing; severe midface hypoplasia with proptosis and
choanal stenosis or atresia; humeroradial synostosis; medial bowing of ulnas; long, slender fingers
with camptodactyly; narrow iliac wings; anterior bowing of femurs; and malformations of the heart
and kidneys.
 52

6. Studies of mutant mice suggest that the metabolic defects responsible for these anomalies include
defective metabolism of retinoic acid, leading to elevated levels of this teratogenic compound, and
deficient biosynthesis of cholesterol.
EPIDEMIOLOGY
The prevalence is not known with certainty. It must be rare compared with 21-hydroxylase deficiency
but might occur at similar frequencies to the other forms of CAH.
LABORATORY FINDINGS
1. Serum steroids that are not 17- or 21-hydroxylated are most increased, including pregnenolone and
progesterone. 17-Hydroxy, 21- deoxysteroids are also increased, including 17-hydroxypregnenolone,
17-hydroxyprogesterone, and 21-deoxycortisol.
2. Urinary steroid metabolites may be determined by quantitative mass spectrometry. Metabolites
excreted at increased levels include pregnanediol, pregnanetriol, pregnanetriolone, and
corticosterone metabolites.
3. Urinary cortisol metabolites are decreased.
4. Genetic analysis demonstrates mutations in the POR gene.
DIFFERENTIAL DIAGNOSIS
1. This disorder must be distinguished from 21-hydroxylase deficiency in females, which is far more
common and has similar laboratory findings.
2. Suspicion for POR deficiency may be raised if the mother is virilized or if the associated abnormalities
of Antley-Bixler syndrome are present.
3. Conversely, virilization of both the mother and her daughter can result from a luteoma of pregnancy,
but in this case postnatal abnormalities of corticosteroid biosynthesis should not be observed.
4. Antley-Bixler syndrome may also occur without abnormalities of steroid hormone biosynthesis,
resulting from mutations in the fibroblast growth factor receptor FGFR2.

Aldosterone Synthase Deficiency
ETIOLOGY
1. This is a rare autosomal recessive disorder in which conversion of corticosterone to aldosterone is
impaired; a group of Iranian Jewish patients has been the most thoroughly studied. The majority of
cases result from mutations in the CYP11B2 gene coding for aldosterone synthase;
2. Aldosterone synthase mediates the 3 final steps in the synthesis of aldosterone from
deoxycorticosterone (11β-hydroxylation, 18- hydroxylation, and 18-oxidation).
3. These patients have normal cortisol biosynthesis.
CLINICAL MANIFESTATIONS
1. Infants may have severe hyponatremia, hyperkalemia, and metabolic acidosis.
2. Because cortisol synthesis is unaffected, infants rarely become as ill as untreated infants with salt-
losing forms of CAH such as 21-hydroxylase deficiency. Thus, some infants escape diagnosis.
3. Later in infancy or in early childhood they may exhibit failure to thrive and poor growth.
LABORATORY FINDINGS
1. Infants have elevated plasma renin activity.
2. Aldosterone levels are decreased;
3. Corticosterone levels are often elevated.
DIFFERENTIAL DIAGNOSIS
1. primary adrenal insufficiency in which both cortisol and aldosterone are affected (including salt-
wasting forms of CAH) is usually associated with a much greater risk of shock and hyponatremia. This
becomes apparent after the appropriate laboratory studies.
2. Adrenal hypoplasia congenita may initially present with aldosterone deficiency;
TREATMENT
1. Treatment consists of giving enough fludrocortisone (0.05-0.3 mg daily) or sodium chloride, or both,
to return plasma renin levels to normal.
2. With increasing age, salt-losing signs usually improve and drug therapy can often be discontinued.
 53


Glucocorticoid-Suppressible Hyperaldosteronism
ETIOLOGY
1. Glucocorticoid-suppressible hyperaldosteronism is an autosomal dominant form of low-renin
hypertension in which hyperaldosteronism is rapidly suppressed by glucocorticoid administration.
This unusual effect of glucocorticoids suggests that aldosterone secretion in this disorder is regulated
by ACTH instead of by the renin– angiotensin system.
2. In addition to abnormally regulated secretion of aldosterone, there is marked overproduction of 18-
hydroxycortisol and 18-oxocortisol.
3. The disorder is caused by unequal meiotic crossing-over events between the CYP11B1 and CYP11B2
genes, resulting in the inappropriate expression of a CYP11B2- like enzyme with aldosterone synthase
activity in the adrenal fasciculata.
CLINICAL MANIFESTATIONS
1. Some affected children have no symptoms, the diagnosis being established after incidental discovery
of moderate hypertension, typically approximately 30 mm Hg higher than unaffected family members
of the same age.
2. Others have more symptomatic hypertension with headache, dizziness, and visual disturbances. A
strong family history of early-onset hypertension or early strokes may alert the clinician to the
diagnosis.
3. Some patients have chronic hypokalemia, but this is not a consistent finding and is usually mild.
LABORATORY FINDINGS
1. Patients have elevated plasma and urine levels of aldosterone and suppressed plasma renin activity.
2. Hypokalemia is not consistently present.
3. Urinary and plasma levels of 18-oxocortisol and 18-hydroxycortisol are markedly increased.
4. The hybrid CYP11B1/CYP11B2 gene can be readily detected by molecular genetic methods.
DIFFERENTIAL DIAGNOSIS
1. This condition should be distinguished from primary aldosteronism based on bilateral hyperplasia or
an aldosterone-producing adenoma.
TREATMENT
1. Glucocorticoid-suppressible hyperaldosteronism is managed by daily administration of a
glucocorticoid, usually dexamethasone, 25 μg/kg/ day in divided doses.
2. If necessary, effects of aldosterone can be blocked with a potassium-sparing diuretic such as
spironolactone, eplerenone, or amiloride.
3. If hypertension is long standing, additional antihypertensive medication may be required, such as a
calcium channel blocker.

SPASMUS NUTANS
Introduction:
1. This disorder presents with a triad of nystagmus, head tilt, and head nodding.
2. If diurnal fluctuation occurs, symptoms may look like epileptic seizures. Brain MRI should be
performed, as the triad has been associated with masses in the optic chiasm and third ventricle.
3. Retinal disease should also be ruled out. In the absence of these associations, remission occurs before
5 yr of age.
Etiology
1. Spasmus nutans is a rare, idiopathic disorder that includes the clinical triad of nystagmus, head
nodding, and torticollis, although diagnosis does not require all three findings. Latin for “nodding
spasm,” spasmus nutans presents in the first year of life, may persist until puberty, and has been
associated with lower socioeconomic status.
2. First described by Raudnitz in 1897, the pathogenesis and neuroanatomical substrate of this typically
self-limiting form of disconjugate nystagmus is still unknown.
 54

3. Electroretinography, electrooculography, and neuroimaging can help distinguish the clinical picture of
spasmus nutans from that of other forms of nystagmus that have significant morbidity and potential
mortality.
Epidemiology
1. The precise incidence and prevalence of spasmus nutans are unknown, but it is considered rare.
Correlation of demographic and socioeconomic factors has been reviewed since the early 1900s.
2. Several studies confirm spasmus nutans to be associated with a high incidence of rickets disease,
more frequent onset of nystagmus in the darker months of the year, poor social and hygienic
conditions in families, and a higher incidence in crowded sections of large cities and in children of
African American descent.
3. A more recent study at a tertiary referral center administered questionnaires to the families of 23
patients diagnosed with spasmus nutans based on clinical findings and on the analysis of eye
movement recordings. The epidemiologic analysis validated that non-white ethnicity, low home
luminance, and low socioeconomic status (ie, low annual income and availability of private insurance)
are all associated with an increased risk for the development of spasmus nutans
4. The onset of spasmus nutans has been reported to range from age 2 weeks to 3 years, and is
generally quoted as 6-12 months of age. Though initially thought to resolve between 3 and 6 years of
age, more recent evidence from long-term follow up suggests there may be a persistence of
subclinical nystagmus up to age 12 years.
Pathophysiology
1. The cause of the nystagmus in spasmus nutans remains unknown.
2. The disconjugate nature of the nystagmus suggests a yoking abnormality whose anatomic location
may lie at the level of the ocular motor nuclei and may be caused by a delayed developmental change
in the associated connections within this system. These delayed modifications may account for both
the transient nature and the variability of the dissociated nystagmus.
3. Other systems implicated in the development of spasmus nutans include the vergence, saccadic, and
pursuit systems, though none in isolation can explain the observed high-frequency, dissociated, rapid
ocular oscillations and normal saccades typical of the disorder.
4. In contrast, the head nodding in spasmus nutans is not thought to be pathological but rather a
voluntarily nod as a neurovisual adaptation to compensate for nystagmus and to improve vision. In a
study of 35 patients with spasmus nutans, Gottlob et al found an influence of head nodding on eye
movements of 21 patients (60%). The fine, fast, dissociated nystagmus changes to a larger, slower,
symmetric eye movement during head nodding, with both eyes oscillating in phase at the same
amplitude and oscillating 180 degrees out of phase to the head movements.

5. The head nodding disappears during sleep, is lower frequency than the nystagmus, and becomes
more prominent when the child inspects an item of interest.
Clinical Features
1. Reports of nystagmus in spasmus nutans vary widely, but it often appears as an extraordinarily fine,
high frequency, pendular nystagmus that has been likened to an ocular “quiver”. It is usually
horizontal in direction but may also be vertical or torsional, and it is often described as an
intermittent nystagmus that is asymmetric or even monocular. On electrooculography, the two eyes
may be out of phase with each other, which is noted clinically as dissociation.
2. Head nodding may be the abnormality that first attracts attention but, as previously mentioned, it is
generally agreed to be compensatory and not pathologic. Electrooculographic recordings have
suggested that head nods are characterized by oblique, sinusoidal, intermittent, slow frequency, and
large amplitude movements. In order to suppress nystagmus, the amplitude of the head nod must be
higher than a certain threshold (which may differ amongst individuals).
3. The head tilt, or torticollis, is present in less than half of cases of spasmus nutans. Not many theories
have been suggested about why it is present, though some authors feel it may help direct the head
nodding to its optimal trajectory.
4. As visual development is affected by specific alterations in early visual experience (including
nystagmus), it is logical to suspect long-term visual comorbidities in patients with spasmus nutans. A
 55

retrospective study compared 18 patients with spasmus nutans against published, age-matched
controls to evaluate associated visual problems including strabismus, amblyopia, anisometropia, and
astigmatism. There was a significantly higher incidence of strabismus (56%, P < 0.001), most
commonly esotropia, and amblyopia (44%, P < 0.01) when compared to controls.
5. Another prospective case series followed 10 patients with spasmus nutans from a mean age of 20
months until a mean age of 7 years, and concluded approximately two thirds of patients had signs of
congenital esotropia, dissociated vertical deviation, amblyopia, and/or latent nystagmus.
Evaluation and differential diagnosis
1. Congenital nystagmus, retinal disease, brain tumors, and other neurologic diseases all share clinical
findings with spasmus nutans. Since a few patients are later found to have congenital retinal
dystrophies or neurodegenerative diseases, some experts advocate postponing the diagnosis of
spasmus nutans until after resolution of the nystagmus—though it is rare in medicine for a diagnosis
to require the future resolution of clinical findings.
2. Head nodding can be found in up to 12.6% of visually impaired individuals with nystagmus, which can
confuse physicians suspicious of spasmus nutans. Given the overlap of head nodding between
sensory- and motor-type nystagmus and spasmus nutans, these entities cannot be distinguished by
eye movement recordings alone. Congenital nystagmus is another condition that shares features with
spasmus nutans. Gottlob et al have published criteria by which one can distinguish the two.

3. Retinal diseases such as achromotopsia, Bardet-Biedl syndrome, congenital stationary night
blindness, and other photoreceptor dystrophies have all been reported in association with spasmus
nutans-like nystagmus. Findings of photophobia, decreased vision, night blindness, and myopia all

suggest an underlying congenital retinal dystrophy. Further investigation, including
electroretinography, should be carefully considered, especially when visual function remains below
normal.
4. Particularly notable are the diseases with spasmus–nutans-like nystagmus that have significant
morbidity and potential mortality. Suprasellar chiasmal gliomas have been known to cause Russell
diencephalic syndrome, which was likely the cause of what was thought to be rickets or malnutrition
associated with spasmus nutans in the era before neuroimaging. This constellation of signs that are
indistinguishable from spasmus nutans highlight the need for neuroimaging. In 1986, a series of 14
patients with spasmus nutans underwent neuroimaging without evidence of anterior pathway
gliomas; 1 patient (7%) had an empty sella and an arachnoid cyst. Over 1 decade later, the largest
series of 67 patients with spasmus–nutans-like nystagmus found no evidence of anterior pathway

gliomas on neuroimaging. Less than half of these patients had the full triad of spasmus nutans and
only 43% underwent neuroimaging; the authors also reported optic nerve hypoplasia in 2 children
(7%) and white matter changes on cerebral MRI in another 2 children (7%).
5. The most recent retrospective review by Kiblinger et al studied 22 patients with spasmus–nutans-like
nystagmus and found chiasmal gliomas in 2 patients (9%). Only 14% of the patients had the full triad,
but 91% underwent neuroimaging; the authors also reported Chiari I malformations in 2 children
(9%), and 1 child each with evidence of “small optic nerves,” enlarged cisterna magna, and a small,
incidental subdural hematoma. There are other reports of brain tumors associated with spasmus–
nutans-like nystagmus, including thalamic neoplasm and arachnoid cyst.
6. Another sizable percentage of patients presenting with spasmus–nutans-like nystagmus have
important underlying neurologic or systemic disease. Evaluation for opsolclonus-myoclonus in
association with neuroblastoma should include urinary catecholamines and complete body magnetic
resonance imaging. Pelizaeus-Merzbacher disease and subacute necrotizing encephalomyelopathy
(Leigh disease) should be suspected in children with spasmus–nutans-like nystagmus and clinical signs
of ataxia and/or developmental delay; neuroimaging is likely to demonstrate evidence of white
matter signal abnormalities. Another report describes a child with a history of spasmus nutans,
congenital ocular motor apraxia, and developmental delay whose MRI of the brain demonstrated
hypoplasia of the cerebellar vermis.
Prognosis
 56

1. As with most self-limiting ocular conditions, the prognosis for visual function in spasmus nutans is
quite good. One long-term follow up study observed 10 patients over a mean of 5.5 years and
concluded that all 10 subjects had vision better than 20/50.
2. Additionally, 90% of patients had 20/30 vision or better in at least 1 eye, and orthotropia with normal
stereovision will likely develop in approximately one-third of these patients.

ROLE OF PERIPHERAL SMEAR IN DIAGNOSING DIFFICULT CLINICAL SITUATIONS IN PEDIATRICS
Thick smear:
1. Make thick smear by joining the 3 drops of blood and spreading it with corner of another slide. Correct
thickness is attained when newsprint is barely legible through the smear.
2. It should be 10 mm diameter; 10 mm away from the edge of the slide; contains 10 layers of RBCs and 10
wbcs should be visible per oil immersion field of microscope.
Thin smear
1. With the edge of the slide spread a new drop of blood to the surface of the first slide. Air dry, allowing 10
minutes for the thin smear.
2. It is uniformly spread over the slide. It is tongue shaped. Thin enough so that newsprint can be read
through the smear. Consists of a single layer of RBCs.
3. After drying, only thin smear is fixed by dipping thin smear into methanol for 5 seconds.
4. Leisman staining:
a. Leishman’s stain contains eosin and methylene blue in acetone free methyl alcohol. Methyl alcohol
acts as a fixative. (acetone if present, will destroy the cell membrane). Methylene blue, the basic dye
and eosin, the acidic dye exists as thiazine eosinate which dissociates into the component dyes, when
diluted with distilled water
b. Methyl blue stains the nucleus and the basophilic granules of the WBC, where as eosin stains the
eosinophilic granules.
c. Pour the stain drop by drop till it covers the smear. Keep it for 1-2 minutes for fixing the smear. Then
dilute the stain using distilled water, double the amount of stain. Mix gently by blowing air. A golden
scum is seen to form over the diluted stain. Keep it for 7-10 minutes, when the smear gets stained,
wash the smear in running tap water till the smear turns pink and the water flowing out is colourless.
d. The film is first examined under the low power. Focus a well stained area where the cells are
uniformly distributed without rouleaux formation.Put two drops of cedar wood oil on the smear and
examine under oil immersion objective (with plane mirror, condenser raised and iris diaphragm fully
opened).
e. Criteria for a good smear:
a. The smear should not be serrated or wavy and should not contain any holes.
b. It should neither be too thick nor too thin.
c. The smear should occupy only the middle two thirds of the slide.
d. 4.An ideally taken smearwill be tongue shaped with a head, body and tail.
e. The stained smear should be pink in colour and free from stain particles.
f. RBC5 should be pink in colour and WBC5 should taken up appropriate colours Neutrophilic
granules - lilac, Eosinophilic granules - deep blue, Platelets should be pink to purplish blue.
2. Other Romanosky stains include Wright’s stain, Giemsa’s stain and Jenner’s stain.
5. Giemza staining:
Dry; fix thin smear with methanol and not thick smear; add 3% giemza stain; allow 30-45 mts; wash
with water; dry.
6. JSB stain: Jeswant singh Battacharia field stain for MP
a. After dehemoglobinisation by treating with distilled water for 10 mts, dip the thick smear in JSB ii
stain two to three times.
b. Wash it by dipping in buffer water two to three times. Then keep the thick film dipped in jsb i
stain for 40-60 seconds. Wash it with buffer water. Drain, dry and examine.
Smear study:
 57

a. Examination of the peripheral smear and estimation of the full blood counts are the most basic and
yet the most informative investigations performed in hematology.
b. The ideal approach is to look at the smallest cellular elements, the platelets, first and work his way up
in size to red cells and then white cells
Platelets:
1. The platelets are usually 1–2 μm in diameter and have a blue granulated appearance.
2. There is usually 1 platelet for every 20 or so red cells. Platelets are seen in good clumps; lack of
clumping may indicate low platelet count
3. It is expected that we see approximately 7– 15 platelets on x100 objective. A platelet/hpf is
equivalent to approximately 15,000- 20,000 platelets in circulation. An increase in platelet count is
termed thrombocytosis while a decrease is termed thrombocytopenia. Qualitative abnormalities of
platelets are termed thrombasthenia and require platelet functional studies to identify them.
4. Thrombocytosis in children is often benign and secondary to bleeds and inflammatory conditions.
5. Thrombocytopenia is seen in malaria, viral fevers like dengue haemorrhagic fever and bacterial
infections. Combination of thrombocytopenia, eczema and recurrent infections, is seen in Wiskott
Aldrich Syndrome.
6. Large platelets may be a sign of rapid platelet turnover, as young platelets are often larger than old
ones; alternatively, certain rare inherited syndromes can produce large platelets. Giant platelet
(about the size of a normal red cell or more) is seen in inherited conditions like Bernard Soulier
syndrome, May-Haggelin anomaly or Wiskott Aldrich syndrome and acquired states like megaloblastic
anaemia and myeloproliferative disorders.
RBC:
1. The size of the red cell is equal to the nucleus of a small lymphocyte.
2. Red cells that are smaller than the small lymphocyte nucleus may be microcytic; those larger than the
small lymphocyte nucleus may be macrocytic.
3. Macrocytic cells also tend to be more oval than spherical in shape and are sometimes called
macroovalocytes.
4. RBCs are either normal in color (normochromic) or pale in color (hypochromic). They are never
"hyperchromic." Hypochromic microcytic red cells with anisopoikilocytosis due to iron deficiency.
There is also associated thrombocytosis. The other causes of hypochromic microcytic anemia is
hereditary hemolytic anemia eg; β Thalassemia. The differentiating factors is the presence of
polychromasia and normoblasts. Platelets are normal or low in thalassemia unlike the thrombocytosis
seen in iron deficiency.
5. All abnormally shaped red cells are poikilocytes.
6. Small red cells without the central pallor are spherocytes; they can be seen in hereditary
spherocytosis, hemolytic anemias of other causes, and clostridial sepsis.
7. Dacrocytes are teardrop-shaped cells that can be seen in hemolytic anemias, severe iron deficiency,
thalassemias, myelofibrosis, and myelodysplastic syndromes.
8. Schistocytes are helmet-shaped cells that reflect microangiopathic hemolytic anemia or
fragmentation on an artificial heart valve.
9. Echinocytes are spiculated red cells with the spikes evenly spaced; they can represent an artifact of
abnormal drying of the blood smear
10. Acanthocytes are spiculated red cells with the spikes irregularly distributed. This process tends to be
irreversible and reflects underlying renal disease, abetalipoproteinemia, or splenectomy.
11. Elliptocytes are elliptical-shaped red cells that can reflect an inherited defect in the red cell
membrane, but they also are seen in iron deficiency, myelodysplastic syndromes, megaloblastic
anemia, and thalassemias.
12. Stomatocytes are red cells in which the area of central pallor takes on the morphology of a slit instead
of the usual round shape. Stomatocytes can indicate an inherited red cell membrane defect and also
can be seen in alcoholism.
 58

13. Target cells have an area of central pallor that contains a dense center, or bull's-eye. These cells are
seen classically in thalassemia, but they are also present in iron deficiency, cholestatic liver disease,
and hemoglobin C.
14. Red cell clumping (called agglutination) is seen in certain paraproteinemias and autoimmune
hemolytic anemias.
15. Rouleaux formation reflects abnormal serum protein levels: multiple myeloma or Waldenstrom
macroglobulinemia.
16. Red cell fragmentation syndrome can occur in a child with hemangioma where the peripheral smear
shows red cell fragments (schistocytes). Red cell fragments with thrombocytopenia is seen in
Kasabach Merrit Syndrome, a complication of hemangioma where there is localized intravascular
coagulation with consumption of platelets. Red cell fragments can be seen in other situations like
Hemolytic Uremic syndrome, prosthetic valves etc.
17. Peripheral smear revealing many red cells in the form of tear drop cells, normoblasts, myelocytes,
metamyelocytes and thrombocytopenia is charecteristic of leucoerythroblastic reaction in marrow
infiltration disorders such as osteopetrosis.
RBC inclusions:
1. Nucleated RBCs (NRBC, normoblasts): severe anemia, myelofibrosis, thalassemia,
2. Reticulocytes: haemolytic anemia
3. Siderocyte, sideroblast, ringed sideroblast: When RBCs are stained with Prussian blue dye, iron
granules may be seen.
4. Basophilic stippling: lead poisoning
5. Heinz bodies: (G6PD) deficiency, unstable hemoglobin variant, thalassemia, and autoimmune
hemolytic anemia.
6. Howell-Jolly bodies (small, round remnants of nuclear DNA inside cell): present in sickle cell anemia,
hemolytic or megaloblastic anemias, and may be seen after a splenectomy.
7. Cabot’s Rings: threadlike inclusions that form a ring within the RBC; may be seen in a variety of
anemias.
8. Hemoparasites: Malaria, kala azar, trypnozomia
Granulocytes:
Three types of granulocytes are usually present: neutrophils, eosinophils, and basophils, in decreasing
frequency.
Neutrophils:
1. Contain a lobulated nucleus with two to five lobes connected by a thin chromatin thread.
2. Bands are immature neutrophils that have not completed nuclear condensation and have a u-
shaped nucleus. Bands reflect a left shift in neutrophil maturation in an effort to make more cells
more rapidly.eg. Neonatal sepsis.
3. The commonest indicator of sepsis is neutrophilic leucocytosis in the peripheral smear. There is
associated toxic granulation or vacuolation in the cytoplasm. In newborns and young infants with
sepsis, there may be neutropenia and toxic changes are often seen in the neutrophils, which may
indicate sepsis. There may be associated thrombocytopenia.
4. The presence of 1- to 2-μm blue cytoplasmic inclusions, called döhle bodies, can reflect
infections, burns, or other inflammatory states.
5. If the neutrophil granules are larger than normal and stain a darker blue, "toxic granulations" are
said to be present, and they also suggest a systemic inflammation.
6. The presence of neutrophils with more than five nuclear lobes (hypersegmentation) suggests
megaloblastic anemia.
7. Macrocytes, hypersegmented polymorphs and abnormal looking myeloid precursors with
thrombocytopenia. Clincally pigmentation over hands and feet with associated anemia. Urine
protein-creatinine ratio was increased: Immerslund Grasbeck Syndrome:
8. Large misshapen granules may reflect the inherited chédiak-higashi syndrome.
Eosinophils:
1. They are slightly larger than neutrophils, have bilobed nuclei, and contain large red granules.
 59

2. Diseases of eosinophils are associated with too many of them rather than any morphologic or
qualitative change.
th
3. They normally total less than 1/13 the number of neutrophils.
4. Eosinophils increase in no (absolute eosinophil count more than 400) in tropical eosinophilia, and
helminthic infections. Hypereosinophilia is seen in infections like filariasis, eosinophilic facitis,
hypereosinophilic syndrome and eosinophilic leukemia.
Basophils:
1. They are even more rare than eosinophils in the blood.
2. They have large dark blue granules and may be increased as part of chronic myeloid leukemia.
Lymphocytes:
1. They can be present in several morphologic forms. Most common in healthy individuals are small
lymphocytes with a small dark nucleus and scarce cytoplasm.
2. In the presence of viral infections, more of the lymphocytes are larger, about the size of
neutrophils, with abundant cytoplasm and a less condensed nuclear chromatin. These cells are
called reactive lymphocytes.
3. About 1% of lymphocytes are larger and contain blue granules in a light blue cytoplasm; they are
called large granular lymphocytes.
4. In chronic lymphoid leukemia, the small lymphocytes are increased in number, and many of them
are ruptured in making the blood smear, leaving a smudge of nuclear material without a
surrounding cytoplasm or cell membrane; they are called smudge cells.
5. Lymphoblasts: These cells have scanty cytoplasm with opened out nuclear chromatin and
indistinct nucleoli suggestive of lymphoblastic leukemia.
6. Atypical lymphocytes i.e large lymphocytes with pale abundant cytoplasm with monocytoid,
plasmacytoid or lymphocytoid nuclei. This is characteristic of infectious mononucleosis and
Cytomegalovirus infections.
Monocytes:
1. Are the largest white blood cells .The nucleus can take on a variety of shapes but usually appears
to be folded; the cytoplasm is gray.
2. Increase in viral infections
3. Special preparations: L.E cells in SLE

Bone marrow transplant
1. Blood and marrow transplantation (BMT) refers to the transplantation of haematopoietic stem cells
and has offered the only hope of ‘cure’ in a variety of haematological and non-haematological
disorders.
2. Type of BMT:
1. Allogeneic BMT: the stem cells come from a donor—either related (usually an HLA-identical
sibling) or from a closely HLA-matched volunteer unrelated donor (VUD).
2. Autologous transplant: the stem cells are harvested from the patient and stored in the
vapour phase of liquid nitrogen until required. Stem cells can be harvested from the bone
marrow or from the blood.
3. Indications:
1. General indications for allogeneic BMT
i. Neoplastic disorders affecting stem cell compartments (e.g. leukaemias)
ii. Failure of haematopoiesis (e.g. aplastic anaemia)
iii. Major inherited defects in blood cell production (e.g.thalassaemia,
immunodeficiency diseases)
iv. Inborn errors of metabolism with missing enzymes or cell lines
1. Haematological indications for bone marrow transplantation
a. Allogeneic transplant
i. Acute myeloid leukaemia (AML) high-risk CR1, CR2
 60

ii. Adult acute lymphoblastic leukaemia (ALL) CR1, CR2
iii. Chronic myeloid leukaemia (CML) resistant to imitanib
iv. Myelodysplastic syndrome
v. Severe aplastic anaemia
vi. Myelofibrosis
vii. Severe immune deficiency syndromes
b. Autologous transplant
i. AML CR2
ii. Myeloma
iii. Poor-risk Hodgkin lymphoma
iv. High-grade non-Hodgkin lymphoma second response
v. Mantle cell lymphoma
Allogeneic BMT
a. Healthy marrow or blood stem cells from a donor are infused intravenously into the recipient, who
has been suitably ‘conditioned’.
b. The conditioning treatment (chemotherapy with or without radiotherapy) destroys malignant cells
and immunosuppresses the recipient, as well as ablating the recipient’s haematopoietic tissues.
c. The injected donor cells ‘home’ to the marrow, engraft and produce enough erythrocytes,
granulocytes and platelets for the patient’s needs after about 3–4 weeks.
d. During this period of aplasia patients are at risk of infection and bleeding, and require intensive
supportive care.
e. It may take several years to regain normal immunological function and patients remain at risk from
opportunistic infections, in particular in the first year.
f. An advantage of receiving allogeneic donor stem cells is that the donor’s immunological system can
recognise residual malignant recipient cells and destroy them. This immunological ‘graft versus
disease’ effect is a powerful tool against many haematological tumours and can be boosted post-
transplantation by the infusion of T cells taken from the donor, so-called donor lymphocyte infusion
(DLI). There is considerable morbidity and mortality associated with BMT.
g. The best results are obtained in patients with minimal residual disease, and in those under 20 years of
age who have an HLA-identical sibling donor.
h. Older patients can be transplanted, but results become progressively worse with age and an upper
age limit of 55 years is usually applied.
i. Complications
1. Mucositis
2. Infection
3. Bleeding
4. Cataract formation
5. Pneumonitis
6. Infertility
7. Chronic graft-versus-host disease
8. Acute graft-versus-host disease
9. Secondary malignant disease
j. The risks and outcomes of transplantation:
a. In general, 25% die from procedure-related complications such as graft-versus-host disease
(see below), and there remains a significant risk of relapse in haematological malignancy.
b. The long-term survival for patients undergoing allogeneic BMT in acute leukaemia is around
50%.
c. Graft-versus-host disease (GVHD)
i. GVHD is due to the cytotoxic activity of donor T lymphocytes which become
sensitised to their new host, regarding it as foreign.
 61

ii. This may cause either an acute or a chronic form of GVHD. Acute GVHD occurs in
the first 100 days after transplant in about one-third of patients. It can affect the
skin, causing rashes, the liver, causing jaundice, and the gut, causing diarrhoea, and
may vary from mild to lethal.
iii. Prevention includes HLA-matching of the donor, immunosuppressant drugs,
including methotrexate and ciclosporin, and antithymocyte globulin.
iv. The more severe forms are very difficult to control and, despite high-dose
corticosteroids, may result in death.
v. Chronic GVHD may follow acute GVHD or arise independently; it occurs later than
acute GVHD. It often resembles a connective tissue disorder, although in mild cases
a rash may be the only manifestation.
vi. Chronic GVHD is usually treated with corticosteroids and prolonged
immunosuppression with, for example, ciclosporin.
d. Reduced-intensity BMT
i. This concept has been developed in an attempt to reduce the mortality of
allografting.
ii. Rather than use very intensive conditioning which causes morbidity from organ
damage, relatively low doses of drugs such as fludarabine and cyclophosphamide
are used simply to immunosuppress the recipient and allow donor stem cells to
engraft.
iii. The emerging donor immune system then eliminates malignant cells via the ‘graft
versus disease’ effect, which may be boosted by the elective use of donor T cell
infusions post-transplant.
iv. This approach is less toxic and allows BMT to be offered to an older group of
patients.
v. However, relapse and infections posttransplant remain a concern and the role of
this type of transplant is still under investigation.
Autologous BMT
a. This procedure can also be used in haematological malignancies.
b. The patient’s own stem cells from blood or marrow are first harvested and frozen.
c. After conditioning therapy, the autologous stem cells are reinfused in order to rescue the patient
from the marrow damage and aplasia caused by chemotherapy.
d. Autologous BMT may be used for disorders which do not primarily involve the haematopoietic
tissues, or in patients in whom very good remissions have been achieved.
e. The preferred source of stem cells for autologous transplants is peripheral blood. These stem cells
engraft more quickly, marrow recovery occurring within 2–3 weeks.
f. There is no risk of GVHD and no immunosuppression is required.
g. Thus autologous stem cell transplantation carries a lower procedure-related mortality rate than
allogeneic BMT at around 5%, but there is a higher rate of recurrence of malignancy.

BLOOD COMPONENT THERAPY

1. Blood components are prepared from blood collected from individual human donors and include whole
blood,red cells, platelets, plasma or cryoprecipitate
2. Plasma derivatives are licensed pharmaceutical products produced on a factory scale from large volumes
of human plasma obtained from many individuals and treated to remove virus contamination.
3. Examples include the following:
a. Coagulation factors. Concentrates of factors VIII and IX were used for the treatment of conditions
such as haemophilia A, haemophilia B and von Willebrand disease. Coagulation factors made by
recombinant DNA technology are now preferred due to perceived lack of infection risk.
b. Immunoglobulins.
i. Intravenous immunoglobulin (IVIgG) is administered as regular replacement therapy to
reduce infective complications in patients with antibody deficiencies. A short highdose
 62

course of IVIgG may also be effective in some immunological disorders, including
immune thrombocytopenia and Guillain–Barré syndrome.
ii. Anti-zoster immunoglobulin has a role in the prophylaxis of varicella zoster.
iii. Anti-Rhesus D immunoglobulin is used in pregnancy to prevent haemolytic disease of
the newborn.
c. Human albumin. This is available in two strengths. The 5% solution can be used as a colloid
resuscitation fluid, but it is no more effective and is more expensive than crystalloid solutions.
Human albumin 20% solution is used in the management of hypoproteinaemic oedema with
nephrotic syndrome, and ascites in chronic liver disease. It is hyperoncotic and expands plasma
volume by more than the amount infused.
d. Red cell concentrate
1. Most of the plasma is removed and replaced with a solution of glucose and adenine in saline
to maintain viability of red cells ABO compatibility with recipient essential
2. Indication: Severe anaemia
e. Platelet concentrate
1. One adult dose is made from 4–5 donations of whole blood, or from a single platelet
apheresis; ABO compatibility with recipient preferable
2. Ind: Thrombocytopenia, e.g. in acute leukaemia
f. Fresh frozen plasma (FFP)
1. 150–300 mL plasma from one donation of whole blood; ABO compatibility with recipient
recommended
2. Ind: Replacement of coagulation factor deficiency
g. Cryoprecipitate
1. Fibrinogen and coagulation factor concentrated from plasma by controlled thawing 10–20
mL pack contains fibrinogen 150–300 mg, factor VIII 80–120 U, von Willebrand factor 80–120
U In UK supplied as pools of 5 units
2. Ind: von Willebrand disease and haemophilia


NEURODEGENERATIVE DISORDERS OF CHILDHOOD
Introduction
1. The hallmark of a neurodegenerative disease is regression and progressive deterioration of neurologic
function with loss of speech, vision, hearing, or locomotion, often associated with seizures, feeding
difficulties, and impairment of intellect.
2. Upper motor neuron signs and progressive spasticity are the hallmarks of white matter disorders;
convulsions and intellectual and visual impairments that occur early in the disease course are the
hallmarks of gray matter disorders.
3. The outcome of a neurodegenerative condition is usually fatal and it is important to make the correct
diagnosis so that genetic counseling may be offered and prevention strategies can be implemented.
Prevention by prenatal diagnosis (chorionic villus sampling or amniocentesis) is possible. Carrier detection
is also often possible by enzyme assay
4. Differences between white and grey mater degeneration:
Differentiating features White matter disorders Gray matter disorders
Age of onset Usually late (childhood) Usually early (infancy)
Head size May have megalencephaly Usually microcephaly
Seizures Late, rare Early, severe
Cognitive functions Initially normal Progressive dementia
Peripheral neuropathy Early demyelination Late, axonal loss
Spasticity Early, severe Later, progressive
Reflexes Absent (neuropathy) or Normal or exaggerated
exaggerated (long tracts)
 63

Cerebellar signs Early, prominent Late
Fundal examination May show optic atrophy Retinal degeneration
EEG Diffuse delta slowing Epileptiform discharges
EMG Slowed nerve conduction velocity Usually normal
Evoked potentials :visual Prolonged or absent Usually normal
evoked potential; auditory
brain stem response,
ERG electroretinogram Normal Abnormal
Etiology of neurodegeneration:
1. Disorders predominantly involving the white matter
a. Canavan disease: Autosomal recessive
b. Alexander disease: Sporadic
c. Krabbe Leukodystrophy: Autosomal recessive
d. Metachromatic Leukodystrophy: Autosomal recessive
e. Pelizaeus Merzbacher disease: Autosomal recessive
f. Adrenoleukodrystrophy: Autosomal recessive
g. Multiple Sclerosis: Sporadic
2. Disorders predominantly involving the Gray matter
a. Menkes kinky hair syndrome: X linked recessive
b. Symptomatic progressive myoclonic
epilepsies (such as Unverricht-Lundborg
disease, lafora disease): Autosomal recessive
c. Progressive infantile poliodystrophy: Autosomal recessive
d. Sialidosis (Type I): Autosomal recessive
e. Neuronal ceroid lipofuscinosis: Autosomal recessive
f. Mitochondrial encephalopathies: Variable
3. Disorders predominantly involving the basal ganglia
a. Juvenile Huntington disease: Autosomal dominant
b. Dystonia musculorum deformans: Autosomal dominant
c. Hallervorden Spatz disease: Autosomal recessive
d. Wilson disease: Autosomal recessive
4. Spinocerebellar degeneration and related conditions
a. Friedreich Ataxia: Autosomal recessive
b. Spinocerebellar ataxia: Autosomal dominant
c. Olivopontocerebellar atrophy: Autosomal dominant
d. Roussy Levy disease: Autosomal recessive
5. Spastic paraplegia
a. Familial Spastic paraplegia: Autosomal dominant
6. Neuromuscular & Peripheral neuropathy
a. Spinal muscular atrophy: Autosomal recessive
b. Infantile neruoaxonal dystrophy: Autosomal recessive
c. Charcot Marie Tooth Disease: Autosomal dominant
d. Refsum Disease: Austosomal recessive
Clinical examination.
1. The neurological examination may be normal in the early stages of some NDD.
2. Behavioral symptoms (such as ADHD) may be the initial manifestation of certain NDD, specifically
metachromatic leukodystrophy, juvenile adrenoleukodystrophy, and subacute sclerosing
panencephalitis, but will all eventually manifest other clinical signs.
3. Megalencephaly is an important feature of certain white matter disorders (such as Canavan and
Alexander disease).
7. Microcephaly is a usual feature of many gray matter disorders due to progressive neuronal loss.
 64

8. Examination of the skin and hair can be of diagnostic value in certain metabolic disorders such as
Hartnup disease (pellagra-like skin rash) and Menkes disease (kinky hair or pili torti under the
microscope).
9. The skin and nervous system have the same embryological origin (ectoderm). Therefore,
developmental CNS disorders may have associated skin signs such as neurocutaneous disorders.8
Some of these disorders may result in progressive loss of CNS function (such as Sturge Weber
syndrome).
10. Examination of the spine for deformities, particularly scoliosis, is important to exclude these
commonly associated complications.
11. Examination for dysmorphic features is needed, as some NDD may have associated facial
dysmorphism (such as Zellweger syndrome, Neonatal Adrenoleukodystrophy).9
12. Gargoyle-like facial features are characteristic of mucopolysaccharidosis and oligosaccharidosis.
13. Examination of eyes (the window of the brain) may give important diagnostic information as shown in
Table:
Ocular finding Disorder
Optic atrophy Peroxisomal disorders; Leukodystrophies
Cherry red spot GM1, GM2, Niemann-Pick disease
Pigmentary retinal degeneration Mitochondrial disorders
Corneal clouding Mucopolysaccaridosis; Mucoplipidosis
Conjunctival telangiectasia Ataxia-telengiectasia
Lenticular opacities (cataracts) Cockayne syndrome
Kayser-Fleisher corneal ring Wilson disease
Vertical gaze palsy Niemann-Pick disease (type C, D)
Progressive external Kearns-Sayre syndrome
ophthalmoplegia
Pendular nystagmus Pelizaeus-Merzabacher disease

14. In general, white matter disorders may result in optic atrophy (demylination) while gray matter
disorders may result in retinal degeneration, as retinal receptors are in fact neuronal cells. Other
system examination may provide important clues to the diagnosis.
15. Hepatomegaly, splenomegaly, or both are evident in the neuroviscer sphingolipidosis,
mucopolysaccharidosis, peroxisomal, and mitochondrial disorders.
16. Cardiopathy occurs in mitochondrial disorders, friedreich ataxia, and mucopolysaccharidosis. Features
of progressive renal failure are evident in fabry disease, sialidosis II, and Lowe syndrome.
Investigations.
1. Basic blood works may prove useful in certain disorders. Complete blood count may reveal
pancytopenia in certain organic acidopathies (such as isovaleric, proprionic, and methylmalonic
acidemias). Blood film may show vacuolated lymphocytes in neuronal ceroid lipofuscinosis,
fucosidosis, and sialidosis.
2. Acanthocytosis are characteristic of choreoacanthocytosis, abetalipoproteinemia, and hallervorden-
spatz disease. Blood gas analysis will detect metabolic acidosis in many metabolic disorders such as
organic acidopathies, urea cycle disorders, and mitochondrial encephalopathies.
3. Serum electrolyte abnormalities may result from adrenal insufficiency in adrenoleukodystrophy.
4. Liver function tests are disturbed in neurovisceral sphingolipidosis and certain gray matter NDD (such
as progressive infantile poliodystrophy).
5. Renal function tests and urinalysis may reveal tubular dysfunction (Lowe syndrome, Wilson disease),
nephrotic syndrome (storage diseases), or renal failure (fabry disease, sialidosis II, and Lowe
syndrome).
6. Chest x-ray may reveal cardiomegaly in early mitochondrial disorders, friedreich ataxia, and
mucopolysaccharidosis.
7. Electrocardiogram could identify conduction abnormalities that may complicate some of these
 65

disorders (such as refsum disease).
8. Skeletal survey may reveal specific bony abnormalities such as dysostosis multiplex in
mucopolysaccharidosis.
9. Neuroimaging, particularly brain magnetic resonance imaging (MRI), is critical in all children with
suspected NDD.
10. CharacteristicMRI features are noted in several white and gray matter NDD including; Alexander
disease, Leigh disease, and Hallervorden-Spatz disease.
11. Neuroimaging would exclude slow growing brain tumors, which may result in developmental
regression simulating NDD. Magnetic resonance imaging would also identify developmental
abnormalities and malformations. Patients with peroxisomal disorders (Zellweger disease) have
associated cortical neuronal migration abnormalities and agenesis of corpus callosum.
12. Serum ammonia, lactate, pyruvate, amino acids, and urine for amino acids and organic acids would
screen for most amino acid disorders, organic acidopathies, and urea cycle abnormalities.
13. Frequently, specific diagnostic tests and enzyme assays are needed to reach a definitive diagnosis.
14. Specialized tests:
Neurodegenerative disorders Diagnostic test
Alexander disease β-crystallin (CSF)
Krabbe leukodystrophy β-galactosidase (leukocytes/fibroblasts)
Metachromaticleukodystrophy Arylsultatase A (leukocytes/fibroblasts)
Adrenoleukodystrophy Very long chain fatty acids (VLCFA)
Canavan disease N-acetylaspartic acid (urine)
Mucopolysaccaridosis Mucopolysaccarides (urine)
Mucolipidosis Oligosaccharides (urine)
Menkes kinky hair syndrome Serum copper and ceruloplasmin
Lafora disease Skin biopsy (intracytoplasmic lafora bodies)
Sialidosis (Type 1) α-neuraminidase (leukocytes/ fibroblasts)
Neuronal ceroid lipofuscinosis Skin, conjunctival, or rectal biopsy
Mitochondrial encephalopthies Lactate (CSF/blood), muscle biopsy
Wilson disease Urine copper, serum copper and
ceruloplasmin
Friedreich ataxia DNA studies (blood)
Charcot Marie Tooth disease Nerve biopsy, DNA studies (blood)
Spinal muscular atrophy Muscle biopsy, DNA studies (blood)
Infantile neuroaxonal dystrophy Nerve biopsy
Refsum disease Phytanic acid (blood)
Lesch-Nyhan disease Hyperuricuria and hyperuricemia

15. When possible, prenatal diagnosis can be offered in subsequent pregnancies. Specific enzyme levels
can be measured in cultures of chorionic villus or amniocytes, but may not be entirely reliable.
16. The use of molecular analysis and specific DNA mutationscould improve the accuracy of prenatal
diagnosis.
Treatment.
1. Treatment of children with NDD is directed towards the underlying disorder, other associated
features, and complications.
2. The treatable complications include; epilepsy, sleep disorder, behavioral symptoms, feeding
difficulties, gastroesophageal reflux, spasticity, drooling, skeletal deformities, and recurrent chest
infections. These children require a multidisciplinary team approach with the involvement of several
specialties including pediatrics, neurology, genetics, orthopedics, physiotherapy, and occupational
therapy.
3. Many newer antiepileptic drugs are now available to treat intractable epilepsy.
4. Melatonin, 3mg at bedtime, has been documented to regulate the sleep-wake cycle, particularly in
 66

those with visual impairment.
5. Lioresal or diazepam may relieve spasticity, improve motility of the limbs, and combat pain.
6. Allogeneic bone marrow transplantation could provide an exogenous source of normal enzymes in
several lysosomal storage diseases
7. Recombinant human α-L-iduronidase has been recently shown to be effective in ameliorating some
clinical manifestation of mucopolysaccharidosis.
8. Counseling the families and educating the public about these potentially preventable disorders is very
important in the management of these children.
9. Consanguinity needs to be strongly discouraged in order to prevent most NDD in our region.
10. Treatment of major disorders:
Neurodegenerative disorders Specific treatment
Krabbe leukodystrophy Bone marrow transplantation
Metachromatic leukodystrophy Bone marrow transplantation
Adrenoleukodystrophy Glyceryl trioleate and trierucate, steroids for
adrenal insufficiency, diet low in VLCFA, bone
marrow transplantation
Mucopolysaccaridosis Bone marrow transplantion,
Recombinant human α-L-iduronidase
Menkes kinky hair syndrome Copper sulfate
Mitochondrial encephalopathies Nicotinamide, riboflavin,
dichloroacetate, L-carnitine, CoQ10
Wilson disease D-penicillamine, trietine, zinc acetate,
Liver transplantation;
Refsum diseas Reduction of phytanic acid intake
Lesch-Nyhan disease Allopurinol
Fabry’s Disease Recombinant human α galactosidase A

2 st
Pre and post ductal O saturation for CHD screening of 1 day of NB
1. Congenital heart disease (CHD) affects 8 per 1,000 live births and refers to structural disorders of the heart
and great vessels that are present at birth. Globally, CHD affects over one million live births annually and is
the leading cause of infant mortality attributable to birth defects.
2. Although there is no universally agreed on definition of critical CHD (CCHD), it usually refers to CHD that
requires surgical or interventional cardiologic management in the first year after birth, typically in early
infancy, to prevent mortality and/or severe morbidity.
3. The most common types of CCHD include transposition of the great arteries (TGA), hypoplastic left heart
(HLH), total anomalous pulmonary venous drainage, and coarctation/interruption of the aorta. Pulmonary
atresia, tricuspid atresia, critical obstruction of either ventricular outflow tracts, and several other
complex cardiac lesions are less common forms of CCHD
4. Preductal oxygen saturation is higher than postductal in the first 4 hours after birth. This difference has
been shown to disappear by 24 hours of age.
5. Pulse oximetry screening can be used to identify CCHD in asymptomatic newborns to lessen the burden of
undiagnosed CCHD.
6. Some studies have assessed oxygen saturation from postductal sites alone and others from both pre- and
postductal sites.
7. Simultaneous pre- and postductal oxygen saturation in asymptomatic newborns undergo screening for
CCHD at ∼24 hours after birth.
8. The probes were placed on the right palm or wrist for preductal and on either foot for postductal
saturation.
9. The pulse oximetry screen is considered “pass” if either the pre- or postductal saturation is ≥95% and the
difference between the 2 is ≤3%. The screen is considered a “fail” if either the pre- or postductal
saturation is <90%. A fail triggered a prompt clinical evaluation by a pediatric provider and transfer to the
 67

NICU if indicated. The screen is repeated if either the pre- and postductal saturations were 90% to 94%, or
there is a >3% difference. If the repeat screen within 4 hours remained the same, then it is considered a
fail. Failed screens are followed with an echocardiogram before discharge.
10. With abnormal screening, in the absence of other findings to explain hypoxia, a cardiology review is
recommended. Other evaluations such as chest x-ray, ECG and hyperoxia test can be inaccurate for
diagnosing Congenital Heart Defects (CHD)

BLEEDING DISORDERS IN CHILDREN
Haemorrhage and its Forms
1. Haemorrhage: extravasations of blood
2. Haematoma: accumulation of haemorrhagic blood in a tissue.
3. Petechiae: < 2 mm haemorrhagic spots
4. Purpura: > 3 mm into skin and mucous membrane.
5. Ecchymosis: haematoma > 2 cm.
Haemostasis
1. Haemostasis refers to spontaneous arrest of bleeding caused by injury of small blood vessels
2. Haemostasis depends on the following components
1. Vascular wall
2. Platelets
3. Coagulation proteins
4. Anticoagulant proteins, and
5. Fibrinolytic system
3. Hemostasis is achieved by plugging the vessel leakage by a stable clot
4. Clot consists of:
a. Platelets
b. Erythrocytes
c. Fibrin mesh
5. Circulation is reestablished by resolution of clot
Mechanism of hemostasis: Hemostasis can be divided into two stages
Primary hemostasis by platelet
1. Response to vascular injury
2. Formation of the “platelet plug” adhering to the endothelial wall
3. Limits bleeding immediately
4. Injury àarteriolar constriction (reflex neurogenic and endothelin) à exposure of highly
thrombogenic sub-endothelial matrix à von-willebrand factor releasedà platelets become
activated à release ADP and TX-A2 àrecruit additional platelets à formation of primary
haemostatic plug.
Secondary Hemostasis by coagulation
1. The intrinsic pathway ((surface activation):
a. Involves high-molecular weight kininogen, prekallikrein, and factors XII, XI, IX and VIII.
b. Factor VIII acts as a cofactor (with calcium and platelet phospholipid) for the factor IX-mediated
activation of factor X.
c. In intrinsic pathway, factor XII is activated by kallikrein
d. Factor XIIa activate XI and forms active XIa which interacts with factor IX and produce active IXa.
e. Factor IXa forms a complex with XIIIa, Ca++, and phospholipids to complete the factor X activator,
termed tenase.
f. The extrinsic and intrinsic pathways converge at the activation of factor X.
2. The extrinsic pathway:
a. The extrinsic pathway involves the tissue factor and factor VII complex.
b. One of the subendothelial matrix proteins that are exposed after vascular injury is tissue factor:
Tissue Thromboplastin (Factor III)
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c. Activated Factor VII in turn activates factor X.
3. Common pathway:
a. This involves the factor X-mediated generation of thrombin from prothrombin (facilitated by
factor V, calcium and platelet phospholipid)
b. Thrombin converts circulating soluble fibrinogen to insoluble fibrin threads.
c. Fibrin threads bind to platelets firmly and converts primary platelet aggregates into a solid plug.
4. Regulation of clotting
a. Tissue plasminogen activator is simultaneously activated and prevents the extensive coagulation.
b. Gradually the stable plug will be dissolved by fibrinolysis by anticoagulant facors:
a. In the presence of the cofactor protein S, activated protein C proteolyses and inactivates
factor Va and factor VIIIa. Inactivated factor Va is, in fact, a functional anticoagulant that
inhibits clotting.
b. Plasmin, generated from plasminogen by either urokinase-like or tissue-type
plasminogen activator, degrades the fibrin clot. In the process of dissolving the fibrin
clot, fibrin degradation products are produced.

Features of Abnormal Bleeding
1. Epistaxis
a. Unrelieved by 15 minutes of pressure
b. Requiring ED visit
2. Menorrhagia
a. Frequent pad changes (< 2 hour frequency)
b. Menses lasting > 7 days
c. >1 menstrual period in a month
3. Post-surgical/ dental
a. Uncontrolled bleeding in the field
b. Bleeding lasting beyond the day of dental work
c. Requiring a blood transfusion
4. Bruising
a. Bruises other than on distal extremities
b. Larger than a quarter
c. Associated with hematoma
d. Out of proportion to mechanism of injury
Clinical Significance of Haemorrhage:
1. Clinical effects of haemorrhage depend on volume and rate of blood loss.
2. Rapid removal of up to 20% of blood volume or slow losses of even larger amount may have little
impact in healthy adult. Greater losses may result in haemorrhagic shock.
3. Site of haemorrhage is also important. Bleeding that would be trivial in subcutaneous tissue may
 69

cause death if located in the brain because the skull is unyielding and bleeding can result increased
intracranial pressure and herniated.
4. Chronic or recurrent external blood loss may lead to iron deficiency anaemia.
Classification of bleeding disorders:
1. Platelets: manifest as petechiae ; thrombocytopenias & thrmobocytopathy
a. Immune: Eg: Idiopathic thrombocytopenic purpura:
b. Non Immune: Eg:
i. Hemolytic-uremic syndrome:
ii. Thrombotic thrombocytopenic purpura:
iii. Disseminated intravascular coagulopathy
2. plasma coagulation factors: present as ecchymoses or hemarthrosis
a. hemophilias
b. Von Willebrand disease
3. Dosorders of blood vessels present with palpable purpura
a. Henoch-Schönlein purpura
Differential Diagnosis of Bleeding and Bruising Disorders:
Is the defect inherited or acquired?
1. Inherited Disorders
a. Family history of bleeding disorder
b. Family history
i. Transfusions for minor surgery or menses
ii. Post-partum hemorrhage
iii. Chronic iron deficiency anemia
c. Usually present in infancy and early childhood. Milder forms may present later in life —
mild hemophilia, von Willebrand disease. Child or adolescent has had undue bleeding
after tonsillectomy or major dental extractions, may indicate hereditary bleeding
disorder.
d. In von Willebrand disease (VWD), mothers and family members may have the same mild
bleeding disorder and adolescent girl may have heavy bleeding during menarche or
menstrual periods.
e. Sex: Some of the inherited hemostatic defects such as hemophilia A (FVIII deficiency),
hemophilia B (FIX deficiency), Wiskott-Aldrich syndrome/Xlinked thrombocytopenia, and
X-linked thrombocytopenia with dyserythropoiesis are due to mutations on the X
chromosome. A family history of bleeding limited to males suggests an X-linked disorder.
f. Additional congenital anomalies may suggest the presence of a syndromic bleeding
disorder
2. Aquired:
a. The development of bleeding later in childhood usually indicates an acquired disorder.
b. Acquired bleeding disorders may present in the context of coexisting illness.
c. Lymphadenopathy and/or organomegaly suggest an infiltrative process such as
malignancy or a storage disease.
d. Signs of liver failure suggest acquired coagulation factor deficiencies.
Type and pattern of bleeding:
a. Patients with defects in platelet-blood vessel wall interaction (VWD or platelet function defects):
a. mucocutaneous bleeding like epistaxis, menorrhagia, petechiae, ecchymoses, occasional
hematomas, and less commonly, hematuria and gastrointestinal bleeding
b. There may be prolonged bleeding following surgery and/or dental extractions.
b. Disorders of coagulation factors:
a. Spontaneous or excessive bleeding into soft tissues, muscles and joints, or delayed surgical
bleeding suggests. May also cause mucocutaneous bleeding, epistaxis, or gastrointestinal
bleeding.
b. ICH, postcircumcision bleeding in infancy
 70

c. Bleeding from the umbilical cord stump within the first days of life is strongly suggestive of
FXIII deficiency or afibrinogenemia.
c. Patients with mild VWD or other mild bleeding disorders may have no abnormal findings on physical
examination.
d. Individuals with disorders of the collagen matrix and vessel wall may have loose joints and lax skin
associated with easy bruising (Ehlers-Danlos syndrome)

No Disorder Findings or clues to diagnosis

Bleeding
1 Platelet disorders 1. Bleeding, bruising, petechia, or purpura
(quantitative) 2. Consider idiopathic thrombocytopenic purpura, thrombotic
thrombocytopenic purpura, malignancy, viral disease
2 Platelet disorders 1. Consider in a patient with a lifelong history of bleeding
(functional) despite negative laboratory work-up
2. Consider glycoprotein disorders (Bernard-Soulier syndrome,
Glanzmann thrombasthenia), storage pool disease, von
Willebrand’s disease
3. If platelets are abnormally shaped, consider May-Hegglin
anomaly, Wiskott-Aldrich syndrome
3 Hemophilia type A or B 1. Classically presents with joint or soft-tissue bleeding;
(VIII or IX deficiency) or 2. Family history of bleeding in men (skipped generations)
other factor deficiencies
4 Factor inhibitors 1.
Presentation similar to hemophilia,
2.
Onset is typically sudden with no patient or family history of
bleeding
5 Hereditary hemorrhagic 1. Telangiectasias over lips, tongue, nasal cavity, and skin;
telangiectasia 2. Epistaxis
6 Vasculitis or 1. Neuropathy;
cryoglobulinemia 2. Pulmonary-renal involvement;
3. Purpura
7 Leukemia Abnormal complete blood count or peripheral blood smear

8 Disseminated 1. Bleeding from multiple sites;

intravascular 2. prolonged prothrombin time and partial thromboplastin time
coagulation
9 Vitamin K deficiency 1. Malabsorption
2. Poor diet (alcoholism, total parenteral nutrition)
3. Drugs that bind vitamin K (cholestyramine).
Bruising
10 Purpura simplex (easy Typically found in women on the upper thighs and arms
bruising)
11 Abuse (including child 1. Atypical pattern of bruising or bleeding;
abuse) 2. Bruises that pattern after objects;
3. Bruises in children who are not yet mobile;
4. History that is inconsistent with the patient’s injuries
12 Cushing’s disease 1. Facial plethora; hirsutism; hyperglycemia; hypertension; poor
wound healing; stria
13 Marfan’s syndrome 1. Enlarged aortic root; eye involvement;
2. Mitral valve prolapse; scoliosis; pectus excavatum;
3. Stretch marks; tall and slim, with long limbs and digits
 71

14 Vitamin C deficiency Dietary history

15 Ehlers-Danlos syndrome 1. Atrophic scarring or joint dislocations;

or connective tissue 2. Hypermobile joints; skin hyperextensibility
diseases

Laboratory tests:
1. Platelet abnormalities
a. Platelets No:
NORMAL 100,000 - 400,000 CELLS/MM3
Thrombocytopenia < 100,000
Mild Thrombocytopenia 50,000 - 100,000
Severe Thrombocytopenia < 50,000
b. Platelet size: Large sizes of platelets are abnormal and thrombocytopathy is functional defect
of platelets. Giant platelets are observed in Bernard–Soulier syndrome & May–Hegglin
anomaly.
c. Platelet aggregation: In Glanzmann thrombasthenia, the platelets do not aggregate in
response to ADP, epinephrine (adrenaline), arachidonic acid, or collagen. Platelet adhesion is
defective in von Willebrand syndrome.
d. Platelet function tests:
i. (Thrombasthenia) has historically been assessed by the bleeding time, using a
standardised incision. However, many centres have abandoned this test as it is non-
specific.
ii. Platelet function can be assessed in vitro by measuring aggregation in response to
various agonists such as adrenaline (epinephrine), collagen, thrombin or ADP, or by
measuring the constituents of the intracellular granules, e.g. ATP/ADP.
e. Bleeding time: provides assessment of platelet count and function; normal value 2-8 minutes
2. Extrinsic pathway:
a. Prothrombin time: measures effectiveness of the extrinsic pathway; In most laboratories, the
normal PT value is 10-13 sec. PT is standardized using the International Normalized Ratio
(INR) so that values can be compared from 1 laboratory or instrument to another.
b. PT is not prolonged with deficiencies of factors II, V, VII or X & Severe fibrinogen deficiency
3. Intrinsic pathway:
a. Partial thromboplastin time: Measures Effectiveness of the Intrinsic pathway; normal value
25-40 secs;
b. Indicates deficiencies of factors II, V, VIII,IX, X, XI, XII, Severe fibrinogen deficiency,
unfractionated heparin therapy, Antibodies against clotting factors & Lupus anticoagulant
4. Fibrinolytic pathway:
a. Thrombin time: time for thrombin to convert fibrinogen to fibrin; a measure of fibrinolytic
pathway; normal value 9-13 secs
5. Steps in coagulation studies:
a. In patients who have a positive bleeding history or who are actively hemorrhaging, a platelet
count, PT, and partial thromboplastin time (PTT) should be performed.
b. If the results are normal, a thrombin time to evaluate fibrinogen function and VWF testing
should be considered.
c. Mixing Studies:
i. If there is unexplained prolongation of PT, PTT, or thrombin time, a mixing study is
performed.
ii. Normal plasma is added to the patient’s plasma, and the PT or PTT is repeated.
Correction of PT or PTT by 1 : 1 mixing with normal plasma suggests deficiency of a
clotting factor, because a 50% level of individual clotting proteins is sufficient to
produce normal PT or PTT.
 72

iii. If the clotting time is not corrected or only partially corrected, an inhibitor is
present.
6. Test to rule out heparin tharpy as a cause for coagulation disorder: Reptilase Time
a. Reptilase time uses snake venom to clot fibrinogen. Unlike thrombin time, reptilase time is
not sensitive to heparin and is prolonged only by reduced or dysfunctional fibrinogen and
fibrin split products.
b. Therefore, if thrombin time is prolonged but reptilase time is normal, the prolonged
thrombin time is due to heparin and does not indicate the presence of fibrin split products or
reduced concentration or function of fibrinogen.
7. Platelet Function Analyzer
a. To evaluate platelet function in vitro platelet analyzers have been developed. The PFA-100
measures platelet adhesion-aggregation in whole blood at high shear when exposed to
either collagen-epinephrine or collagen-ADP.
b. Results are reported as the closure time measured in sec. The PFA-100 appears to be
sensitive to severe forms of VWD and platelet dysfunction.
8. D-Dimer
a. D-dimer is formed by plasmin degradation of cross-linked fibrin, produced when fibrinogen is
clotted by thrombin and crosslinked by factor XIIIa, and is more specific for fibrinolysis than
FDPs.(fibrin degradation products)
b. D-dimer is elevated in patients with DIC or acute deep vein thrombosis
9. Clotting Factor Assays
a. Each of the clotting factors can be measured in the clinical laboratory using individual factor–
deficient plasmas.
b. Clotting factors activity is measured against pooled normal plasma or against a standard, by
which 100% activity is expressed as 100 IU/dL. By definition, 1 international unit (IU) of each
factor is defined as that amount in 1 mL of normal plasma. For most clotting factors, the
normal range is 50-150 IU/ dL (50-150%)

EMERGENCY PEDIATRICS
1. Status epilepticus
2. Status asthmaticus / Acute severe asthma
3. Shock and anaphylaxis
4. Burns
5. Hypertensive emergencies
6. Gastrointestinal bleeding
7. Comatose child
8. Congestive cardiac failure
9. Common poisonings and snakebite
10. Acute renal failure
11. Diabetic ketoacidosis
12. Pneumothorax
13. Acute laryngotracheobronchitis
 73

STATUS ASTHMATICUS OR ACUTE SEVERE ASTHMA IN CHILDREN

Definition: a severe exacerbation of asthma that does not improve with standard therapy is termed status
asthmaticus.
Steps in management:
Step 1. Assessment of severity of attack and risk factors
step 2. Initial bronchodilator therapy and treatment of hypoxia.
Step 3. Assessment of response to therapy and modification of therapy.
Step 4. Intensive care and ventilation in refractory case
1. Assessment of severity of attack
a. Moderate exacerbation:
i. Spo2 ≥ 92%
ii. No clinical features of severe asthma
b. Severe exacerbation
i. Spo2 < 92%
ii. Too breathless to talk or eat
iii. Hr > 140/min
iv. Rr > 40/min
v. Use of accessory neck muscles
c. Life threatening
i. Spo2 < 92%
ii. Agitated/altered consciousness
iii. Cyanosis
iv. Poor respiratory effort
v. Silent chest
vi. Exclude upper airway obstruction like vocal card dysfunction and foreign body
2. Assessment of risk for clinical deterioration: The patient is at risk if there is
a. Previous severe asthma exacerbation: intensive care unit admission, intubation for asthma)
b. Sudden asphyxia episodes: previous h/o of respiratory failure
c. Two or more hospitalizations for asthma in past year
d. Three or more emergency department visits for asthma in past year
3. Initial bronchodilator therapy and treatment of hypoxia.
a. Immediate Home management:
i. “Rescue” medication (inhaled SABA 100 µg x 2 puffs or salbutamol nebulizer solution
(5mg/ml) in the dose of 0.1-0.15 mg/kg diluted in 3 ml of normal saline over a period of 10-
15 min. Repeat every 20 minutes up to 3 doses/hour
ii. A short course of oral corticosteroid therapy - prednisone 1-2 mg/kg/day for 4 days
b. Emergency department management:
i. Supplemental oxygen,
ii. Inhaled β-agonist therapy: salbutamol 100 µg x 6 puffs every 20 min for 1 hr, and, if
necessary,
iii. Systemic corticosteroids given either orally or intravenously
iv. Inhaled ipratropium may be added to the β-agonist treatment if no significant response is
seen with the first inhaled β-agonist treatment; 2 puffs of 80mcg (or 250mcg by nebulizer)
every 20 minutes for 1 hour only.
v. Intramuscular injection of epinephrine or other β-agonist may be administered in severe
cases.
vi. Oxygen to be continued for at least 20 min after SABA administration to compensate for
possible ventilation-perfusion abnormalities caused by SABAS.
4. Assessment of response to initial therapy
 74

a. The patient should be assessed after initial therapy of 2-3 doses of bronchodilator along with oxygen
over a period of one hour.
b. Good response to initial therapy will be free of wheeze and have no breathlessness. PEFR > 70% of
normal for the child
c. Partial response: PEFR 40 to 70%
d. Poor Response: severe persistent wheeze and significant pulsus paradoxus; transfer to intensive care.
5. Intensive Hospital management of asthma exacerbations
a. Supplemental oxygen to maintain o2 saturation >92%
b. SABAS can be delivered frequently (every 20 min to 1 hr) or continuously (at 5-15 mg/hr).
c. Inhaled ipratropium bromide is added to albuterol every 6 hr; 0.5 mg q6-8h (tid-qid) as needed
d. Short-course oral or intravenous coticosteroid.
e. Administration of fluids at or slightly below maintenance fluid requirements is recommended
6. In refractory cases:
a. Parenterally administered epinephrine sc or im: 0.01 mg/kg (max dose 0.5 mg); may repeat after 15-
30 min,
b. Β-agonists: continuous iv infusion (terbutaline only): 2-10 μg/kg loading dose, followed by 0.1-0.4
μg/kg/min
c. Methylxanthines: Aminophylline A bolus dose (5-6 mg/kg) depending upon previous treatment with
methylxanthines is given followed by infusion of maintenance dose (0.9 mg/kg/h).
d. Magnesium sulfate (25-75 mg/kg, maximum dose 2.5 g, given intravenously over 20 min), and acts by
counteracting calcium mediated smooth muscle contraction, through its influence on calcium
homeostasis, inhibition of acetylcholine release at the neuromuscular junction, inhibition of
histamine release, direct inhibition of smooth muscle contraction and sedation
e. Inhaled heliox (helium and oxygen mixture)
7. In respiratory failure:
a. Intubation and mechanical ventilation when:
i. Failure of maximal pharmacologic therapy.
ii. Cyanosis and hypoxaemia (PaO2 less than 60 mm Hg).
iii. PaCO2 greater than 50 mmHg and rising by more than 5 mmHg/h
iv. Minimal chest movements.
b. Volume-cycled ventilators, using short inspiratory and long expiratory times, 10-15 ml/kg tidal
volume, 8-15 breaths/min, peak pressures <60 cm h2o, and without positive end-expiratory pressure
are starting mechanical ventilation parameters
c. Ketamine: loading dose of 0.5-1.0 mg/kg, followed by an infusion of 1.0-2.5 mg/kg/h in ventilated
children relaxes smooth muscle directly, increases chest wall compliance and also decreases
bronchospasm in ventilated asthmatic children.
8. Recovery Phase and Advice at Discharge
a. PEFR >75% predicted
b. Oral or inhaled beta-2 agonist maintenance
9. Prevention
a. Education regarding home management
b. Children should be supervised regularly
c. They should learn to use MDI

Pneumothorax

1. Definition: accumulation of extrapulmonary air within the chest
2. Most often it is due to leakage of air from lung
3. Not so common in childhood
4. Types :
1. Primary spontaneous
 75

2. Secondary spontaneous
3. Traumatic
4. Iatrogenic
5. Catamenial
Primary
1. Pneumonia : high in staph pneumonia
2. Bronchiolitis
3. Tuberculosis
4. Cystic fibrosis
5. Lung abscess
6. Pulmonary infarct
7. Rupture of cyst
8. Rupture of emphysematous bleb (asthma)
9. Foreign body in lung
10. Lymphoma
Secondary
1. Traumatic:
i. Penetrating injury
ii. Blunt trauma
iii. Loud music
2. Iatrogenic:
i. Thoracotomy
ii. Tracheostomy
iii. Needle punctutre
iv. Mechanical ventilation
v. Resuscitation
3. Catamenial: during menstruation
Pathophysiology
1. Air in pleural space abolishes negative pressure
2. Lung collapses upto 30%
3. In tension pneumothorax:
i. Mediastinal shift
ii. Decreased venous return
iii. Decreased cardiac output
4. Hypoxemia
Clinical manifestations
1. Abrupt onset of symptoms
2. Dyspnea, chest pain, cyanosis
3. Chest retraction
4. Signs:
i. Decreased breath sounds
ii. Tympanitic percussion note
iii. Tracheal shift
DD
1. Diaphragmatic hernia
2. Emphysema
3. Large cyst or cavity
4. Compensatory expansion
5. Distended stomach
Treatment
1. A small (<5%) or even moderate-sized pneumothorax in an otherwise normal child may resolve without
 76

specific treatment, usually within 1 wk

2. 100% o2 helps resolution
3. Tension pneumothorax: emergency needle thoracostomy; 2nd intercostal space at mid-clavicular line.
Needle aspiration is as effective as tube thoracostomy in the emergency room management of primary
spontaneous pneumothorax.
4. Chemical pleurodesis (76oxycycline in pleural space)
5. Thoracoscopic blebectomy
6. For collapse lung: chest tube drainage
th th
7. Intercostal drainage with under water seal: 4 or 5 intercostal space; between the mid- to anterior
axillary line. insertion of a chest tube) and drainage of the trapped air through a catheter, the external
opening of which is kept in a dependent position under water, is adequate to reexpand the lung in most
patients; pigtail catheters are frequently used.

Croup (acute laryngotracheobronchitis)

1. Croup refers to a group of acute infectious processes characterized by a bark-like or brassy cough with hoarseness,
inspiratory stridor, and respiratory distress.
2. Croup typically affects the larynx, trachea, and bronchi.
3. Croup syndrome is also called acute laryngotracheo bronchitis, inflammation of mainly glottis and subglottic region
and laryngitis may cause life threatening airway obstruction.
4. Spasmodic croup is a condition due to an allergic component and improves rapidly without treatment, whereas
laryngotracheobronchitis is always associated with a viral infection of the respiratory tract.
5. Stridor is a harsh, high-pitched respiratory sound, which is usually inspiratory but can be biphasic and is produced
by turbulent airflow; it is not a diagnosis but a sign of upper airway obstruction
6. Etiology:
1) The parainfluenza viruses (types 1, 2, and 3) account for approximately 75% of cases;
2) Other viruses associated with this disease include influenza a and b, adenovirus, respiratory syncytial virus
(rsv), and measles.
3) Mycoplasma pneumonia has rarely been isolated from children with croup and causes mild disease
7. Epidemiology:
1) Most patients with croup are between the ages of 3 mo and 5 yr, with the peak in the second year of life.
2) Higher in males,
3) Most common during winter
4) Approximately 15% of patients have a strong family history of croup
10. clinical features:
1) An upper respiratory tract infection with some combination of rhinorrhea, pharyngitis, mild cough, and
low-grade fever for 1 to 3 days before the signs and symptoms of upper airway obstruction become
apparent.
2) The child then develops the characteristic "barking" cough, hoarseness, and inspiratory stridor.
3) The low-grade fever may persist, although temperatures may reach 39-40°c; some children are afebrile.
4) Symptoms are characteristically worse at night and often recur with decreasing intensity for several days
and resolve completely within a week.
5) Agitation and crying greatly aggravate the symptoms and signs.
6) The child may prefer to sit up in bed or be held upright.
7) Older children usually are not seriously ill. Most young patients with croup progress only as far as stridor
and slight dyspnea before they start to recover.
8) Other family members might have mild respiratory illnesses with laryngitis.
11. Physical examination:
1) Hoarse voice, coryza, slightly increased respiratory rate.
 77

2) on progression: increasing respiratory rate; nasal flaring; suprasternal, infrasternal, and intercostal
retractions; and continuous stridor.
3) croup is a disease of the upper airway, and alveolar gas exchange is usually normal. Hypoxia and low
oxygen saturation are seen only when complete airway obstruction is imminent.
4) Occasionally, the pattern of severe laryngotracheobronchitis is difficult to differentiate from epiglottitis,
despite the usually more acute onset and rapid course of the latter.
12. Investigations:
1) Croup is a clinical diagnosis and does not require a radiograph of the neck.
2) Radiographs of the neck may show the typical subglottic narrowing or "steeple sign" of croup on the
posteroanterior view. However, the steeple sign may be absent in patients with croup, may be present in
patients without croup as a normal variant, and may rarely be present in patients with epiglottitis.
3) Lateral neck radiography could help detect epiglottitis (thickened epiglottis- thumb sign), retropharyngeal
abscess (widening of the retropharyngeal soft tissues), and bacterial tracheitis (thickened trachea)
13. Differential diagnosis:
1) Bacterial tracheitis
2) Diphtheritic croup
3) Measles croup almost always coincides with the full manifestations of systemic disease and the course
may be fulminant
4) Aspiration of a foreign body
5) Retropharyngeal or peritonsillar abscess
6) Angioedema of the subglottic areas
7) Hypocalcemic tetany,
14. Complications:
1) Pneumonia, cervical lymphadenitis, otitis media,
2) Bacterial tracheitis may be a complication of viral croup. If associated with s. Aureus, toxic shock
syndrome can develop.
15. Treatment:
1) The mainstay of treatment is airway management. Provide cool mist through a tube held in front of
the patient by the parent: it moistens airway secretions to facilitate clearance,
2) Nebulized epinephrine:
A dose of 0.25 to 0.75 ml of 2.25% racemic epinephrine in 3 ml of normal saline can be nebulized
as often as every 20 min or 0.5 ml per kg (maximal dose: 5 ml) of l-epinephrine 1:1,000 via
nebulizer,
3) Corticosteroids:
1. decrease the edema in the laryngeal mucosa through their anti-inflammatory action.
2. Dexamethasone used a single dose of 0.6 mg/kgim
4) Antibiotics: are not indicated in croup.
5) Helium-oxygen mixture (heliox) may be effective in children with severe croup

Acute epiglotitis

1. Epiglottitis is an infection of the epiglottis and supraglottic structures
2. Etilogy:
a. In the past, haemophilus influenzae type b was the most commonly identified etiology of acute
epiglottitis.
b. After hib vaccine invasive disease due to h. Influenzae type b in pediatric patients has been reduced
c. Therefore, other agents, such as streptococcus pyogenes, s. Pneumoniae, and staphylococcus aureus,
now represent a larger proportion of pediatric cases of epiglottitis.
3. Age: mostly 2-4 yr of age
4. Clinical features:
 78

a. This is a dramatic, potentially lethal condition

b. High fever, sore throat, dyspnea, and rapidly progressing respiratory obstruction.
c. The initial lack of respiratory distress can deceive the unwary clinician
d. Often, the otherwise healthy child suddenly develops a sore throat and fever. Within a matter of hours,
the patient appears toxic, swallowing is difficult, and breathing is labored.
e. Drooling is present and the neck is hyperextended in an attempt to maintain the airway.
f. The child may assume the tripod position sitting upright and leaning forward with the chin up and mouth
open while bracing on the arms.
g. Restlessness may be followed by rapidly increasing cyanosis and coma.
h. Stridor is a late finding and suggests near-complete airway obstruction.
i. The barking cough typical of croup is rare.
j. Complete obstruction of the airway and death can ensue unless adequate treatment is provided.
5. The diagnosis:
1. Visualization of a large, "cherry-red" swollen epiglottis by laryngoscopy.
2. Classic radiographs of a child who has epiglottitis show the "thumb sign"
6. Complicatiopns:
1. Pneumonia, cervical adenopathy, or otitis media, meningitis, arthritis are rarely found in conjunction with
epiglottitis.
2. Mediastinal emphysema and pneumothorax are the most common complications of tracheotomy.
7. Management:
1. Anxiety-provoking interventions such as phlebotomy, intravenous line placement, placing the child
supine, or direct inspection of the oral cavity should be avoided until the airway is secure.
2. Pulmonary edema can be associated with acute airway obstruction.
3. Establishing an airway by nasotracheal intubation or, less often, by tracheostomy is indicated urgently.
4. The duration of intubation depends on the clinical course probably 2-3 days
5. Drugs:
a. Racemic epinephrine and corticosteroids are ineffective.
b. Cultures of blood, epiglottic surface, and, in selected cases, cerebrospinal fluid, should be
collected at the time of airway stabilization.
c. Ceftriaxone, cefotaxime, or a combination of ampicillin and sulbactam should be given
parenterally pending culture
d. Epiglottitis resolves after a few days of antibiotics, and the patient may be extubated; antibiotics
should be continued for 7-10 days.
e. Rifampin prophylaxis (20 mg/kg orally once a day for 4 days;) should be given to all household
members
8. Prevention:
a. Hib vaccine is routinely given with dpt at 6,12,16 weeks and a booster at 18 months
9. Prognosis:
Untreated epiglottitis has a mortality rate of 6% in some series,

SHOCK
Definition:
It is an acute syndrome, characterized by inadequate circulatory provision of oxygen, so that the
metabolic demands of vital organs and tissues are not met.
Pathogenesis:
a. Shock can result from several different causes, including
i. Inadequate blood volume
ii. Inappropriate distribution of blood flow
iii. Impaired pumping of the heart
iv. Obstructed blood flow
 79

b. Stages of shock:
i. Compensated: vital organ function is maintained by intrinsic compensatory mechanisms
Blood flow to vital organs i.e. heart and brain is spared at the expense of non-essential
organs. Sympathetic-mediated reflexes preserve cardiac output. Blood pressure and warmth
of body are mintained.
ii. Progressive decompensated: In this stage despite intense arteriolar constriction and
increased heart rate, there is decline in blood pressure and cardiac output. MODS begins and
there is progression in refractoriness:
1. Fluid refractory
2. Catecholamine refractory
3. Steroid refractory
iii. Irreversible: Irreversible shock is a term applied to the clinical situation in which even
correction of hemodynamic derangement does not halt the downward spiral. There is
evidence of MODS
Clinical Types:
There are 6 major types of shock: hypovolemic, septic, cardiogenic, distributive, and obstructive and
others.
1. Hypovolemic shock:
a. Decreased preload secondary to internal or external losses. Eg:
i. Blood: Hemorrhage
ii. Plasma: burns, nephrotic syndrome
iii. Water and electrolytes: diarrhoea, vomiting, diabetes
b. Tachycardia and an increase in systemic vascular resistance are the initial compensatory
responses to maintain cardiac output and systemic blood pressure.
c. Without adequate volume replacement, hypotension develops, followed by tissue ischemia
and further clinical deterioration.
2. Septic shock:
a. Occurs in overwhelming infections.
b. Includes combination of distributive, hypovolemic, and cardiogenic shock.
c. Hypovolemia from intravascular fluid losses occurs through capillary leak into third spaces.
Cardiogenic shock results from the myocardium-depressant effects of sepsis, and distributive
shock is the result of decreased systemic vascular resistance.
d. Causes:
i. Bacterial
ii. Viral
iii. Fungal (immunocompromised patients are at increased risk)
e. Host immune response produces an inflammatory cascade of toxic mediators, including
hormones, cytokines, and enzymes.
f. The systemic inflammatory response syndrome (SIRS) is an inflammatory cascade that is
initiated by the host response to an infectious or noninfectious trigger. The inflammatory
cascade is initiated by toxins or superantigens via macrophage binding or lymphocyte
activation.
g. The inflammatory cascade can lead to:
i. hypovolemia,
ii. cardiac and vascular failure,
iii. acute respiratory distress syndrome (ARDS),
iv. insulin resistance,
v. decreased cytochrome P450 (CYP450) activity (decreased steroid synthesis),
vi. coagulopathy, and
vii. Unresolved or secondary infection.
 80

h. Tumor necrosis factor (TNF) and other inflammatory mediators increase vascular
permeability, causing diffuse capillary leak, decreased vascular tone, and an imbalance
between perfusion and metabolic demands of the tissues.
i. TNF and interleukin-1 (IL-1) stimulate the release of proinflammatory and anti-inflammatory
mediators, causing fever and vasodilatation.
j. Arachidonic acid metabolites lead to the development of fever, tachypnea, ventilation-
perfusion abnormalities, and lactic acidosis.
k. Nitric oxide, released from the endothelium or inflammatory cells, is a major contributor to
hypotension.
l. Myocardial depression is caused by myocardium-depressant factors, TNF, and some
interleukins through direct myocardial injury, depleted catecholamines, increased β-
endorphin, and production of myocardial nitric oxide.
3. Cardiogenic shock:
a. Cardiac pump failure secondary to poor myocardial function. In these instances, myocardial
contractility is affected, leading to systolic and/or diastolic dysfunction. Eg:
i. Congenital heart disease,
ii. Immediately after cardiac surgery to repair a congenital heart defect,
iii. Cardiomyopathy
iv. Myocarditis (viral, kawasaki disease),
v. Dysrhythmias
4. Distributive:
a. It is a state of abnormal vasodilation & redistribution of blood flow away from vital organs
to non-vital organs
b. Causes:
1. Sepsis,
2. hypoxia,
3. poisonings,
4. anaphylaxis,
5. spinal cord injury: loss of sympathetic vascular tone secondary to spinal cord or
brainstem injury
6. mitochondrial dysfunction
5. Others:
a. Heat stroke: Characterized by hypovolemia due to salt and water losses, and decreased
peripheral vascular resistance
b. Obstructive:
i. large pulmonary embolism leading to right-sided heart failure,
ii. critical coarctation of aorta leading to left-sided heart failure
iii. Pericardial tamponade
iv. Tension pneumothorax
Clinical manifestations.
1. If untreated, all forms of shock follow a common and lead to irreversible shock and death
2. Signs of Compensated shock
a. Tachycardia: 1st or only sign of early compensated shock
b. Vasoconstriction: and tachycardia to maintain BP by sympathetic nervous system and
catecholamines
c. Increased respiratory rate: is increased to promote the excretion of CO2 from metabolic
acidosis
d. pH: Increased renal excretion of hydrogen ions and retention of bicarbonate to maintain
normal pH.
e. Vascualr volume: Maintenance of vascular volume by the renin-angiotensin-aldosterone and
atrial natriuretic factor
 81

3. Signs of decompensated shock:

a. Increasing tachycardia and tachypnea
b. Skin may be mottled or pale
c. Capillary refill > 4 secs
d. Oliguria
e. GIT: decreased motility, distension
f. CNS: irritability progresses to agitation, confusion, stupor, and finally coma
g. R.S
i. Damage to the capillary endothelium
ii. Fluid fills the interstitium
iii. Dyspnea, tachypnea, cyanosis refractory to oxygen therapy, decreased lung
compliance, and diffuse alveolar infiltrates.
iv. These signs, when grouped together, represent acute respiratory distress syndrome
(ARDS).
h. Criteria for Organ Dysfunction
i. Decrease in BP (hypotension)
ii. Need for vasoactive drug to maintain BP in normal range
iii. Unexplained metabolic acidosis: base deficit >5.0 mEq/L
iv. Increased arterial lactate >2 × upper limit of normal
v. Oliguria: urine output <0.5 mL/kg/hr
vi. Prolonged capillary refill: >5 sec
vii. Core to peripheral temperature gap >3° C
viii. Need for mechanical ventilation
ix. Acute change in mental status with a decrease in Glasgow Coma score ≥3 points
from abnormal baseline
3
x. Platelet count <80,000/mm
xi. 2-fold increase in baseline creatinine
xii. Total bilirubin ≥4 mg/dL (not applicable for newborn)
xiii. Alanine transaminase level 2 × upper limit of normal for age
4. Hypovolemic shock usually presents as changes in mental status, tachypnea, tachycardia,
hypotension, poor peripheral pulses, cool extremities, and oliguria
5. Septic shock, in particular, has 2 phases:
a. Early, or warm, shock: In the early stages, the cardiac output increases in an attempt to
maintain adequate oxygen delivery and meet the greater metabolic demands of the organs
and tissues. This is called “warm” shock. It is diagnosed by low SVR (systemic vascular
resistance), warm extremities, & bounding pulse.
b. Late, or cold, shock: As septic shock progresses, cardiac output falls in response to the
effects of numerous inflammatory mediators, leading to a compensatory elevation in
systemic vascular resistance and this is called “cold” shock. It is diagnosed by by cold
extremities and week pulse.
6. Cardiogenic shock presents with cool extremities, delayed (>2–3 sec) capillary filling time,
hypotension, poor peripheral or central pulses, tachypnea, increasing obtundation, and decreased
urination.
7. Additional clinical findings in shock include cutaneous lesions such as petechiae, diffuse erythema,
ecchymoses, ecthyma gangrenosum, and peripheral gangrene. Jaundice can be present either as a
sign of infection or as a result of MODS.
Diagnosis:
a. Shock is diagnosed clinically on the basis of a thorough history and physical exam
b. In cases of suspected septic shock, an infectious etiology should be sought through culture of clinically
appropriate specimens.
Laboratory Findings
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1. Hematologic abnormalities:
a. Thrombocytopenia,
b. Prolonged prothrombin and partial thromboplastin times,
c. Reduced serum fibrinogen level,
d. Elevations of fibrin split products etc
2. Glucose and electrolytes:
a. Hyperglycemia or hypoglycemia.
b. Hypocalcemia,
c. Hypoalbuminemia, and
d. Metabolic acidosis.
3. Renal and/or hepatic function may also be abnormal.
4. RS:
a. Decreased PaO2
b. Increased PaCO2
5. Metabolic:
a. increased lactic acid production (high anion gap, metabolic acidosis) due to anaerobic
metabolism
Treatment
a. The initial treatment in pediatric shock is to stabilize the ABCs and provide appropriate fluid resuscitation.
Intubation and mechanical ventilation, may be necessary
i. Oxygen: Restoration of normal oxygen delivery to vital tissues can be accomplished by
ii. Improving oxygen-carrying capacity (maintaining normal hematocrit at 35–40%),
iii. Improving oxygen saturation (95–99%) and pao2 (if severely anemic), and
iv. Enhancing depressed cardiac output.
b. Fluid resuscitation:
i. An initial fluid bolus of 20 mL/kg of normal saline or lactated Ringer solution should be given
rapidly (5–10 min). This bolus should be repeated quickly up to 60-80 mL/kg if needed. Smaller
boluses of fluid (5-10 mL/kg) should be given in cardiogenic shock.
ii. After initial stabilization, ongoing losses (continued diarrhea, vomiting, burns) should be replaced
with appropriate fluids
iii. Glucose levels should be checked routinely and treated appropriately
c. Indicators of response:
i. Normal heart rate
ii. Urine output (>1 ml/kg/hr),
iii. Capillary refill time (to <2 sec), and
iv. Improved mental status.
d. Fluid refractory shock:
i. If the patient continues in a state of shock following 60-80 mL/kg of volume resuscitation,
inotropic support vasopressor therapy (norepinephrine, or epinephrine) should be instituted
ii. Epinephrine: Increases heart rate and strength of contractions; 0.05–3.0 μg/kg/min; may lessen
renal perfusion
iii. Norepinephrine: Strong vasoconstrictor; 0.05–1.5 μg/kg/min; increases SVR. Norepinephrine is
the vasoactive agent of choice for the child with warm shock with poor perfusion or hypotension.
e. Cardiovascular drugs:

DRUG EFFECT(S) DOSE RANGE

Dopamine Strengthens contractions (throughout dose range)

Intermediate dose = 5–15
μg/kg/min

 83

Increases renal blood flow (low/intermediate doses) High dose = 15–25

μg/kg/min

Vasoconstriction (high doses)

Epinephrine Increases heart rate and strength of contractions 0.05–3.0 μg/kg/min

Potent vasoconstrictor

Dobutamine Increases strength of heart contraction 1–20 μg/kg/min

Little effect on heart rate

Peripheral vasodilator, especially in vessels to viscera

Norepinephrine Strong vasoconstrictor 0.05–1.5 μg/kg/min

Weak effect on strength of heart contraction

Phenylephrine Strong vasoconstrictor 0.5–2.0 μg/kg/min

Can be used to slow tachycardia through reflex

cardiac slowing

Milrinone Potent inotrope Load 50 μg/kg over 15 min

Potent chronotrope 0.5–1 μg/kg/min

Peripheral vasodilator

f. Whole blood: If the child's hypovolemia is from loss of blood or protein-rich fluid, replacement with whole
blood or packed red blood cells or with fresh frozen plasma or albumin, respectively, may be given.
g. Intravenous hydrocortisone in stress doses should be considered in patients with:
a. septic shock (Purpura fulminans)
b. Patients receiving or recently weaned from steroids.
c. Secondary adrenal insufficiency;
h. Septic shock: early administration of broad-spectrum antimicrobial therapy should also be initiated. The
choice of antimicrobial agents depends on the predisposing risk factors and the clinical situation.
i. Distributive shock:
Epinephrine is the treatment of choice for patients with anaphylaxis. Epinephrine has peripheral α-
adrenergic as well as inotropic effects that may improve the myocardial depression seen with anaphylaxis
and its associated inflammatory response
j. Cardiogenic shock:
a. Early initiation of myocardial support with epinephrine or dopamine to improve cardiac output is
important
b. Milrinone therapy may improve systolic function and decrease SVR without causing a significant
increase in heart rate. Furthermore, this agent has the added benefit of enhancing diastolic
relaxation.
k. Obstructive shock:
a. Examples: pericardiocentesis for pericardial effusion, pleurocentesis or chest tube placement for
pneumothorax, thrombectomy/ thrombolysis for pulmonary embolism
Other modes of support in shock.
 84

1.Intravenous immunoglobulin infusion or plasmapheresis may also be considered in certain circumstances

as therapeutic adjuncts for shock.
2. Other interventions include correction of coagulopathy with fresh frozen plasma or cryoprecipitate and
platelet transfusions as necessary, especially in the presence of active bleeding.
3. Electrolyte levels should be monitored closely and corrected as needed. Correction of severe acidosis and
hypercarbia is important;
4. Calcium can act as a direct myocardial stimulant, particularly in the neonate; therefore, hypocalcemia
should be corrected
5. When shock leads to ARDS may require mechanical ventilation with lung-protective strategies to keep
plateau pressure below 30 cm H2O and tidal volume at 6 mL/ kg
6. Extracorporeal membrane oxygenation (ECMO) or ventricular assist devices may be effective in treating
young children with septic shock or severe cardiogenic shock.
7. For SIRS: Trials have been conducted with anti-endotoxin antibodies, antioxidant compounds, an IL-1
receptor antagonist, IL-1 antibodies, bradykinin receptor antibodies, cyclooxygenase inhibitors,
thromboxane antagonists, platelet-activating factor (PAF) antagonists, inhibitors of leukocyte adhesion
molecules, nitric oxide antagonists, anti-TNF antibody, bactericidal permeability–increasing protein, and
recombinant human activated protein C (drotrecogin-α: not used presently).
PROGNOSIS
1. In septic shock, mortality rates are as low as 3% in previously healthy children and 6-9% in children
with chronic illness (compared with 25-30% in adults).
2. With early recognition and therapy, the mortality rate for pediatric shock continues to improve, but
shock and MODS remain one of the leading causes of death in infants and children.

ANAPHYLAXIS
Definitions:
1. Anaphylaxis is a potentially life-threatening, systemic allergic reaction caused by the release of histamine
and other vasoactive mediators from mast cells.
2. The risk of death is increased in patients with pre-existing asthma, particularly if this is poorly controlled,
and in individuals in whom treatment with adrenaline (epinephrine) is delayed.
3. Anaphylactoid reactions result from the nonspecific degranulation of mast cells by drugs, chemicals or
other triggers, and do not involve IgE antibodies. The clinical presentations are indistinguishable, and in
the acute situation discriminating between them is unnecessary.
Etiology:
I. Anaphylaxis: IgE-mediated mast cell degranulation
a. Foods
i. Peanuts
ii. Tree nuts
iii. Fish and shellfish
iv. Milk
v. Eggs
vi. Soy products
b. Insect stings
i. Bee venom • Wasp venom
c. Chemicals, drugs and other foreign proteins
i. Intravenous anaesthetic agents, e.g. suxamethonium, propofol
ii. Penicillin and other antibiotics
iii. Latex
2. Anaphylactoid: non-IgE-mediated mast cell degranulation
1. Drugs
a. Aspirin and non-steroidal anti-inflammatory drugs (NSAIDs)
 85

b. Opiates
c. Radiocontrast media
2. Physical
a. Exercise • Cold
3. Idiopathic
a. No cause is identified in 20% of patients with anaphylaxis
Clinical Features:
1. Dermatologic/mucosal
1. Eyes: periorbital swelling/erythema, injected conjunctiva, tears
2. Oral mucosa: angioedema of the tongue and lips
3. Skin: urticarial rash, pruritus or flushing, morbilliform rash, piloerection, angioedema
2. Respiratory
a. Lower airway: bronchospasm with wheezing or cough, chest tightness, tachypnea,
decreased peak expiratory flow, cyanosis, respiratory collapse/arrest
b. Upper airway: sensation of throat constriction; dry cough; difficulty breathing,
swallowing, speaking; changes in voice; stridor; cyanosis; respiratory collapse/arrest
3. Cardiovascular
a. Early: tachycardia, diaphoresis, delayed capillary refill, hypotension
b. Late: bradycardia, shock, T-wave inversion and ST depression in multiple leads,
cyanosis, cardiac arrest
2. Gastrointestinal
a. Nausea, vomiting, diarrhea, abdominal cramps
3. Neurologic
a. Throbbing headache, dizziness, lightheadedness, confusion, tunnel vision, loss of
consciousness
4. General
a. Anxiety, feeling of impending doom, metallic taste, paresthesia in extremities,
malaise, weakness
b. In children: sudden behavior changes, irritability, cessation of play
Investigations
a. Measurement of acute and convalescent serum mast cell tryptase concentrations is useful to confirm the
diagnosis.
b. Specific IgE tests may be preferable to skin prick tests
Clinical Criteria for Diagnosing Anaphylaxis
Anaphylaxis is highly likely when any one of the following three sets of criteria is fulfilled:
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal tissue, or both
(e.g., generalized hives; pruritus or flushing; swollen lips, tongue, or uvula), and at least one of the
following:
a. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced peak
expiratory flow, hypoxemia)
b. Reduced blood pressure or associated symptoms of end-organ dysfunction (e.g., hypotonia
[collapse], syncope, incontinence)
2. Two or more of the following that occur rapidly (minutes to several hours) after exposure to a likely
allergen for that patient:
a. Involvement of the skin, mucosal tissue, or both (e.g., generalized hives; pruritus or flushing;
swollen lips, tongue, or uvula)
b. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced peak
expiratory flow, hypoxemia)
c. Reduced blood pressure or associated symptoms (e.g., hypotonia [collapse], syncope,
 86

incontinence)
d. Persistent gastrointestinal symptoms (e.g., abdominal cramps, vomiting)
3. Reduced blood pressure that occurs rapidly (minutes to several hours) after exposure to a known allergen
for that patient.
DIFFERENTIAL DIAGNOSIS

a. Any condition that may result in the sudden, dramatic collapse of the patient, such as myocardial
ischemia, pulmonary embolism, foreign body aspiration, acute poisoning, hypoglycemia, and seizure, can
be confused with severe anaphylaxis.
5,6
b. However, a vasovagal event is the most common condition confused with anaphylaxis. Bradycardia
3
helps differentiate vasovagal events from anaphylaxis, because tachycardia is typical in the latter.
However, tachycardia can transition into bradycardia during the end stages of a severe anaphylactic
reaction when vascular collapse occurs.
c. Additional diagnostic considerations include flushing syndromes in postmenopausal women, spicy food
consumption, metastatic carcinoid tumors, and alcohol use in persons with aldehyde dehydrogenase
deficiency.
d. Mastocytosis, a rare condition involving overpropagation of mast cells to the point of organ infiltration,
5
may present as anaphylaxis without a trigger.
e. Psychiatric disorders, such as panic attack or severe generalized anxiety, can also be confused with
anaphylaxis.
f. Finally, patients may have urticaria, angioedema, and reactive airway symptoms occurring individually,
without fulfilling the criteria for anaphylaxis.

LABORATORY TESTING
a. Anaphylaxis is a clinical diagnosis.The value of confirmatory blood testing is limited.
b. Two tests that have been evaluated for use in the acute setting are serum histamine and tryptase levels;
elevations from baseline levels may be helpful in confirming anaphylaxis.
c. Allergen skin testing and in vitro assay for serum IgE of specific allergens do not reliably predict who will
5,6
develop anaphylaxis. Allergen testing identifies sensitivity to an allergen, but not whether the patient
will have a systemic reaction.
d. Testing is more helpful after an episode of anaphylaxis to identify which allergen most likely caused the
1,3
reaction and to promote future avoidance.

Management
a. Anaphylaxis is an acute medical emergency.
b. Individuals who have recovered from an anaphylactic event should be referred for specialist assessment.
The aim is to identify the trigger factor, to educate the patientregarding avoidance and management of
subsequent episodes,and to identify whether specific treatment such as immunotherapy is indicated. If
the trigger factor cannot be identified or cannot be avoided, recurrence is common.
c. Patients who have previously experienced an anaphylactic event should be prescribed self-injectable
adrenaline and they and their families or carers should be instructed on its use (Box 4.20). The use of a
MedicAlert (or similar)bracelet will increase the likelihood that adrenaline (epinephrine) will be
administered in an emergency.
Emergency management of anaphylaxis
a. Prevent further contact with allergen: e.g. Removal of bee sting
b. Ensure airway patency
c. Administer intramuscular adrenaline (epinephrine) promptly
a. Adult dose: 0.3–1.0 mL 1:1000 solution
b. Acts within minutes; Repeat at 5–10 min intervals if initial response is inadequate
d. Administer antihistamines
a. e.g. Chlorphenamine 10 mg i.m. or slow i.v. injection
b. Directly opposes effects of mast cell activation
 87

e. Administer corticosteroids
a. e.g. Hydrocortisone 200 mg i.v.
b. Prevents rebound symptoms in severely affected patients
f. Provide supportive treatments
a. e.g. Nebulised β2-agonists to decrease bronchoconstriction
b. I.v. fluids to restore or maintain blood pressure
c. Oxygen

KEROSENE POISONING
1. Kerosene is a hydrocarbon complex derived from petroleum. It is made up of varying mixed proportions of
paraffins and naphthenes.
2. The toxicity of kerosene depends upon its contents of naphthenic and aromatic hydrocarbons
3. Kerosene is kept in many homes in bottles. Toddlers often mistake it for water especially in summer months.
4. The main risks are due to the pulmonary and neurological complications.
5. Pulmonary complications:
a. Penetration into the tracheobronchial tree, produce inflammation and bronchospasm.
b. The volatile chemical may displace alveolar oxygen, leading to hypoxia.
c. Direct contact with alveolar membranes can lead to hemorrhage, hyperemia, edema, surfactant
inactivation, leukocyte infiltration, and vascular thrombosis. The result is poor oxygen exchange,
atelectasis, and pneumonitis.
d. Respiratory symptoms generally begin in the first few hours after exposure and usually resolve in
2-8 days.
e. Cough, cyanosis and rapid shallow breathing are associated with a chemical pneumonitis of
bronchopneumonic distribution.
f. Pneumonitis can occur due to aspiration while drinking or absorption from gut in which case it
takes 1-2 days to manifest respiratory complications when kerosene is excreted as evaporation
through lungs
g. Complications include hypoxia, barotrauma due to mechanical ventilation, and acute respiratory
distress syndrome (ARDS). Prolonged hypoxia may result in encephalopathy, seizures, and death.
h. A secondary bacterial infection may supervene and makes chemical pneumonitis into bacterial
pneumonia.
6. The central nervous system disorder manifests itself by drowsiness, irritability, stupor or coma and
occasionally convulsions due to hypoxia.
7. Gastro-intestinal disturbances consist of nausea, vomiting, constipation or diarrhoea.
8. Cardiac effects: Dysrhythmias are a major concern. Etiologies include hypoxia, myocardial sensitization to
catecholamines, and direct myocardial damage. Sudden death has been reported as a result of coronary
vasospasm due to hydrocarbon inhalation
9. Treatment:
1. it is not advisable to do gastric lavage or induce vomiting because of the danger of aspiration of
kerosene into the lungs
2. Large volume could be aspirated by nasogastric tube
3. Cutaneous decontamination in cases of cutaneous exposure
4. No specific antidotes are available for hydrocarbon poisoning.
5. Treatment with corticosteroids and prophylactic antibiotics is not beneficial.
6. Antibiotics for secondary infection, o2 and respiratory support are indicated.

SYSTEMIC HYPERTENSION
1. Definitions:
1. Hypertension is defined as average systolic blood pressure (SBP) and/ or diastolic blood pressure
(DBP) that is > 95th percentile for age, sex and height on 3 occasions.
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2. Severe Hypertension (also described as stage 2 hypertension): Average of 3 readings SBP and / or
DSP >5mmHg above the 99th percentile.
3. A hypertensive emergency exists when there is organ damage, or impending organ damage
2. Classification Systolic or diastolic blood pressure*
1. Normal < 90th percentile
2. Prehypertension 90th to < 95th percentile or ≥ 120/80 mm Hg†
3. Stage 1 hypertension 95th to < 99th percentile plus 5 mm Hg
4. Stage 2 hypertension > 99th percentile plus 5 mm Hg

3. Causes:
1. Primary: idiopathic rare in children;
2. Secondary
1. Renal parenchymal disease
1. Glomerulonephritis
2. Pyelonephritis
3. Polycystic kidney
4. Hydronephrosis
5. Haemolytic uremic syndrome
6. SLE
7. Nephrotoxic drugs
2. Renal arterial disease:
1. Stenosis
2. Thrombosis
3. Cardiovascular: systolic hypertension
1. Coarctation of Aorta
4. Endocrine:
1. Pheochromocytoma
2. Neuroblastoma
3. Cong.adrenal hyperplasia
4. Cushing’ syndrome
5. Hyperaldosteronism
5. Neurological:
1. Increased intracranial pressure
2. Guillain – Barre syndrome
3. Riley-Day-syndrome
6. Drugs:
1. Steroids
2. Contraceptives
7. Miscellaneous:
1. Hypernatremia
2. Stevens-Johnson syndrome
8. Obesity
4. Physical findings:
1. High BP measurement in all limbs in recumbent and erect postures
2. Delayed growth- renal disease
3. Collapsing pulse: AI; PDA
4. Absent femoral or Radio femoral delay: COA
5. Abdominal bruit- renal artery stenosis
6. Renal angle tenderness- UTI
7. High Body mass index- obesklity
5. Lab:
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1. Urine analysis
2. Urine culture
3. Electrolytes: for hypokalemia
4. BUN
5. Serum creatinine
6. Uric acid level >5.5 mg/dl
7. ECG
8. Echo
9. Lipid profile
10. Thyroid profile
11. Blood glucose levels
6. Specialized studies:
1. Excretory urography
2. Plasma rennin activity
3. Aldosterone level
4. Urinary catecholamine- pheochromocytoma
5. Urinary VMA levels- neuroblastoma
6. Renal sonography and radio nucleotide scan - renal scarring
7. Renal Doppler and angiography
7. Management:
Primary hypertension:
1. Non pharmacologic:
1. Weight reduction
2. Low salt food
3. Aerobic exercise
4. Avoid smoking\avoid oral contraceptives
2. Pharmacologic:
1. Start with thiazide and add other drugs as per response
2. Diuretics: produce hyponatremia, hyperglycemia, hypercholesterolemia
a. Hydrochlorothiazide: 1 mg/kg/day od ;
b. Furosemide: . 1 to 2 mg/kg/day od or bd
c. Spironolactone: 1 mg/kg/day od or bd
d. Triamterene: 1-2 mg/kg/day bd
3. Adrenergic inhibitors: contraindicated in asthma and diabetes
a. Propranolol : 1-2 mg/kg/day 2 or 3 times
b. Metoprolol: 1-2 mg/kg/day bd
c. Atenolol: 0.5 to 1 mg/day 1-2 doses
4. ACE inhibitors: leukopenia; cough
a. Captopril: 0.3 to .5 mg /dose 3 doses
b. Enalapril: 0.08 mg/kg/day 1-2 dose
c. Lisinopril: 0.07 mg/kg/day 1 dose
5. Angiotensin receptor blocker: angioedema
a. Losarton: 0 .07 mg/kg/day 1 dose
6. Calcium channel blocker: headache; flushing; ankle edema
a. Amolodipine: 2.5 – 5 mg/day 1 dose
b. Extended release nifedipine: 0.25 to 0.5 mg/kg/day 1-2 dose
7. Vasodilators: headache; flushing; SLE; hypertrichosis
a. Hydralazine: 0.75 mg/kg/day 4 doses
b. Minoxidil: 5 mg/day 1-3 doses >12 yrs
2. Secondary hypertension:
1. Surgical correction of COA
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2. Treat renal parenchymal disease/ nephrectomy

3. Reconstruction of stenotic renal artery
4. Excision of pheochromocytoma, neuroblastoma etc
8. Hypertensive crisis:
1. Rapidly rising BP; neurological manifestation; heart failure; pulmonary edema
2. Accelerated malignant hypertension: Papilledema; hemorrhage; exudates
3. Hypertensive encephalopathy: severe headache; altered consciousness; convulsions
4. Treatment:
1. Labetalol .2 to 2 mg/kg/hour IV drip
2. Diazoxide 3-5 mg/kg iv bolus or
3. nitroprusside 1-3 µg/kg IV per minute as drip
4. Hydralazine 0.15 mg/kg IV/IM
4. Nifedipine 0.2 to 0.5 mg/kg(up to 10 mg) orally every 4-6 hours
5. Furosemide 1 mg/kg IV

MANAGEMENT OF CONGESTIVE CARDIAC FAILURE IN CHILDREN
1. Definition:
It is syndrome in which heart is unable to pump enough blood to the body to meet its needs, to
dispose of systemic or pulmonary venous return adequately or a combination of all.
2. Important Causes:
a. Volume overload: CHDs like VSD, PDA, ECD ,rheumatic valvular HD, Anemia
b. Pressure overload: aortic stenosis; Coarctation of aorta; Systemic hypertension
c. Systemic hypertension: Nephritis
d. Pulmonary hypertension: PPH, PPHN, Sec.PH
e. Tachyarrhythmia: Supraventricular tachycardia
f. Heart block
g. Myocarditis: viral, Kawasaki; Rheumatic
h. Cardiomyopathy: primary , secondary
3. Where CCF is uncommon:
a. Children with tetralogy of Fallot (TOF)
b. Atrial septal defect (ASD)
a. Large left-to-right shunt lesions, such as VSD and PDA, do not cause CHF before 6 to 8 weeks of
age because the pulmonary vascular resistance does not allow left-to-right shunt until this age.
4. Pathophysiology:
a. Increase in volume overload is compensated by increase in cardiac output which is no longer
possible after a stage
b. Compensatory features:
1. Cardiac hypertrophy
2. The sympathetic nervous system (SNS) provides the rapid response reflexes, including
adrenergic-mediated tachycardia, stimulation of myocardial contractility, and regional
vasoconstriction.
3. Activation of the renin-angiotensin-aldosterone system (RAAS), which stimulates renal fluid
retention to expand vascular volume. The rise in vascular volume improves cardiac filling and
restores cardiac output
5. Clinical features:
a. Infants:
1. Feeding difficulties
2. Cold sweat on the forehead suggest CHF in infants
3. Heart rates are of more than 160 beats/minute in the neonate and more than 120 in the
older infant.
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4. Tachypnea (a resting respiratory rate greater than 60 breaths/minute in the neonate or

greater than 40 in the older infant)
5. wheezing
6. Hepatomegaly
7. Peripheral edema with only very severe heart failure.
8. Cool extremities, weakly palpable pulses, and a low arterial blood pressure
9. Mottling of the extremities and slow capillary refill
b. In Childhood:
1. Breathlessness
2. Exertional dyspnea
3. Chronic hacking cough,
4. Orthopnea
5. Fatigue
6. Malnourished and wasted
c. Signs:
1. Tachycardia and tachypnea.
2. Peripheral vasoconstriction, resulting in coolness, pallor, and cyanosis of the digits, with
poor capillary refill.
3. Venous pulsations visible above the clavicle while the patient is sitting.
4. Hepatomegaly
5. Peripheral edema with facial puffiness
6. Ascites, pericardial effusion, and, occasionally, hydrothorax.
d. CVS signs:
1. Cardiomegaly. It is usually hyperactive.
2. A third heart sound.
3. Pulsus alternans-alternating strong and weak pulsations,
4. Pulsus paradoxus (a fall in blood pressure on inspiration and a rise on expiration),
secondary to marked swings in intrapulmonary pressure.
e. Other findings:
1. Proteinuria and high specific gravity of the urine
2. Increase in the blood urea nitrogen and creatinine levels, secondary to reduced renal
blood flow.
3. Hyponatremia, secondary to increased water retention
4. Congestive hepatomegaly and cardiac cirrhosis may lead to abnormalities in liver
enzymes
6. Diagnosis:
a. CXR:
1. X-ray shows cardiac enlargement
2. Interstitial pulmonary edema: kerley's lines, sharp linear densities in the interlobar septa
b. ECG: points to heart defect
c. Echo:
i. Enlargement of ventricular chambers and impaired LV systolic function
ii. It helps to determine the cause of CHF.
iii. Echo is also helpfulin serial evaluation of the efficacy of therapy.
a. Biochemical Markers:
a. Severity of heart failure can be assessed by measurement of natriuretic peptides, serum
troponin level, creatinine phosphokinase
b. Plasma and atrial natriuretic peptides are increased
MANAGEMENT:
1. Management of heart failure is a four-pronged approach for correction of inadequate cardiac output.
The are:
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(i) reducing cardiac work,

(ii) augmenting myocardial contractility,
(iii) improving cardiac performance,
(iv) correcting the underlying cause
2. Reducing Cardiac Work
i. The work of the heart is reduced by restricting patient activities, sedatives, treatment of
fever, anemia, obesity, and by vasodilators. Mechanical ventilation helps when heart failure
is severe by eliminating the work of breathing
ii. Vasodilators counteract the compensatory mechanisms in heart failure and improve cardiac
output. ACE inhibitors (captopril, enalapril) are effective for treating heart failure in infants
and children. These agents are effective vasodilators, suppress renin-angiotensinaldosterone
system, reducing vasoconstriction and salt and water retention. By suppressing
catecholamines, they prevent arrhythmias and other adverse effects on the myocardium.
iii. beta-blockers reduce tachycardia. Useful agents include metoprolol and carvedilol. The
latter is preferred since it has properties of betablockers with peripheral vasodilation;
iv. In the acute care setting, sodium nitroprusside is used as a vasodilator
3. Augmenting myocardial contractility:
i. by inotropic agents like
1. digitalis
2. catecholamine inotropes, like dopamine, dobutamine and adrenaline and
3. phosphodiesterase inhibitors like amrinone and milrinone.
ii. by Reducing Venous Return (Preload): Diuretics reduce the blood volume, decrease venous
return and ventricular filling. This tends to reduce the heart size.
iii. restricting the sodium intake
4. Correcting the Underlying Cause:
i. Surgery for defects
ii. Drugs for hypertension; hyperthyroidism
iii. Pacemaker for arrhythmias

i. Drugs:
DRUG DOSAGE
DIGOXIN

Digitalization (½ initially, Premature: 20 μg/kg NOTE: These doses are PO;

followed by ¼ q12h × 2) IV dose is 75% of po dose

Full-term neonate (up to 1 mo):20–30 μg /kg

Infant or child: 25–40 μg /kg

Maintenance digoxin 5–10 μg/kg/day, divided q12h

DIURETICS

Furosemide (Lasix) IV:1–2 mg/dose PO:1–4 mg/kg/day, divided qd–qid

Spironolactone PO:1–3 mg/kg/day, divided bid or tid

(Aldactone)

Nesiritide (B-type IV:0.001–0.03 μg/kg/min

natriuretic peptide)

ADRENERGIC AGONISTS (ALL IV)

Dobutamine 2–20 μg/kg/min

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DRUG DOSAGE
Dopamine 2–30 μg/kg/min

Isoproterenol 0.01–0.5 μg/kg/min

Epinephrine 0.1–1.0 μg/kg/min

Norepinephrine 0.1–2.0 μg/kg/min

PHOSPHODIESTERASE INHIBITORS (ALL IV)

Amrinone 3–10 μg/kg/min

Milrinone 0.25–1.0 μg/kg/min

AFTERLOAD-REDUCING AGENTS

Captopril (Capoten), PO Children: 0.1–2 mg/kg/day q8–12h

Enalapril (Vasotec), PO 0.08–0.5 mg/kg/dose q12–24h

Hydralazine (Apresoline) IV:0.1–0.5 mg/kg/dose

PO:0.25–1.0 mg/kg/dose q6–8h (maximum, 200 mg/day)

Nitroprusside (Nipride) IV:0.5–8 μg/kg/min

Prazosin PO:0.005–0.025 mg/kg/dose q6–8h (maximum, 0.1 mg/kg/dose)

β-ADRENERGIC BLOCKERS

Carvedilol PO:initial dose 0.1 mg/kg/day divided bid; maximum of 0.5–1

mg/kg/day

Metoprolol PO, 0.2 mg/kg/day divided bid; maximum dose 1–2 mg/kg/day

Control of CCF :
1. Semi upright position (infant chair)
2. O2
3. High calorie diet in frequent small feeding
4. Diet:
i. Low salt diet(<.5 g/day) and fluid restriction in older children;
a. Human breast milk is the ideal low sodium nutritional source.
b. Formula or EBM can be enriched by adding:
1. Medium-chain triglycerides (MCT) oil
2. Microlipid (safflower oil emulsion),
3. Polycose
c. Older children can be managed with “no added salt” diets
iv. Diuretics:
a.Thiazides no longer popular
b.Frusemide and ethacrynic acid are used
c.Spironolactone used in combination with other diuretics
d. Side effects:
1. Hypokalemia
2. Hypochloremic alkalosis
v. Acute condition:
1. Dopamine for ianotrophic and vasodilator actions (5-10 mcg/kg/min IV)
2. Amrinone, a phosphodiestrase inhibitor has similar action
 94

vi. Digoxin:
1. Slows HR
2. Increases diuresis
3. Increases contractility
4. Oral or IV; IM not recommended
5. IV dose is 75% of oral dose
6. Dose:
Total dose is divided into 3 doses:
• 1/2dose initially
• 1/4dose after8hs
• 1/4dose after another 8hs
• Maintenance dose is divided into 2 equal doses every 12 hs
vii. Beta - Blockers:
a. Helps in counteracting adrenergic overstimulation in CCF
b. Given only in compensated CCF with adequate fluid balance and BP
c. Carvedilol and metoprolol used in dilated Cardiomyopathy
d. Propranolol used with some benefits in large Lt to Rt shunts
viii. Carnitine: a cofactor for transport of long chain fatty acids is used for dilated Cardiomyopathy
ix. Surgery: cardiac transplant when other measures fail.


STATUS EPILEPTICUS
Definition:
Status epilepticus is defined as a continuous convulsion lasting longer than 20–30 min or the occurrence
of serial convulsions between which there is no return of consciousness.
Classification:
a. generalized (tonic-clonic, absence)
b. partial (simple, complex, or with secondary generalization).
c. Status epilepticus is a medical emergency
Etiology:
There are three major subtypes of status epilepticus in children:
1. Prolonged febrile seizures
2. Idiopathic epilepsy leading to status epilepticus
3. Symptomatic epilepsy leading to status epilepticus:Eg: encephalitis, meningitis, Inborn errors
Initial treatment:
1. The oral airway is secured;
2. Suction and oxygen
3. If necessary intubation and assisted ventilation.
4. A nasogastric tube is placed in position, and an IV catheter is inserted.
5. If hypoglycemia is confirmed by Dextrostix, a rapid infusion of 5 mL/kg of 10% dextrose is provided.
Baseline investigations:
1. Blood is obtained for a CBC and electrolytes (including calcium, phosphorus, and magnesium),
glucose, creatinine, lactate, and anticonvulsant levels, if indicated.
2. Blood and urine may be obtained for metabolic studies and toxicology,
3. Arterial blood gases should be determined,
4. Examination of the CSF.
Baseline neurologic examination:
A physical and neurologic examination should be carried out concurrently to assess the following:
1. evidence of trauma;
2. papilledema, a bulging anterior fontanel, or lateralizing neurologic signs suggesting increased ICP;
 95

3. manifestations of sepsis or meningitis;

4. retinal hemorrhages that may indicate a subdural hematoma;
5. Kussmaul breathing and dehydration suggestive of metabolic acidosis or irregular respirations
signifying brainstem dysfunction;
6. evidence of failure to thrive, a peculiar body odor or abnormal hair pigmentation that suggests an
inborn error of metabolism;
7. Constriction or dilatation of pupils suggesting a toxin or drugs as the cause of the status epilepticus.
Management:
1. Steps in drug therapy:
Step I:
a. Diazepam: should be given IV directly into the vein (not the tubing) in a dose of 0.1-0.3 mg/kg at a
rate no greater than 2 mg/min for a maximum of three doses.
OR
b. Lorazepam 0.05-0.1 mg/kg IV administered slowly.
OR
c. midazolam is 0.15-0.3 mg/kg IV.
d. Alternatives: If an IV line cannot be established or the child is some distance from a medical center:
i. Buccal or nasal midazolam (0.5 mg/kg) is another option
ii. Rectal diazepam or lorazepam can be used safely. 0.3-0.5 mg/kg. lorazepam 0.05-0.1
mg/kg.
iii. Sublingual lorazepam 0.05-0.1 mg/kg.
Step II:
if the seizures persist:
a. Phenytoin 15 up to 30 mg/kg IV (given in 10 mg/kg increments) at the rate of 1 mg/kg/min.
OR
b. The phenytoin prodrug fosphenytoin has advantages over the older formulation because it is water
soluble, less irritating after IV injection, and well absorbed after intramuscular injection. The dosage
in PE units is the same as phenytoin preparation.
OR
c. Phenobarbital is given in a loading dose of 15-20 mg/kg or in neonates 20-30 mg/kg IV during 10-30
min. With control of the seizures, the maintenance dose is 3-5 mg/kg/24 hr divided into two equal
doses
Step III:
a. Constant IV infusion of either midazolam (0.20 mg/kg bolus, 20-400 μg/kg/hr infusion) or propofol (1-
2 mg/kg, 2-10 mg/kg/hr infusion)
OR
b. If seizures continue, induction of barbiturate coma. The initial IV loading dose of thiopental is 2-4
mg/kg and is then titrated to achieve a burst suppression EEG pattern.
OR
c. A 5% solution of paraldehyde is prepared by adding 1.75 mL of paraldehyde (1 g/mL) to D5W to a
total volume of 35 mL. The loading dose is 150-200 mg/kg IV slowly for 15-20 min, and then seizure
control is maintained with an infusion of 20 mg/kg/hr in a 5% concentration in a glass bottle, because
the drug is incompatible with plastic.
OR
d. Valproic acid loading dose 10-15 mg/kg. IV may become a useful drug
If still refractory: General anesthesia
Continuation of anticonvulsant therapy:
a. A long-term antiepileptic should be maintained in children with a progressive neurologic disorder or
with a history of recurrent seizures before the onset of status epilepticus.
b. In a prolonged febrile seizure was the cause, anticonvulsant therapy is maintained arbitrarily for 3 mo
in this case and is discontinued if the child remains asymptomatic.
 96

Prognosis: Status epilepticus produces potentially life-threatening disturbances in physiologic function, and the
mortality rate of status epilepticus is 5%.

ACUTE RENAL FAILURE

Definition: Acute kidney injury (AKI), formerly called acute renal failure, is a clinical syndrome in which a sudden
deterioration in renal function results in the inability of the kidneys to maintain fluid and electrolyte homeostasis.
AAP: AKI is classically defined as an acute (within 48 hours) decrease in glomerular filtration rate, which results in
an increase in serum creatinine.
AKI is defined as any of the following:
1. Increase in SCr by > 0.3 mg/dl within 48 hours;
2. Increase in SCr to > 1.5 times baseline, which is known or presumed to have occurred within the prior 7
days;
3. Urine volume < 0.5 ml/kg/h for 6 hours
It is a clinical syndrome of sudden deterioration of renal function in which kidney is unable to maintain fluid and
electrolyte homeostasis and characterized by an increase in:

1. Blood urea nitrogen (BUN)
2. Serum creatinine values,

3. Hyperkalemia,
4. Metabolic acidosis,
5. Hypertension. Rifle (pRIFLE)
Pediatric-Modified Rifle (pRIFLE) Criteriateria:

CRITERIA ESTIMATED CCL (creatinine clearence) URINE OUTPUT

Risk Decrease by 25% <0.5 mL/kg/hr for 8 hr
Injury Decrease by 50% <0.5 mL/kg/hr for 16 hr
Failure Decrease by 75% <0.3 mL/kg/hr for 24 hr
or anuric for 12 hr
Loss Persistent failure >4 wk
End-stage End-stage renal disease (persistent failure >3 mo)

Incidence: 2-3 % pediatric intensive care

Etiologic classification
1. Prerenal:
2. Dehydration
3. Hemorrhage
4. Septic Shock

5. Hypoalbuminemia : Redistribution of extracellular fluid
6. CCF
2. Renal:
1. Glomerulonephritis :
1. Post streptococcal
2. SLE
3. Henoch - Schonlein Purpura
4. Membranoproliferative
2. Hemolytic uremic syndrome
3. Acute tubular necrosis
4. Cortical necrosis
5. Renal vein thrombosis
6. Acute interstitial nephritis
7. Tumor infiltration
 97

8. Tumor lysis syndrome

3. Post renal:
1. Posterior urethral valve
2. Urolithiasis
3. Hemorrhagic cystitis
4. Neurogenic bladder
Prerenal ARF:
1. Inadequate renal perfusion
2. Decreased GFR
3. No kidney disease
4. Correction of hypovolemia in time cures the condition
5. If not corrected in time renal parenchymal damage occurs
Etio-pathogenesis:
1. The causes of AKI are classified as (i) Pre-renal (ii) Renal and (iii) Post-renal.
2. Prerenal AKI:
1. Characterized by diminished effective circulating arterial volume, which leads to inadequate
renal perfusion and a decreased GFR.
2. Autoregulatory mechanisms compensate for some degree of reduced renal perfusion in an
attempt to maintain the glomerular filtration rate. In patients with preexisting chronic
kidney disease, however, these mechanisms are impaired.
3. Angiotensin -converting enzyme inhibitors and angiotensin receptor blockers can impair
renal perfusion by causing dilation of the efferent arteriole and reduce intraglomerular
pressure.
4. Nonsteroidal anti-inflammatory drugs also can decrease the glomerular filtration rate by
changing the balance of vasodilatory/vasoconstrictive agents in the renal microcirculation.

3. Renal: (intrinsic)
1. Intrinsic renal causes are also important sources of acute kidney injury and can be
categorized by the component of the kidney that is primarily affected (i.e., tubular,
glomerular, interstitial, or vascular).
2. Severe and prolonged ischemic/hypoxic injury and nephrotoxic insult lead to acute tubular
necrosis (ATN)
3. Tumor lysis syndrome: AKI is primarily caused by obstruction of the tubules by uric acid
crystals
4. Acute interstitial nephritis is a result of a hypersensitivity reaction to a therapeutic agent or
various infectious agents. Eosinophiluria may be found.
5. Acute events involving renal arteries or veins can also lead to intrinsic acute kidney injury.
Renal atheroembolic disease is the most common cause
4. Postrenal AKI:
1. Includes a variety of disorders characterized by obstruction of the urinary tract.
2. In neonates and infants, congenital conditions, such as posterior urethral valves and bilateral
ureteropelvic junction obstruction, account for the majority of cases of AKI.
Clinical features
History
1. Vomiting and diarrhea - prerenal
2. Recent pharyngitis – post streptococcal
3. Exposure to nephrotoxic drugs
4. Hydronephrosis diagnosed antenataly
5. Dribbling of urine with supra pubic swelling - PUV
Physical examination
1. Tachycardia and poor peripheral perfusion - prerenal
 98

2. Edema and cardiac gallop – post sreptococcal

3. Rash and arthritis: SLE; HSP
4. Bilatreal renal mass: obstructive uropathy
Some definitions
1. Proteinuria: >150 mg/24 hour
2. Haematuria: > 5 RBCs/HPF on 3 urine tests
3. Oliguria: < 0.5 ml/kg/hour; <1ml/kg/hr in infants
5. Azotemia: Refers to high levels of urea, the abnormality can be measured chemically but is not
yet so severe as to produce symptoms.
6. Uremia: Illness accompanying kidney failure proceeding to decreased mental acuity and coma
7. BUN: Measurement of urea content of blood; urea is split into Co2 and ammonia and ammonia is
measured which is the nitrogen part of urea: 5-15 mg/dL
Lab findings
1. Anemia: dilutional; hemolytic in HUS
2. Leukopenia: SLE
3. Thrombocytopenia: HUS
4. Hyponatremia: dilutional
5. Metabolic acidosis
6. Elevated BUN, creatinine, uric acid, potassium, phosphates
7. Low C3: PSGN, SLE
8. Hematuria: Renal-Glomerular
9. WBCs in urine: interstitial disease
10. eosinophils: drug induced interstitial nephritis
11. Prerenal:
1. Sp.gravity : > 1020
2. U Osm : > 500 mOsm/kg
3. U Na : < 20 mEq/L
12. Renal:
1. Sp.gravity : < 1010
2. U Osm : < 350 mOsm/kg
3. U Na : > 40 mEq/L
Imaging
1. CXR: cardiomegaly; pulmonary congestion
2. Ultrasound:
1. Hydronephrosis
2. Hydroureter
3. Renal biopsy
Treatment
Medical
1. Bladder catheter to estimate urine output
2. Correction of hypovolemia: 20 ml/kg NaCl over 30 mts
3. Diuretic challenge after correction of hypovolemia to rule out prerenal condition:
1. Mannitol 0.5 gm/kg - single dose
2. Furosemide 2-4 mg/kg
3. Or Bumetanide 0.1 mg/kg
4. Dopamine: 2-3 μg/kg/mt
4. Persisting ARF after diuretic challenge:
1. Fluid restriction: 400 ml/m2 / 24 hr+ equivalent of urine output
5. Management of Hyperkalemia
1. Serum K: >6 mEq / L
2. Produces cardiac arrhythmia; cardiac arrest, death
 99

3. ECG:
1. Peaked T wave; 2.widening QRS; 3. ST depression; 4. Ventricular arrhytmia;
5. Cardiac arrest
1. Treatment:
1. Oral kayexalate (resin) 1 g/kg/ 2 hourly
2. 10% Calcium gluconate1 ml/kg IV over 3- 5mts: counteracts myocardial irritability due to
hyperkalemia
3. Sodium bicarbonate 1-2 mEq/kg IV over 5-10 mts:
1. Insulin 0.1 u/kg with glucose 50% 1 ml/kg over 1 hour: Both shift potassium from
intravascular to intracellular compartment
6. Metbolic acidosis
1. Causes: Retention of H ions, phoasphate, and sulphate
2. Severe acidosis contributes to hyperkalemia
3. It is corrected by IV sodabicarb to raise pH to 7.2
4. Full correction may precipitate hypocalcemic tetany- alkalotic tetany:
As the pH of blood increases, the protein in the blood becomes more ionised into anions.
This causes the free calcium present in blood to bind strongly with protein
7. Hypocalcemia
1. Treated by reducing serum phosphorus level and not by IV Ca to avoid Ca deposition in tissues
2. Low phosphate diet
3. Phosphate binders:
1. Calcium carbonate
2. Calcium acetate
8. Hyponatremia
1. Dilutional and hence fluid restriction
2. 3% Na Cl for convulsions
9. Uremic platelet dysfunction: GI bleeding is treated by H2 blocker
10. Hypertension:
1. Salt retsriction
2. Isradipine 0.05-0.15 mg/kg/dose
3. Amlodipine, propranolal etc
4. IV nitroprusside 1 – 10 μg/kg infusion for encephalopathy
4. Diazepam for seizures
11. Other measures:
1. Washed red cell transfusion for anemia
2. Dietary restriction:
1. Sodium
2. Potassium
3. Phosphate
4. Protein
12. Dialysis
1. Indication:
1. Pulmonary edema due to volume overload
2. Persistent hyperkalemia
3. Severe metabolic acidosis
4. Uremic coma and Seizures
5. BUN > 100 mg/dL
6. Dialysis
2. Intermittent hemodialysis – large venous catheter attached to extracorporeal circuit
3. Peritoneal dialysis:
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Hyperosmolar dialysate is infused into peritoneal cavity via trancutaneous

catheter and drained by gravity after 45 mts; done in cycles
4. Continuous renal replacement therapy (CRRT)
Double lumen catheter in subclavian or femoral vein; connected to CRRT circuit;
Continuos passage of blood across highly permeable filter
13. Prognosis
1. Depends on underlying disease
2. Renal limited ARF: 1% mortality
3. Multiorgan failure: 90% mortality
4. Better recovery from prerenal causes
5. Poor recovery from bilateral renal vein thrombosis and rapidly progressing
glomerulonephritis
1. DIABETIC KETOACIDOSIS:
i. Commonest cause of death due to DM
ii. Induced by stress, infection, omitting insulin dose
iii. Ketoacidosis: DKA
1. 20% of present with symptom before diagnosis
2. Very low insulin levels
3. Ketoacids produce abdominal discomfort, nausea, vomiting and further dehydration
4. Signs of dehydration are masked as intravascular volume is maintained at the expense of
intracellular volume
5. Deep heavy rapid breathing: Kussmaul’s respiration
6. Fruity odor due to acetone
7. Increased ion gap, decreased sodium bicarbonate and pH
8. Confusion leading to coma
iv. Complications:
1. Cerebral edema
2. Hypokalemia
3. Septic shock
4. Hypoglycemia
5. Cerebral hemorrhage
6. Pancreatitis
v. Problems to be managed:
1. Dehydration/shock
2. Acidosis
3. Hypokalemia
4. Hypoglycemia
5. Hyperosmolality
6. Cerebral edema
7. infection
vi. Diagnosis:
1. Hyperglycemia (BG > 200mg/dL or 11 mmol/l)
2. pH < 7.3
3. Bicarbonate < 15 mmol/l
4. More than 3% dehydration
5. Clinical:
a. Vomiting
b. Drowsiness
c. Clinical acidosis
vii. Management: Milwaukee protocol
1. Insulin therapy
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2. Fluid replacement
3. Treatment of underlying cause
viii. Insulin:
1. Insulin to drive glucose into cells; it is given as infusion 0.1U/kg/hour
ix. Intravenous fluids to correct dehydration:
Phase Type of Type of fluid Amount ml/kg Duration
management
1 Shock treatment 0.9 % NaCl or RL 10-20 ml /kg 0-1 hour
2 Treatment for 0.45% NaCl Eg: 5% dehydration: 1-48
dehydration 50 ml x Kg body weight minus shock hours
fluid already given
3 Maintenance 0.45% NaCl 100 ml/kg first 10 kg; plus 50 ml/kg
for next 10 kg; plus 25 ml/kg for
remaining wt

a. Total Requirement for 24 hours = Maintenance + Deficit – shock fluid already given
b. 5% GDW added when glucose level falls below 250 mg/dl
c. Potassium 20 mEq/L as K.phosphate and 20 mEq/L as K acetate in maintenance fluid.
d. Bicarbonate is not necessary as fluid and insulin correct acidosis
e. Hourly rate = 48 hr maintenance + deficit – resuscitation fluid already given
48

SCORPION STING MANAGEMENT
i. The scorpion is a nocturnal arthropod; Buthus (Leiurus) in India are one of the most toxic scorpions
ii. The majority of stings, even by toxic species, cause only a painful local reaction. However, given their
small size, infants and young children who are stung are at risk for severe autonomic dysfunction,
multisystem organ failure, and even death
iii. Pathogenesis:
1. Scorpion venoms have hyaluronidase, serotonin, histamine releasers, and neurotoxins.
2. These neurotoxins can bind to the presynaptic membranes, causing release of acetylcholine
and stimulation of both the sympathetic and parasympathetic nervous systems
iv. Clinical Manifestations:
i. Local reaction that can vary from mild burning to severe pain.
ii. Autonomic dysfunction: Agitation, irritability, salivation, blurred vision, and tremulousness
with signs of hypertension, tachycardia, tachypnea, and nystagmus.
iii. Rarely, in small children or infants, respiratory failure, convulsions, or coma may occur.
iv. Stings by Tityus species are a major cause of pancreatitis, and envenomation by Buthus can
cause severe hypertension, direct toxic myocarditis, and life-threatening myocardial
ischemia
v. Treatment:
1. Localized pain can be treated with application of ice and analgesics; pain usually markedly
diminishes within 24 hr.
2. Autonomic instability requires hospital admission for sedation and observation. Symptoms
usually resolve within 24-48 hr.
3. If cardiopulmonary compromise occurs, consideration should be given to administering
antivenin which is specific for prevailing species.
4. Prazosin:
1. Prazosin (Minipress), a postsynaptic alpha –1 blocker, counteracts the effects of excessive
catecholamines and arrests the development of severe systemic features. It has been
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found to be an effective drug for scorpion sting envenomation and it has reduced the
mortality rate to 1% as compared to a 30% mortality rate in the pre-Prazosin era.
2. dose of Prazosin (30ug/kg) tablet either through a naso-gastric tube or per oral,
3. Prazosin should be repeated in the same dose at the end of 3 hours according to clinical
response and later every 6 hours till extremities are warm, dry and peripheral veins are
visible easily. No more than four doses have been required in majority of children treated
at our center.
4. The time lapse between the sting and administration of prazosin for symptoms of
autonomic storm determines the outcome

SNAKE BITE ENVENOMATION
1. Of the more than 3,000 known species of snakes, only 200 are poisonous to humans. Of poisonous snakes,
90% are members of one of three families: the Hydrophidae, or poisonous sea snakes; the Elapidae, which
includes the cobras, mambas, and coral snakes; and the Viperidae, or true vipers. The Crotalidae, or pit vipers
are a subfamily of the true vipers
2. Pathogenesis:
a. Snake venom is a mixture of polypeptides, proteolytic enzymes, and toxins, which are species
specific.
b. Venom from the Elapidae and the Hydrophidae is primarily neurotoxic and has a curare-like effect by
blocking neurotransmission at the neuromuscular junction. Death due to envenomation results from
respiratory depression.
c. Crotalidae venom is cytolytic, causing tissue necrosis, vascular leak, and coagulopathies.
d. Death from pit viper bites results from hemorrhagic shock, adult respiratory distress syndrome, and
renal failure
3. Clinical Manifestations:
a. Local:
i. Pit viper bites usually occur on the extremities; pain and swelling occur at the site within
minutes.
ii. As the venom moves proximally, edema and ecchymosis advance and, in severe cases, bulla
formation and tissue necrosis ensue.
b. Systemic:
i. Systemic symptoms include nausea, vomiting, diaphoresis, weakness, tingling around the
face, and muscle fasciculations.
ii. Rarely, patients may present in shock with generalized edema or cardiac arrhythmias.
iii. Complex clotting abnormalities often occur
4. Treatment:
a. The first task is to determine if the bite was by a poisonous snake and if envenomation occurred. If
the snake has been killed, it should be brought to the emergency department for identification.
b. More than 80% of snakebites are by nonpoisonous snakes; these bites cause minimal pain and no
swelling and require only local wound care.
c. Local measures:
i. If the bite is by a venomous snake, immediate care is directed toward decreasing lymphatic
flow to limit the spread of venom into the circulation.
ii. Immobilization of the extremity, pressure at the site of envenomation, and a proximal
tourniquet accomplish this goal. The tourniquet should be loose enough to insert a finger
and allow arterial blood flow, because ischemia only exacerbates local tissue damage.
iii. Similarly, applying ice to the bite site or using excision and suction is believed to cause more
tissue damage than benefit and should be avoided.
d. Resuscitation:
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i. On arrival at the emergency department, the patient should have a large-bore intravenous
line inserted and blood for baseline laboratory studies should be obtained.
ii. Baseline vital signs and measurement of the circumference of the bitten extremity should be
obtained, and demarcation of ecchymosis and swelling should be marked on the limb so
progression can be monitored.
iii. The wound should be cleansed and tetanus toxoid given if appropriate
e. Lab:
i. Initial blood tests should include type and crossmatch because a progressive coagulopathy
may make later typing impossible.
ii. Other needed tests include complete blood cell and platelet counts; prothrombin and partial
thromboplastin times; fibrinogen and fibrin degradation products; and
iii. Blood urea nitrogen, creatinine, and creatine phosphokinase levels. These studies need to be
repeated at intervals, depending on the severity of envenomation.
f. Antivenin:
i. The decision to use antivenin depends on the severity and progression of symptoms. In
general, rattlesnake envenomation requires antivenin and copperhead bites do not, with
cottonmouth bites falling between these extremes. The severity of envenomation is
commonly graded on a four-point scale:
ii. Children, because of their smaller size, are far more likely to have severe envenomation, and
more than 75% of children have a grade 2 or 3 envenomation, which requires antivenin.
iii. Antivenin is most effective if delivered within 4 hr of the bite and is of little value if
administration is delayed beyond 12 hr.
iv. Antivenin poses a small but significant risk of an immediate hypersensitivity reaction with an
apparent greater risk in equine-derived products compared with ovine-derived antivenin.
v. Antivenin polyvalent is administered in increments of 5 vials and repeated as needed to
neutralize circulating venom, as measured by normalization of clotting parameters and a halt
in the progression of swelling of the affected limb.
vi. Children often require more antivenin than a similarly envenomated adult because of their
small volume-to-venom ratio.
5. Prognosis:
a. Despite the potential for mortality and severe morbidity with poisonous snakebites, both can be
minimized by early and judicious use of appropriate antivenin.
Even extremities with marked tissue necrosis will return to full function with the resolution of
swelling, and only rarely is delayed skin grafting required.



Foreign body aspiration

1. Children younger than 3 yr of age account for 73% of cases.
2. One third of aspirated objects are nuts, particularly peanuts.
3. Clinical manifestations:
1. Initial event: stage i
1. Violent paroxysms of coughing, choking, gagging, and airway obstruction occur immediately
when the foreign body is aspirated.
2. Asymptomatic interval: stage ii
1. The foreign body becomes lodged and the immediate irritating symptoms subside.
2. This stage accounts for a delayed diagnoses and overlooked foreign bodies.
3. Complications: satge iii
1. Obstruction or infection develops
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2. Complications include fever, cough, hemoptysis, pneumonia, and atelectasis.

4. Symptoms:
a. Acute:
1. Respiratory distress-with stridor; leaning chin forward and drooling.
2. Inability to speak or cough.
3. Partial obstruction: violent paroxysms of coughing, and wheezing.
5. Laryngial fb:
b. Complete obstruction asphyxiates the child unless promptly relieved with the heimlich
maneuver.
6. Tracheal foreign bodies:
1. Produce stridor and wheezing.
7. Bronchial foreign body:
1. During expiration the bronchial foreign body obstructs the exit of air from the obstructed lung,
producing obstructive emphysema
8. Acute management:
1. The current guidelines for pediatric basic life support recommend that when airway

obstruction from a foreign body is mild, no intervention is required. The patient should be
allowed to clear his or her airway by coughing while the clinician watches for signs of
impending severe airway obstruction.
2. Blind finger sweeps should not be performed in infants or children because the finger may
actually push the foreign body further into the airway
3. Step i: jaw thrust
1. The airway may be opened by jaw thrust, and if the foreign body can be directly
visualized, it should be removed;
2. If the patient resumes adequate spontaneous ventilation, the patient's body is
turned on its side to the recovery position with the head to the side (if in the field).
4. Step ii: back flow and chest thrust
1. In the infant younger than 1 yr, a combination of five back blows and five chest
thrusts are administered. The foreign body is removed if it is seen.
5. Step iii:
1. A conscious child older than 1 yr is administered a series of five abdominal thrusts
(the heimlich maneuver) with the child standing or sitting.
2. If unconscious, this is done with the child lying down.
3. After the abdominal thrusts, the airway is examined for a foreign body, which
should be removed if visualized.
6. Step iv:
1. When the airway is obstructed and foreign body could not be removed needle
cricothyrotomy is indicated
2. For foreign body bronchus, child should be treated by bronchoscopic removal of
foreign body under anaesthesia.


BURNS
Classification:
1. First-degree burns involve only the epidermis and are characterized by swelling, erythema, and pain
2. 2nd-degree burn involves injury to the entire epidermis and a variable portion of the dermal layer (vesicle
and blister formation are characteristic
3. Full-thickness, or 3rd-degree, burns involve destruction of the entire epidermis and dermis, leaving no
residual epidermal cells to repopulate the damaged area. The wound cannot epithelialize and can heal
only by wound contraction or skin grafting. Pain nerves are destroyed.
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4. Estimation of Body Surface Area for a Burn

a. The rule of nines used in adults may be used only in children older than 14 yr or as a very rough
estimate to institute therapy before transfer to a burn center. Head & Neck = 9% } Each upper
extremity (Arms) = 9% } Each lower extremity (Legs) = 18% } Anterior trunk= 18% } Posterior trunk =
18% } Genitalia (perineum) = 1% 1
b. In small burns, <10% of BSA, the rule of palm may be used, especially in outpatient settings: The area
from the wrist crease to the finger crease (the palm) in the child equals 1% of the child’s BSA.
Serious burn requiring hospitalization -
1. Greater than 10% burns in a child
2. Any full thickness burn
3. Burns of special regions: face, hands, feet, perineum
4. Circumferential burns
5. Inhalation injury
6. Associated trauma or significant pre-burn illness: e.g. diabetes
Wound care
First aid
1. If the patient arrives at the health facility without first aid having been given, drench the burn
thoroughly with cool water to prevent further damage and remove all burned clothing.
2. If the burn area is limited, immerse the site in cold water for 30 minutes to reduce pain and oedema
and to minimize tissue damage.
3. If the area of the burn is large, after it has been doused with cool water, apply clean wraps about the
burned area (or the whole patient) to prevent systemic heat loss and hypothermia.
Fluid Resuscitation Parkland formula :
a. 4 mL lactated Ringer solution/kg/% BSA burned.
b. Half of the fluid is given over the 1st 8 hr, calculated from the time of onset of injury; the
remaining fluid is given at an even rate over the next 16 hr.
c. The rate of infusion is adjusted according to the patient’s response to therapy.
d. Pulse and blood pressure should return to normal, and an adequate urine output (>1 mL/kg/hr in
children; 0.5-1.0 mL/ kg/hr in adolescents) should be accomplished by varying the IV infusion
rate.
Colloid replacement:
a. One preference is to use colloid replacement concurrently if the burn is >85% of total BSA.
Colloid is usually instituted 8-24 hr after the burn injury.
b. A 5% albumin infusion may be used to maintain the serum albumin evels at a desired 2 g/dL.
Blood:
a. Infusion of packed red blood cells is recommended if the hematocrit falls to <24% (hemoglobin =
8 g/dL).
b. Fresh-frozen plasma is indicated if clinical and laboratory assessment shows a deficiency of
clotting factors, a prothrombin level >1.5 times control, or a partial thromboplastin time >1.2
times control in children who are bleeding or are scheduled for an invasive procedure or a
grafting procedure
Sodium and K:
a. Sodium supplementation may be required for children with burns of >20% of BSA if 0.5% silver
nitrate solution is used as the topical antibacterial burn dressing. Sodium losses with silver
nitrate therapy are regularly as high as 350 mmol/m2 burn surface area.
b. Oral sodium chloride supplement of 4 g/m2 burn area/24 hr is usually well tolerated, divided into
4-6 equal doses to avoid osmotic diarrhea. The aim is to maintain serum sodium levels >130
mEq/L and urinary sodium concentration >30 mEq/L.
c. IV potassium supplementation is supplied to maintain a serum potassium level >3 mEq/ dL.
Prevention of Infection
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a. 5-day course of penicillin therapy is used for all patients with acute burns; standard-dose
crystalline penicillin is given orally or intravenously in 4 divided doses. Erythromycin may be used
as an alternative in penicillin-allergic children.
b. Topical treatment of the burn wound with 0.5% silver nitrate solution, silver sulfadiazine cream,
or mafenide acetate (Sulfamylon) cream or topical solution at a concentration of 2.5-5% to be
used for wounds with multidrug–resistant bacteria aims at prevention of infection
c. Children with a burn of >30% of BSA should be housed in a bacteria-controlled nursing unit to
prevent cross-contamination

CONGENITAL INFECTIONS IN NEONATES / VERTICAL TRANSMISSION / MOTHER TO CHILD OR PERINATAL
1. “Vertical transmission” is a term that refers to the spread of infections from mother-to-baby. These
infections may occur while the foetus is still in the uterus (transplacenta), during labour and delivery, or
after delivery while breastfeeding.(Perinatal transmission)
2. Congenital infections (passed in utero): TORCH is an acronym for several of the more common
congenital infections. These are:
a. Across the placenta
1. Toxoplasmosis
2. Other infections (syphilis, hepatitis B, Coxsackie virus, Epstein-Barr virus,varicella-zoster
virus (chicken pox), and human parvovirus)
3. Rubella
4. Cytomegalovirus (CMV)
5. Herpes simplex virus
6. HIV
7. Listeria monocytogenes,
8. Plasmodium falciparum
b. Perinatal infections (during labour and delivery)
1. Ascending maternal infection and chorioamnionitis causing fetal infection, usually
subsequent to prolonged rupture of membranes (PROM).
2. Perinatal infection acquired during birth via the haematogenous or genital route. These
include:
1. Gonorrhoea
2. Chlamydia
3. Herpes simplex virus
4. Human Papilloma Virus (genital warts)
5. Group B Streptococci (GBS)
6. human immunodeficiency virus (HIV),
7. herpes zoster virus (HZV),
8. hepatitis B virus (HBV)
c. Postnatal infection transmitted via breastfeeding.
i. HIV

CONGENITAL RUBELLA
I. Definition. Rubella is a viral infection capable of causing chronic intrauterine infection and damage to the
developing fetus.
II. Pathophysiology.
a. Rubella virus is an RNA virus with epidemic seasonal pattern
b. Fetal effects is greater the earlier in gestation that infection occurs, especially at 1-11 weeks, when 90% of
infected fetuses will be damaged; 24% at 15-16 weeks.
III. Clinical presentation.
a. Teratogenic effects. These include
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a. Intrauterine growth retardation,

b. Congenital heart disease (patent ductus arteriosus or pulmonary artery stenosis),
c. Sensorineural hearing loss,
d. Cataracts or glaucoma,
e. Neonatal purpura, and
f. Dermatoglyphic abnormalities.
b. Systemic involvement can be manifested by:
1. Adenitis,
2. Hepatitis,
3. Hepatosplenomegaly,
4. Jaundice,
5. Anemia,
6. Decreased platelets with or without petechiae,
7. Myocarditis,
8. Eye lesions (iridocyclitis or retinopathy),
9. Pneumonia.
c. Late defects.
1. Including immunologic dyscrasias,
2. Hearing deficit,
3. Psychomotor retardation,
4. Autism,
5. Brain syndromes such as subacute sclerosing panencephalitis,
6. Diabetes mellitus, and
7. Thyroid disease.
Diagnosis: ELISA for IgM and IgG antibodies are the most commonly performed tests. Rubella is difficult to
differentiate clinically from other rash-causing infections such as measles and parvovirus BE19
Management.
8. There is no specific treatment for rubella.
9. Prevention consists of vaccination of the susceptible population (especially young children).
10. Vaccine should not be given to pregnant women.

Human immunodeficiency virus
Etiology
1. Family: Retroviridae
2. Genus: Lentivirus
3. HIV I: contains 2 copies of single stranded RNA; most common infection
4. HIV II: common among monkeys; rare in Ped.HIV difficult to identify with HIV I tests; specific
antibody test or III generation ELIZA should be used for testing
Mother To Child Transmission
1. Transmission rate is 12-30 %
2. Intra uterine: 30-40 %
3. Intrapartum: 60-70 %
4. Breastfeeding:
Transplacental
1. PCR is positive in fetal tissue by 10 weeks of gestation
st
2. In situ hybridization and immuno cytochemistry identify virus in fetal tissue in 1 trimester
3. Viral detection soon after birth
Intrapartum
1. Infected blood, cervico vaginal secretions in birth canal à conjunctiva, skin abrasions, gastric
mucosa
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2. Infected infant negative for viral detection in first week of life

3. First born twin 3 times more infected
Breast feeding
1. Both virus and viral laden cells are present breast milk
2. Mother infected before pregnancy: 14 %
3. Mother infected postnatally: 29 %
4. Benefit of breastfeeding outweighs the risk of HIV in developing countries
5. WHO: breastfeed first 6 months and rapid weaning thereafter
Risk factors for MTCT
1. Preterm < 34 weeks
2. Low CD4 count in mother
3. Birt weight < 2500 gms
4. Rupture of membranes for > 4 hours
5. Mother’s viral load > 1000 copies/mL
6. Vaginal delivery
7. Instrumental delivery
8. Caserian + ART to infant decrease transmission by 87 %
Diagnosis
1. Viral Culture: 100% specific; costly and needs sophisticated laboratory set up
2. Polymerase Chain Reaction (PCR) RNA/DNA:
1. Two PCRs have to be positive, done beyond one month and at least one of them after age of
3 months.
2. Detect nearly 100% of infected newborns
3. Enzyme Linked Immunosorbent Assay (ELISA)
1. I Generation ELISA: antigen from crude viral lysate
2. II generation: part of virus
3. III Generation ELISA: synthetic peptides as the antigen
4. Rapid tests
20. Management Care immediately after birth
1. Cord clamped soon; no milking;
2. Early baby bathing
3. Single dose NVP to mother during labour and to the baby within 72 hours after birth.
4. Exclusive replacement feeding is afass — acceptable, feasible, affordable, sustainable and safe
5. Quick weaning at 6 mo
6. CTX prophylaxis from age of 4–6 weeks; 5 mg/kg/day
7. Growth monitoring
8. Screen for infections
21. When to start ART in children, guided by CD4
1. < 11 month infants : if CD4 < 1500 cells/mm3
2. 12–35 months : if CD4 < 750 cells/mm3
3. 36–59 months : if CD4 <350 cells/mm3
4. > 5 years old : < 350 cells/mm3 especially if symptomatic; or
5. Before CD4 drops below 200 cells/mm3.
ARV regimens
1. Zidovudine (AZT) + Lamivudine (3TC) + Nevirapine NVP
2. Stavudine (D4T) + Lamivudine (3TC) + Nevirapine (NVP)
3. Vaccine:
1. if the HIV-infected child is asymptomatic or mildly symptomatic – vaccinations should be
given.
2. Withold vaccine (live vaccines) for HIV-infected children who are symptomatic and severely
immuno-compromised.
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Prevention
1. Transmission from the mother to child is likely to be about 15-45%.
2. There is 16.2% greater risk of mother-to-infant transmission of HIV when children are breast-fed as
opposed to formula-fed.
3. Single dose NVP 200mg given at the onset of labour and
4. single dose of syrup NVP 2mg/kg weight to the baby within 72 hours decreases risk of transmission by
13.1% (breast feeding)..
5. Transmission of the HIV virus occurs most commonly during the first few months after birth
6. Avoid manipulations like amniocentesis and external cephalic version increase the risk of
transmission of HIV.
7. Long duration of rupture of membranes increase the transmission risk. It has been estimated that
with every hour, the risk of transmission increases by 2%.
8. Placental disruption and infections also adversely affect transmission.
9. Invasive fetal monitoring should be avoided, as should all invasive obstetric procedures.
10. Where facilities are available, elective LSCS should be offered.
11. If instrumental delivery is necessary, then forceps are a better option than vacuum suction cup
delivery.
12. Emergency LSCS is associated with high transmission
13. In India – normal delivery is recommended unless the woman has obstetric reasons
14. When replacement feeding (infant formula) is acceptable, feasible, affordable, sustainable and clean
water is available, HIV-infected mothers should avoid breastfeeding completely.
15. Otherwise, exclusive breastfeeding is recommended during the first months of life, with early
abrupt weaning at 3-4 months or 6 months of age

Cytomegalovirus
1. Cytomegalovirus (CMV) is a DNA virus and a member of the herpesvirus group (human herpesvirus 5). CMV is
the most common cause of congenital infection.
2. CMV is a ubiquitous virus that may be transmitted in secretions, including saliva, tears, semen, urine, cervical
secretions, blood (white blood cells), and breast milk. CMV may also be transmitted to the infant intrapartum
(through exposure to CMV in cervical secretions), via breast milk, and via blood transfusion. CMV infection
acquired during delivery or via breast milk has no effect on future neurodevelopmental outcome in full-term
infants.
3. CMV is capable of penetrating the placental barrier as well as the blood–brain barrier. During early pregnancy,
CMV has a teratogenic potential in the fetus. In primary maternal infection the virus is transmitted to the
fetus in ~35% of cases. Infection in early pregnancy causes more severe fetal infection with significant CNS
sequelae.
4. More than 85% of infants born with CMV have a subclinical infection.
5. When the placenta becomes infected, placental enlargement due to viral placentitis and revascularization.
6. Eventual fetal viremia leads to fetal multiorgan involvement. The primary target organs are the CNS, eyes,
liver, lungs, and kidneys.
7. Characteristic histopathologic features of CMV include focal necrosis, inflammatory response, formation of
enlarged cells with intranuclear inclusions (cytomegalic cells), and the production of multinucleated giant cells.
A sepsis-like illness has been described in premature infants.
8. Risk factors: Risk factors for primary CMV infection during pregnancy include prolonged exposure to young
children (daycare workers, multiparous women) and sexual contact (young maternal age, greater numbers of
sexual partners, abnormal cervical cytology, and having a sexually transmitted infection during pregnancy).
9. Prenatal presentation.
a. Pregnant women who acquire primary CMV may develop a mononucleosis-like illnesses.
b. Fetal anomalies consistent with congenital CMV infection that can be detected on prenatal
ultrasound examination include fetal growth restriction, cerebral periventricular echogenicity or
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calcifications, cerebral ventriculomegaly, microcephaly, polymicrogyria, cerebellar hypoplasia,

hyperechogenic fetal bowel, hepatosplenomegaly, amniotic fluid abnormalities, ascites and/or
pleural effusion, and placental enlargement
c. Amniocentesis to perform polymerase chain reaction (PCR) for CMV DNA in amniotic fluid is the
preferred diagnostic approach for identifying an infected fetus.
10. Postnatal presentation
a. Subclinical infection. Occurs in 85–90% of cases. Despite being asymptomatic at birth, these
infants are at risk for sensorineural hearing loss (SNHL) during the first 6 years of life.
b. Low birthweight. Maternal CMV infection is associated with low birthweight and small for
gestational age infants, even when the infant is not infected.
11. Classic CMV inclusion disease. Occurs in 10–15% of the cases and consists of intrauterine growth restriction,
hepatosplenomegaly with jaundice, abnormal liver function tests (LFTs), thrombocytopenia with or without
purpura, and severe central nervous system (CNS) involvement (CNS and sensory impairments are seen in 50–
90% of symptomatic newborns). Neurologic complications include microcephaly, intracerebral calcifications
(most characteristically in the subependymal periventricular area), chorioretinitis, and progressive SNHL (10–
20% of cases).
12. Other symptoms include hemolytic anemia and pneumonitis. The most severely affected infants have a
mortality rate of ~30%.
13. Deaths are usually due to hepatic dysfunction, bleeding, disseminated intravascular coagulation, or secondary
bacterial infection.
14. Late sequelae.
a. SNHL occurs in 22–65% of symptomatic and 6–23% of asymptomatic infants
b. Visual impairment and strabismus are common in children with clinically symptomatic CMV
infection. Visual complications may occur, usually secondary to chorioretinitis, pigmentary
retinitis, macular scarring, optic atrophy, and central cortical defects.
15. Diagnosis
a. Culture for demonstration of the virus. The gold standard for the diagnosis of congenital CMV is
urine or saliva culture obtained before 3 weeks of age.
b. Most urine specimens from infants with congenital CMV are positive within 48–72 hours,
especially if shell vial tissue culture techniques are used.
c. rapid assay for detection of CMV in saliva as a screening method for congenital infection have
shown it to be at least as sensitive a method for detecting congenital infection as for detection of
viruria (viruses in the urine).
d. Polymerase chain reaction (PCR). PCR for CMV DNA is as sensitive as a urine culture for the
detection of CMV infection. PCR has been used successfully in retrospective diagnosis of
congenital CMV beyond 3 weeks of age through CMV DNA analysis of dried blood spots (Guthrie
cards). A positive PCR assay result from a neonatal dried blood spot confirms congenital
infection, but a negative result does not rule out it out.
e. Serologic tests. Serologic tests based on the detection of immunoglobulin M (IgM) should not be
used to diagnose congenital CMV because they are less sensitive and more subject to false-
positive results than culture or PCR. Only 70% of neonates infected with congenital CMV have
IgM antibodies at birth.
f. Other laboratory tests. Other lab tests that are indicated in the workup include complete blood
count, LFTs, disseminated intravascular coagulation panel and cerebrospinal fluid analysis,
culture, and PCR.
16. Imaging and other studies.
g. Ultrasound or CT scans of the head may demonstrate characteristic periventricular calcifications.
h. Brain MRI is preferred over other modalities because it is likely to identify most of the brain
anomalies associated with congenital CMV.
17. Management
A. Prevention and treatment of maternal infection during pregnancy.
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a. changes in hygienic behavior for seronegative pregnant women: frequent hand washing;
wearing gloves for specific child-care tasks; avoiding kissing children under age 6 on the
mouth or cheek; not sharing food, drinks, or oral utensils
b. administration of CMV hyperimmune globulin (HIG) to pregnant women
c. administering antiviral therapy to women
d. vaccines administered to girls or women well before pregnancy or during pregnancy. HIG, a
multicenter nonrandomized study in Italy enrolled pregnant women with primary congenital
e. In CMV infection diagnosed before 21 weeks’ gestation a study demonstrated that HIG (100
U/kg) given monthly until delivery reduces congenital infection in the newborn infants (16%
vs 40%) compared with mothers who refused therapy.
B. Antiviral agents. No antiviral agent is yet approved for treatment of congenital CMV infection.
C. Based on the results of this study, some experts suggest that ganciclovir therapy may be offered to
CMV-infected neonates who manifest CNS disease for prevention of hearing impairment. Another
possible indication is chorioretinitis, which involves the macula and may result in blindness. A third
possible indication is the critically ill preterm infant who acquires the infection natally (intrapartum)
or postnatally. Such infants have life-threatening CMV infection manifested by pneumonitis,
hepatitis, or encephalitis, and ganciclovir may modify the course of the disease.
D. Valganciclovir is a prodrug of ganciclovir that is suitable for oral administration. Valganciclovir
administered orally to young infants at 16 mg/kg/dose, twice daily, provides the same systemic
ganciclovir exposure as does intravenous ganciclovir at 6 mg/kg/dose.
18. Prognosis. Congenital CMV is the leading cause of SNHL regardless of the seroprevalence in the population.
For symptomatic infants at birth, mortality is up to 30%, and up to 90% will have late complications
(intellectual or developmental impairment, hearing loss, spasticity).
Chickenpox
• Infection occurs in 1/2,000 pregnancies with a 10-15% risk of fetal infection. The majority of fetal infection
is transient and asymptomatic. A minority - 2-3% of infants of women with chickenpox in the first half of
pregnancy - does develop varicella syndrome (skin scarring, ipsilateral limb hypoplasia, visceral,
neurological and eye lesions).
• Neonatal zoster can occur if mother infected 5 days before to 2 days after delivery. It is associated with up
to 30% neonatal mortality. Babies of mothers developing perinatal chickenpox should receive varicella-
zoster immune globulin (VZIG).
• Varicella zoster vaccine is not currently recommended for susceptible women of child-bearing age or
routine use in children in the UK, although it is used widely elsewhere in the world, for example America
11
and Australia.
Hepatitis B
• The most important mode of transmission of Hepatitis B globally is vertical from mother to child.
Significantly, congenital infection is less likely to be cleared (indicated by the persistence of HBsAg) and
individuals are more likely to chronic infection compared to adults contracting the infection.
• Less than1% of pregnant women in the UK is HBsAg positive compared to approximately 25% in parts of
Africa and Asia.
• In an HBsAg positive/HBeAg negative mother, the risk of transmission is 5-20% compared to 70-90% in an
HBsAg/HBeAg positive woman.
• Transmission rates can be significantly reduced by active immunisation with hepatitis B vaccine combined
with passive immunisation using hepatitis B immunoglobulin within 12 hours of birth.
13
Hepatitis C
• Vertical transmission in hepatitis C virus (HCV) RNA-negative pregnant women is approximately 1-3%
versus approximately 4-6% in HCV RNA-positive women. Risk increases to 23% if women are also HIV-
positive.
• Infected infants become viraemic and at risk of chronic hepatitis. Interferon may be used postpartum.
 112

• Elective Caesarean section, formula feeding and use of immune globulin do not appear to reduce vertical
transmission in women who are HIV-negative.
• The use of a scalp electrode and duration of membrane rupture beyond 6 hours may increase risk of
transmission.
8
Group B streptococci
• Group B streptococci are found in 12-26% of pregnant women, especially in the urine. Infection has been
associated with pre-term delivery and ascending infection following rupture of membranes may result in
fetal infection.
• Neonatal sepsis with associated mortality of 6% occurs in 0.5-3.7/1,000 live births. It can be prevented
with intrapartum penicillin in high-risk cases.
• Currently there is no consensus regarding preventative strategies - some centres treat on the basis of risk
alone (previous history of intrapartum fever, pre-term labour, PROM >18 hours), others treat on the
combination of screening (third trimester vaginal and anal swabs) and risk factors.
• Universal screening of all pregnant women, rather than a targeted high risk approach, may be more
14
effective but even where this occurs, neonatal sepsis still occurs at a level of about 0.5/1000 live births.
8,9
Listeria monocytogenes
• Pregnant women are particularly susceptible to listeriosis. It can cause fetal death or chronic intrauterine,
congenital or perinatal infection.
• Infection is via the ingestion of infected foods (for example, salads contaminated with animal faeces,
undercooked meats, unpasteurised milk, soft cheeses and pates).
• Maternal disease manifests as bacteraemia with fever, sore throat, headaches and chills and sometimes
mild diarrhoea. Investigate these symptoms in pregnant women with a recent dietary history and blood
cultures.
• Transplacental infection of the fetus is more usual than ascending infection. Early infection in pregnancy
usually results in miscarriage; later infections may result in stillbirth or prematurity. In live infants,
listeriosis presents as granulomatosis infantiseptica (baby and placenta covered in miliary granulomata) or
pneumonia without granulomata. Meningitis may also occur. Infant mortality is over 30%.
• Diagnosis is from blood and CSF culture, meconium and placental examination.
• Treatment is with ampicillin with aminoglycoside.
8
Syphilis
• 0.02% pregnant women are infected with syphilis in the UK but screening, even with such low incidence,
remains cost-effective. Syphilis remains endemic in many other parts of the world (Africa, South East Asia
15
and ex-USSR).
• Transplacental transmission occurs in 90% of untreated women, with highest risk early in the disease. At
birth, infection manifests as neonatal rhinitis, osteitis, skin bullae. Hutchinson's triad (abnormal teeth,
interstitial keratitis and sensorineural deafness) arise later in untreated children.
• Maternal infection is usually detected by antenatal screening using a non-treponemal test (e.g. VDRL) but
note there is a risk of false-positive results (due to concomitant infection or autoimmune disease) and
confirmation with a specific treponemal test (e.g. FTA-ABS) is required.
• Treatment is with parenteral benzylpenicillin.
Chlamydia trachomatis
• Chlamydia affects 5-7% of pregnant women and is usually asymptomatic.
• The main symptom of neonatal infection is conjunctivitis (occurs in 50% exposed infants) and, more rarely,
16
a pneumonia at about 4-6 weeks old.
Gonorrhoea
• Gonorrhoea is usually asymptomatic in pregnancy.
• Gonococcal cervicitis is associated with chorioamnionitis and increased risk of premature labour. 40% of
untreated maternal cases cause ophthalmia neonatorum - presenting with purulent discharge, lid
swelling, corneal hazing within 4 days of birth.
8,9
Toxoplasmosis
 113

• Like CMV, toxoplasmosis is usually asymptomatic or has mild, non-specific symptoms and primary
infection during pregnancy can cause serious fetal effects. Unlike CMV, toxoplasmosis acquired during
pregnancy can be treated, reducing the fetal adverse effects.
• Toxoplasmosis is acquired by eating raw or undercooked meat, contaminated salad or ingesting soil
17
contaminated with toxoplasma oocysts which are excreted in the faeces of infected cats. Pregnant
women should be advised to avoid these exposures (wear gloves when gardening, avoid handling cat
litter). Direct contact with cats is rarely a source of infection - most acquire infection as kittens and excrete
oocysts for a short amount of time.
• There is very little good evidence that prenatal education about the risks of CMV reduces the risk of
18
congenital infection.
• A third of infants become infected if their mother becomes infected during pregnancy, especially in later
pregnancy (but the severity of disease decreases).
• There are many different presentations:
o Systemic neonatal disease - rash, jaundice, thrombocytopenic purpura, hepatosplenomegaly,
pneumonia, progressive uveitis.
o Neurological disease - hydrocephalus, microcephaly, microphthalmia, retinochoroiditis, cerebral
calcification.
o Mild disease - isolated retinochoroiditis or mild cerebral calcification and no sign of cerebral
injury.
o Sub-clinical - occurs in 70% of infected babies.
o Relapsing - retinochoroiditis with flare-ups can occur at any age.
• About 75% pregnant women are susceptible but seroconversion during pregnancy is uncommon.
• Diagnosis is difficult: serological tests have poor sensitivity, false positive toxoplasma IgM is not
uncommon and low levels of IgM persist for many years following primary infection. Confirmation of fetal
infection is best done with amniotic fluid PCR.
• Established congenital toxoplasmosis is treated with pyrimethamine, sulfadiazine and folic acid from the
second trimester until a year old.
Malaria
• Malaria tends to be more severe in pregnant women, with higher risk of complications such as cerebral
malaria, pulmonary oedema and renal failure. Severe anaemia associated with malaria may also cause
spontaneous miscarriage, stillbirth and intrauterine growth restriction (IUGR).
• Congenital malaria occurs in about 1% of infected pregnancies. Neonates develop fever, respiratory
distress, pallor, anaemia, hepatomegaly, jaundice and diarrhoea.
• Antimalarial chemoprophylaxis during pregnancy appears to have an acceptable risk-benefit ratio in areas
of high risk - reducing severe antenatal anaemia, increasing birthweight and decreasing perinatal deaths in
19 20
low parity women. Insecticide-treated bednets used during pregnancy are also beneficial.
Travel outside the UK can increase the risk of other potential congenital infections (e.g. leishmaniasis, Japanese
encephalitis, typhoid fever, leptospirosis, dengue fever) besides malaria and a pregnant woman considering
21
foreign travel should be advised accordingly.
Screening
Routine antenatal screening tests in the UK completed prior to 16 weeks' gestation

Test Purpose Action

Rubella IgG To determine rubella susceptibility. If negative, give MMR before conception or
post-partum.

Hepatitis B To determine chronic carriers. If positive, administer hepatitis B immune

surface globulin and vaccine to infant at birth
 114

antigen (prevents carriage in 95%).

Syphilis To detect active infection. If reactive, treat with penicillin and consult a
GUM specialist.

HIV antibody To enable measures to be taken to reduce If positive, antiretroviral treatment for both
vertical transmission. mother and infant reduces vertical
transmission rates significantly. Refer to a
GUM/HIV specialist.

Urine culture Treatment of asymptomatic UTI is thought to If culture shows asymptomatic bacteriuria,
reduce adverse pregnancy outcomes treat with antibiotics and repeat culture to
(premature labour) and risk of maternal ensure fully treated.
pyelonephritis.

Surveillance indicates that rates of maternal infection are variable across the country with high concentrations in
particular geographic areas. Based on data from women receiving antenatal care in London between 2000-2007,
prevalence of HIV infection was 3/1,000 women, of hepatitis B was 11/1,000, of syphilis was 4/1,000 and of
23
rubella susceptibility was 39/1,000. Uptake of screening amongst this group of pregnant women was between
95-97%.
Currently there are no tests recommended nationally for antenatal screening of CMV, toxoplasma, parvovirus or
group B streptococci.
Do not forget that acute maternal infection may occur after screening - in resource-rich settings such as the UK
and America, a significant proportion of perinatal transmission of HIV occurs due to infection acquired during
pregnancy.

Newer antiseptic drugs for children
The newer AEDs are used as an adjunct to conventional AEDs in children with intractable epilepsy. These newer
drugs are more efficacious and have a better safety as compared to conventional AED. Intractable epilepsy
refractory to appropriate conventional AED is an indication for the newer drugs.
Vigabatrin
1. Vigabatrin is a structural analogue of gamma-aminobutyric acid (GABA), which irreversibly inhibits the enzyme
GABA transaminase.
2. Indications: It is used as a first line drug for treatment of infantile spasms in children with tuberous sclerosis.
As there is insufficient evidence for the use of other AEDs in infantile spasms, it may be considered as a first
line treatment in other patients with infantile spasms in whom the use of hormonal treatment
(corticosteroids, ACTH) is contraindicated.
3. Efficacy: Clinical trials have shown that spasm cessation is greatest in patients with tuberous sclerosis complex
(74%) compared with other symptomatic etiologies (50%). In a large randomized controlled trial, it was shown
that hormonal treatment (ACTH and prednisolone) was associated with better outcome at 2 weeks (73%)
when compared to vigabatrin (54%).
4. Advantages: It has good oral bioavailablity and the drug is excreted unchanged by kidney. Drug interactions
are minimal with conventional AEDs.
5. Side effects: The major concern with the use of vigabatrin is the development of bilateral concentric
peripheral visual field constriction, which has been seen in one third of adults and 20% of children treated
with vigabatrin [5]. Because of the difficulties and inconsistencies with formal visual field testing in young
infants and children, visual fields in children have been tested using highly sensitive electroretinograms. The
earliest finding of the first abnormal field examination in adults was after 9 months of treatment; in children,
the earliest sustained onset of the vigabatrin induced retinal defect in infants was 3.1 months. Most patients
 115

with abnormalities received treatment for at least 6 months, and even those treated for more than 2 years
have been reported to have stable visual fields. As infantile spasms comprise a severe epileptic
encephalopathy with poor develop-mental outcome if uncontrolled, the risks and benefits should be weighed
before starting vigabatrin treatment. Myoclonic seizures and abscence seizures are known to be precipitated
by vigabatrin.
6. Dosage: Pediatric doses range from 50 mg/kg/day to 150 mg/ kg/day. The dose may be increased by 30-40
mg/kg/day every 4-5 days till the maximum dose is reached. The time to response with vigabatrin is quite
short, usually within 2 weeks. If the infant has not shown improvement in spasms within 2 weeks, vigabatrin
should be discontinued. In infants with good response consider stopping the drug after 6 months.
Levetiracetam
1. Levetiracetam is a broad spectrum AED which selectively inhibits high-voltage-activated calcium channels and
reduces calcium release from intraneuronal stores. It also binds to a specific target in the brain, the synaptic
vesicle protein 2A (SV2A), an integral membrane glycoprotein, which is involved in the control of vesicle fusion
and exocytosis.
2. Indications: Levetiracetam is effective as adjunctive therapy in pediatric patients with partial onset seizures
and in primary generalized tonic-clonic seizures. Intravenous preparation has recently shown efficacy in
neonatal seizures and status epilepticus.
3. Efficacy: In a randomized, double-blind, placebo-controlled, multicenter trial in 101 children with refractory
partial seizures, >50% seizure reductions was seen in 44.6% receiving levetiracetam and 19.6% in patients
receiving placebo. Levetiracetam has been evaluated in childhood epilepsy syndromes including rolandic
epilepsy, electrical status epilepticus in slow sleep, myoclonic and tonic clonic seizures of Lennox Gastaut
syndrome and as an alternative to valproate in juvenile myoclonic epilepsy in adolescent girls. Beneficial
effects on language development have been reported.
4. Advantages: Levetiracetam has a favourable pharmacokinetic profile in terms of safety in patients with liver
disease and minimal drug interaction with other AEDs.
5. Side effect: Levetiracetam is well tolerated in children with minor adverse events like headache, anorexia, and
somnolence. However, there are concerns of behavioural side effects like aggression, emotional lability,
oppositional behavior, and psychosis in children.
6. Dosage: Pediatric dose start from 10 mg/kg/day (divided tweice daily) to be hiked by 10-20 mg/kg every two
weeks to a maximum dose of 40-60 mg/kg/day.
Topiramate
1. Topiramate is a sulphamate substituted monosaccharide, a broad spectrum AED acting on voltage
dependent sodium channels, enhancement of GABA, decrease in glutamate and inhibition of carbonic
anhydrase.
2. Indications: Topiramate is a useful adjunct in refractory partial or generalized epilepsy and other epileptic
syndromes.
3. Efficacy: Topiramate has demonstrated efficacy as an adjuctive therapy in partial epilepsy, intractable
epilepsy, Lennox Gastaut syndrome, infantile spasms, generalized epilepsy of infancy and myoclonic–
astatic epilepsy. Pooled data from two randomized, double-blind studies found that topiramate
adjunctive therapy may be efficacious for juvenile myoclonic seizures in adults and children.
4. Side effects: Topiramate has good safety with no evidence of life threatening adverse effects or organ
toxicity. The most frequently reported side effects are dizziness, mental slowing, somnolence, ataxia,
impaired concentration and confusion [24]. Most of these are transient and observed during the initial
weeks of therapy and can be reduced by slow titration of the dose. Anorexia and mild weight loss has
been observed during the therapy. Other reported side effects include metabolic acidosis, nephrolithiasis,
decreased sweating and resultant hyperthermia [26]. Children on combination of topiramate and
valproate should be monitored for signs of encephalopathy resulting from hyperammonemia.
5. Dosage: Pediatric dosage is 1-3 mg/kg/day (divided twice daily) hiked bi-weekly to 3-8 mg/kg/day.
Lamotrigine
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1. Lamotrigine is another broad spectrum AED which acts by blocking the voltage dependent sodium
channels and thus blocks the release of glutamate through stabilization of presynaptic membrane.
Enzyme inducing drugs like phenytoin and carbamazepine may shorten the half life of Lamotrigine.
2. Indications and efficacy: It is an effective adjunct to refractory partial and generalized epilepsy. It is
particularly useful in typical and atypical absence seizure in Lennox Gastaut syndrome and in children with
myoclonic-astatic epilepsy. It is also useful as a first line agent in children with idiopathic generalized
epilepsy.
3. Side effects: Common dose related side effectsinclude somnolence, sleep disturbances, dizziness,
diplopia, ataxia, nausea and vomiting. Serious side effects of lamotrigine which often require drug
withdrawls include skin rash and rarely Steven Johnson syndrome and toxic epidermal necrolysis. The
neurotoxicity and skin rash is more often seen when lamotrigine is administered with valproate or when
the dose is titrated rapidly. Lamotrigine may exacerbate myoclonic seizures in patients with Dravet
syndrome.
4. Dosage: Lamotrgine is started at 1-2 mg/kg followed by slow hiking biweekly to 3-8 mg/kg/day. The drug
dosage is reduced to half when used in combination with valproate as the latter prolongs the half life of
lamotrigine.
Oxcarbazepine
1. Oxcarbazepine is the 10-keto analogue of carbamazepine which blocks high frequency voltage dependent
repetitive firing of sodium channels.
2. Indications and efficacy: Oxcarbazepine is used as first line drug for partial and secondarily generalized
seizures. Amongst the newer AED, oxcarbazepine is established as evidence-based effective initial
monotherapy for children with partial-onset seizures and focal epilepsy.
3. Side effects: Unlike carbamazepine, oxcarbazepine is not metabolized to epoxide derivative thus
minimizing side effects like skin rash encountered with carbamazepine. Reported side effects of
oxcarbazepine include hyponatremia, headache, dizziness, and ataxia. The advantage of oxcarbazepine
over carbamazepine is that it does not cause hepatic induction nor does it undergo auto-induction.
4. Dosage: Oxcarbazepine can be started with initial dose of 5 to 8 mg/kg/day in 2 divided doses increasing
by 5 to 8 mg/kg after 5 to 7 days up to a maximum of 30 mg/kg. The usual effective dose ranges from 10
to 30 mg/kg/day.
Zonisamide
1. Zonisamide is a sulphonamide derivative, a broad spectrum AED that acts through multiple actions:
facilitation of dopaminergic and serotoninergic neurotransmission through the blockade of T-type calcium
channels, prolongation of sodium channel inactivation and as a weak inhibitor of carbonic anhydrase.
2. Indications: Zonisamide has also been found useful in progressive myoclonic epilepsy syndromes such as
Unverricht-Lundborg disease and Lafora body disease. Useful as a second-line agent for infantile spasms,
Lennox-Gastaut syndrome, and juvenile myoclonic epilepsy.
3. Side effects: Somnolence, poor appetite, weight loss, headache, pruritus, and skin rash are commonly
observed adverse effects. Other rare side effects include kidney stones, oligohydrosis and hyperthermia.
Higher doses (6-8 mg/kg) has been associated with problems of language development like vocabulary
acquisition.
4. Dosage: The usual starting dose is 2–4 mg/kg/day, and the maintenance dose is 4–8 mg/kg/day;divided
once or twice daily.
Lacosamide
1. Lacosamide is a functionalized amino acid that selectively enhances slow inactivation of voltage-gated
sodium channels, increasing the proportion of sodium channels unavailable for depolarization.
2. Indication: Lacosamide is used in children with refractory epilepsy with 30-50% of children having more
than 50% reduction in seizure frequency.
3. Efficacy: Lacosamide is available in both oral and as an injection for intravenous preparation, which may
have a role in status epilepticus. Pediatric experience with lacosamide has been limited. Most of the
available literature are retrospective data on small number of patients with an efficacy rate of 30-50% .
 117

4. Side effect: Lacosamide is generally well tolerated with reports of irritability, oral tics, and prolonged
crying as adverse effects in children.
Rufinamide
1. Rufinamide is a triazole derivative that was approved by FDA in 2008 for adjunctive use in the treatment
of seizures associated with Lennox–Gastaut syndrome in children aged above 4 years. Its mechanism of
action is not completely understood but it is believed to work by prolonging the inactive state of sodium
channels and therefore limiting excessive firing of sodium-dependent action potentials.
2. Indication: The only approved indication in children (>4 yrs) is with refractory Lennox Gastaut syndrome].
3. Efficacy: In Lennox-Gastaut syndrome, rufinamide was studied in a randomized, double-blind, parallel-
group, placebo-controlled, multicenter trial in patients aged 4 to 37 years with multiple seizure types. At
the end of 12 weeks of therapy, median total seizure frequency was decreased by 32.7% in the rufinamide
group compared to 11.7% in the placebo group. Rufinamide has demonstrated efficacy in partial onset
seizures in older adolescents and adults. Rufinamide has also been evaluated in a prospective study for
the treatment of refractory partial onset seizure and childhood onset refractory epileptic encephalopathy.
4. Side effect: The most commonly observed adverse are headache, dizziness, fatigue, somnolence, and
nausea.
Stiripentol
1. Stiripentol is an AED used as an adjunctive to clobazam and valproate in the treatment of refractory
generalized tonic-clonic seizures in patients with severe myoclonic epilepsy in infancy i.e., Dravet
syndrome. It enhances central gamma-aminobutyric acid transmission and inhibits the metabolism of
concurrently administered anticonvulsants that are substrates for various cytochrome P450 isoenzymes,
such as clobazam.
2. In a randomized, double-blind, placebo controlled trial conducted in France, stiripentol was used as an
adjunctive therapy in children with Dravet syndrome who failed to respond to valproate and clobazam
and was shown to have better response rate (71%) as compared to placebo (5%).
Retigabine (ezogabine)
1. It is a novel investigational AED developed as an adjunctive treatment for partial epilepsy. Retigabine
opens voltage-gated KCNQ2/3 and KCNQ3/5 potassium channels leading to cellular membrane
hyperpolarization.
2. In a pooled analysis of three randomized controlled trials, 1240 patients were included, with 813 patients
randomized to retigabine and 427 to placebo. Responder rates (>50% reduction in seizure frequency)
were 35% and 45% for retigabine dose at 600 and 900 mg/day, respectively.
3. There is no pediatric experience so far, but retigabine may potentially be a useful agent in the treatment
of benign familial neonatal convulsions which is caused by loss of function mutations involving the
KCNQ2/3 genes.
Brivaracetam:
1. It is an analogue of levetiracetam, which has been found useful in adults with photosensitive epilepsy,
and as an adjunctive treatment in refractory partial-onset epilepsy.
2. There is no pediatric experience till now.
Ganaxolone
3. It is a synthetic analogue of allopregnenolone, a neurosteroid, which is an allosteric modulator of the
GABA-A receptor complex. In a 3-month pediatric add-on study, 20 subjects aged 6 months to 7 years
with refractory infantile spasms, or with continuing seizures after a prior history of infantile spasms were
titrated up to 12 mg/kg. Sixteen patients completed the study; 25% showed a > 50% reduction in
seizures, and one patient was seizure free.
4. Ganaxolone may also have efficacy for catamenial seizures.
Eslicarbazepine actetate
1. It is structurally related to carbamazepine and oxcarbazepine and has been used as adjunctive therapy
for adults with partial seizures. There is no pediatric experience so far.
Perampanel
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2.
It is a selective, non-competitive antagonist of a-amino-3-hydroxy 5-methyl-4-isoxazolepropionic acid
(AMPA) -type glutamate receptors, currently in clinical development as adjunctive therapy for the
treatment of refractory partial-onset seizures.
3. Efficacy and tolerability of adjunctive perampanel in patients aged >12 years with refractory partial-onset
seizures has been demonstrated in three phase III, randomized, double-blind, placebo-controlled trials.
Current Status of the Newer AEDs
1. The dosages and adverse effects of the newer AED currently available in India are summarized in Table I.
2. Amongst the newer AED, oxcarbazepine is established as effective as initial monotherapy for children with
partial-onset seizures. Vigabatrin is the drug of choice for infantile spasms associated with Tuberous
sclerosis. Lamotrigine may be considered as monotherapy in adolescent females with idiopathic
generalized epilepsy. Certain newer AEDs such as lamotrigine and vigabatrin are known to worsen
myoclonic seizures. There is paucity of data on the use of newer AEDs in children from India. Indian
Guidelines for diagnosis and management of childhood epilepsy were recently published.
3. As per these guidelines, the only newer AED which are recommended for use as monotherapy in new-
onset epilepsy are lamotrigine in partial and generalized seizures, and oxcarbazepine in partial seizures.
The others are recommended as adjunctive treatment in children who have failed conventional AED.

TABLE I Characteristics of the New Antiepileptic Drugs
Drug Initial dose Maintenance Daily Side effects Formulation
doses
(mg/kg/day) (mg/kg/day)
no
Lamotrigine
Tab 5 mg; 25 mg, 50
Monotherapy 0.5 2-10 2 Skin rash, somnolence, dizziness,
mg
nausea, diplopia

With enzyme 2 5-15 2
inducing AEDs
With valproate 0.2 1-5 1-2

Vigabatrin 20-50 50-150 2 Hyperkinesia, weight gain, Tab 500 mg
insomnia, visual field defects

Tab 150 mg, 300
Oxcarbazepine 5-8 10-30 2 Dizziness, ataxia, somnolence
mg,
hyponatremia Syrup 300 mg/5 mL

Tab 25 mg, 50 mg,
Topiramate 1 6-9 2 Wt. loss, lethargy, anorexia,
100 mg
hyperpyrexia, renal calculi

Cap 25mg, 50 mg,
Zonisamide 1-2 8-12 2 Ataxia, renal
100 mg
calculi hyperpyrexia

Tab 250 mg, 500
Levetiracetam 10 20-60 2 Headache, anorexia, somnolence,
mg,
behavioral problems Syrup 500 mg/5 mL

Lacosamide 1-2 6-9 2 Dizziness, headache, diplopia, Tab 50 mg, 100 mg
nausea

TABLE II Pharmacokinetic Properties of Newer Antiepileptic Drugs
Drug Oral bioavailability Elimination t1/2 Protein binding Metabolism
Vigabatrin 80-100% 5-8 hrs Nil Renal
Levetiracetam 100% 6-8 hrs <10% 2/3rd renal1/3rd enzymatic
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hydrolysis
30% metabolised70% excreted
Topiramate >80% 21 hours 15-40%
unchanged
Lamotrigine <100% 29 hours 55% Metabolized in liver
Metabolized in liver to active
Oxcarbazepine >95% 8-10 hours 38%
metabolite
Zonisamide 100% 60 hours 40-60% Metabolized in liver
Lacosamide 100% 13 hours <15% Metabolized in liver
Rufinamide Dose dependent 6-10 hours 34% Metabolized in liver
Stiripentol Quick absorption 4.5 hours 99% Metabolized in liver

TABLE III Mechanism of Action, Indications and Main Adverse Effects of Newer Antiepileptic Drugs
Drug Principal Indications in Main adverse Remarks
mechanism pediatric epilepsy effect
of action
Vigabatrin Inhibition of Monotherapy in Visual field It can aggravate
GABA infantile spasm, defects absence and
transaminase tuberous sclerosis; Myoclonic seizure
adjuctive therapy in
resistant partial
epilepsy

Levetiracetam Inhibition of N- Adjunctive therapy in Behavioural No drug

type calcium partial onset seizure; disturbances interaction; good
channel Myoclonic seizure of safety profile;
JME; GTCS in IGE safe in liver
disease
Topiramate Blockage of Adjunctive therapy Behavioural and Slow titration
voltage (>2 yrs) in refractory cognitive mandatory;
dependent Na+ partial, generalized problem; never withdraw
channel, and seizures weight loss; drug abruptly
inhibition associated with LGS metabolic
of GABA acidosis;
nephrolithiasis
Lamotrigine Inhibition of Adjunctive treatment Allergic Slow titration;
voltage gated for focal or rash/Steven half dose when
sodium channel generalized seizures Johnson used with
and seizures of LGS syndrome valpraote; can
precipitate
Myoclonic
seizures
Oxcarbazepine Inhibition of Monotherapy or CNS side Can worsen
voltage sensitive adjunctive effects, absence and
sodium channel therapy (>4 yr) for hyponatremia Myoclonic
focal seizure with or seizure,
without secondary
generalization
 120

Zonisamide Acts on sodium Adjunctive therapy in CNS side Drug interactions

and voltage refractory focal effects, with other AEDs
dependent seizures cognitive effect,
calcium channel weight loss
Lacosamide Enhances slow Adjunctive therapy in Frequent CNS Limited
inactivation of refractory focal effects, experience in
voltgage gated and generalized prolongation of children; more
sodium channel epilepsy PR interval studies required
Rufinamide Reduces recovery Adjunctive treatment Occasional CNS Avoid in patients
capacity of in refractory seizures side effects with familial
sodium channel in LGS short QT
inactivation syndrome
Stiripentollevel Increase in GABA Adjunctive therapy Few minor CNS Limited
refractory for dravet syndrome effects of drug experience;
seizures i interaction

Conclusion:
1. Levetiracetam is a good option as monotherapy for females with juvenile myoclonic epilepsy. Topiramate and
zonisamide are good options in patients with infantile spasms who have failed hormonal therapy and
vigabatrin.
2. Topiramate is a good add-on drug in patients with epileptic encephalopathies such as Lennox-Gastaut
syndrome and Myoclonic astatic epilepsy.
3. Lamotrigine, levetiracetam and lacosamide are good add-on drugs for patients with refractory partial seizures.
Lamotrigine is also effective in tonic seizures seen in children with Lennox-Gastaut syndrome.
4. Rare but serious side effects must always be borne in mind while prescribing newer AEDs: irreversible
peripheral field defect with vigabatrin, allergic rash/Steven Johnson syndrome with lamotrigine, arrhythmias
with rufinamide (short QT interval) and lacosamide (prolonged PR interval) and fatal hyperammonemic
encephalopathy with topiramate. Role of monitoring serum levels of newer AEDs are limited as the
recommended levels are not well defined.

BLEEDING NEONATE
Approach to Bleeding Disorders in Neonate
Hemostasis in Newborn: Salient Features
1. Physiological immaturity with quantitative and qualitative decrease in hemostatic functions
2. Capillary fragility is increased in preterm. Vasoconstriction following injury is therefore incomplete in
preterms and hence intracranial hemorrhage is more common in premature babies.
3. Platelet count in both term and preterm babies are normal but adhesion, aggregation and release of
factors like adp and thrombaxane a2 are abnormal.
4. The concentrations of vitamin k dependent factors (ii, vii, ix and x) and contact factors (xi, xii,
prekalliekrien, high molecular weight kininogen) are 50% reduced.
5. Von willebrand factor (vwf) levels are increased at birth and although they decline slightly, they remain
high.
6. Factor xiii level in cord blood is 50 percent of that in adults, but as only small amount of factor xiii is
required for its activation or clot stabilization.
7. Fibrinogen in the newborn is found to coagulase more slowly and hence often newborn babies have
prolonged thrombin time.
8. Coagulation factors are not transferred transplacentally from mother to the baby.
Clinical assessment:
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1. Bleeding in the newborn may be manifested by signs of shock, anemia, signs related to pressure from
‘hidden’ bleeding (eg, intraventricular hemorrhage), or bleeding from the gastrointestinal tract,
respiratory system or skin.
2. With bleeding from the gastrointestinal tract, it is important to distinguish bleeding in the baby from
swallowed maternal blood (an Apt test will distinguish fetal from adult hemoglobin).
3. Bleeding in the baby may occur before or during birth, presenting as cardiovascular or respiratory
instability at birth and/or anemia.
Origin of bleeding
1. Intrauterine transfusions:
a. Twin to twin
b. Fetomaternal
2. Placental:
a. Abruption
b. Placenta previa
c. Cord accident
3. Neonatal
a. Intracranial
b. Cephal and subgaleal hematoma
c. Rupture abdominal organs
Maternal History
1. Maternal ITP,
2. Thiazides
3. Aspirin, anticonvulsants like phenobarbitone and phenytoin Na
4. Anticoagulants
5. History of collagen vascular disorder,
6. Past history of ITP in mother.
7. Detailed Birth History
a. Type of delivery, birth asphyxia, trauma.
b. Gestational age should be noted.
c. History of vitamin K given to neonate, use of antibiotics and whether neonate is receiving only
breastfeeds.
Family History
1. Family history of bleeding disorder, e.g. history of excessive bleeding after injury or history of
menorrhagia in female members.
2. Pedigree charting of any affected members,
a. X-linked inheritance: Factor VIII, IX deficiency— enquire similar history of bleeding episodes in
male siblings, maternal cousins, maternal uncles, etc.
b. Autosomal dominant: von Willebrand’s disease, dysfibrinogenemia, hemorrhagic telangiectasia
c. Autosomal recessive: Other factor deficiencies— enquire history of consanguinity.
Physical Examination
a. General examination.
a. Well Baby—A ‘Healthy’ Baby with Bleeding Indicates
1. Hemorrhagic disease of newborn
2. Inherited coagulation factor deficiency
3. Isoimmune thrombocytopenia
4. Platelet function disorders
5. Vascular causes, slipped ligature, etc.
b. Sick Baby with Bleeding Indicates
1. Sepsis, asphyxia, RDS, hypothermia, apnic spells, acidosis, hypoglycemia, seizures,
prematurity, hypovolemia, shock, etc.
2. In such babies bleeding is likely to due to DIC, consumption platelet coagulopathy, liver
 122

dysfunction, etc.
c. Site of Bleeding
1. Bleeding from umbilicus: suspect factor XIII deficiency or hypo/dysfibrinogenemia.
2. Bleeding from circumcision or hematoma at injection site: hemorrhagic disease of
newborn.
3. Bleeding from GIT:
1. Swallowed maternal blood
2. Vitamin K deficiency.
4. In a sick child: suspect DIC.
5. Big cephalhematoma: inherited bleeding disorders.
6. Purpura or petechiae: immune thrombocytopenia and differentiate it from
mosquito bites
Associated Findings
1. If associated hepatosplenomegaly jaundice or chorioretinitis present, it may suggest:
a. Congenital/acquired infections
b. Leukemia
c. Erythroblastosis fetalis
2. If associated with eczema—
a. Wiskott-Aldrich syndrome.
3. Associated Congenital Anomalies
a. TAR syndrome—absent radius with thrombocytopenia
b. Large hemangioma with DIC suggest Kasabach–Merritt syndrome
c. Syndactyly with bleeding: Factor V deficiency
d. Ehler-Danlos syndrome: Ecchymosis, bruises, purpura with hyperelastic skin.
Laboratory Approach
1. Apt test: 1 part of vomitus is mixed with 5 parts of saline and centrifuged at 2000 rpm for 10 minutes.
Add 4 cc of 10 percent NaOH to 1 cc of supernatant centrifuged fluid. Brown color indicates maternal
blood and pink color fetal blood.
2. Screening Tests
a. CBC
b. Peripheral smear examination
c. PT, APTT, BT and clot retraction.
3. Suggested clinical and laboratory approach to the differential diagnosis of bleeding in newborn babies
INR
Platelets (PT) APTT
Sick Disseminated intravascular coagulation (usually low
↑ ↑
↓ factor VIII)
Platelet consumption (infection, necrotizing
↓ N N enterocolitis, renal vein thrombosis)
↑ ↑
N Liver disease, heparinization (usually normal factor VIII)
Altered vascular integrity (eg, extreme prematurity,
N N N severe hypoxia and acidosis
Immune thrombocytopenia, occult infection or
Healthy ↓ N N thrombosis, abnormal bone marrow function
Hemorrhagic disease of the newborn (vitamin K
↑ ↑
N deficiency)
↑
N N Hemophilia
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INR
Platelets (PT) APTT
Bleeding due to trauma or anatomic abnormalities,
N N N qualitative platelet abnormalities

Confirmatory Tests
1. Platelet Disorders
a. Thrombocytopenia with normal PT/APTT in a healthy neonate suggest allo- or autoimmune
thrombocytopenia.
i. If autoimmune thrombocytopenia mother’s platelet count study for
thrombocytopenia to rule out chronic ITP/Test for collagen disorder should be done.
ii. If alloimmune thrombocytopenia mother’s platelet count study is normal. Platelet
study in the mother and child—mother will be PLA1 antigen negative and a child PLA1
positive.
b. Low platelet count with normal PT/APTT in a sick child suspect platelet consumption as in
septicemia and if associated with prolonged PT/APTT it suggest DIC. Do peripheral smear
examination for burr cells, broken RBCs, helmet cells, serum fibrinogen which is decreased and
FDP is increased.
2. Coagulation Factors Defects
a. Normal platelet count with prolonged PT/APTT in a healthy child suspect vitamin K deficiency or
defect in the common pathways and hence do thrombin time and serum fibrinogen estimation.
Therapeutic trial with vitamin K will normalize PT/APTT in hemorrhagic disease of newborn.
b. Low serum fibrinogen with prolonged thrombin time suggest hypofibrinogenemia. If fibrinogen
level is normal and thrombin time is prolonged then it suggests dysfibrinogenemia or presence of
inhibitors, heparin, etc.
c. In a sick child normal platelet count and prolonged PT and APTT suggest liver disorder—liver
function test are needed.
d. Normal platelet count with normal PT and increased PTT in a healthy child suggest intrinsic
pathway defect like hemophilia A, B or factor XI deficiency. Correction studies are required and
estimation of factor levels.
e. Normal platelet count with normal APTT with increased PT suggest extrinsic pathway defect due
to deficiency of factor VII—correction studies and factor assay are needed for establishing
diagnosis. If all screening tests are normal including normal platelet count, PT and APTT following
conditions should be kept in mind.
3. Qualitative platelet disorders: Bleeding time will be prolonged with poor clot retraction. Do aggregation
study.
4. Factor XIII deficiency: Do urea solubility test.
5. Ehler-Danlos syndrome: Clinical examination for skin elasticity.
6. Hemorrhagic telangiectasia: See for telangiectasia in mucous membrane of nose, bulbar conjuctiva,
tongue and tips of the fingers.
7. Vitamin K
a. Phylloquinone or vitamin K1 is from plant origin.
b. K2 differ in the number of isoprenyl units in the side chain and are synthesized by the bacteria in
humans and animal intestine.
c. Menadione or vitamin K3 is a synthetic and water soluble vitamin K without a side chain. This
preparation is not preferred as it has been shown to cause hemolytic anemia, indirect
hyperbilirubinemia and kernicterus.
d. Vitamin K acts as a cofactor for gamma glutamyl carboxylase (GGCX) serving as an electron donor
for the post-translational conversion of protein bound glutamate into gamma carboxyglutamate.
e. Early Vitamin K Deficiency Bleeding
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i. Presents within 24 hours of birth.

ii. Seen in infants of mothers taking drugs which inhibit vitamin K
1. Anticonvulsants (carbamazepine, phenytoin and barbiturates)
2. Anti-tubercular drugs (isoniazid, rifampicin)
3. Antibiotics (cephalosporins)
4. Vitamin K—antagonists (coumadin, warfarin).
f. In preterms the liver is immature and incapable of optimal synthesis of many of precursor
proteins. The action of vitamin K, as cofactor for gamma glutamyl carboxylase is therefore limited
in preterm because precursor proteins themselves are deficient, often below 30 percent of adult
value.
g. Though colostrums contain adequate amount of vitamin K, lesser colonization by bacterial flora
of the gut of exclusively breastfed infants contribute to lower plasma level of vitamin K. Cow’s
milk contains 6 ug/dL of vitamin K1 as compared to breast milk which contains 1.5 ug/dL.
8. Vtamin K deficiency is classified based on timing of presentation as follows:
a. Early VKDB
b. Classical VKDB
c. Late VKDB.
9. Clinical Presentation
a. Early VKDB: Hemorrhagic disease of newborn.
i. Clinical presentation is often mild, with bruises, gastrointestinal bleeding. Severe
manifestations include cephalohematoma, intracranial and intra-abdominal
hemorrhage.
ii. The incidence in an at-risk group without vitamin K supplementation 6 to 12
percent. Occurs between 24 hours and 7 days of life. Classical VKDB: Associated with
delay or insufficient feeding.
b. Clinical presentation—without vitamin K supplementation incidence estimated is 0.01 to 0.44
percent.
i. Bruises, gastrointestinal blood loss or bleeding from the umbilicus and puncture
sites
ii. Blood loss, however, can be significant, and intracranial hemorrhage, although rare,
has been described.
c. Predisposing Factors
i. Prolonged antibiotic use
ii. Prolonged/recurrent diarrhea
iii. Cholestasis
iv. Malabsorption syndromes
d. Clinical presentation may be severe with mortality rate as high as 20 percent. Intracranial
hemorrhage is seen in 50 percent of these infants with residual neurological damage in survivors.
e. In fully breastfed infants who did not receive vitamin K at birth, the incidence is between
1/15,000 and 1/20,000.
10. Diagnosis of HDN
a. The diagnosis of vitamin K deficiency may be suspected from the results of coagulation
screening. Initially there is isolated prolongation of the prothrombin time followed by
prolongation of the APTT, in association with the normal concentrations of fibrinogen, normal
CBC and platelet count.
b. Confirmation of the diagnosis requires measurements of PIVKA II.
11. Treatment
a. Intravenous vitamin K should be administered to correct the existing deficiency.
b. Factor replacement therapy may also be required with fresh frozen plasma or prothrombin
complex concentrate (FII, FIX, FX).
12. Prevention
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a. Routine prophylaxis with 1 mg vitamin K at birth. (Daily requirement of 5 to 10 μg in infants) and

given intramuscularly simply because that was the only product available.
b. In 1990 an epidemiological study described an association between intramuscular (IM) vitamin K
at birth and childhood cancer and leukemia. In response to these findings, several European
countries, Australia and New Zealand changed their policy to oral prophylaxis. In the following
years, new studies failed to confirm the association between IM vitamin K at birth and childhood
cancer. A risk of solid tumors can now almost definitely be ruled out.13,14 The American
Academy of Pediatrics has always endorsed the IM route.
c. No oral liquid preparation is available, the injectable product has been found to be safe and
effective when given by the oral route.
d. Several countries currently use an alternative synthetic preparation of vitamin K1 (Konakion®
MM; Roche) for multidose oral prophylaxis. Unfortunately this preparation is not available in
most of the countries including India.
e. Single dose (1.0 mg) of intramuscular vitamin K after birth is effective in the prevention of classic
HDN. Vitamin K, should be given to all newborn as a single, intramuscular dose of 0.5 to 1 mg. All
premature infants should receive vitamin K. Reports have shown very high plasma vitamin K
levels in preterm infants receiving 0.5 to 1 mg at birth and adequate levels in those receiving 0.2
mg at birth.
f. Current empirical dosage recommendations for preterm infants:
i. Dose of 0.3 mg for birth weights <1,000 g
ii. 0.5 mg for those >1,000 g and <1,500 g.

Bronchial asthma
Definition:
1. Asthma is a:
a. Heterogeneous disease, characterized by:
b. The recurrent episodes of respiratory symptoms such as wheeze, shortness of breath, chest
tightness and cough that vary over time and in intensity, together with
c. Variable expiratory airflow limitation.
2. Variable airway limitation means:
a. Documented airflow limitation: At least once during diagnostic process when FEV1 is low,
FEV1/FVC is reduced to < 0.8
b. Reduction in lung function after exercise or challenge tests:
i. 15% decrease in FEV1 or 20% decrease in PEF
ii. FEV1/FVC < 0.8
c. Diurnal variation in PEF (peek flow meter) >20 % (Nelson)
d. Bronchodilator reversibility: Improvement in lung function by >12% or >200 mL from baseline in
FEV1 (spirometry) after bronchodialator;
Etiology:
1. Br asthma results from interplay of 3 factors: genetic, biologic and environmental
2. Genetic: more than 100 genetic loci have been linked with loci containing proallergic, proinflammatory
genes: Eg.
a. The interleukin - 4 gene cluster on chromosome 5
b. Adam-33 genes
c. polymorphism in β2 adrenergic receptors
3. Environment:
a. Viral infections
b. Indoor and home allergen exposures
c. Environmental tobacco smoke and air pollutants (ozone, sulfur dioxide)
d. Cold dry air and strong odors
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4. Biologic factors:
1. The development of asthma in children is thought to be the final step in a disease process
described as the “allergic march.” the allergic march may begin in infancy with food allergy–
associated gastrointestinal disorders and dermatitis. Allergic rhinoconjunctivitis follows in early
childhood, and asthma often completes the picture.
2. Repeated respiratory infections in early childhood leads to persistent inflammation, remodelling
of airways and airway hyper responsiveness.
3. Remodelling includes:
1. Inflammation
2. Mucus hypersecretion
3. Subepithelial fibrosis
4. Airway smooth muscle hypertrophy
5. Angiogenesis
Epidemiology:
a. Worldwide, childhood asthma appears to be increasing in prevalence
b. Prevalence of current wheeze vary from 0.8- 37.6% in different populations
c. Approximately 80% of all asthmatic patients report disease onset prior to 6 yr of age.
Types of childhood asthma:
1. Recurrent wheezing in early childhood, primarily triggered by common viral infections of the
respiratory tract
2. Chronic asthma associated with allergy that persists into later childhood and often adulthood.
3. Asthma in obesc adolescent females who experience obesity and early-onset puberty (by 11 yr of
age).
Pathogenesis:
1. Hypersensitivity or susceptibility to a variety of provocative exposures or triggers lead to airways
inflammation, hyperresponsiveness of airway, edema, basement membrane thickening, subepithelial
collagen deposition, smooth muscle and mucous gland hypertrophy, and mucus hypersecretion—all
processes that contribute to airflow obstruction.
2. Helper t lymphocytes and other immune cells that produce proallergic, proinflammatory cytokines (il-4, il-
5, il-13), and chemokines (eotaxin) mediate this inflammatory process.
Environmental factors:
1. Exposure to tobacco smoke: mother or father
2. Viral infections in early childhood
3. Dust mites, animal dander, cockroaches and some molds
4. Food rarely provoke allergy
5. Exercise induced asthma
6. Psychological exacerbation possible
7. High levels of cat allergens found to prevent asthma by inducing Ig.G
8. Indoor and home allergens cold air, ozone and strong odor produce bronchospasm without inflammation
9. DRUGS
a. Aspirin and other nonsteroidal antiinflammatory drugs
b. β-Blocking agents
Pathology:
1. Shedding of epithelium
2. Mucosal edema and hypertrophy
3. Mucus plugs
4. Cellular infiltration
5. Hypertrophy of bronchial musculature
6. Increased goblet cells
Types of childhood asthma
1. Acute asthma: triggered by viral infection only
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2. Chronic asthma: due to allergy; persists to adulthood

3. Obese girl with early onset puberty developing asthma- produce inflammatory mediators from adipose
tissue plus reduced pulmonary compliance
Clinical manifestation:
1. Expiratory wheeze
2. Intermittent cough
3. Shortness of breath
4. Chest tightness
5. Chest pain
6. Nocturnal aggravation
7. Inaudible breath sounds or wheeze in severe cases
DD:
1. Sinusitis
2. Gastroesophegeal reflex
3. Tracheobronchomalacia
4. Foreign body aspiration
5. Tuberculosis
6. Cystic fibrosis
7. Ciliary dyskinesia
8. Meditational mass
9. Cardiomegaly
10. CCF
11. Vocal cord dysfunction (VCD)
Pulmonary Function Testing
1. Spirometry:
a. FEV1 recorded by 3 attempts; highest taken; 220 L/sec normal for child; 80-50% yellow signal; <
50% red signal.
b. Bronchodilator response: >12 % improvement in FEV1 is diagnostic.
c. Expiratory flow-volume loop is “scooped” or concave
d. Bronchial challenge test: methacholine , cold air, or exercise induced bronchospasm measured by
FEV1
2. Peek flow meter: less sensitive; Diurnal variation in PEF >20 % is consistent with asthma
Diagnosis:
1. Peek flow meter: FEV1 recorded by 3 attempts ; highest taken as personnel best; 220 L/sec is normal for
child;
2. Diurnal variation in PEF >20 %
3. Bronchodilator response: imrovemnt by >12 % of FEV1 after therapy
4. Allergy testing to assess sensitization to inhalant allergens, help with the management and prognosis of
asthma
5. Measuring exhaled nitric oxide (FENO): A positive FeNO test suggests eosinophilic inflammation and
provides supportive, but not conclusive, evidence for an asthma diagnosis.
CXR:
1. Hyperinflation of lung
2. Tubular heart
3. Flattening of diaphram
4. Peribronchial thickening
5. Bird’s wing sign
Treatment: Consists of
1. Assessment and monitoring of disease activity;
2. Education for self-management;
3. Management of precipitating factors and comorbid conditions
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4. Appropriate selection of medications to address the patient’s needs.

Assessment and monitoring of disease activity
1. This consists of assessing severity and control in two domains of impairment and risk and responsiveness
to therapy.
2. Severity: 2 categories according to severity are:
a. Intermittent asthma
i. Frequent intermittent: Asthma symptoms > once in 6 weeks
ii. Infrequent intermittent: Asthma symptoms < once in 6 weeks
b. Persistent asthma: subdivided into mild, moderate, and severe.
i. Mild: Day time > 1 week; Night > 2 month
ii. Moderate: day time > daily; or night >1 week
iii. Severe: day time symptoms continuous; frequent night symptoms; activity restriction
3. Control: control is categorized into well controlled, not well controlled, and very poorly controlled. Well
controlled means:
a. Daytime symptoms ≤2 days/wk and
b. Need a rescue bronchodilator ≤2 days/wk;
c. An FEV1 of >80% of predicted
4. Both control and severity focuses on two domains- current impairment and future risk:
a. Impairment:
i. The frequency and intensity of symptoms
ii. Functional limitations
iii. Requirement of frequent use of short-acting beta2-agonist (SABA).
iv. Night time awakenings
v. Interference with normal activity
b. Risk—
i. The likelihood of future asthma attacks,
ii. Progressive decline in lung function
iii. Side effects due to medications
5. Responsiveness to therapy: is the ease or difficulty with which asthma control is attained by treatment.
Education for self-management: family education for
a. Basic facts about asthma
b. What defines well-controlled asthma and the patient's current level of control
c. Roles of medications
d. Encourage adherence
e. Skills: e.g., inhaler technique, use of a valved holding chamber (VHC) or spacer, and self-monitoring
f. When and how to handle signs and symptoms of worsening asthma
g. When and where to seek care
h. Environmental exposure control measures
Management of precipitating factors and co morbid conditions
a. Precipitating factors: Patients who have persistent asthma should be evaluated for the role of indoor
and outdoor allergens as possible contributing factors; eg. reducing exposure to cockroach, dust-
mite, and rodent allergens
b. Co morbid conditions: Treating the following conditions may improve asthma management:
aspergillosis, obstructive sleep apnea gastroesophageal reflux, obesity, OSA, rhinitis/sinusitis, chronic
stress/depression.
Treatment:
1. The long-term goals of asthma management are symptom control and risk reduction.
2. Controller medications: these are used for regular maintenance treatment. They reduce airway
inflammation, control symptoms, and reduce future risks such as exacerbations and decline in lung
function. Eg.
a. Inhaled corticosteroids (ICS) (pMDIs or DPIs)
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i. e.g. beclometasone, budesonide, ciclesonide, fluticasone propionate

ii. Dose: Budesonide 25-400 µg/ 12 hr
iii. Local side-effects include oropharyngeal candidiasis and dysphonia
b. Leukotriene modifiers (tablets) e.g. montelukast )dose 4 mg /day, pranlukast, zafirlukast,
zileuton
c. Chromones (pMDIs or DPIs) e.g. sodium cromoglycate , dose 5 mg / puff 1-2 puffs 3times /day
and nedocromil sodium
d. Systemic corticosteroids : (tablets,suspension or intramuscular (IM) or intravenous (IV) injection)
e.g. prednisone, prednisolone, methylprednisolone, hydrocortisone; Short-term treatment
(usually 5–7 days)
3. Reliever (rescue) medications: for relief of breakthrough symptoms, including during worsening asthma
or exacerbations.Eg.
a. Short-acting inhaled beta2-agonist bronchodilators (SABA):
i. (pMDIs, DPIs and, rarely, solution for nebulization or injection) e.g. salbutamol
(albuterol), terbutaline
ii. salbutamol inhaler dose: 100 µg/puff; 1-2 puffs 4-6 hr
iii. Salbutamol neb dose: 5 mg/ml; 0.03 mL/kg/dose to a maximum of 1 mL, diluted with
saline to 4 mL, every 3–6 hrs
b. Short-acting anticholinergics (pMDIs or DPIs) e.g. ipratropium bromide, oxitropium bromide
4. Add-on therapies for patients with severe asthma: Eg.
a. Long-acting anticholinergic (tiotropium)
b. Anti-IgE (omalizumab)
c. Anti-IL5 (mepolizumab)
Stepwise management of bronchial asthma.
1. Severity of Asthma varies over time, and treatment is "stepped up" or "stepped down" according to
classification of severity
2. Classification

Intermittent Mild persistent Moderate persistent Severe persistent

Exacerbations are brief Activity may cause May last days Frequent

No activity limitation Exacerbations Activity causes exacerbations

Exacerbations Limited physical

Activity

Symptoms < 2 times a Symptoms more than 2 Daily symptoms Continual

Week; times/week but less Exacerbations 2 or symptoms

than 1 time/day More times a week;

Nocturnal symptoms < > 2 times/month > 1 time/week Frequent

2 times/month

Stepwise management:
1. Helps to achieve a well-controlled state by reducing
a. Impairment:
i. Preventing chronic and troublesome symptoms,
ii. Allowing infrequent need of quick-reliever medications,
iii. Maintaining “normal” lung function,
iv. Maintaining normal activity levels including physical activity and school attendance,
v. Meeting families’ expectations and satisfaction
b. Risk
i. Preventing recurrent exacerbations,
ii. Reduced lung growth, and
iii. Medications’ adverse effects.
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2. The recommendations for initial therapy are based on assessment of asthma severity
3. The NIH guidelines emphasize initiating higher-level controller therapy at the outset to establish prompt
control, and then to “step down” once good asthma control is achieved.
4. If a child has not-well-controlled asthma, the therapy level should be increased by 1 step; For a child with
very poorly controlled asthma, the recommendations are that treatment go up 2 steps
Steps in management:
STEP 1: Management of intermittent asthma is simply by the use of a SABA as needed for symptoms and
for pretreatment in those with exercise-induced bronchospasm; no controller medications
STEP 2: Regular low dose ICS plus as-needed SABA
STEP 3: Low dose ICS/LABA either as maintenance treatment plus as-needed SABA
STEP 4: Medium dose ICS/LABA as maintenance plus as-needed SABA
STEP 5: Refer for expert investigation and add-on treatment
Prevention:
1. Family education
2. Avoid exposure to allergens
3. Exposure to microbes: a “hygiene hypothesis” purports that naturally occurring microbial exposures in
early life might drive early immune development away from allergic sensitization, persistent airways
inflammation, and remodeling.
4. Avoidance of environmental tobacco smoke (beginning prenatally),
5. Prolonged breastfeeding (>4 mo),
6. An active lifestyle, and a healthy diet—might reduce the likelihood of asthma development.
7. Immunizations are currently not considered to increase the likelihood of development of asthma;
therefore, all standard childhood immunizations are recommended for children with asthma, including
varicella and annual influenza vaccines.

Management of status asthmaticus or acute severe asthma in children
Definition: a severe exacerbation of asthma that does not improve with standard therapy is termed status
asthmaticus.
Steps:
Step 1. Assessment of severity of attack and risk factors
step 2. Initial bronchodilator therapy and treatment of hypoxia.
Step 3. Assessment of response to therapy and modification of therapy.
Step 4. Intensive care and ventilation in refractory case
10. Assessment of severity of attack
a. Moderate exacerbation:
i. Spo2 ≥ 92%
ii. No clinical features of severe asthma
b. Severe exacerbation
i. Spo2 < 92%
ii. Too breathless to talk or eat
iii. Hr > 140/min
iv. Rr > 40/min
v. Use of accessory neck muscles
c. Life threatening
i. Spo2 < 92% plus any of:
ii. Agitated/altered consciousness
iii. Cyanosis
iv. Poor respiratory effort
v. Silent chest
vi. (Exclude upper airway obstruction)
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11. Assessment of risk for clinical deterioration:

a. Previous severe asthma exacerbation (intensive care unit admission, intubation for asthma)
b. Sudden asphyxia episodes (respiratory failure, arrest)
c. Two or more hospitalizations for asthma in past year
d. Three or more emergency department visits for asthma in past year
12. Initial bronchodilator therapy and treatment of hypoxia.
a. Home management:
i. “Rescue” medication (inhaled SABA 100 µg x 2 puffs or salbutamol nebulizer solution
(5mg/ml) in the dose of 0.1-0.15 mg/kg diluted in 3 ml of normal saline over a period of 10-
15 min. Repeat every 20 minutes up to 3 doses/hour
ii. A short course of oral corticosteroid therapy - prednisone 1-2 mg/kg/day for 4 days
b. Emergency department management:
i. Supplemental oxygen,
ii. Inhaled β-agonist therapy: salbutamol 100 µg x 6 puffs every 20 min for 1 hr, and, if
necessary,
iii. Systemic corticosteroids given either orally or intravenously
iv. Inhaled ipratropium may be added to the β-agonist treatment if no significant response is
seen with the first inhaled β-agonist treatment; 2 puffs of 80mcg (or 250mcg by nebulizer)
every 20 minutes for 1 hour only.
v. Intramuscular injection of epinephrine or other β-agonist may be administered in severe
cases.
vi. Oxygen to be continued for at least 20 min after SABA administration to compensate for
possible ventilation-perfusion abnormalities caused by SABAS.
13. Assessment of response to initial therapy
a. The patient should be assessed after initial therapy of 2-3 doses of bronchodilator along with oxygen
over a period of one hour.
b. Good response to initial therapy will be free of wheeze and have no breathlessness. PEFR > 70% of
normal for the child
c. Partial response: PEFR 40 to 70%
d. Poor Response: severe persistent wheeze and significant pulsus paradoxus
14. Intensive Hospital management of asthma exacerbations
a. Supplemental oxygen to maintain o2 saturation >92%
b. SABAS can be delivered frequently (every 20 min to 1 hr) or continuously (at 5-15 mg/hr).
c. Inhaled ipratropium bromide is often added to albuterol every 6 hr; 0.5 mg q6-8h (tid-qid) as needed
d. Short-course oral or intravenous coticosteroid.
e. Administration of fluids at or slightly below maintenance fluid requirements is recommended
15. In refractory cases:
a. Parenterally administered epinephrine sc or im: 0.01 mg/kg (max dose 0.5 mg); may repeat after 15-
30 min,
b. Β-agonists: continuous iv infusion (terbutaline only): 2-10 μg/kg loading dose, followed by 0.1-0.4
μg/kg/min
c. Methylxanthines: Aminophylline A bolus dose (5-6 mg/kg) depending upon previous treatment with
methylxanthines is given followed by infusion of maintenance dose (0.9 mg/kg/h).
d. Magnesium sulfate (25-75 mg/kg, maximum dose 2.5 g, given intravenously over 20 min), and acts by
counteracting calcium mediated smooth muscle contraction, through its influence on calcium
homeostasis, inhibition of acetylcholine release at the neuromuscular junction, inhibition of
histamine release, direct inhibition of smooth muscle contraction and sedation
e. Inhaled heliox (helium and oxygen mixture)
16. In respiratory failure:
a. Intubation and mechanical ventilation when:
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i. Failure of maximal pharmacologic therapy.

ii. Cyanosis and hypoxaemia (PaO2 less than 60 mm Hg).
iii. PaCO2 greater than 50 mmHg and rising by more than 5 mmHg/h
iv. Minimal chest movements.
b. Volume-cycled ventilators, using short inspiratory and long expiratory times, 10-15 ml/kg tidal
volume, 8-15 breaths/min, peak pressures <60 cm h2o, and without positive end-expiratory pressure
are starting mechanical ventilation parameters
c. Ketamine: loading dose of 0.5-1.0 mg/kg, followed by an infusion of 1.0-2.5 mg/kg/h in ventilated
children relaxes smooth muscle directly, increases chest wall compliance and also decreases
bronchospasm in ventilated asthmatic children.
17. Recovery Phase and Advice at Discharge
a. PEFR >75% predicted
b. Oral or inhaled beta-2 agonist maintenance
18. Prevention
a. Education regarding home management
b. Children should be supervised regularly
c. They should learn to use MDI

CLUBBING
1. Hippocrates described the phenomenon in a patient with empyema
2. Digital clubbing, alternatively called Hippocratic fingers, watch-glass nails, or drumstick fingers, can be an
isolated finding or may occur as part of the syndrome of hypertrophic osteoarthropathy (HOA).
3. HOA is characterized by periostosis of long bones,joint pain, and clubbing; it may be primary, also known as
pachydermoperiostosis, or secondary to a variety of disease processes. Primary HOA is an autosomal
dominant disorder that presents in otherwise healthy children as clubbing, periostosis
4. Clubbing develops in five steps:
1. Fluctuation and softening of the nail bed (increased ballotability)
2. Loss of the normal <165° angle (Lovibond angle) between the nailbed and the fold (cuticula)
3. Increased convexity of the nail fold
4. Thickening of the whole distal (end part of the) finger (resembling a drumstick)
5. Shiny aspect and striation of the nail and skin
6. Unilateral clubbing is seen in hemiplegia and AV fistula in digit
5. Schamroth's test or Schamroth's window test (originally demonstrated by South African cardiologist Dr Leo
Schamroth on himself) is a popular test for clubbing. When the distal phalanges (bones nearest the fingertips)
of corresponding fingers of opposite hands are directly apposed (place fingernails of same finger on opposite
hands against each other, nail to nail), a small diamond-shaped "window" is normally apparent between the
nail beds. If this window is obliterated, the test is positive and clubbing is present.

6. Hypertrophic pulmonary osteoarthropathy (or Bamberger-Marie disease) is a medical condition combining
clubbing and periostitis of the long bones of the upper and lower extremities. Distal expansion of the long
bones as well as painful, swollen joints and synovial villous proliferation are often seen. The condition may be
primary or secondary to diseases like lung cancer.

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Cuses:
1. Primary: autosomal dominant
2. Pulmonary
a. malignancy. Primary lung cancer, lymphoma, pleural mesothelioma, and secondary pulmonary
malignancies can all be accompanied by clubbing.
b. Painful clubbing is more likely in patients with bronchogenic carcinoma, lung abscess, and
bronchiectasis.
3. Chronic infection (or inflammation).
a. Digital clubbing has classically been associated with chronic infections such as bronchiectasis,
lung abscess, empyema, pulmonary tuberculosis, and infective endocarditis.8 Both inflammatory
bowel disease (Crohn disease more than ulcerative colitis) and chronic liver disease have been
associated with clubbing.
4. Clubbing has been seen with HIV
5. Chronic parasitic infections with Trichuris trichiura (whipworm) and schistosomia
6. Colonic polyposis.
7. Cyanotic congenital heart disease.
Pathogenesis:
1. Chronically elevated prostaglandin E2 levels plasma levels of vascular endothelial growth factor (VEGF)
are higher than in control subjects. VEGF appears to be a promoter of angiogenesis
2. Resection of the vagus nerve can abate or abolish both clubbing and pulmonary osteoarthropathy led to
the theory that the vagus nerve may be a key signalling pathway
3. In the pathogenesis of digital clubbing, local hypoxia, platelet activation, release of signal proteins such as
VEGF, and stimulation of angiogenesis and other cellular activities are probably contributory.

RESPIRATORY FAILURE
1. Respiratory failure is traditionally defined as respiratory dysfunction in which the arterial oxygen tension falls
below 60 mm Hg (acute hypoxemia), the carbon dioxide tension rises above 50 mm Hg (acute hypercarbia,
hypercapnia) and the pH drops below 7.35 (resp.acidosis), or both.
2. Respiratory failure occurs when oxygenation and ventilation are insufficient to meet the metabolic demands
of the body. Respiratory failure may result from an abnormality in
(1) Lung and airways,
(2) Chest wall and muscles of respiration, or
(3) Central and peripheral chemoreceptors
3. Pathophysiology of Respiratory Failure:
a. Respiratory failure can be classified into 2 categories:
(1) Type I: Hypoxic respiratory failure (failure of oxygenation)
(2) Type II: Hypercarbic respiratory failure (failure of ventilation).
(3) Mixed: The two entities may coexist as a combined failure of oxygenation and ventilation.
(4) types I and II relates to the absence or presence of hypercapnia (raisedPaCO2)
b. Type I respiratory failure:
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(1) Admixture of blood from the underventilated (eg.pnemonitis) and normal regions results
in hypoxia with normocapnia, which is called ‘type I respiratory failure’.
(2) Blood gas abnormality:
1. Hypoxia (PaO2 < 8.0 kPa (60 mmHg))
2. Normal or low PaCO2 (< 6.6 kPa (50 mmHg))
(3) Etiology
1. Acute
a. Acute asthma
b. Pulmonary oedema
c. Pneumonia
d. Lobar collapse
e. Pneumothorax
f. Pulmonary embolus
g. ARDS
2. Chronic:
a. Emphysema
b. Lung fibrosis
c. Lymphangitis carcinomatosa
d. Right-to-left shunts
e. Brain-stem lesion
c. Type II respiratory failure:
(1) Arterial hypoxia with hypercapnia (type II respiratory failure) is seen if there is severe
generalised ventilation–perfusion mismatch (insufficient normal lung to correct PaCO2 ) or
a disease which reduces total ventilation.
(2) Blood gas abnormality:
1. Hypoxia (PaO2 < 8.0 kPa (60 mmHg))
2. Raised PaCO2 (> 6.6 kPa (50 mmHg))
(3) Etiology:
1. Acute:
a. Acute severe asthma
b. Acute exacerbation COPD
c. Upper airway obstruction
d. Acute neuropathies/paralysis
e. Narcotic drugs
f. Primary alveolar hypoventilation
g. Flail chest injury
2. Chronic:
a. COPD
b. Sleep apnoea
c. Kyphoscoliosis
d. Myopathies/muscular dystrophy
e. Ankylosing spondylitis
4. Clinical Examination:
a. The signs and symptoms of acute respiratory failure reflect the underlying disease process and the
associated hypoxemia or hypercapnia.
b. Localized pulmonary findings reflecting the acute cause of hypoxemia (eg, pneumonia, pulmonary
edema, asthma, or chronic obstructive pulmonary disease [COPD]), may be readily apparent.
c. In patients with ARDS, the manifestations may be remote from the thorax, such as abdominal pain or
long-bone fracture.
d. Neurologic manifestations include restlessness, anxiety, confusion, seizures, or coma.
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e. Asterixis may be observed with severe hypercapnia. Tachycardia and a variety of arrhythmias may
result from hypoxemia and acidosis.
f. Cyanosis, a bluish color of skin and mucous membranes, indicates hypoxemia.
g. Dyspnea, an uncomfortable sensation of breathing, often accompanies respiratory failure. Excessive
respiratory effort, vagal receptors, and chemical stimuli (hypoxemia and/or hypercapnia) all may
contribute to the sensation of dyspnea.
h. Both confusion and somnolence may occur in respiratory failure.
i. Myoclonus and seizures may occur with severe hypoxemia.
j. Polycythemia is a complication of long-standing hypoxemia.
k. Pulmonary hypertension frequently is present in chronic respiratory failure. Alveolar hypoxemia
potentiated by hypercapnia causes pulmonary arteriolar constriction. If chronic, this is accompanied
by hypertrophy and hyperplasia of the affected smooth muscles and narrowing of the pulmonary
arterial bed. The increased pulmonary vascular resistance increases afterload of the right ventricle,
which may induce right ventricular failure. This, in turn, causes enlargement of the liver and
peripheral edema. The entire sequence is known as cor pulmonale.
5. Evaluation :
(1) Pulse oximetry to monitor level of oxygenation
(2) Capnography (end-tidal CO2 measurement) to determine the effectiveness of ventilation
and pulmonary circulation, especially in intubated patients
(3) Acid base status can be analysed by arterial blood sampling
(4) Chest radiography is essential.
(5) Echocardiography is not routinely done but is sometimes useful.
(6) Pulmonary functions tests (PFTs), if feasible, may be helpful.
(7) Electrocardiography (ECG) should be performed to evaluate the possibility of a
cardiovascular cause of respiratory failure;
6. Management:
a. O2: Oxygen is humidified in a bubble humidifier and delivered via nasal prongs inserted in to the
nares. In children, a flow rate <5 L/min is most often used because of increasing nasal irritation with
higher rates.
b. Airway Adjuncts: Maintenance of a patent airway: Artificial pharyngeal airways may be useful in
patients with oropharyngeal or nasopharyngeal airway obstruction and in those with neuromuscular
weakness in whom native extrathoracic airway resistance contributes to respiratory compromise.
c. Inhaled Gases:
(1) Helium-oxygen mixture (heliox) is useful in overcoming airway obstruction and improving
ventilation. Helium is much less dense and slightly more viscous than nitrogen. When
substituted for nitrogen, helium helps maintain laminar flow across an obstructed airway,
decreases airway resistance, and improves ventilation.
(2) Nitric oxide (NO) is a powerful inhaled pulmonary vasodilator. Its use may improve
pulmonary blood flow and V- Q mismatch in persistent pulmonary hypertension of the
newborn (PPHN), primary pulmonary hypertension, and secondary pulmonary
hypertension due to chronic excess pulmonary blood flow (e.g., VSD) or collagen vascular
diseases. NO is administered in doses ranging from 5 to 20 parts per million (ppm).
Although administration of NO to unintubated patients is possible, it is usually
administered to patients receiving mechanical ventilation through endotracheal tubes,
because of the need for precision in NO dosing.
7. Positive Pressure Respiratory Support:
a. Continuous Positive Airway Pressure or CPAP is a modality of respiratory support in which increased
pulmonary pressure is provided artificially during the expiratory phase of the respiration in a
spontaneously breathing neonate.
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b. It is distinct from Intermittent Positive Pressure Ventilation (IPPV) or intermittent Mandatory

Pressure Ventilation (IMV) in which breathing is taken over by the ventilator machine completely and
the increase in pulmonary pressure occurs during both inspiratory as well as expiratory phases.
c. CPAP: Positive airway pressure helps aerate partially atelectatic or filled alveoli, prevent alveolar
collapse at end exhalation, and increase functional residual capacity (FRC). This improves pulmonary
compliance and hypoxemia and decreases intrapulmonary shunt. CPAP can also be provided through
snugly fitting nasal prongs or a tight-fitting facial mask attached to a ventilator or other positive
pressure device.
d. CPAP is most useful in diseases of mildly decreased lung compliance and low FRC, such as atelectasis
and pneumonia.
e. Diseases of extrathoracic airway obstruction (e.g., laryngotracheitis, obstructive sleep apnea,
postextubation airway edema) may also benefit from CPAP.
f. Bilevel positive airway pressure (BiPAP) machines provide positive airway pressure during exhalation
and additional positive pressure during inspiration. A BiPAP device allows one to set an expiratory
positive pressure (EPAP) and an inspiratory positive pressure (IPAP).
8. Endotracheal Intubation and Mechanical Ventilation:
a. Indications:
(1) Persistent hypoxemia or significant hypoventilation
(2) Potential neurologic deterioration
(3) Patients with hemodynamic instability
b. Pretreatment with a sedative, an analgesic, and possibly a muscle relaxant is recommended before
intubation unless the situation is an emergency (i.e., apnea, asystole, unresponsiveness)
c. Rapid sequence intubation:
(1) Take proper history. Assemble equipment, medications
(2) Preoxygenate the patient with bag/mask
(3) Premedicate the patient with lidocaine, atropine
1. Lidocaine minimizes the ICP rise with intubation and can be applied topically to the
airway mucosa for local anesthesia
2. Atropine helps blunt the bradycardia associated with upper airway manipulation
and reduces airway secretions
(4) Induce sedation and analgesia Sedatives:
1. Thiopental (2-5 mg/kg): Very rapid onset; can cause hypotension.
2. Diazepam (0.1 mg/kg): Onset 2-5 min; elimination in 30-60 min or more.
3. Ketamine (2 mg/kg): Onset 1-2 min; elimination in 30-40 min. May cause
hallucinations if used alone; causes higher ICP, mucous secretions, increased vital
signs, and bronchodilation.
(5) Analgesics:
1. Fentanyl (3-10 μg/kg, may repeat 3-4×): Rapid administration risks “tight chest”
response, with no effective ventilation. Effects wear off in 20-30 min.
2. Morphine (0.05-0.1 mg/kg dose): May last 30-60 min; may lead to hypotension in
hypovolemic patients.
d. Pretreat with nondepolarizing paralytic agent (Neuromuscular blocking agents)
1. Small dose of a nondepolarizing paralytic agent, with intent of diminishing the
depolarizing effect of succinylcholine, which is administered next
2. Rocuronium (1 mg/kg), has a very rapid onset and short duration. Other
nondepolarizing agents include vecuronium and pancuronium, both dosed at 0.1
mg/kg.
(2) Perform a Sellick maneuver: Pressure on the cricoid cartilage, to occlude the esophagus
and prevent regurgitation or aspiration
(3) Perform endotracheal intubation ET:
1. Select the proper size for the age and weight of the child
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2. Laryngoscope blades: A variety of Miller and the Macintosh blades

3. Patient supine; the neck is extended moderately to the “sniffing” position
(4) Secure the tube and verify the position with a roentgenogram; ET secured with tape to the
cheeks and upper lip or to an adhesive patch applied to the skin near the mouth.
(5) Begin mechanical ventilation. Verify tube placement before ventilating with positive
pressure; if an ET tube is in one bronchus, barotraumas may occur.

MECHANICAL VENTILATION
1. Definition of Common Terms
1. Tidal Volume: This is the volume of air inspired or expired in each breath.
2. Functional residual capacity FRC: It is a measure of the volume of the lungs at end expiration. It is
critical that the infant has an adequate volume of gas in the lungs at the end of expiration, i.e. an FRC.
It is critical for effective gas exchange that newborns quickly achieve and maintain an FRC. The key
determinant of FRC in ventilated infants is the mean airway pressure (MAP).
3. Mean airway pressure (MAP): It is the average pressure in the respiratory passage during ventilation.
It is determined by the inspiratory flow rate, PIP, Ti, PEEP and ventilator rate.
4. Inspiratory time (Ti) and Expiratory time (Te): Time allowed for inflow and outflow of the air-gas
mixture. I:E ratio: Ratio between inspiratory time and expiratory time.
5. Peak inspiratory pressure (PIP): Highest pressure reached during the inspiratory phase. It is guided by
good chest excursions and air entry.
6. Positive end expiratory pressure (PEEP), is a pressure applied by the ventilator at the end of each
breath to ensure that the alveoli are not so prone to collapse. This ‘recruits’ the closed alveoli in the
sick lung and improves oxygenation.
7. FiO2 : Fraction of oxygen in the inspired air gas mixture.
8. PaO2 : This denotes the partial pressure of O2 in arterial blood.
9. PaCO2 : This denotes the partial pressure of CO2 in arterial blood.
10. SpO2 : This denotes the oxygen saturation of hemoglobin in arterial blood.
11. Compliance. It is the stiffness or distensibility of the lung and chest wall, i.e., the change in volume
produced by a change in pressure.
12. Resistance: It is the sum of the impediment to airflow due to friction between gas and airway (airway
resistance) and between tissues of the lung and chest wall (viscous resistance).
2. Four phases of the respiratory cycle:
a. Initiation of respiration and a variable that is controlled, often referred to as mode;
b. Inspiratory phase: duration of inspiration and the pressure or volume
c. Termination of inspiration, often referred to as cycle;
d. Expiratory phase characteristics.
3. Initiation of Inspiration
a. Breath either is controlled entirely by the ventilator (control mode)
b. Ventilator supports the patient’s inspiratory effort (support mode)
4. Control Variable (Mode):
a. volume-controlled ventilation (VCV)
b. pressure-controlled ventilation (PCV)
c. Positive Pressure Ventilators are devices which, when connected to the respiratory tract of the
patient, deliver air/oxygen under pressure at a preset frequency. They are classified by clinicians as
either pressure type (i.e. pressure-limited) or volume type (i.e. volume-limited).
d. The pressure-limited ventilators generate a predetermined inspiratory or inflating pressure, whatever
the resultant tidal volume. In contrast, the volume-limited ventilators aim at delivering a
predetermined tidal volume, whatever the required inflating pressure.
e. While both types of ventilators have relative merits and demerits, most neonatologists prefer
pressure limited ventilators.
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f. Many of the commonly used neonatal ventilators are pressure-limited ventilators. Their cycling
(inspiration-expiration-inspiration………) is generally governed by the preset inspiratory and expiratory
times. They are, therefore, also specified as time-cycled ventilators.
2. Ventilator modes:
a. Intermittent Positive Pressure Ventilation (IPPV) or Intermittent Mandatory Ventilation (IMV) In
functional terms, both the IPPV and IMV denote the same ventilators mode wherein the ventilator is
set to provide a predetermined number of ventilatory breaths irrespective of the fact whether the
infant does or does not breathe spontaneously.
b. Intermittent mandatory ventilation mode (IMV): inspiration is initiated at a set frequency with a
timing mechanism independent of patient effort; allows for adjustment of ventilator support
according to the patient’s needs and is therefore useful in the weaning process.
c. Synchronized IMV (SIMV): machine-delivered breaths are triggered by the patient’s inspiratory
efforts; In the absence of patient effort, the patient receives a backup rate much like in IMV mode
d. Assist-control mode: patient breath is triggered by patient inspiratory effort and “assisted” with
either preselected inspiratory pressure or volume
e. Continuous Positive Airway Pressure (CPAP)
3. Support Modes: are designed to support the patient’s spontaneous respirations.
a. Pressure support ventilation (PSV): initiation of inspiration is triggered by the patient’s spontaneous
breath, which is then “supported” by a rapid rise in ventilator pressure to a preselected level.
b. Volume support ventilation (VSV): inspiratory pressure in spontaneous breaths is adjusted to
guarantee a preset tidal volume.
4. Inspiratory Phase Characteristics
a. Inspiratory time: In PCV, the duration of inspiratory time (Ti) is directly set in seconds. In VCV, the
inspiratory time can be adjusted by adjusting the inspiratory flow (volume/time).
b. Increasing the inspiratory time can give the Patient a longer time to get air and O2 in and improve
oxygenation & ventilation. Too long of an inspiratory time may inhibit exhalation and cause the CO2
to rise.
c. Expiratory time (Te): at a given ventilator rate, an increase in Ti decreases expiratory time. Te is to be
sufficient for complete exhalation.
5. Termination of Inspiration (Cycle)
a. With a time-cycled mechanical breath, inspiration is terminated after a preselected inspiratory time
has elapsed, whereas with volume cycled breath, the inspiration ends after a preselected volume has
been delivered by the machine into the ventilator circuit.
6. Expiratory Phase Manoeuvres
a. PEEP:
(1) can prevent airway closure during expiration and improve ventilation.
(2) recruits atelectatic alveoli and helps to increase FRC in patients with alveolar-interstitial
diseases and thereby improve oxygenation.
Initial Ventilator Settings in Common Diseases
Disease PIP (cm water) PEEP (cm water) Rate (per I:E ratio
minute)
Bronchopneumonia 15-25 0-3 20-30 1:2 (Ti 0.3-0.4)
Bronchial asthma 30-40 0-4 8-12 1:4
Meconium aspiration 25-35 0-3 40-60 1:3 (Ti 0.2-0.3)
Respiratory Failure 15-20 4-6 20-30 1:1.5
(Post operative,
Gullain Barre
syndrome)
PIP: Peak inspiratory pressure; PEEP: Positive end expiratory pressure; I:E = Inspiration to expiration
ratio; Ti: Inspiration time (seconds).
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7. Settings for preterm:
a. Rate: 30-40/minute
b. Peak inspiratory pressure (PIP) - determined by adequate chest wall movement.
(1) An infant weighing less than 1500 grams: 16-28 cm H2O.
(2) An infant weighing greater than 1500 grams: 20-30 cm H2O.
c. Positive end expiratory pressure (PEEP): 4 cm of H2O OR 5-6 cm if FiO2 > 0.90.
d. FiO2: 0.4 to 1.0, depending on the clinical situation.
e. Inspiratory time: 0.3-0.5 sec.
8. Ventilator-induced lung injury:
a. High volume and high pressure can damage lung parenchyma(volutrauma and barotrauma)
b. high inspired oxygen concentration is another potential source of lung injury (oxytrauma).
c. Ventilator-associated pneumonia (VAP) is due to aspiration of oral and/or gastric secretions,
colonization of ETs, and suppression of cough reflexes.
d. Traumatic endotracheal intubation and subglottic swelling from the ET irritation, especially in
patients who exhibit agitation while receiving mechanical ventilation, are common causes of airway
narrowing after extubation. Administration of intravenous corticosteroids (dexamethasone 0.5 mg/kg
every 6 hours for 4 doses prior to extubation) has been shown to minimize the incidence of
postextubation airway obstruction. In patients in whom postextubation airway obstruction develops,
the need for re-intubation may be obviated by administration of nebulized racemic epinephrine and
helium-oxygen mixture.
9. Weaning
a. Weaning from mechanical ventilation should be considered as a patient’s respiratory insufficiency
begins to improve. Most paediatricians favor gradual weaning from ventilator support.
b. With SIMV, the ventilator rate is slowly reduced, allowing the patient’s spontaneous breaths (typically
assisted with pressure or volume support) to assume a larger proportion of the minute ventilation.
10. High-Frequency Ventilation:
a. HFV is different from conventional ventilation, in that HFV is less dependent on tidal volume and
more dependent on dispersion of inspired gas.
b. Problems of conventional ventilation:
(1) Barotrauma refers to alveolar and small airway destruction when high inspiratory
pressures are applied.
(2) Volutrauma recognizes that alveolar overdistension is more likely to occur as a result of
excessive volume and not pressure per se.
(3) The cyclic repetition of collapse and reopening generates shearing forces capable of
causing damage, hence the term atelectrauma.
(4) biotrauma contributing to the genesis of organ failure is related to exacerbation of
inflammation and locally produced cytokines.
(5) positive-pressure ventilation with large tidal volumes damages pulmonary capillary
endothelium, alveolar and airway epithelium, and basement membranes. This mechanical
damage results in leakage of fluid, protein, and blood into the airways, alveoli, and
interstitial spaces, leading to inhibition of surfactant activity and further injury to the lung.
(6) ventilator strategy that avoids large changes in lung volume may reduce lung injury.
Consequently, considerable interest has been generated over the past 15 years in the
application of high-frequency ventilation (HFV) in newborns who have respiratory failure
because this technique allows ventilation with very small tidal volumes.
c. Definitions of HFV and Types of Ventilators
1. HFV has been defined in several ways. Most definitions include the following characteristics:
a. Ventilation at a high rate, at least two to four times the natural breathing
frequency,
b. Ventilation with small tidal volumes that are less than the anatomic dead space.
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c. In addition, gas transport during HFV cannot be explained by classic concepts of

ventilation and lung mechanics.
d. All high-frequency ventilators are capable of delivering extremely rapid rates (300
to 1,500 breaths/min, 5 to 25 Hz or cycles per second).
e. They apply a continuous distending pressure to maintain lung volume, and small
tidal volumes are superimposed at a rapid rate.
f. High frequency ventilation (HFV) has:
(1) Small tidal volume (VT),
(2) Small intrathoracic pressure variations
(3) Disengagement of ventilation from oxygenation
d. Types of HFV:
(1) High-frequency positive pressure ventilation (HFPPV) : rarely used
(2) High-frequency jet ventilation (HFJV) – high-frequency transtracheal gas under high
pressure or ‘‘jets’’were introduced through a small catheter placed in the ET tube
(3) High frequency flow interrupter (HFFI) – HFFI is similar to HFJV but the gas control
mechanism is different. A rotating bar or ball with a small opening is placed in the
(4) path of a high-pressure gas. As the bar or ball rotates, a small pulse of gas is allowed to
enter the airway. Expiration, again, is passive.
(5) High-frequency oscillatory ventilation (HFOV). gas exchange is made possible by
generating oscillations in the airways at a frequency of 15 Hz. The oscillations could be
generated either by a loudspeaker or an electronically driven piston pump. Gas is pushed
into the lung during inspiration, and actively pulled out during expiration. Thus, both
expiration and inspiration are active processes.
e. Gas exchange mechanisms during HF: There are seven potential mechanisms:
(1) Direct ventilation of most proximal alveoli units by bulk convection
(2) Pendalluft effect – asynchronous flow among alveoli due to asymmetries in airflow
impedance. This cause gas to recirculate among lung units and improve gas exchange
(3) Turbulence in the large airways causing enhanced gas mixing
(4) Turbulent flow with lateral convective mixing
(5) Taylor dispersion – laminar flow with lateral transport by diffusion
(6) Collateral ventilation through non-airway connections between neighbouring alveoli
(7) Asymmetric velocity profiles – convective gas transport is enhanced by asymmetry
between inspiratory and expiratory velocity profiles that occur at branch points in the
airways.

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f. Clinical indications:
(1) Neonate with DAD (Diffuse alveolar damage): ARDS, lung contusion, pneumonia.
(2) Children with air leak or small airway disease (SAD): problems with an increased airway
resistance and hyperinflation on chest X-ray.
(3) Patients with severe persistent hypoxic failure are most likely to benefit from HFV. HFV is
also helpful in patients with bronchopleural fistula and persistent air leaks
g. Settings:
(1) The two most investigated techniques of HFV are high-frequency oscillation (HFO) and
high frequency jet ventilation (HFJV).
(2) The most commonly used HFV modality is HFO, which employs a mechanism to generate
to-and-fro air movement. Air is pushed in during inspiration and actively sucked out during
expiration.
(3) Commonly used respiratory frequency varies from 5 Hz (300 breaths/min) in adults and
older children, to 6-8 Hz (360-480 breaths/min) in young children, 8-10 Hz (480-600
breaths/min) in infants, and 10-12 Hz (600-720 breaths/min) in newborn and premature
babies.

EXTRA CORPOREAL MEMBRANE OXYGENATION (ECMO)
1. It is a modification of conventional cardio pulmonary bypass used to support heart and lungs for extended
periods of time till the underlying disease process is treated. The advent of cardio pulmonary bypass for open
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heart surgery has paved the way for establishing other life supporting systems like ECMO.
2. In 1937, the first attempt at extracorporeal oxygenation was made by the direct bubbling of oxygen gas into
blood. These oxygenators caused severe hemolysis and protein denaturation, which was a result of the direct
blood-gas interface. In order to overcome this complication, use of a semi permeable membrane oxygenator
was implemented. This prevented direct contact of blood and gas, and the concept of prolonged
extracorporeal support was born.
3. Indications of ECMO
a. Cardiac indications have been limited to children with intractable cardiac failure after cardiothoracic
surgery, but the use has been increased in patients with severe viral myocarditis, toxic myocardial
depression, intractable arrhythmias.
b. Most recently, ECMO has been used as a tool for resuscitation on patients with cardiopulmonary
arrest, and some centers have used ECMO for support of donor abdominal organs.
4. Eligibility criteria for Respiratory ECMO :
a. Reversible respiratory failure is an absolute basic requirement to consider ECMO in any patient.
b. The patient should have been treated with maximal conventional support for the optimal time period
before considering ECMO.
c. Patient shouldn't have any contra-indication for anti-coagulants like heparin.
d. There should not be any intra cerebral bleed or intra ventricular bleed greater than grade 2( in
premature, term newborns or infants).
5. Clinical Indications for ECMO for respiratory conditions in Pediatrics:
a. Severe ARDS refractory to maximal conventional treatment stands out as the major factor for which
we consider respiratory ECMO. The etiology of ARDS might differ. It could be secondary to bacterial
pneumonias, malaria, tuberculosis or viruses. In recent days, the efficacy of ECMO in supporting
patients with H1N1 has been very well established. Other common indications include
b. Meconium aspiration syndrome
c. Severe bronchiolitis
d. Inhalation pneumonia (post burns)
e. Post traumatic lung contusions
f. Acute chest syndrome (Sickle chest)
g. Status asthmaticus
h. Persistent air leaks
a. Reactive Pulmonary hypertension in neonatal period (reversible)
b. Congenital diaphragmatic hernia
c. Near drowning etc.
6. Cardiac ECMO Indications:
a. Reversible cardiac failure
b. Pre – operative stabilization
c. Failure to wean from Cardiopulmonary Bypass
d. Low cardiac output syndrome (post operatively)
e. Myocarditis (post viral, poisonings like scorpion sting etc)
f. Intractable arrhythmias
g. Post Cardiac arrest
h. Reversible pulmonary Hypertension
7. Technique
a. The two basic types of ECMO are venoarterial (VA) and venovenous (VV). This terminology describes the
direction of blood flow. The outflow is always venous but the inflow can be arterial (VA) or venous (VV).
b. Outflow of blood in VA and VV ECMO is from the right atrium through a catheter placed through the right
internal jugular vein. In older patients, other venous sites have been used. In VA mode, after oxygenation
in the ECMO circuit, the blood is returned to the patient through an arterial cannula, which is placed in
the ascending aorta through the right common carotid artery.
c. A cannula can also be placed directly into the right atrium and the aorta through a sternotomy. Patients
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with profound left ventricular failure need a left atrial or ventricular catheter to obtain decompression of
the left heart.
d. The artery that was cannulated is permanently ligated. The effect of this is unknown. Some centers have
begun repairing the artery at decannulation. Repairs had an early patency rate of 90 percent in some
centers.
e. VV: Patients with normal cardiac function, as well as those with severe pulmonary disease, may be
candidates for VV ECMO support. Cannulation is done at the bedside under deep sedation and analgesia.
A double lumen venous cannula has been used in neonates, and in adults, the blood is returned to the
distal iliac vein of the inferior vena cava.
Membrane oxygenator:
a. After exiting the bladder, the blood is actively pumped by a roller pump into a membrane oxygenator. The
oxygenator consists of a hollow silicon envelope placed inside a silicone sleeve. The blood flows on the
outside of the coiled envelope, and the gas flows in a counter-current direction inside the membrane. The
size of the membrane is chosen according to patient size. There is an effective gas exchange here. Next,

the blood flows into a heat exchanger, and then, it is infused back into the patient.
Mechanical Complications
a. The most common mechanical problems are oxygenator failure, tubing rupture or leak, cannula kinking,
power failure, air in the circuit, and accidental decannulation.
Patient Complications
a. Bleeding from heparinization is a common complication. Intracranial hemorrhage is catastrophic. Daily
head ultrasounds are performed on infants with open fontanels. As any other site can be involved just as
easily, a high index of suspicion is needed.
b. Since infection is also problematic, frequent surveillance cultures are ordered on all ECMO patients
Prophylactic antibiotics are not used to treat infection.
c. Embolization is another risk, especially with VA ECMO, and can consist of a clot, air, or particulate matter.
A bubble trap is added to the arterial side of the circuit in an attempt to reduce this risk.
d. Sensorineural hearing loss is a long-term complication with a reported incidence rate as high as 24
percent.
APPARENT LIFE-THREATENING EVENTS IN CHILDREN
Definition:
Apparent life-threatening event (ALTE): sudden event, frightening to the observer, in which the infant
exhibits a combination of symptoms, including apnea, change in color (pallor, redness, cyanosis,
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plethora), change in muscle tone (floppiness, rigidity), choking, gagging, or coughing. In some cases, the
observer fears that the infant has died.
Incidence:
1) The exact frequency and prevalence of ALTEs are not known, although rates have been estimated as
0.21% of all children and 0.6% of all patients younger than 1 year seeking care at an emergency
department or as 9.4 per 1000 live births.
2) Recurrence rates for ALTEs vary from 0% to 24%.
3) The median age of presentation of infants with an ALTE ranges between 7 and 8 weeks of age;
4) sex distribution is relatively equal.
5) Approximately one third of patients with an ALTE had a history of prematurity, and 19% had a history of a
previous ALTE.
6) The morbidity and mortality resulting from an ALTE vary by the underlying diagnosis; the mortality of
infants with apnea of infancy ranges between 0% and 6%.
Etiology:
1. Approximately 50% of all ALTE will be idiopathic; Most common specific diagnoses associated with
ALTEs include gastroesophageal reflux, seizures, and lower respiratory tract infections.
2. The following is a list of common etiologies for ALTE
1) Gastrointestinal (appox. 50%)
i. GERD
ii. Gastric volvulus
iii. Intussusception
iv. Swallowing abnormalities
2) Neurologic (approx. 30%)
i. Seizure disorder
ii. Febrile seizure
iii. Intracranial hemorrhage
iv. Brain malformations (Budd-Chiari, brainstem malformation)
v. Hydrocephalus
vi. CNS infection (meningitis, encephalitis)
vii. Malignancy
3) Respiratory (approx. 20%)
i. Infection (RSV, Pertussis, Mycoplasma, Croup, pneumonias)
ii. Obstructive sleep apnea
iii. Breath-holding spells
iv. Laryngotracheomalacia
v. Foreign body aspiration
4) Cardiovascular (up to 5%)
i. Arrhythmia (prolonged QT, WPW)
ii. Congenital heart disease
iii. Myocarditis
iv. Cardiomyopathy
5) Metabolic (up to 5%)
i. Inborn errors of metabolism
ii. Endocrine, electrolyte abnormalities
iii. UTI/Sepsis
6) Child Abuse (3%)
i. Munchausen syndrome by proxy
ii. Smothering
7) Other
i. Food allergy
ii. Anaphylaxis
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iii. Medication (OTC, prescription, herbal)

8) Recurrences occur in 0-24% of patients, depending on the study.
Evaluation and Hospitalization
1) Almost all ALTE patients require hospitalization for observation and/or further work-up.
2) Any patient with an abnormal physical exam or that required resuscitation should definitely be
admitted.
3) Physical examination must include a growth chart (wt, ht, hc) as well as focus on dysmorphic
features, neurologic exam, and signs of trauma (bleeding from nose or mouth, bruising)
4) Laboratory and imaging studies should be performed on the basis of the history and physical
examination
Management:
1) Apnea requires vigorous stimulation and CPR.
2) Management of GERD includes feeding management (i.e., keeping the child upright after feeding,
adequate burping, raising the head of the bed for sleep, placing the child on his or her side for sleep,
thickening formula), medical management with histamine H2-receptor antagonists and, in severe
cases, surgical intervention (Nissen fundoplication).
3) Continuous home monitoring
Prognosis:
1) Overall mortality rate of zero to 4 percent in childhood.
2) In terms of the risk for SIDS, ALTEs are observed in a small number of children who eventually die of
SIDS.
SUDDEN INFANT DEATH SYNDROME
Crib or Cot death
Definition:
The sudden, unexpected death of an infant that is unexplained by postmortem examination, which
includes a complete autopsy, investigation of the scene of death, and review of the medical history,
constitutes sudden infant death syndrome (SIDS).
Epidemiology:
1. SIDS is the 3rd leading cause of infant mortality in the USA, accounting for 8% of all infant deaths. It is the
most common cause of postneonatal infant mortality, accounting for 40-50% of all deaths between 1 mo
and 1 yr of age.
2. In countries with decreased prone sleeping prevalence it is ≤2%,
Pathology:
1. There are no autopsy findings pathognomonic for SIDS and no findings required for the diagnosis,
although there are some common findings.
2. Petechial hemorrhages are found in 68-95% of cases and pulmonary edema is often present. The reasons
for these findings are unknown. SIDS victims have several identifiable changes in the lungs and other
organs and in brainstem structure and function.
3. Nearly 65% of SIDS victims have structural evidence of pre-existing, chronic low-grade asphyxia, and other
studies have identified biochemical markers of asphyxia.
4. SIDS infants have hypoplasia of the arcuate nucleus.
5. There are extensive serotoninergic brainstem abnormalities in SIDS infants, including increased 5-HT
neuronal count, a lower density of 5-HT1A receptor-binding sites in regions of the medulla.
Environmental risk factors:
1. Maternal:
a. Elevated 2nd trimester serum α-fetoprotein
b. Smoking
c. Alcohol use
d. Drug use (cocaine, heroin)
e. Nutritional deficiency
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2. Infant:
a. Age (peak 2-4 mo, but may be decreasing)
b. Male gender
c. Race and ethnicity (African-American and Native American)
d. Growth failure
e. No breast-feeding
f. No pacifier (dummy)
g. Prematurity
h. Prone and side sleep position
i. Recent febrile illness (mild infections)
j. Inadequate immunizations
k. Infants with an unexplained apparent life-threatening event (ALTE) are at increased risk for SIDS.
Genetic risk factors: The following genetic abnormalities are considered in the etiopathogenesis of SIDS:
1. Cardia channelopathies
2. Serotonin (5-ht)
3. Genes pertinent to development of autonomic nervous system
4. Mitochondrial dna (mtdna) polymorphisms
5. Vascular endothelial growth factor (vegf) (pro-inflammatory)
Pregnancy-Related Factors
1. SIDS infants are more commonly of higher birth order, independent of maternal age, and of
gestations after shorter interpregnancy intervals. Mothers of SIDS infants generally receive less
prenatal care and initiate care later in pregnancy.
2. Additionally, low birthweight, preterm birth, and slower intrauterine and postnatal growth rates are
risk factors.
3. Cigarette Smoking: There is a major association between intrauterine exposure to cigarette smoking
and risk for SIDS.
4. Maternal prenatal drug use, especially opiates, with an increased risk of SIDS
5. A number of studies have demonstrated a protective effect of breast-feeding
Reducing the Risk of SIDS:
1. Full-term and premature infants should be placed for sleep in the supine position. Side sleeping is not
recommended.
2. Placing the crib or bassinette near the mother’s bed facilitates nursing and contact.
3. Infants should be put to sleep on a firm mattress.
4. Consider offering a pacifier at bedtime and naptime.
5. Mothers should not smoke during pregnancy and infants should not be exposed to second hand
smoke.


SYSTEMIC LUPUS ERYTHEMATOSUS
Definition:
1. Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by multisystem
inflammation and the presence of circulating autoantibodies directed against self-antigens.
2. SLE occurs in children and adults, disproportionately affecting women of reproductive age.
3. It is a multisystem disease and most commonly affected organs are the skin, joints, kidneys, blood-
forming cells, blood vessels, and central nervous system.
4. children and adolescents with SLE have more severe disease
ETIOLOGY
1. The pathogenesis of SLE remains unknown, but genetics, hormone (estrogen), and environmental
exposures play a role.
2. Genetics:
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a. family history often present

b. congenital deficiencies of C1q, C2, and C4 seen in SLE
c. HLA types (including HLA-B8, HLADR2, and HLA-DR3)
3. Estrogen:
a. Ninety percent of individuals with SLE are female, making gender the strongest risk factor for
SLE.
b. Estrogens are likely to play a role in SLE, and in vitro and animal model studies suggest that
estrogen exposure promotes B-cell autoreactivity.
c. Estrogen-containing oral contraceptives do not appear to induce flares in quiescent SLE, but the
risk of flares may be increased in postmenopausal women receiving hormone replacement.
4. Environmental exposure:
a. Viral infections (including Epstein-Barr virus)
b. ultraviolet light exposure is known to aggravate SLE
EPIDEMIOLOGY
1. In children and adolescents: 1-6/100,000 is lower than that
2. In adults: 20-70/100,000.
3. Female: male - 5 : 1 ratio prior to puberty, a 9 : 1 ratio during reproductive years
4. Rare before 5 yr of age and is usually diagnosed in adolescence.
PATHOLOGY
1. Renal biopsies: Immune complexes are found with “full house” deposition of immunoglobulin and
complement.
2. Discoid rash is characterized on biopsy by hyperkeratosis, follicular plugging, and infiltration of
mononuclear cells into the dermal-epidermal junction.
3. 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
1. Autoantibodies, cytokines, and aberrant lymphocyte function have important roles in 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.
2. 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.
3. 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.
4. Circulating autoantibodies may form immune complexes and deposit in tissues, leading to local
complement activation, initiation of a proinflammatory cascade, and, ultimately, tissue damage.
5. Antibodies to double-stranded DNA can form immune complexes, deposit in glomeruli, and initiate
inflammation leading to glomerulonephritis. Many individuals with SLE have circulating antibodies to
double-stranded DNA yet do not have nephritis, suggesting that autoantibodies alone are not sufficient
to causedisease.
6. Individuals with SLE frequently demonstrate abnormal cytokine levels.
7. Both B and T cells demonstrate functional impairments in SLE.
8. T-cell abnormalities in SLE include increased numbers of memory T cells and decreased number and
function of T regulatory cells. SLE T cells display aberrant signaling and increased autoreactivity. As a
result, they are resistant to attrition by normal apoptosis pathways.
CLINICAL MANIFESTATIONS
1. Any organ system can be involved in SLE, so the potential clinical manifestations are protean.
2. 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,
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and arthritis. Renal disease in SLE is often asymptomatic; thus careful monitoring of blood pressure and
urinalyses is critical.
3. SLE is often characterized by periods of flare and disease quiescence or may follow a more smoldering
disease course.
4. The neuropsychiatric complications of SLE may occur with or without apparently active SLE and are
particularly difficult to detect in adolescents, who are already at high risk for mood disorders.
5. Long-term complications of SLE and its therapy, including accelerated atherosclerosis and osteoporosis,
become clinically evident in young to middle adulthood.
6. SLE is a disease that evolves over time in each affected individual, and new manifestations may arise even
many years after diagnosis.
DIAGNOSIS
1. The diagnosis of SLE requires a comprehensive clinical and laboratory assessment revealing characteristic
multisystem disease and excluding other etiologies, including infection and malignancy.
2. Presence of 4 of the 11 American College of Rheumatology 1997 Revised Classification Criteria for SLE
simultaneously or cumulatively establishes the diagnosis of SLE.
3. Of note, although a positive antinuclear antibody (ANA) test result is not required for the diagnosis of SLE,
ANA-negative lupus is extremely rare.
4. Hypocomplementemia, although common in SLE, is not represented among the classification criteria.
DIFFERENTIAL DIAGNOSIS
1. Multi organ disease is the hallmark of SLE, and 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.
2. 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.
3. 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. Unlike SLE, drug-induced lupus affects males and females equally. An
inherited predisposition toward slow acetylation may increase the risk of drug-induced lupus. Circulating
antihistone antibodies are often present in drug-induced SLE, and these antibodies are detected in up to
20% of individuals with SLE. Hepatitis, which is rare in SLE, is more common in drug-induced lupus.
Individuals with drug-induced lupus are less likely to demonstrate antibodies to double-stranded DNA,
hypocomplementemia, and significant renal or neurologic disease. In contrast to SLE, manifestations of
drug-induced lupus resolve after withdrawal of the offending medication; complete recovery may take
several months to years.
American College Of Rheumatology 1997 Revised Classification Criteria For SLE
1. Malar rash
2. Discoid rash
3. Photosensitivity
4. Oral or nasal ulcers
5. Arthritis: Nonerosive, affecting 2 or more joints
6. Serositis: Pleuritis, pericarditis, peritonitis
7. Renal manifestations: Persistent proteinuria or cellular casts; Consistent renal biopsy
8. Seizure or psychosis
9. Hematologic manifestations:
a. Hemolytic anemia
b. Leukopenia (<4,000 leukocytes/mm3)
c. Lymphopenia (<1,500 leukocytes/mm3)
d. Thrombocytopenia (<100,000 thrombocytes/mm3)
10. Immunologic abnormalities:
a. Positive anti–double-stranded DNA or anti-Smith antibody test result
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b. False-positive rapid plasma regain RPR test result, positive lupus anticoagulant test result, or
elevated anticardiolipin immunoglobulin (Ig) G or IgM antibody
c. Positive antinuclear antibody test result
*The presence of 4/11 criteria establishes the diagnosis of SLE.
LABORATORY FINDINGS
a. A positive ANA test result is present 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.
b. Antibodies to double-stranded DNA are more specific for SLE, and in some individuals, anti dsDNA levels
correlate with disease activity, particularly nephritis.
c. Anti-Smith antibody, although found specifically in patients with SLE, does not correlate with disease
activity.
d. Serum levels of total hemolytic complement (CH50), C3, and C4 are typically decreased in active disease
and often improve with treatment.
e. Hypergammaglobulinemia is a common but nonspecific finding.
f. Inflammatory markers, particularly erythrocyte sedimentation rate, are often elevated in active disease.
C-reactive protein (CRP) correlates less well with disease activity, and elevated CRP values may reflect
infection.
g. Antiphospholipid antibodies, which increase clotting risk, can be found in up to 66% of children and
adolescents with SLE. Antiphospholipid antibodies can be detected by several means, and laboratory
features that point to the presence of these antibodies include the presence of anticardiolipin antibodies,
prolonged phospholipid-dependent coagulation test results (partial thromboplastin time, dilute Russell
viper-venom time), and a circulating lupus anticoagulant (which confirms that a prolonged partial
thromboplastin time is not corrected with mixing studies).
TREATMENT
a. Treatment of SLE is tailored to the individual, being based on specific disease manifestations and
tolerability.
b. For all patients, sunscreen and avoidance of prolonged direct sun exposure and other ultraviolet light may
help control disease.
c. Hydroxychloroquine (5-7 mg/kg/day) is recommended for all individuals with SLE if tolerated. In addition
to treating mild SLE manifestations such as rash and mild arthritis, hydroxychloroquine prevents SLE
flares, improves lipid profiles, and may have a beneficial impact on mortality and renal outcomes.
Potential toxicities include retinal pigmentation, impairing color vision; therefore, ophthalmology exams
every 6-12 mo are recommended.
d. Nonsteroidal anti-inflammatory agents (NSAIDs) can be useful for management of arthralgias and
arthritis; it is important to keep in mind their potential hepatic, renal, and cardiovascular toxicities.
e. Corticosteroids are a mainstay for treatment of significant manifestations of SLE; side effects often limit
patient compliance, especially in adolescence, and potential toxicities are worrisome. severe disease is
often treated with 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.
f. Steroid-sparing immunosuppressive agents often used in the treatment of pediatric SLE include
methotrexate, leflunomide, azathioprine, mycophenolate mofetil, and cyclophosphamide.
g. While a randomized, controlled, double-blind trial did not suggest that rituximab is an effective treatment
for significant glomerulonephritis, this agent has not been studied in children or in refractory disease.
h. Clinical trials are in progress to assess the safety and efficacy of several biologic agents in SLE, including
monoclonal antibodies targeting antiphospholipid antibody syndrome are treated with long-term
anticoagulation to prevent future thrombotic events.
i. 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.
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j. Adequate intake of calcium and vitamin D is necessary to prevent future osteoporosis.

k. Infections commonly complicate SLE, so routine immunization is recommended, including annual
influenza vaccination and administration of the 23-valent pneumococcal vaccine.
l. 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
a. Within the first several years of diagnosis, the most common causes of death in individuals with SLE
include infection and complications of glomerulonephritis and neuropsychiatric disease
b. Over the long term, the most common causes of mortality include complications of atherosclerosis and
malignancy.
c. 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.
PROGNOSIS
a. Owing to advances in the diagnosis and treatment of SLE, survival has improved dramatically over the
past 50 years. Currently, the 5-year survival rate for pediatric SLE is >90%.