LBM 4 SYARAF REZTRY

STEP 1
1. Parethesi : perasaan yang menyimpang, sensasi abnormak seperti
kesmutan, rasa terbakar, di tusuk-tusuk.
2. hipotensi orthostatic : decrease blood pressure after change position from
sit to stand.

STEP 2
1. why the patient difficulty in walking, numbness in her two legs ?
2. why the patient complain of burning in her leg and stiffness in lower
extremity?
3. Why she has fine motor disturbances like unscrewing jar lids and
paresthesia in fingers?
4. What are the risk factor and etiology in scenario ?
5. What the diagnosis and DD?
6. Why does the autonomic show a sweating abnormality and orthostatic
hypotension ?
7. How are the pathogenesis and patofisologi of the scenario?
8. What is the relation between increase glucose and the symptom patient ?
9. What kind of the pharmacological ?
10.What are the physical and additional examination?

STEP 7
1. why the patient difficulty in walking, numbness in her two legs ?
Diabetic neuropathy can be classified as peripheral, autonomic, proximal, or focal. Each
affects different parts of the body in various ways.

Peripheral neuropathy, the most common type of diabetic neuropathy, causes pain or

loss of feeling in the toes, feet, legs, hands, and arms.

Autonomic neuropathy causes changes in digestion, bowel and bladder function,

sexual response, and perspiration. It can also affect the nerves that serve the heart and
control blood pressure, as well as nerves in the lungs and eyes. Autonomic neuropathy
can also cause hypoglycemia unawareness, a condition in which people no longer
experience the warning symptoms of low blood glucose levels.
Proximal neuropathy causes pain in the thighs, hips, or buttocks and leads to

weakness in the legs.

Focal neuropathy results in the sudden weakness of one nerve or a group of nerves,
causing muscle weakness or pain. Any nerve in the body can be affected.

Neuropathy Affects Nerves Throughout the Body

Peripheral neuropathy affects

toes
feet
legs
hands
arms

Autonomic neuropathy affects

heart and blood vessels

digestive system
urinary tract
sex organs
sweat glands
eyes
lungs

Proximal neuropathy affects

thighs
hips
buttocks
legs

Focal neuropathy affects

eyes
facial muscles
ears
pelvis and lower back
chest
abdomen
thighs
legs
feet
http://diabetes.niddk.nih.gov/dm/pubs/neuropathies/

Peripheral Neuropathy
This type usually affects the feet and legs. Rare cases affect the arms, abdomen, and back.
Symptoms include:

Tingling

Numbness (which may become permanent)

Burning (especially in the evening)

Pain
Early symptoms usually get better when your blood sugar is under control. There are
medications to help manage the discomfort.
What you should do:

Check your feet and legs daily.

Use lotion on your feet if they're dry.

Take care of your toenails. Ask your doctor if you should go to a podiatrist.

Wear shoes that fit well. Wear them all the time, so your feet don't get injured.

Autonomic Neuropathy

This type usually affects the digestive system, especially the stomach. It can also affect the
blood vessels, urinary system, and sex organs.
In your digestive system:
Symptoms include:

Bloating

Diarrhea

Constipation

Heartburn

Nausea

Vomiting

Feeling full after small meals

What you should do: You may need to eat smaller meals and take medication to treat it.
In blood vessels:
Symptoms include:

Blacking out when you stand up quickly

Faster heartbeat

Dizziness

Low blood pressure

Nausea

Vomiting

Feeling full sooner than normal

If you have it: Avoid standing up too quickly. You may also need to wear special stockings
(ask your doctor about them) and take medicine.
In Men:
Symptoms include: He may not be able to have or keep an erection, or he may have dry or
reduced ejaculations.
What you should do: See your doctor, because there are other possible causes than diabetes.
Treatment includes:

Counseling

Penile implant or injections

Vacuum erection device

Medication
In Women:

Symptoms include: Can include less vaginal lubrication and fewer or no orgasms.
What you should do: See your doctor. Treatments include:

Vaginal estrogen creams, suppositories, and rings

Medications to help sex not feel painful

Lubricants
In the Urinary System:
Symptoms include:

Trouble emptying your bladder

Bloating

Incontinence (leaking urine)

More bathroom trips at night

What you should do: Tell your doctor. Treatments may include:

Medication

Inserting a catheter into the bladder to release urine (self-catheterization)

Surgery
http://www.webmd.com/diabetes/diabetes-neuropathy

2. why the patient complain of burning in her leg and stiffness in

lower extremity?
Peripheral neuropathy, also called distal symmetric neuropathy or sensorimotor neuropathy,
is nerve damage in the arms and legs. Feet and legs are likely to be affected before hands
and arms. Many people with diabetes have signs of neuropathy that a doctor could note but
feel no symptoms themselves. Symptoms of peripheral neuropathy may include

numbness or insensitivity to pain or temperature

a tingling, burning, or prickling sensation

sharp pains or cramps

extreme sensitivity to touch, even light touch

loss of balance and coordination

These symptoms are often worse at night.

Peripheral neuropathy affects the nerves in your toes, feet, legs, hands, and arms.

Peripheral neuropathy may also cause muscle weakness and loss of reflexes, especially at
the ankle, leading to changes in the way a person walks. Foot deformities, such as
hammertoes and the collapse of the midfoot, may occur. Blisters and sores may appear on
numb areas of the foot because pressure or injury goes unnoticed. If an infection occurs and
is not treated promptly, the infection may spread to the bone, and the foot may then have to
be amputated. Many amputations are preventable if minor problems are caught and treated
in time.

http://diabetes.niddk.nih.gov/dm/pubs/neuropathies/
3. Why does the autonomic show a sweating abnormality and
orthostatic hypotension ?

Autonomic neuropathy affects the nerves that control the heart, regulate blood pressure,
and control blood glucose levels. Autonomic neuropathy also affects other internal organs,
causing problems with digestion, respiratory function, urination, sexual response, and vision.
In addition, the system that restores blood glucose levels to normal after a hypoglycemic
episode may be affected, resulting in loss of the warning symptoms of hypoglycemia.

Autonomic neuropathy affects the nerves in your heart, stomach, intestines, bladder, sex organs, sweat glands, eyes,
and lungs.

Hypoglycemia Unawareness
Normally, symptoms such as shakiness, sweating, and palpitations occur when blood
glucose levels drop below 70 mg/dL. In people with autonomic neuropathy, symptoms may
not occur, making hypoglycemia difficult to recognize. Problems other than neuropathy can
also cause hypoglycemia unawareness.
Heart and Blood Vessels
The heart and blood vessels are part of the cardiovascular system, which controls blood
circulation. Damage to nerves in the cardiovascular system interferes with the body's ability
to adjust blood pressure and heart rate. As a result, blood pressure may drop sharply after

sitting or standing, causing a person to feel light-headed or even to faint. Damage to the
nerves that control heart rate can mean that the heart rate stays high, instead of rising and
falling in response to normal body functions and physical activity.
Digestive System
Nerve damage to the digestive system most commonly causes constipation. Damage can
also cause the stomach to empty too slowly, a condition called gastroparesis. Severe
gastroparesis can lead to persistent nausea and vomiting, bloating, and loss of appetite.
Gastroparesis can also make blood glucose levels fluctuate widely, due to abnormal food
digestion.
Nerve damage to the esophagus may make swallowing difficult, while nerve damage to the
bowels can cause constipation alternating with frequent, uncontrolled diarrhea, especially at
night. Problems with the digestive system can lead to weight loss.
Urinary Tract and Sex Organs
Autonomic neuropathy often affects the organs that control urination and sexual function.
Nerve damage can prevent the bladder from emptying completely, allowing bacteria to grow
in the bladder and kidneys and causing urinary tract infections. When the nerves of the
bladder are damaged, urinary incontinence may result because a person may not be able to
sense when the bladder is full or control the muscles that release urine.
Autonomic neuropathy can also gradually decrease sexual response in men and women,
although the sex drive may be unchanged. A man may be unable to have erections or may
reach sexual climax without ejaculating normally. A woman may have difficulty with arousal,
lubrication, or orgasm.
Sweat Glands
Autonomic neuropathy can affect the nerves that control sweating. When nerve damage
prevents the sweat glands from working properly, the body cannot regulate its temperature
as it should. Nerve damage can also cause profuse sweating at night or while eating.
Eyes
Finally, autonomic neuropathy can affect the pupils of the eyes, making them less
responsive to changes in light. As a result, a person may not be able to see well when a light
is turned on in a dark room or may have trouble driving at night.
http://diabetes.niddk.nih.gov/dm/pubs/neuropathies/

4. What is the relation between increase glucose and the symptom

patient ?

Abnormalitas vaskuler yang terjadi pada pasien dengan diabetik

polineuropati meliputi penebalan membran basalis dinding pembuluh
darah, endotelial hiperplasia, disfungsi endotelial, peningkatan ekspresi
endotelin dan peningkatan kadar vascular endotelial growth factor
(VEGF). Diabetes secara selektif merusak sel, seperti endotelial sel dan
mesangial sel, dimana kecepatan pengangkutan glukosa tidak merosot
dengan cepat seperti halnya hasil peningkatan kadar gula, hal ini
mendorong ke arah penumpukan glukosa tinggi dalam sel. Berdasarkan
teori ini, terjadi proses iskemia endoneurial yang berkembang karena
adanya peningkatan endoneural vascular resistance terhadap daerah
hiperglikemi. Berbagai faktor berkenaan dengan metabolisme,
termasuk pembentukan glycostatin end product, juga telah mencakup,
mendorong ke arah kerusakan kapiler, inhibisi transpor aksonal,
aktivitas Na+/K+ATPase, dan akhirnya ke degenerasi aksonal.(Sjahrir,
2006)

Jalur utama Hiperglikemi Menyebabkan Injury Sel.

Hyperglycemia activates many signaling mechanisms in cells. Four major pathways that can
lead to cell injury downstream of hyperglycemia are illustrated. 1) Excess glucose shunts to the
polyol pathway that depletes cytosolic NADPH and subsequently GSH. 2) Excess glucose also
undergoes autooxidation to produce AGEs that impair protein function and also activate RAGEs
that useROSas second messengers. 3) PKC activation both further increases hyperglycemia
and also exacerbates tissue hypoxia. 4) Overload and slowing of the electron transfer chain
leads to escape of reactive intermediates to produce O2_. as well as activation of NADH
oxidase that also produces O2 A unifying mechanism of injury in each case is the production of
ROS that impair protein and gene function. TCA, Trichloroacetic acid; PAI-1, plasminogen
activator inhibitor-1.

Dikutip dari : Vincent A.M, Russel JW, Low P, Feldman EL. 2004.
Oxidative Stress in the Pathogenesis of Diabetic Neuropathy. Endocrine
Reviews. 26(4):S12-S28.
5. What are the risk factor and etiology in scenario ?

Dikutip dari :Fazan V.P.S.,Vasconcelos, Nessler.2010. Diabetic

Peripheral Neuropathies: a morphometric overview.
Int.J.Morphol.28(1):51-64.
RISK FACTOR
Anyone who has diabetes can develop neuropathy, but these factors make you more susceptible to
nerve damage:

Poor blood sugar control. This is the greatest risk factor for every complication of diabetes,
including nerve damage. Keeping blood sugar consistently within your target range is the best way to
protect the health of your nerves and blood vessels.

Length of time you have diabetes. Your risk of diabetic neuropathy increases the longer you
have diabetes, especially if your blood sugar isn't well-controlled.

Kidney disease. Diabetes can cause damage to the kidneys, which may increase the toxins
in the blood and contribute to nerve damage.

Being overweight. Having a body mass index greater than 24 may increase your risk of
developing diabetic neuropathy.

Smoking. Smoking narrows and hardens your arteries, reducing blood flow to your legs and

feet. This makes it more difficult for wounds to heal and damages the integrity of the peripheral
nerves.

http://www.mayoclinic.org/diseases-conditions/diabeticneuropathy/basics/risk-factors/con-20033336
7. What the diagnosis and DD?

Diagnostik neuropati ditegakkan berdasarkan adanya gejala dua atau lebih dari empat
kriteria dibawah ini : (Sjahrir,2006)
1. Kehadiran satu atau lebih gejala
2. Ketidakhadiran dua atau lebih refleks ankle atau lutut
3. Nilai ambang persepsi getaran/vibration-abnormal.
4. Fungsi otonomik abnormal (berkurangnya heart rate variability (HRV) dengan
rasio RR kurang dari 1,04 postural hypotension dengan turunnya tekanan darah
sistolik 20 mmHg atau lebih, atau kedua-duanya).

Differential Diagnosis
Disease/Condition

Differentiating Signs/Symptoms

Differentiating Tests

Uremia

Various signs associated with the

primary cause for end-stage renal
disease (ESRD) may be present.

Abnormal BUN, creatinine, GFR consistent

with ESRD.

May coexist with DN.

Cyanocobalamin
deficiency

Poor nutrition, alcoholism, certain drugs CBC reveals macrocytic anemia.

(e.g., trimethoprim, methotrexate,
phenytoin), pernicious anemia, atrophic Reduced serum vitamin B12 levels.
gastritis, malabsorption, or infection
withHelicobacter pylori more likely to be
present.
Patients are more likely to be older (>65
years).

Hypothyroidism

Fatigue, cold intolerance, weight gain, TSH elevated in primary hypothyroidism.

constipation, myalgia, menstrual
irregularities, delayed relaxation of deep Free serum T4 may be low.
tendon reflexes, bradycardia (if severe).

Acute intermittent

Abdominal pain, vomiting, muscle

Elevated aminolevulinic acid,

Disease/Condition

Differentiating Signs/Symptoms

Differentiating Tests

porphyria

weakness, constipation, fever, diarrhea, porphobilinogen.

sensory loss, seizures, tachycardia,
hypertension may all occur.
Abdominal pain is severe and more
typical than in DN.

Chronic high
alcohol intake

Signs of malnutrition, Wernicke

encephalopathy, and Korsakoff
amnestic syndrome may be present.

Severe cases present with associated

anemia, thiamine deficiency, and deranged
LFTs.

Heavy metal
poisoning

May present with a peripheral

Abnormally high blood levels of lead or other
neuropathy that frequently manifests
metals.
with extensor weakness (or wrist/ankle
drop), due to an axonal degeneration,
primarily affecting motor nerves.
Abdominal pain ("lead colic"),
constipation, joint pains, muscle aches,
headache, anorexia, decreased libido,
difficulty concentrating and deficits in
short-term memory, anemia,
nephropathy, and other symptoms and
signs in various combinations.

Drug-induced
neuropathy

Diabetes less likely and drug history

No differentiating investigations.
likely to include a drug that is known to
be a risk for development of
neuropathy, such as (in descending
order of likelihood of association)
antivirals, antibacterials, antineoplastic
and immunosuppressants, and
cardiovascular, CNS, GI, and
metabolism agents.
History may include the following
specific drugs suspected of causing
neuropathies: stavudine, didanosine,
lamivudine, thalidomide, ritonavir,

Disease/Condition

Differentiating Signs/Symptoms

Differentiating Tests

zalcitabine, and amiodarone.

Chronic
People with diabetes may develop
inflammatory
features of CIDP.
demyelinating
neuropathy (CIDP) Severe, predominantly motor
neuropathy that is progressive in
nature. Features progress despite
optimal glycemic control.

May be difficult to differentiate.

Nerve conduction studies show a
combination of slowed conduction velocities,
prolonged distal latencies, prolonged F-wave
latencies, and conduction block in 1 nerves.
Nerve biopsies demonstrate increased
numbers of macrophages.
Unusually high CSF protein.

Sarcoidosis

Various signs, including fever, skin

signs (e.g., erythema nodosum), joint
and/or eye lesions.

CXR may show bilateral hilar

lymphadenopathy and pulmonary reticular
opacities.
Biopsies of accessible lesions are diagnostic.

Leprosy

Polyarteritis
nodosa (PAN)

Travel to or residence in endemic

countries.

Skin smear is positive for acid-fast bacilli

(AFB).

Nerves commonly involved include the

ulnar and median (claw hand), the
common peroneal (foot drop), the
posterior tibial (claw toes and plantar
insensitivity), facial, radial cutaneous,
and great auricular.

Biopsy of lesions reveal the presence of AFB

plus other associated signs.

Systemic symptoms (fatigue,

weakness, fever, arthralgias) and signs
(hypertension, renal insufficiency,
neurologic dysfunction, abdominal pain)
of multisystem involvement more likely.

There is no diagnostic laboratory test for

PAN.
Basic laboratory tests help ascertain the
extent of organs affected and their degree of
involvement.

Disease/Condition

Differentiating Signs/Symptoms

Differentiating Tests

Amyloidosis

Muscle weakness and enlargement due

to amyloid infiltration (myopathy),
disorders of the joints (arthropathy), and
lesions of bone (osteopathy) more likely
to be present.

Presence of a paraprotein in the serum (as

an M protein on protein
immunoelectrophoresis or immunofixation) or
urine (as monoclonal light chains) in
approximately 90% of cases.

Dysproteinemias
and
paraproteinemias

May be no differentiating signs or

symptoms.

Presence of a monoclonal protein in the

serum or urine.

Paraneoplastic
syndrome

Varies, based on primary etiology.

Varies, based on primary etiology.

History of a primary neoplastic

condition.

Leukemias and
lymphomas

Symptoms and signs vary but may

Abnormal blood cell count and bone marrow
include anemia, fever, weight loss, and aspirate.
lymphadenopathy.
Specific abnormalities are diverse depending
on the type of leukemia or lymphoma present.

Hereditary
neuropathies (e.g.,
Charcot-MarieTooth disease)

Both motor and sensory nerve

manifestations more likely, with distal
leg weakness, foot deformities (pes
cavus, hammer toes), and sensory
deficits.

Psychophysiologic May also present with pains and

disorder
paresthesias but without neurologic
deficit.

Genetic testing is diagnostic.

Specific psychological evaluations help to

confirm the diagnosis.

There is no sensory loss.

Multiple system
atrophy/ShyDrager syndrome

May present with symptoms and signs

of autonomic neuropathy, as in DN.

An excellent response to dopaminergic

therapy is an important supportive feature for
establishing the diagnosis.

Disease/Condition

Differentiating Signs/Symptoms

Differentiating Tests

May also have parkinsonism, varying

degrees of dysautonomia, cerebellar
involvement, and pyramidal signs.

Riley-Day
syndrome

Progressive sensorimotor neuropathy,

but sympathetic autonomic dysfunction
is responsible for most clinical
manifestations (orthostatic hypotension,
swallowing dysfunction, GI motility
dysfunction, bladder dysfunction,
decreased or absent tearing, pupil
dilation, hypohidrosis, and episodic
hyperhidrosis).

Genetic evaluation is sensitive and specific

for the diagnosis: a truncated form of I kappa
B kinase complex-associated protein
(IKBKAP) mutation on chromosome 9q31.

Autonomic
neuropathy:
idiopathic
orthostatic
hypotension

Severe postural dizziness and

weakness.

Reduction of systolic BP of at least 20 mmHg,

or diastolic BP of at least 10 mmHg, within
the first 3 minutes of standing.

Guillain-Barre
syndrome

Progressive, fairly symmetric muscle

weakness accompanied by absent or
depressed deep tendon reflexes.

Albuminocytologic dissociation in CSF

(elevated protein with a normal WBC count),
present in 80% to 90% of patients at 1 week
after onset of symptoms.

Weakness can vary from mild difficulty

with walking to nearly complete
paralysis of all extremity, facial,
respiratory, and bulbar muscles.

Myasthenia gravis Fluctuating degree and variable

combination of weakness in ocular,
bulbar, limb, and respiratory muscles.

Antibodies against acetylcholine receptors or

receptor-associated proteins are present.
Tensilon test, ice pack test, repetitive nerve
stimulation studies, and single-fiber EMG
help to confirm diagnosis.

Degenerative

May present with symptoms and signs

MRI demonstrates specific vertebral disk

Disease/Condition

Differentiating Signs/Symptoms

Differentiating Tests

spinal disk disease of a femoral neuropathy, including

asymmetric pain, weakness, and
sensory loss.

pathology.

Femoral
neuropathy:
intrinsic spinalcord-mass lesion

May present with symptoms and signs

of a femoral neuropathy, including
asymmetric pain, weakness, and
sensory loss.

MRI demonstrates the spinal cord mass.

Cauda equina
lesions

May present with symptoms and signs

of a femoral neuropathy, including
weakness and sensory loss.

Diagnosis usually confirmed by MRI.

Carotid aneurysm

May present with symptoms and signs

of a cranial neuropathy, including
diplopia and Bell palsy.

Magnetic resonance angiography and CT

angiography confirm diagnosis.

Mononeuropathy May present with symptoms and signs

multiplex: vasculitis including nerve damage in 2 named
nerves in separate parts of the body.

Vasculitis and lymphocytic infiltrates on nerve

biopsies.

Wrist drop, for example, is caused by

infarction of the radial nerve, and foot
drop by damage to either the sciatic or
peroneal nerve.

Acromegaly

Very slow onset over decades.

Abnormal IGF-1 levels.

Typical clinical phenotype, including

Pituitary MRI may reveal pituitary tumor.
acral and soft tissue overgrowth;
enlargement of jaw, nose, frontal bones,
hands, and feet; articular overgrowth.

Coagulopathies

May present with hemorrhages or

thrombosis.

Abnormal platelets, prothrombin time, Ddimer, fibrinogen, and fibrin degradation

Disease/Condition

Differentiating Signs/Symptoms

Differentiating Tests

products.
diabetes.diabetesjournals.org/.../46/.../S54.full.pdf

6. How are the pathogenesis and patofisologi of the scenario?

PATOPHISIOLOGI
1. Faktor vaskular
Abnormalitas vaskuler yang terjadi pada pasien dengan diabetik polineuropati
meliputi penebalan membran basalis dinding pembuluh darah, endotelial
hiperplasia, disfungsi endotelial, peningkatan ekspresi endotelin dan peningkatan
kadar vascular endotelial growth factor (VEGF). Diabetes secara selektif merusak
sel, seperti endotelial sel dan mesangial sel, dimana kecepatan pengangkutan
glukosa tidak merosot dengan cepat seperti halnya hasil peningkatan kadar gula,
hal ini mendorong ke arah penumpukan glukosa tinggi dalam sel. Berdasarkan
teori ini, terjadi proses iskemia endoneurial yang berkembang karena adanya
peningkatan endoneural vascular resistance terhadap daerah hiperglikemi.
Berbagai faktor berkenaan dengan metabolisme, termasuk pembentukan
glycostatin end product, juga telah mencakup, mendorong ke arah kerusakan
kapiler, inhibisi transpor aksonal, aktivitas Na+/K+ATPase, dan akhirnya ke
degenerasi aksonal.(Sjahrir, 2006)
2. Teori berkenaan dengan metabolisme
Ada 2 teori utama berhubungan dengan efek yang berkenaan dengan
metabolisme dari hiperglikemi kronis dan efek iskemia pada saraf periferal. Efek
hiperglikemia yang berkenaan dengan metabolisme meliputi pembuatan potensi
neurotoksin (seperti jenis oksigen reaktif dan sorbitol) dan perubahan tingkatan
enzimntraseluler dan molekul pemberian isyarat (seperti Na+/K+ATPase, protein
kinase C, dan protein mitogen-activated kinase).
2.1. The polyol pathway
Di dalam status yang normoglikemik, kebanyakan glukosa intrasellular
adalah di phosphorylated ke glucose-6-phosphate oleh hexoginase.
Hanya sebagian kecil dari glukosa masuk polyol pathway. Dibawah
kondisi-kondisi hiperglikemi, hexoginase disaturasi, maka akan terjadi
peningkatan influks glukosa ke dalam polyol pathway aldose reductase,
yang mengkatalisa pengurangan glukosa ke sorbitol, adalah rate limiting
enzim didalam pathway ini.
Aldose reductase, yang secara normal mempunyai fungsi mengurangi
aldehid beracun didalam sel ke alkohol non aktif, tetapi ketika konsentrasi
glukosa di dalam sel menjadi terlalu tinggi, aldose reductase juga
mengurangi glukosa itu ke sorbitol, yang mana kemudian dioksidasi
menjadi fruktose. Sedang dalam proses mengurangi glukosa intraselluler
tinggi ke sorbitol, aldose reductase mengkonsumsi co-factor NAPH
(nicotinamide adenin dinucleotide phospat hydrolase). NADPH adalah
juga co-factor yang penting untuk memperbaharui suatu intraselluler
critical antioxidant, dan pengurangan glutathione. Dengan mengurangi
jumlah glutathione,polyol pathway meningkatkan kepekaan ke intracelluler

oxidative stress. Oxydative stress berperan utama didalam patogenesis

diabetik periferal neuropati. (Sjahrir, 2006)
Oxidative stress terjadi didalam sistem selluler ketika produksi radikal
bebas melebihi kemampuan antioksidan didalam sel. Jika antioksidan
tidak membuang radikal bebas, radikal akan menyerang dan merusak
protein, lipid dan asam nukleat. Hasil dari oksidasi atau nitrosilasi dari
radikal bebas akan menyebabkan penurunan aktivitas biologik, kehilangan
kemampuan metabolisme energi, transport, dan kehilangan kemampuan
fungsi utama lainnya. Akumulasi dari proses ini akan menyebabkan sel
mati melalui mekanisme apoptosis atau nekrotik. ( Vincent dkk, 2004)
Suatu teori mengatakan bahwa gula yang berlebihan dalam sirkulasi
darah di tubuh saling berinteraksi dengan suatu enzim di dalam sel
Schwann, yang disebut aldose reductase. Aldose reductase mengubah
bentuk gula ke dalam sorbitol, yang pada gilirannya menarik air ke dalam
sel Schwann, menyebabkan sel Schwann membengkak. Ini pada
gilirannya menjepit serabut saraf, menyebabkan kerusakan dan
menimbulkan rasa nyeri. Akhirnya sel Schwann dan serabut saraf dapat
nekrosis. (Sjahrir, 2006)
2.2 Aktivasi protein kinase C pathway
Berperan dalam patogenesis diabetic peripheral neuropathy. Hiperglikemi
didalam sel meningkatkan sintesa suatu molekul yang disebut
dicylglycerol (DAG), yaitu suatu critical activating factor untuk isoforms
protein kinase-C,,,. Protein kinase C juga diaktifkan oleh oxydative
stress dan advanced glycation end product. Aktivasi protein kinase C
menyebabkan peningkatan permeabilitas vaskuler, gangguan sintesa
nitric oxyde (NOs), dan perubahan aliran darah.(Sjahrir,2006) advanced
glycation end product sangat toksik dan merusak semua protein tubuh,
termasuk sel saraf. Dengan terbentuknya AGEs dan sorbitol, maka
sintesis dan fungsi NO akan menurun, sehingga vasodilatasi berkurang,
aliran darah ke saraf menurun, dan bersama rendahnya mionisitol dalam
sel saraf, terjadilah neuropati diabetik. (Duby,2004)
2.3 Adenosine diphosphate (ADP)
Ada bukti bahwa poly Adenosine diphosphate (ADP)-ribose polymerase
(PARP) mempunyai suatu peran penting dalam mediator beberapa
pathway dari hyperglicemia induced damage.(Sjahrir, 2006)
2.4 The hexosamine pathway
Ketika hiperglikemia intraselluler berkembang didalam sel target dari komplikasi
diabetes, menyebabkan produksi ROS (reactive oxygen species)
mitokhondria. ROS menerobos inti DNA, yang mengaktifkan PARP. PARP
kemudian memodifikasi enzim GAPDH (glycolytic glyceryldehyde-3 fosfat
dehidrogenase), dengan demikian mengurangi aktivitasnya. Akhirnya,
pengurangan aktivitas GAPDH akan mengaktifkan polyolpathway,
meningkatkan pembentukan AGE intraseluler (lycation and product),
mengaktifkan PKC dan sesudah itu NFxB, dan mengaktifkan hexosamine
pathway flux. (Sjahrir,2006) 3. Faktor neurotropik
Nerve growth factor diperlukan untuk mempercepat dan mempertahankan
pertumbuhan saraf. Pada penderita diabetes kadar NGF serum cenderung turun
dan berhubungan dengan derajat neuropati.
4. Faktor immunologi

Pada penderita diabetes dijumpai adanya antineural antibodies dalam

serum yang secara langsung dapat merusak struktur saraf sensorik
dan motorik yang bisa dideteksi dengan immunoflorens indeks.

PATOGENESIS
Lesi pada saraf perifer akan menimbulkan enam tingkat kerusakan yaitu : (Brushart,
2002)
a. Grade 1 (Neuropraksia)
Kerusakan yang paling ringan, terjadi blok fokal hantaran saraf, gangguan
umumnya secara fisiologis, struktur saraf baik. Karena tidak terputusnya
kontinuitas aksoplasmik sehingga tidak terjadi degenerasi wallerian. Pemulihan
komplit terjadi dalam waktu 1 2 bulan.
b. Grade II (aksonometsis)
Kerusakan pada akson tetapi membrana basalis (Schwann cell tube),
perineurium dan epineurium masih utuh. Terjadi degenerasi wallerian di distal
sampai lesi, diikutu dengan regenerasi aksonal yang berlangsung 1 inch per
bulan. Regenerasi bisa tidak sempurna seperti pada orang tua.
c. Grade III
Seperti pada grade II ditambah dengan terputusnya membrana basalis (Schwann
cell tube). Regenerasi terjadi tetapi banyak akson akan terblok oleh skar
endoneurial. Pemulihan tidak sempurna.
d. Grade IV
Obliterasi endoneurium dan perineurium dengan skar menyebabkan kontinuitas
saraf berbagai derajat tetapi hambatan regenerasi komplit.
e. Grade V
Saraf terputus total, sehingga memerlukan operasi untuk penyembuhan.
f. Grade VI
Kombinasi dari grade II-IV dan hanya bisa didiagnosa dengan pembedahan.
Ada tiga proses patologi dasar yang bisa terjadi pada saraf perifer yaitu : (Adam,
2005)
a. Degenerasi Wallerian
Terjadi degenerasi sekunder pada mielin oleh karena penyakit pada akson
yang meluas ke proksimal dan distal dari tempat akson terputus. Perbaikan
membutuhkan waktu sampai tahunaan, oleh karena pertama terjadi
regenerasi kemudian baru terjadi koneksi kembali dengan otot, organ
sensoris, pembuluh darah.
b. Demielinisasi segmental
Terjadi destruksi mielin tanpa kerusakan akson, lesi primer melibatkan sel
Schwann. Demielinisasimulai daro nodus ranvier meluas tak teratur ke
segmen-segmen internodus lain. Perbaikan fungsi cepat karena tidak terjadi
kerusakan akson.
c. Degenerasi aksonal
Degenerasi pada bagian distal akson saraf perifer dan beberapa
tempat ujung akson sentral kolumna posterior medulla spinalis.

Repository universitas sumatra utara

7. What are the physical and additional examination?
Based on the results of the neurological exam, physical exam, patient history, and any previous screening
or testing, the following additional tests may be ordered to help determine the nature and extent of the
neuropathy:

Nerve conduction velocity (NCV) tests can measure the degree of damage in large nerve fibers,
revealing whether symptoms are caused by degeneration of the myelin sheath or the axon. The
myelin covering is responsible for the very fast speed of nerve conduction. During this test, a probe
electrically stimulates a nerve fiber, which responds by generating its own electrical impulse. An
electrode placed further along the nerves pathway measures the speed of impulse transmission
along the axon. Slow transmission rates and impulse blockage tend to indicate damage to the
myelin sheath, while a reduction in the strength of impulses at normal speeds is a sign of axonal
degeneration.

Electromyography (EMG) involves inserting a fine needle into a muscle to record electrical
activity when muscles are at rest and when they contract. EMG tests detect abnormal electrical
activity in motor neuropathy and can help differentiate between muscle and nerve disorders.

Magnetic resonance imaging (MRI) can show muscle quality and size, detect fatty replacement
of muscle tissue, and can help rule out tumors, herniated discs, or other abnormalities that may be
causing the neuropathy.

Nerve biopsy involves removing and examining a sample of nerve tissue, most often from the
lower leg. Although this test can provide valuable information about the degree of nerve damage, it
is an invasive procedure that is difficult to perform and may itself cause neuropathic side effects.

Skin biopsy is a test in which doctors remove a thin skin sample and examine nerve fiber
endings. This test offers some unique advantages over NCV tests and nerve biopsy. Unlike NCV, it
can reveal damage present in smaller fibers; in contrast to conventional nerve biopsy, skin biopsy
is less invasive, has fewer side effects, and is easier to perform.
"Peripheral Neuropathy Fact Sheet," NINDS. Publication date December 2014.
NIH Publication No. 15-4853

8. What kind of the pharmacological ?

Langkah manajemen terhadap pasien adalah untuk
menghentikan progresifitas rusaknya serabut saraf dengan kontrol
kadar gula darah secara baik. Mempertahankan kontrol glukosa darah
ketat, HbA1c, tekanan darah, dan lipids dengan terapi farmakologis
dan perubahan pola hidup. Komponen manajemen diabetes lain yaitu
perawatan kaki, pasien harus diajar untuk memeriksa kaki mereka
secara teratur. (Sjahrir, 2006)
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ALTERNATIVE TREATMENT
There are a number of alternative treatments that may help relieve the pain of diabetic
neuropathy, such as:

Capsaicin. When applied to the skin, capsaicin cream can reduce pain sensations in some
people. Side effects may include a burning feeling and skin irritation.

Alpha-lipoic acid. This powerful antioxidant is found in some foods and may help relieve the
symptoms of peripheral neuropathy.

Transcutaneous electrical nerve stimulation (TENS). Your doctor may prescribe this
therapy, which can help prevent pain signals from reaching your brain. TENS delivers tiny electrical
impulses to specific nerve pathways through small electrodes placed on your skin. Although safe and
painless, TENS doesn't work for everyone or for all types of pain.

Acupuncture. Acupuncture may help relieve the pain of neuropathy, and generally doesn't
have any side effects. Keep in mind that you may not get immediate relief with acupuncture and will
likely require more than one session.
http://www.mayoclinic.org/diseases-conditions/diabetic-neuropathy/basics/alternativemedicine/con-20033336