LBM 4 SYARAF REZTRY

STEP 11. 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 21. 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 BodyPeripheral neuropathy affects toes feet legs hands armsAutonomic neuropathy affects heart and blood vessels digestive system urinary tract sex organs sweat glands eyes lungsProximal neuropathy affects thighs hips buttocks legsFocal neuropathy affects eyes facial muscles ears pelvis and lower back chest abdomen thighs legs feet

http://diabetes.niddk.nih.gov/dm/pubs/neuropathies/

Peripheral NeuropathyThis 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) PainEarly 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 NeuropathyThis 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 mealsWhat 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 normalIf 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 MedicationIn 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 LubricantsIn the Urinary System:Symptoms include: Trouble emptying your bladder Bloating Incontinence (leaking urine) More bathroom trips at nightWhat you should do:Tell your doctor. Treatments may include: Medication Inserting a catheter into the bladder to release urine (self-catheterization) Surgeryhttp://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 coordinationThese 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 UnawarenessNormally, 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 VesselsThe 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 SystemNerve 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 OrgansAutonomic 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 GlandsAutonomic 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.EyesFinally, 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 FACTORAnyone 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 healthof 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/diabetic-neuropathy/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 DiagnosisDisease/ConditionDifferentiating Signs/SymptomsDifferentiating Tests

UremiaVarious signs associated with the primary cause for end-stage renal disease (ESRD) may be present.May coexist with DN.Abnormal BUN, creatinine, GFR consistent with ESRD.

Cyanocobalamin deficiencyPoor nutrition, alcoholism, certain drugs (e.g., trimethoprim, methotrexate, phenytoin), pernicious anemia, atrophic gastritis, malabsorption, or infection withHelicobacter pylorimore likely to be present.Patients are more likely to be older (>65 years).CBC reveals macrocytic anemia.Reduced serum vitamin B12 levels.

HypothyroidismFatigue, cold intolerance, weight gain, constipation, myalgia, menstrual irregularities, delayed relaxation of deep tendon reflexes, bradycardia (if severe).TSH elevated in primary hypothyroidism.Free serum T4 may be low.

Acute intermittent porphyriaAbdominal pain, vomiting, muscle weakness, constipation, fever, diarrhea, sensory loss, seizures, tachycardia, hypertension may all occur.Abdominal pain is severe and more typical than in DN.Elevated aminolevulinic acid, porphobilinogen.

Chronic high alcohol intakeSigns of malnutrition, Wernicke encephalopathy, and Korsakoff amnestic syndrome may be present.Severe cases present with associated anemia, thiamine deficiency, and deranged LFTs.

Heavy metal poisoningMay present with a peripheral neuropathy that frequently manifests 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.Abnormally high blood levels of lead or other metals.

Drug-induced neuropathyDiabetes less likely and drug history 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, zalcitabine, and amiodarone.No differentiating investigations.

Chronic inflammatory demyelinating neuropathy (CIDP)People with diabetes may develop features of 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.

SarcoidosisVarious 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.

LeprosyTravel to or residence in endemic countries.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.Skin smear is positive for acid-fast bacilli (AFB).Biopsy of lesions reveal the presence of AFB plus other associated signs.

Polyarteritis nodosa (PAN)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.

AmyloidosisMuscle 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 paraproteinemiasMay be no differentiating signs or symptoms.Presence of a monoclonal protein in the serum or urine.

Paraneoplastic syndromeVaries, based on primary etiology.History of a primary neoplastic condition.Varies, based on primary etiology.

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

Hereditary neuropathies (e.g., Charcot-Marie-Tooth disease)Both motor and sensory nerve manifestations more likely, with distal leg weakness, foot deformities (pes cavus, hammer toes), and sensory deficits.Genetic testing is diagnostic.

Psychophysiologic disorderMay also present with pains and paresthesias but without neurologic deficit.There is no sensory loss.Specific psychological evaluations help to confirm the diagnosis.

Multiple system atrophy/Shy-Drager syndromeMay present with symptoms and signs of autonomic neuropathy, as in DN.May also have parkinsonism, varying degrees of dysautonomia, cerebellar involvement, and pyramidal signs.An excellent response to dopaminergic therapy is an important supportive feature for establishing the diagnosis.

Riley-Day syndromeProgressive 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 hypotensionSevere 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 syndromeProgressive, fairly symmetric muscle weakness accompanied by absent or depressed deep tendon reflexes.Weakness can vary from mild difficulty with walking to nearly complete paralysis of all extremity, facial, respiratory, and bulbar muscles.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.

Myasthenia gravisFluctuating 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 spinal disk diseaseMay present with symptoms and signs of a femoral neuropathy, including asymmetric pain, weakness, and sensory loss.MRI demonstrates specific vertebral disk pathology.

Femoral neuropathy: intrinsic spinal-cord-mass lesionMay present with symptoms and signs of a femoral neuropathy, including asymmetric pain, weakness, and sensory loss.MRI demonstrates the spinal cord mass.

Cauda equina lesionsMay present with symptoms and signs of a femoral neuropathy, including weakness and sensory loss.Diagnosis usually confirmed by MRI.

Carotid aneurysmMay present with symptoms and signs of a cranial neuropathy, including diplopia and Bell palsy.Magnetic resonance angiography and CT angiography confirm diagnosis.

Mononeuropathy multiplex: vasculitisMay present with symptoms and signs including nerve damage in 2 named nerves in separate parts of the body.Wrist drop, for example, is caused by infarction of the radial nerve, and foot drop by damage to either the sciatic or peroneal nerve.Vasculitis and lymphocytic infiltrates on nerve biopsies.

AcromegalyVery slow onset over decades.Typical clinical phenotype, including acral and soft tissue overgrowth; enlargement of jaw, nose, frontal bones, hands, and feet; articular overgrowth.Abnormal IGF-1 levels.Pituitary MRI may reveal pituitary tumor.

CoagulopathiesMay present with hemorrhages or thrombosis.Abnormal platelets, prothrombin time, D-dimer, fibrinogen, and fibrin degradation products.

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

6. How are the pathogenesis and patofisologi of the scenario? PATOPHISIOLOGI1. 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.PATOGENESISLesi 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 biopsyinvolves 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 biopsyis 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 dateDecember 2014.NIH Publication No. 15-48538. 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)Repository universitas sumatra utaraALTERNATIVE TREATMENTThere 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/alternative-medicine/con-20033336