1. Diagnosis and Management of Diabetic Neuropathies Aaron I. Vinik, MD, PhD, FCP, MACP Professor of Medicine/Pathology/Neurobiology Director of Research and Neuroendocrine Unit Eastern Virginia Medical School Strelitz Diabetes Center for Endocrine and Metabolic Disorders Norfolk, Virginia Part 2

2. Diabetologia 2000;43(8):957-973. Vinik A et al. Diabetic neuropathies. Adapted from Tables 1, 2. With kind permission of Springer Science+Business Media. Distal Symmetric Diabetic Neuropathies Subtypes TypeDescriptionPresentation Diagnostic TestingDiagnosisRisks Large fiber Deep-seated pain (A  type) Wasting Weakness Numbness Pins and needles Ataxia Nerve conduction velocity testing Sural nerve biopsy Impaired vibration perception Loss of position sense Impaired nerve- conduction velocity Interferes with normal life Falling and fractures Charcot neuropathy Small fiber Superficial pain (C-fiber type) Electric shock Burning Allodynia Autonomic dysfunction Normal strength, reflexes, EMG Historically “invisible” QST Nerve biopsy Skin biopsy Thermal imperception Electro- physiologically silent Early or late hyperesthesia, hyperalgesia Neurovascular impairment Leads to morbidity, mortality

3. Neuropathy Large-fiber 1 Deep-seated pain (A-  type) Wasting and weakness Numbness, pins and needles, tingling, ataxia Impaired vibration perception Loss of position sense Loss of reflexes Impaired nerve conduction velocity Interferes with normal life Risk of falling and fractures Small-fiber 2 Superficial pain (C-fiber type) Electric shock, burning, allodynia Autonomic dysfunction Thermal imperception Normal strength and reflexes Electrophysiogically silent Quantitative sensory testing and skin biopsies Produces symptoms Leads to morbidity and mortality Distal symmetric diabetic neuropathies: subtypes 1 Strotmeyer & Vinik, 2006; 2 Vinik et al, 2001

4. Large Fiber Neuropathies Clinical presentation –Impaired vibration perception –Pain is A-delta type, deep-seated, gnawing –Numbness, ataxia –Wasting of small muscles of hands and feet "intrinsic minus" –Weakness –Increased blood flow, the hot foot Risk – Falling and fractures – Charcot neuropathy Strotmeyer E, et al. J Bone Min Res. 2006;21:1803-1810.

5. Impaired Glucose Tolerance and Neuropathy Prospective screening of patients with “idiopathic sensory neuropathy” –30% to 50% have IGT IGT neuropathy –Overweight, family history of diabetes, primarily sensory (81%), pain (92%) (Hopkins, Utah studies) IGT neuropathy similar to early diabetic neuropathy: 669 patients –60% sensory, impotence in 40%, autonomic involvement in 33% Singleton JR et al. Diabetes. 2003;52:2867.

6. Clinical Presentation: Small Fiber Neuropathy –Pain is C-fiber type, burning, superficial, allodynia –Early hyperesthesia and hyperalgesia, impaired neurovascular function –Late hypoesthesia and hypoalgesia –Impaired warm thermal and pain thresholds, decreased IENF –Decreased sweating –Normal strength, reflexes, and EMG!!! Vinik AI, et al. Exp. Clin. Endocrinol Diabetes. 2001;1099(Suppl 2):S451-S473.

7. Control Metabolic Syndrome Diabetes IENF Loss in Diabetic Neuropathy Vinik AI, et al. Nature Clinical Practice Endocrinol Metab. 2006;2:269-281.

8. Minimum Criteria for Diagnosis of DSP Clinical methods are not sufficient –eg,  ankle reflexes not sensitive enough –Do not account for anthropometric parameters (age, height...) Validated tests of nerve function are required ≥2 abnormalities –Neuropathic symptoms (NSS ≥2) –Neuropathic signs (NIS ≥2) –Nerve conduction (NC) –Quantitative sensory tests (QST) –Quantitative autonomic test (QAT), with one of the two being 3 or 5 American Diabetes Association. Muscle Nerve. 1988;11:661. Dyck et al. Neurology. 1993;43:817. DSP, distal symmetric polyneuropathy

9. Diabetic Neuropathies Statement by American Diabetes Association Diagnosis Asymptomatic –≥2 abnormalities NE, NC, QAFT, QST, QMT Symptomatic –≥ 2 abnormalities NE, NC, QAFT, QST, QMT NE, neurologic examination; NC, nerve conduction; QAFT, quantitative autonomic function test; QST, quantitative sensory test; QMT, quantitative motor test Boulton et al. Diabetes Care. 2005;28:956.

10. Examination Bedside Sensory Tests Sensory ModalityNerve FiberInstrument Vibration A  (large) 128 Hz Tuning fork Pain (pinprick)C (small)Neuro-tips Pressure A , A  (large) 1 g and 10 g Monofilament Light touch A , A  (large) Wisp of cotton Cold A  (small) Cold tuning fork

11. And What We Mistake for Diabetic Neuropathy Claudication Morton’s neuroma Osteoarthritis Radiculopathy Charcot’s neuroarthropathy Plantar fasciitis Fibromyalgia Tarsal tunnel syndrome