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 1

2. An early description of neuropathy in Hittite tablets ‘If King Hattusili III is cured from the fire that burns his feet, I will give a golden cup with a handle of lapis lazuli to Goddess Ningal’ Queen Puduhepa, approx 1250 BC The king could not attend the wedding of his daughter Maathorneferure because of his burning feet Öztürk, 2006

3. 1.15 1.21 1.27 1.36 1.48 EURODIAB: Risk Factors for Incidence of Polyneuropathy Tesfaye S, et al. N Engl J Med. 2005;352:341-350. Model 1: excluding cardiovascular disease and retinopathy Odds ratios (95% CI); n = 1101 with type 1 diabetes; follow-up 7.3 ± 0.6 years Smoking 1.38 Hemoglobin A 1c Change in hemoglobin A 1c Body mass index Total cholesterol 0.9 1234 Triglycerides Hypertension 1.57 Diabetes duration 1.40

4. Multivariate models All subjects (n = 393) Age (years) Weight (kg) Diabetes Peripheral arterial disease (ABI < 0.9) Subjects With Diabetes (n = 195) Age (years) Weight (kg) Peripheral arterial disease (ABI < 0.9) Albuminuria (mg/L) OR (95% CI) 1.08 (1.02, 1.14) 1.03 (1.00, 1.05) 2.61 (1.09, 6.24) 5.72 (2.44, 13.39) OR (95% CI) 1.08 (1.00, 1.16) 1.03 (1.00, 1.06) 9.27 (3.44, 25.0) 1.19 (0.95, 1.51) P value.0085.0415.0305 <.0001 P value.0389.0539 <.0001.1378 Ziegler D, et al. Eur J Pain. 2008, doi:10.1016/j.ejpain.2008.07.007. ABI = ankle brachial index; OR = odds ratio; CI = confidence interval Risk Factors for Neuropathic Pain MONICA/KORA Augsburg Surveys S2+S3

5. Prevalence of Polyneuropathy and Neuropathic Pain MONICA/KORA Augsburg Surveys S2S3 Ziegler D et al. Diabetes Care. 2008;31:464. Ziegler D et al. Eur J Pain. 2009; in press. 0 5 10 15 20 25 30 Control Impaired fasting glucose Impaired glucose tolerance Diabetes Polyneuropathy Neuropathic pain Patients (%)

6. Prevalence of Chronic Neuropathic Pain in French General Population Nationwide postal questionnaire survey –30,155 subjects, 81.2% responded 1631 respondents had chronic pain with neuropathic characteristics: 6.9% prevalence Bouhassira D et al. Pain. 2008;136:380. 40 30 20 10 0 01234567 DN4 Score Patients (%)

7. Review of computerized longitudinal medical records –362,693 persons; 1,116,215 person-years (PY) Incidence (new cases): 8.2/1000 PY; diabetic neuropathy: 0.72/1000 PY; postherpetic neuralgia: 0.42/1000 PY Most treated with NSAIDs and aspirin; <5% treated with anticonvulsants and tricyclic antidepressants 9 7 5 3 1 0 Incidence and Treatment of Neuropathic Pain in Dutch Population Dieleman JP et al. Pain. 2008; 137:681. 0-9 10-1920-2930-3940-4950-5960-6970-7980-89 >90 25 20 15 10 5 0 2.5 2 1.5 1 0.5 0 Incidence rate/1000 PY Ratio female:male Age (years) 0-9 10-1920-2930-3940-4950-5960-6970-7980-89 Incidence rate/1000 PY Age (years) >90 8 6 4 2 DPN PHN Mononeuropathy Incidence rate ratio of women vs men MenWomen

8. Neuropathy in Diabetes Prevalence % Things that he stretched but mainly he tells the truth Mark Twain

9. Neuropathy Is Commonly Underdiagnosed Endocrinologists Non-endocrinologists Herman W et al. Presented at: 63rd Annual Scientific Sessions of the American Diabetes Association. New Orleans, LA; June 13-17, 2003. Abstract 830-P. Herman et al. Diabetes Care. 2005;28:1480. Correct diagnosis (%) For every mistake made for not knowing, 10 are made for not looking 0 20 40 60 80 100 No neuropathy (n=4628) Non-severe neuropathy (n=2209) Severe neuropathy (n=541)

10. Diabetic Neuropathies Large-fiber neuropathy Small-fiber neuropathy Proximal motor neuropathy Acute mono neuropathies Entrapment Sensory loss: 0 – + (thermal allodynia) Pain: + – +++ Tendon reflex: N –  Motor deficit: 0 Sensory loss: 0 – +++ (touch vibration) Pain: + – +++ Tendon reflex: N –  Motor deficit: 0 – +++ Sensory loss: 0 – + Pain: + – +++ Tendon reflex:  Proximal motor deficit: + – +++ Sensory loss: 0 – + Pain: + – +++ Tendon reflex: N Motor deficit: + – +++ Sensory loss in nerve distribution: + – +++ Pain: + – ++ Tendon reflex: N Motor deficit: + – +++ N, normalVinik A et al. Clin Geriatr Med. 2008;24:407. IIIVI Truncal Ulnar Median Lateral popliteal

11. Mononeuritis vs Entrapment Mononeuritis Onset sudden Usually single nerve, but may be multiple Common nerves: C3, C6, C7, ulnar, median, peroneal Not progressive and resolves spontaneously Treatment: symptomatic Entrapment Onset gradual Single nerves exposed to trauma Common nerves: median, ulnar, peroneal, medial and lateral plantar Progressive Treatment: rest, splints, diuretics, steroid injections and surgery for failed medical therapy and weakness Vinik A et al. Diabetes Care. 2004;27:1783.C, cranial nerve

12. A Simplified View of the PNS MotorSensoryAutonomic Myelinated Thinly myelinated Un- myelinated Thinly myelinated Un- myelinated A alpha A alpha/beta A delta C A delta C Large Muscle control Touch, vibration, position perception Cold perception, pain Warm perception, pain Heart rate, blood pressure, sweating, GIT,GUT, function Small Vinik AI, et al. Nature Clinical Practice Endocrinol Metab. 2006;2:269-281.