1. Diagnosis and Management of Diabetic Neuropathies Part 3 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

2. Clinical Examination Inspection (May Be Normal) Insensate foot: repeated minor trauma causes ulceration Autonomic features Dry skin, hairless Distended veins Edema Cold (hot if Charcot’s)

3. Assessment of Footwear Inappropriate Footwear Is the Commonest Form of Trauma

4. Simple Bedside Tests of Large-Fiber Function Controls (n=11) Diabetic controls (n=8) Diabetic neuropathy (n=14) 0 20 40 60 80 100 120 140 160 180 2-minute walk Distance (m) * 30 0 5 10 15 20 25 Tandem stand 1- foot stand Balance walk Foot tapping Time (s) * † * * Resnick et al. Muscle Nerve. 2002;25:43. * P<0.05 vs nondiabetic controls; † P<0.01 vs nondiabetic controls

5. Sensory Nerves Monofilament Testing at Dorsum of Great Toe 3.8 Monofilament Light touch, 1.0 g force Record if felt ¾ touches (y/n) 5.01 Monofilament Standard, 10 g force Only performed if “no” for 1.0 g Record if felt ¾ touches (y/n) 25 lb strain fishing line 4 cm = 10 g8 cm = 1 g Bourcier et al. J Fam Pract. 2006;55:505.

6. Shy ME et al. Neurology. 2003;60:898. Rolke R et al. Eur J Pain. 2006;10:77. Quantitative Sensory Testing Determines threshold for Vibration─large fiber Thermal (warm and cold)─small fiber Hot and cold pain Touch─pressure CHEPS─allows recognition of sites Electrical impulses Strengths Measures both small- and large-fiber deficit Relatively simple, less discomfort Useful tool for screening large populations Limitations Less objective (psychophysical) Less reproducible No standardization of various systems (reliant on normative values for each lab)

7. Vibration Perception Threshold Detects subclinical DSP Predicts foot ulceration 1,2 0–15 V ─ Low risk 16–25 V ─ Intermediate  25 V ─ High risk (  7) Predicts mortality 3 Biothesiometer Neuroasthesiometer Vibrameter Vibratron CASE IV Medoc etc. 1.Young MJ et al. Diabetes Care. 1994;17:557. 2.Abbott CA et al. Diabetes Care. 1998;21:1071. 3.Coppini DV et al. Diabetic Med. 2000;17:488.

8. Nerve-Conduction Studies Ability of Nerves and Muscle to React to Electrical Stimulation Strengths Most objective, accurate, reproducible, sensitive Correlate with clinical end points Represent pathologic hallmark of DSP Diagnostic sensitivity improved by incorporation of anthropometric factors, F-wave testing, etc. Limitations Measure only large-fiber function Limited availability for routine testing Some discomfort Impact of external factors (eg, limb temperature, etc.) Daube JR. Muscle Nerve. 1999;22:1151. Malik RA et al. Diabetologia. 1989;32:92. Perkins BA et al. Diabetes Care. 2001;24:748.

9. Quantitative Measurement of Cutaneous Perception in Diabetic Neuropathy Sensitivity with specificity >90% Warm 78% Cold 77% VDT 88% Tactile 77% CPT <50% Combination thermal (CDT) and VDT Sensitivity 92%–95% Specificity 77%–86% 050100 Specificity (%) Sensitivity (%) 100 50 0 Two-point disc CPT 2000 Hz CPT 250 Hz CPT 5 Hz Pressure Cold Warm Vibration Vinik AI et al. Muscle Nerve. 1995;18:574. CDT, cooling detection threshold; CPT, current perception testing; VDT, vibration detection threshold

10. CHEPS Contact Heat-Evoked Potential Stimulator Objective and noninvasive Selective stimulation and identification of A  and C fibers through EEG signal waveform recording 1,2 Quantifies negative and positive latencies, amplitudes, and conduction velocities 3 –Neuropathic patients demonstrate reduced amplitude and prolonged latencies Medoc, NC 1. Chao CC et al. Clin Neurophsyiol. 2008;119:653. 2. Staud R et al. Pain. 2008;139:315. 3. Granovsky Y et al. Pain. 2005;115:238.

11. CHEPS Response Selective A  and C-Fiber Activation C fibers Thin, unmyelinated fibers, conduction velocity <2 m/s A  fibers Thin, myelinated fibers, conduction velocity 10–30 m/s Receptors located mainly on hairy skin Conduct sensation about first, sharp, pricking pain Activated by temperature <45°C and mechanical stimuli Two main groups of A  mechano-heat (AMH) nociceptors –Type I AMH, threshold >50°C –Type II AMH, heat threshold <50°C EEG response to selective C-fiber stimulation EEG response to selective A  fiber stimulation