Diabetic Peripheral Neuropathy UPDATE 2011: Scott & White Healthcare Department of Neurology

Goals • Evaluate peripheral neuropathy symptoms • Recognize and be able to diagnose diabetic peripheral neuropathy • Review recommendations for treating neuropathic pain

Types of DM Neuropathy:

• Symmetric peripheral axonopathy • Autonomic neuropathy • Focal mononeuropathy (cranial nerve & peripheral/limb) • Thoracic and lumbar radiculopathy (including amyotrophy) • Mononeuropathy multiplex

Why the nerves in DM? • Accumulation of glycosylated proteins/products • Sorbitol accumulation • Oxidative stress • Ischemia ? Inflammation? • Other (hexosamine pathway & protein kinase C pathway disruption)

How Common is DM Neuropathy?

• The most common complication of DM • The most common neuropathy in Western Society • About 50 % of DM patients develop clinically evident neuropathy (* average 7 year lag between onset and dx)

• However, many estimate 100 % have neuropathy (depending on criteria)

Sensory Complaints

Red Flags 1.

Proximal involvement (non-length dependent)

2.

Gait ataxia

3.

Finger joint position loss (severe ataxia)

4.

Autonomic Nervous System Involvement

5.

Multifocality

6.

Acute or subacute onset (sudden or rapidly progressing)

? Lumbar Radiculopathy (Dermatome Map)

Clinical Presentation

Diabetes Defined 1.

DM –

Fasting blood glucose ≥ 126 mg/dl

–

2 hr glucose ≥ 200mg/dl on 75-g OGTT

–

HbA1c > 6.5% (* ADA new recs. 2010)

2. Impaired fasting glucose –

Fasting blood glucose 101-125 mg/dl

3. Impaired glucose tolerance –

2 hr glucose 140-199 mg/dl on 75-g OGTT

Advantage (value) of 2 hour GTT 89 patients w/ idiopathic PN • 28 pts (31%) DM • 12 pts (13%) IGT • 3 pts (3%) IFG ------------------------• 43 pts (48%) abnormal glucose metabolism • 2 hr OGTT is the most sensitive measure of demonstrating abnormal glucose metabolism in cases of idiopathic PN Singleton. Muscle Nerve 2001.

Value of OGTT in PN Work-Up •

100 patients with idiopathic PN (previously screened for DM) – 2003 Revised ADA Criteria (101-125 = impaired fasting) • 61% normal glucose metabolism • 39% abnormal glucose metabolism – 36% impaired fasting glucose – 3% diabetes mellitus – 2hr-OGTT (23 out of 61 patients) • 38% normal glucose metabolism • 62% abnormal glucose metabolism (37% increase in Dx) – 38% impaired glucose tolerance – 24% diabetes mellitus

Hoffman-Snyder. Arch Neurol 2006.

AAN Guidelines 2009 •

Distal symmetrical PN – Fasting blood glucose – 75 gram 2 hour OGTT if FBG negative – Vit B12, homocysteine, & MMA •

– – – –

(↑ 5-10% detection where B12 200-500)

Serum immunofixation EMG Autonomic test Skin biopsy may be useful

Guidelines for Diabetic Neuropathic Pain

Specific Medications • Amitriptyline greater anticholinergic SE than nortriptyline, doxepin in cardiac patients • Duloxetine (cymbalta - SNRI): nausea common, can combine with AED • Venlafaxine (effexor): nausea/somnolence • Pregabalin (lyrica): • Gabapentin (neurontin): • Lidoderm patches • Mexilitine (mexitil): limited benefit • Capsaicin cream: • Alpha-lipoic acid: nausea/vertigo(600 mg/once/day)

AAN Guidelines 2011 • EFFECTIVE: pregabalin

• PROBABLY EFFECTIVE: – TENS (transcutaneous electrical nerve stimulation) Neurology May 2011; Volume 11(9); pp 1,4-5

AAN Guidelines 2011 • PROBABLY NOT EFFECTIVE: – Oxcarbazepine, lamotrigine, lacosamide, clonidine, pentoxifylline, mexiletine, magnetic field treatment, low-intensity laser therapy, Reike therapy, anodyne light therapy

Neurology May 2011; Volume 11(9); pp 1,4-5

Prevent DM Neuropathy? Over 10 years intensive insulin treatment (HbA1C 2 % lower) associated with: •60-70 % reduction in development of definite neuropathy •44 % decrease in abnormal NCS •53% decrease in autonomic dysfunction •** For each 1% rise in HbA1c there is a 1.3 m/s slowing of NCS over 8 years

The Diabetes Control And Complications Trial/Epidemiology Of Diabetes Interventions And Complications Research Group. Sustained effect of intensive treatment of type 1 diabetes mellitus on development and progression of diabetic nephropathy: the Epidemiology of Diabetes Interventions and Complications (EDIC) study. JAMA 2003;290:2159-67. Oslo Study: Diabetologia 1994; 37;579

References Bromberg MB. An approach to the evaluation of peripheral neuropathies. Sem Neurol 2005;25:153-159. Dyck PJ et al. Ten steps in characterizing and diagnosing patients with neuropathy. Neurology 1996;47:10-17. Dyck PJ et al. Intensive evaluation of referred unclassified neuropathies yields improved diagnosis. Ann Neurol 1981;10:222-226. Engelgau et al. Comparison of fasting and 2-hour glucose and Hgb A1c levels for diagnosing diabetes: diagnostic criteria and performance revisited. Diabetes care 1997;20:785-791. England JD et al. Distal symmetrical polyneuropathy: definition for clinical research. Muscle Nerve 2005;31:113-123. Expert committee on the diagnosis and classification of diabetes mellitus. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes care 1997;20:1183-1199. Holland et al. Small-fiber sensory neuropathies: clinical course and neuropathology of idiopathic cases. Ann Neurol 1998;44:47-59. Notermans et al. Chronic idiopathic axonal polyneuropathy: comparison of patients with and without monoclonal gammopathy. Brain 1996;119:421-427. Novella SP et al. The frequency of undiagnosed diabetes and impaired glucose tolerance in patients with idiopathic sensory neuropathy. Muscle Nerve 2001;24:1229-1231. Practice parameter: evaluation of distal symmetric polyneuropathy – role of laboratory and genetic testing (an evidencebased review). Neurology 2009;72:1-1. Practice parameter: evaluation of distal symmetric polyneuropathy – role of autonomic testing, nerve biopsy, and skin biopsy (an evidence-based review). Neurology 2009;72:1-1. Singleton JR et al. Painful sensory polyneuropathy associated with impaired glucose tolerance. Muscle Nerve 2001;24:1225-1228. Smith AG et al. The diagnostic yield of a standardized approach to idiopathic sensory-predominant neuropathy. Arch Int Med 2004;164:1021-1025. Wolfe et al. Chronic cryptogenic sensory polyneuropathy: clinical and laboratory characteristics. Arch Neurol 1999;56:540547.