Diabetic Neuropathy Nicholas J. Silvestri, M.D.
Types of Neuropathies Associated with Diabetes Mellitus p Chronic distal sensorimotor polyneuropathy p Focal compression neuropathies p Autonomic neuropathy p Acute reversible sensorimotor polyneuropathy associated with hyperglycemia p Insulin neuritis p Acute cranial neuropathy (III, IV, VI, VII) p Acute or subacute lumbosacral radiculoplexusneuropathy (diabetic amyotrophy) p Acute thoracic radiculopathy p?mononeuritis multiplex p?cidp
Epidemiology p Diabetes is the most common cause of polyneuropathy in Western countries, though the exact prevalence is unknown EURODIAB study found a prevalance of polyneuropathy of 28% in 3250 randomly selected patients with IDDM Tesfaye S, et al. Prevalence of diabetic peripheral neuropathy and its relation to glycaemic control and potential risk factors. Diabetologia. 1996;39(11):1337-1384. Olmstead County, MN study found 55% of pts with IDDM and 45% of pts with NIDDM had polyneuropathy. However, only 15% of pts with IDDM and 13% of pts with NIDDM were symptomatic Dyck PJ, et al. The prevalance by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population-based cohort. Neurology. 1993;43(4):817-824. p Estimated that patients with type 2 diabetes develop neuropathy at a rate of 6.1 per 100 person-years Sands ML, et al. Incidence of distal symmetric (sensory) neuropathy in NIDDM. Diabetes Care. 1997;20(3):322-329.
Who develops neuropathy? p Rochester Diabetic Neuropathy Study 264 patients with diabetes followed in a longitudinal cohort study Multivariate analysis demonstrated that duration of diabetes and glycosylated hemoglobin concentration were the most important risk factors for development of neuropathy Dyck PJ, et al. Longitudinal assessment of diabetic polyneuropathy using a composite score in Rochester Diabetic Neuropathy Study cohort. Neurology 1997;49:229-239.
Pathophysiology p Axonal loss due to: Microvascular injury from formation of reactive oxygen species Sorbitol formation via action of aldolase reductase Protein kinase C activation Immune complex deposition Development of advanced glycation end products and impairment of normal cellular processing including axonal transport Sheetz MJ, King CL. Molecular understanding of hyperglycemia s adverse effects for diabetic complications. JAMA. 2002;288(20):2579-2588.
Early Clinical Manifestations p Distally-predominant, spontaneous positive or negative sensory symptoms p Neuropathic pain is a typically an early clinical feature p Small fiber involvement typically develops before large fiber, but not always
Clinical Manifestations p On sensory examination, gradient to pin and cold, reduction in vibratory threshold and joint position sense p On motor examination, can see early involvement of foot and toe extensors and flexors (slight wasting of extensor digitorum brevis is often the first sign) p Absent ankle jerks p Antalgic gait
Differential Diagnosis: Other Causes of Polyneuropathy p Associated with underlying medical illnesses? Renal, hepatic, thyroid dysfunction, monoclonal gammopathies, amyloidosis, nutritional deficiencies, HIV, etc. p Alcohol use? p History of toxin exposure? Arsenic, thallium, lead p History of medication use known to lead to neuropathy? Amiodarone, isoniazid, pyridoxine, chemotherapeutic agents p Family history of neuropathy? Charcot-Marie-Tooth disease
Useful Mnemonic p I (inflammatory/immune) p N (nutritional) p D (diabetes) p I (infectious) p C (cancer) p A (alcohol) p T (toxic-metabolic) p E (endocrine)
Diagnostic Workup p Exclusion of other causes of polyneuropathy RFTs, LFTs, TFTs, vitamin B12 level with methylmalonic acid level, SPEP and IFE, UPEP, RPR; other tests based on history and risk factors p Electrodiagnostic testing Not mandatory if diagnosis is clear Indications include atypical features (e.g. rapid course, marked asymmetry, weakness > sensory loss, upper extremity > lower extremity involvement) p Autonomic testing p Quantitative Sensory Testing (QST) p Skin biopsy and evaluation of intra-epidermal nerve fiber (IENF) density Sensitivity for polyneuropathy 40-95%, specificity 85-97% Most useful for confirming the presence of a small fiber neuropathy
Electrodiagnostic Testing
Skin Biopsy p Normal p Reduced IENF density
Treatment p Tight glycemic control p Symptomatic treatment of neuropathic pain Tricyclic antidepressants Anticonvulsants SNRIs Others p Experimental treatments VEGF Others
Glycemic Control The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med 1993;329:977-986.
Complications p Foot ulceration p Restless legs syndrome p Cramps p High morbidity and mortality with concomitant autonomic neuropathy (due to cardiac involvement)