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Diabetes Mellitus and the Peripheral Nervous System: Manifestations and Mechanisms

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Diabetes Mellitus and the Peripheral Nervous System: Manifestations and Mechanisms INVITED REVIEW ABSTRACT: Diabetes targets the peripheral nervous system with several different patterns of damage and several mechanisms of disease. Diabetic polyneuropathy (DPN) is a common disorder involving a large proportion of diabetic patients, yet its pathophysiology is controversial. Mechanisms con- sidered have included polyol flux, microangiopathy, oxidative stress, abnor- mal signaling from advanced glycation endproducts and growth factor defi- ciency. Although some clinical trials have demonstrated modest benefits in disease stabilization or pain therapy in DPN, robust therapy capable of reversing the disease is unavailable. In this review, general aspects of DPN and other diabetic neuropathies are examined, including a summary of recent therapeutic trials. A particular emphasis is placed on the evidence that the neurobiology of DPN reflects a unique yet common and disabling neurodegenerative disorder. Muscle Nerve 36: 144–166, 2007 DIABETES MELLITUS AND THE PERIPHERAL NERVOUS SYSTEM: MANIFESTATIONS AND MECHANISMS DOUGLAS W. ZOCHODNE, MD Department of Clinical Neurosciences and the Hotchkiss Brain Institute, University of Calgary, Room 168, Heritage Medical Research Bldg., 3330 Hospital Drive N.W., Calgary, Alberta T2N 4N1, Canada Accepted 25 February 2007 Diabetes mellitus imposes substantial burdens on including diffuse damage (polyneuropathy) and fo- the nervous system and is the most common cause of cal damage (mononeuropathy). Both contribute to neuropathy or peripheral nerve damage. Moreover, sensory and motor deficits and both are associated diabetic neuropathies are rising in prevalence with with significant disability in patients. In polyneurop- the growing global burden of type II diabetes melli- athy it is now recognized that impaired glucose tol- tus. Although this review emphasizes peripheral erance, even without overt diabetes mellitus, may be nerve disorders, there is now recognition that diabe- a risk factor. tes also targets the central nervous system, especially The San Antonio Consensus criteria are com- white matter (diabetic leukoencephalopathy).15,234 monly used to define diabetic neuropathy for re- 5 Within the peripheral nervous system alone, how- search purposes. For clinical neuropathy, the guide- ever, diabetes renders several types of nerve damage, lines require symptoms and signs, or one of these with abnormal testing (nerve conduction, quantita- tive sensory testing, or autonomic testing). Subclini- Available for Category 1 CME credit through the AANEM at cal neuropathy is identified by abnormal testing www.aanem.org. only. More specific staging of diabetic polyneurop- Abbreviations: AGEs, advanced glycosylation endproducts; AR, aldose re- athy (DPN) has also been described by Dyck and ductase; ARIs, aldose reductase inhibitors; CASE IV, computer assisted sen- Dyck50: NO, no neuropathy; N1, asymptomatic neu- sory examination; CDT, cool detection thresholds; CMAP, compound muscle action potential; CMT 1a, Charcot–Marie–Tooth disease type 1a; CTS, carpal ropathy without (N1a) or with (N1b) findings on tunnel syndrome; DLSP, diabetic lumbosacral plexopathy; DPN, diabetic neurological examination; N2, symptomatic; N3, dis- polyneuropathy; DRG; dorsal root ganglion; HNDT, heat-nociception detec- tion threshold; HSP-27, heat shock protein-27; IENF, intraepidermal skin abling. fibers; IGFs, insulin-like growth factors; MAG, myelin-associated glycoprotein; Both pathophysiology and therapy for diabetic NGF, nerve growth factor; PKC, protein kinase C; POEMS, polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes; QST, neuropathies remain challenging. There has been a quantitative sensory testing; RICF, resistance to ischemic conduction failure; long history of failed clinical trials for polyneurop- SFEMG, single-fiber electromyography; SNAP, sensory nerve action poten- tial; SSRI, selective serotonin reuptake inhibitor; STZ, streptozotocin; UNE, athy, in part related to issues of what was targeted, ulnar neuropathy at the elbow; VPT, vibration perception threshold; WDT, what was being measured, and how well the trial was warm detection thresholds Key words: diabetes mellitus; diabetic neuropathy; neuropathy; peripheral designed. Despite these problems, there are new and neuropathy; polyneuropathy exciting thoughts about how these disorders develop Correspondence to: D. W. Zochodne; e-mail: [email protected] and what avenues may offer significant hope. Be- © 2007 Wiley Periodicals, Inc. Published online 27 April 2007 in Wiley InterScience (www.interscience.wiley. cause of the size of the topic, a number of aspects are com). DOI 10.1002/mus.20785 only covered briefly in this review and the bias is 144 Diabetes Mellitus and the PNS MUSCLE & NERVE August 2007 toward emphasizing aspects of its neurobiology. intensively treatment patients had developed it by 5 Three excellent and comprehensive texts addressing years. For patients in the secondary intervention co- diabetic neuropathy have been published6,81,230 in hort with retinopathy at baseline but not neuropa- addition to recent reviews addressing slightly differ- thy, the rates were 16.1% for conventional and 7.0% ent points of view,18,241 and diagnostic criteria have for intensive treatment. Overall, when looking at a recently been published by the American Diabetes variety of studies (summarized by Shaw et al.197), Association.19 type I diabetic prevalence figures vary from 13%– 17% in hospitalized patients based on symptoms and CLASSIFICATION AND PREVALENCE signs, and 8%–54% with more comprehensive bat- teries in primary care or population-based screening. Diabetic neuropathies comprise diabetic polyneu- For type II diabetic patients, similar figures run from ropathy (DPN), a symmetric diffuse disorder that 19%–58% in hospital-based studies with some ancil- particularly targets sensory neurons with long axons, lary testing and 13%–46% in primary care or popu- and focal neuropathies or mononeuropathies. The lation-based screening more heavily weighted toward latter include classic entrapment neuropathies that testing. There are likely significant flaws, however, are more common in diabetes such as carpal tunnel from relying on hospital-selected data. syndrome (CTS), ulnar neuropathy at the elbow With very comprehensive and extensive batteries (UNE), meralgia paraesthetica (entrapment of the of evaluation, such as that applied to the Rochester lateral femoral cutaneous nerve of the thigh) at the Diabetic Cohort (n ϭ 380), evidence of DPN was inguinal ligament, or peroneal neuropathy at the identified in 54% of type I diabetics and 45% of type fibular head. Other mononeuropathies much more 58 specifically identified in diabetic patients include II diabetics. Using the strict criteria of an abnormal intercostal and abdominal segmental radiculopa- neuropathy impairment scale (NIS) and seven ab- thies, oculomotor palsies, and lumbosacral radiculo- normal laboratory studies, 21% of the Rochester plexus neuropathies. Brown and Asbury 27 subdi- diabetic cohort had DPN. Symptomatic DPN was vided DPN clinically into subtypes, with the group of identified in a smaller proportion, 13%–15%. In mixed motor, sensory, and autonomic neuropathy other cohorts, such as the Pittsburgh epidemiology ϭ representing 70% of patients. A predominantly sen- of diabetes complications (n 400), DPN was iden- sory phenotype was found in 39% that was yet fur- tified in 34% of type I diabetics, whereas in the San ther divided into large-fiber, small-fiber, or mixed Luis Diabetes Study DPN was present in 26% of type ϭ neuropathies. Pure motor DPN or autonomic DPN II diabetics (n 279). In patients with impaired were uncommon (Ͻ1% each). In the author’s expe- glucose tolerance only, as a precursor of type II rience, pure sensory DPN on the basis of clinical diabetes, the prevalence figures have been more evaluation alone (some have subclinical electrophys- controversial. iological motor involvement) represents the large The prevalence of cardiovascular autonomic neu- majority of patients, particularly early in their ropathy detected by heart-rate interval studies (in- course. Some have added a category of an acute cluding the response to Valsalva’s maneuver, or deep ϳ sensory DPN with rapid onset (likely overlapping breathing) has ranged from 16%–25% in type I with a condition known as “insulin neuritis” or neu- and II diabetic patients, with a smaller proportion ropathy after the onset of insulin use), an association having symptoms. Several studies have suggested with acute hyperglycemia, the presence of promi- that cardiovascular autonomic neuropathy is a risk nent pain, and a shorter overall duration related to factor for increased mortality.65,147,158,197,238 For gas- control of hyperglycemia.18,19,241 trointestinal symptoms, prevalence figures are also The reported prevalence of DPN varies with the variable, with numbers for constipation or diarrhea type and the intensity with which it is sought. In the ranging between 3% and 35%. Impotence has been classic Diabetes Control & Complications Trial identified in 23%–57% of type I and II diabetic men, (DCCT) of diabetic complications in intensively with higher rates with increasing age.197 Overall, a rather than conventionally treated patients with type population-based study from the Rochester diabetic I diabetes mellitus,46 clinical neuropathy was defined cohort (n ϭ 231 diabetics) identified a prevalence of as an abnormal clinical neurological examination autonomic dysfunction (using a composite scale of plus either abnormal
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