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Rev. Med. 1990. 41:303-17 Copyright © 1990 by Annual Reviews Inc. All rights reserved

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DIABETIC NEUROPATHY

Annu. Rev. Med. 1990.41:303-317. Downloaded from www.annualreviews.org by WIB6106 - University Munchen on 02/20/13. For personal use only.

Douglas A. Greene, M.D.

Department of Internal Medicine and Diabetes Research and Training Center, University of Michigan, Ann Arbor, Michigan 48109 Anders A. F. Sima, M.D., Ph.D.

Department of Pathology, University of Manitoba, Winnipeg, Manitoba, Canada R3E OW3 Michael A. Pfeifer, M.D.

Department of Medicine, Veterans Administration Medical Center and University of Louisville, Louisville, Kentucky 40202 James W. Albers, M.D., Ph.D.

Department of Neurology, The University of Michigan Hospitals, Ann Arbor, Michigan 48109 KEY WORDS:

diabetes, complications, aldose reductase, foot problems.

ABSTRACT

Diabetic neuropathy, the most common peripheral neuropathy in the Western world, is responsible for most limb amputations and considerable morbidity in diabetic patients. Although it is a sequela to insulin deficiency and/or hyperglycemia, its exact pathogenetic mechanism remains unclear. Therapy is directed at early diagnosis, exclusion of other neuropathic disorders, prudent glucose control, and avoidance of secondary com­ plications of neuropathy such as foot ulceration by aggressive foot care, hygiene, and patient education. 303 0066-4219/90/0401-0303$02.00

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INTRODUCTION Diabetic neuropathy first emerged as a clinical entity more than 200 years ago (1), yet it remains a disorder with an uncertain pathogenesis and with no satisfactory treatment. As the most common form of peripheral neuropathy in the Western world (2), diabetic neuropathy is responsible for most limb amputations in diabetic patients. It encompasses several distinct syndromes of focal and diffuse peripheral autonomic and somatic neuropathy (3-5). The pathological hallmark of diabetic polyneuropathy is a nonspecific diffuse and focal fiber loss (4), with secondary demyelination associated with structural abnormalities of endoneurial connective tissue and microvessels (6), although the picture may vary among subgroups of diabetic patients (7). Once considered a cause of altered carbohydrate metabolism in patients with diabetes (8), neurological involvement in these patients is now generally thought to be a result of insulin deficiency and its metabolic consequcnces (9). Thc cxtent to which glucose-relatcd metabolic factors such as polyol pathway activation or nonenzymatic glycation act directly on peripheral neurons and Schwann cells, or through secondary microvascular alterations in various diabetic neuropathic syndromes, remains controversial (7, 10-12). Its nonspecific nature renders diabetic neuropathy a diagnosis of exclusion. Current therapeutic approaches include early diagnosis (13), establishment of satisfactory diabetic control, elimination of other neuropathic factors, and use of prophylactic measures to protect against secondary consequences of neuropathy such as foot ulceration. New treatment modalities, such as aldose reductase inhibitors (14), are currently under clinical investigation.

EPIDEMIOLOGY Reliable prevalence or incidence estimates for diabetic neuropathy are virtually nonexistent (3). Studies in which widely varying diagnostic criteria and populations were used (15) have estimated a prevalence for clinical and subclinical neuropathy between 10 and 100% (3). A population­ based study of neuropathy in patients with non-insulin-dependent diabetes mellitus (NIDDM) yielded a cumulative incidence of distal symmetric polyneuropathy (the most common variant) of 4% after 5 years and 15% after 20 years of diabetes, with iil median time to development of neuropathy after diagnosis of diabetes of 9 years (3, 16). A referral-based cohort study by Pirart reported an 8% overall prevalence of clinical neuropathy at the time of diagnosis of diabetes (mostly in older NIDDM patients) that increased linearly with time to 40% after 20 years of diabetes (17). These discrepancies notwithstanding, diabetic neuropathy is an

DIABETIC NEUROPATHY

305

extremely common medical problem because of the high incidence of diabetes; it is rarely found before the fifth year of diabetes, except in older patients with NTDDM, in whom antecedent undetected hyperglycemia is difficult to exclude (17); and it ultimately affects up to 50% of patients with long-standing diabetes.

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CLINICAL PRESENTATION AND CLASSIFICATION Diabetic neuropathy is staged as clinical or subclinical, depending on whether clinical signs and/or symptoms accompany objective evidence of impaired peripheral nerve function. Clinical neuropathy is further sub­ divided into syndromes according to the anatomical distribution of pe­ ripheral nervous system involvement. The syndromes are clustered under two general headings, diffuse and focal neuropathies (Table 1). Although each syndrome has a characteristic clinical presentation and course, mul­ tiple neuropathic syndromes overlap and frequently coexist in the same patient, precluding firm classification in some cases (4). The diffuse neuropathies, i.e. distal symmetric sensorimotor polyneuropathy and autonomic neuropathy, are common, generally chronic, and often pro­ gressive. Focal neuropathies such as mononeuropathies, mononeuro­ pathy multiplex, plexopathies, radiculopathies, and cranial neuropathies are rare by comparison, usually acute in onset, and often self-limited (10). Distal symmetric polyneuropathy is characterized by predominantly sensory rather than motor involvement, with a generally symmetric proximal-to-distal gradient of severity (5). Sensory deficits and/or neuro­ pathic symptoms appear first in the distal portions of the lower and then the upper extremities and spread proximally with increasing duration and/ or severity of disease in a "stocking-glove" distribution, which, at its very late stage, may produce bands of sensory denervation on the trunk as well (Figure 1) (18). The signs and symptoms of distal symmetric poly­ neuropathy vary with the spectrum of fiber involvement, with large-fiber disease producing diminished proprioception and light touch and small­ fiber disease impairing pain and temperature sensation (5, 19), but most cases include both large- and small-fiber disease (5). Distal symmetric polyneuropathy may cause positive symptoms (as opposed to neurological deficits), including neuropathic pain, paresthesias, and dysesthesias. Although generally mild (5), pain may develop acutely and remit, but in most cases, positive symptoms occur subacutely and may progress, stabil­ ize, or disappear, only to be replaced by dense sensory deficits. Muscle weakness, especially of the most distal intrinsic muscles of the hands and

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Table 1

Classification and staging of diabetic neuropathy

Class I: Subclinical neuropathy" A. Abnormal electrodiagnostic tests (EDX)

l. Decreased nerve conduction velocity 2. Decreased amplitude of evoked muscle or nerve action potential B. Abnormal quantitative sensory testing (QST)

1.

Vibratory/tactile

2. Thermal warming/cooling

3.

Other

C. Abnormal autonomic function tests (AFT)

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l.

Diminished sinus arrhythmia (beat-to-beat heart rate variation)

2. Diminished sudomotor function 3. Increased pupillary latency Class II: Clinical neuropathy A. Diffuse neuropathy l.

Distal symmetric sensorimotor polyneuropathy a.

Primarily small-fiber neuropathy

b. Primarily large-fiber neuropathy

c.

Mixed

2. Autonomic neuropathy a.

Abnormal pupillary function

h. Sudomotor dysfuncti on c.

Genitourinary autonomic neuropathy (I) Bladder dysfunction

(2)

d.

Sexual dysfunction

Gastrointestinal autonomic neuropathy

(I) Gastric atony (2) Gallbladder atony (3) Diabetic diarrhea (4) Hypoglycemic unawareness (adrenal medullary neuropathy)

e.

Cardiovascular autonomic neuropathy

f.

Hypoglycemic unawareness

B. Focal neuropathy

I. Mononeuropathy 2. Mononeuropathy multiplex

3.

Plexopathy

4. Radiculopathy 5. Cranial neuropathy Neurological function tests are abnormal but no neurological symptoms or clinically detectable neurological deficits indicative of a difu f se a

opathy," is further subdivided into class Ia if an AFT or QST abnormality is present, class Ib if EDX or

AFT and QST abnormalities are present, and class Ie if an or both are present.

EDX and

either AFT or QST abnormalities

feet, is a late finding, but diminished Achilles tendon reflex responses occur early in the disease (5). Secondary complications of the diminished pain sensation of distal symmetric polyneuropathy include acute and chronic foot ulceration,

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DIABETIC NEUROPATHY

;'', I

�:""'":

307

PINPRICK ABSENT

Figure 1 Sensory deficits in patients with distal symmetrical polyneuropathy, (From Sabin, T. D., et al. 1978. Physiology and Pathobiology oj Axons, pp. 431-38. New York: Raven.)

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GREENE ET AL

extremity burns, and neuroarthropathy (Charcot's joints). Acute ulcer­ ation results from abrasion of the dermis of the foot by unnoticed foreign objects within the shoe or by ill-fitting footwear. Chronic foot ulceration occurs over weight-bearing areas (plantar ulcer) (20, 21). Atrophy of the intrinsic extensor muscles of the foot produces chronic metatarsal­ phalangeal flexion (claw toe deformity), which shifts anterior weight bear­ ing over the now-uncovered metatarsal heads, leading to thinning and atrophy of the normal fat pad and formation of thick cornified calluses (21) that ultimately crack, fissure, become infected, and form deep ulcers (20, 21). Associated vascular ischemia probably contributes to the pro­ gression and/or refractoriness of diabetic foot ulcers. Coexisting archi­ tectural deformities, e.g. from neuroarthropathy, shift ulcer formation to alternative weight bearing sites. Diabetic neuroarthropathy affecting the tarsal-metatarsal and meta­ tarsal-phalangeal joints or the ankle is conditioned by impaired pro­ prioception as well as pain sensation (22). Presentation is usually painless or moderately painful swelling and redness of the foot without fever or leukocytosis, with a differential diagnosis of cellulitis or osteomyelitis depending upon the extent of radiographic bony destruction. Unhealed painless fractures and/or a recent history of painless trauma are often present (22). In advanced cases, gross architectural distortion and destruc­ tion of the foot with extensive bone demineralization and resorption leaves the foot a nonfunctional "bag of bones" (20). Autonomic neuropathy often complicates symmetric polyneuropathy so that isolated autonomic involvement should suggest other disorders, such as Shy-Drager syndrome. Diabetic autonomic neuropathy can impair virtually any autonomic function. Symptoms and signs confined to a single organ system generally accompany widespread subclinical autonomic dys­ function (except that diabetic impotence may occur as an isolated finding) (23). Cardiovascular autonomic neuropathy first impairs cardiac para­ sympathetic function and then cardiac and peripheral sympathetic function, diminishing the normal sleep bradycardia, interfering with the normal cardiovascular response to exercise, hypersensitizing the heart to circulating catecholamines, and hence predisposing to tachyarrythmias (23). Gastrointestinal autonomic neuropathy produces esophageal dis­ motility, relative achlorhydria, delayed gastric emptying, chronic alternat­ ing diarrhea and constipation, and rectal incontinence (23). Genitourinary autonomic neuropathy produces retrograde ejaCUlation (infertility and a postcoital "cloudy" urine), erectile impotence, and bladder dysfunction predisposing to recurrent urinary tract infections (23). Hypoglycemic unawareness (loss of the usual adrenergic· warning signs of impending hypoglycemia) is thought to reflect adrenal medullary and peripheral

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DIABETIC NEUROPATHY

309

sympathetic dysfunction. Sudomotor dysfunction presents as distal anhydrosis, which compromises thermoregulation, and troubling com­ pensatory central hyperhidrosis (23). Focal diabetic neuropathies are relatively uncommon, usually of sudden onset, generally self-limited, and most commonly observed in older pa­ tients (10). Cranial neuropathy most commonly affects the third nerve (diabetic ophthalmoplegia), thereby producing unilateral headache, diplopia, and ptosis with pupillary sparing; it may be recurrent and/or bilateral, and may occur in the absence of diffuse neuropathy. Differential diagnosis includes internal carotid aneurysm. Radiculopathy produces unilateral bandlike thoracic or abdominal pain, which is sometimes mis­ diagnosed as an intra-abdominal or thoracic emergency. Diabetic "femoral neuropathy" produces pain and sensory impairment in the distribution of the femoral nerve. Motor weakness, which may extend to the iliopsoas, quadriceps, and adductor muscles but usually spares the hip extensors and hamstrings (24), is more widespread and sensory impairment is less marked (24, 25) than in patients with nondiabetic femoral neuropathy. This atypi­ cal distribution plus the accompanying mild elevation in cerebrospinal protein implies that diabetic femoral neuropathy includes a component of sacral plexopathy-radiculopathy. Other mononeuropathies mimic the compression neuropathies seen in nondiabetic individuals, implying an increased sensitivity of the diabetic nerve to compression.

PATHOLOGY A myriad of lesions involving peripheral nerve axons, Schwann cells, perineurial cells, and endoneurial vascular elements have been found in diabetic autopsy and biopsy material, but no pathognomonic neural lesion has emerged. Diabetic distal symmetric polyneuropathy is accompanied by atrophy and loss of large and small myelinated fibers, with evidence of wallerian degeneration; segmental and paranodal demyelination (7); and proliferation of endoneurial connective tissue, including thickening and reduplication of neural, vascular, and subperineurial basement membranes (6, 26). The proximal-to-distal gradient in severity and the subtle intra­ axonal ultrastructural lesions in nerve biopsies from young diabetic pa­ tients suggest a primary axonal degeneration, selectively involving longer axons (27-32). Focal fiber loss in proximity to abnormally diseased vessels has been interpreted as suggesting a specific ischemic component to dia­ betic distal symmetric polyneuropathy (6, 26), although this thesis remains somewhat controversial (7). Autonomic and focal neuropathies have not been well studied.

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PATHOGENESIS Rather compelling clinical and experimental evidence supports the gen­ erally accepted belief that insulin deficiency and its metabolic consequences such as hyperglycemia contribute to the development of diabetic neu­ ropathy (9): cross-sectional and retrospective epidemiological studies cite the duration and severity of hyperglycemia as major risk factors for the development of diabetic neuropathy (17, 47); diabetic neuropathy com­ plicates secondary forms of diabetes such as hemochromatosis or following surgical pancreatectomy (21); spontaneous or experimental diabetes in animals produces functional, biochemical, and structural changes in pe­ ripheral nerves that mirror those of human diabetes (34, 35); and metabolic intervention in humans with diabetes improves nerve function (36-43). However, the development of neuropathy in diabetic patients is unpre­ dictable and may assume various forms, suggesting the presence of inde­ pendent modifying factors and multiple pathogenetic variables (44). Thus, the mechanism(s) by which insulin deficiency and hyperglycemia produces nerve damage is controversial. Two currently popular and not mutually exclusive pathogenetic schema are illustrated in Figures 2 and 3. Both invoke the concentration-dependent conversion of glucose to sorbitol by the enzyme aldose reductase, as well as secondary abnormalities in myo­ inositol, phosphoinositide, and Na,K-ATPase metabolism. One stresses the importance of phosphoinositides in the transmembrane signaling of neurotrophic factors (45), and the other stresses intervening abnormalities in nerve blood flow and oxygen delivery (46). The localization of the enzyme aldose reductase to both endoneurial microvessels and large myelinated nerve fibers could easily reconcile these two pathogenetic hypotheses (45).

DIAGNOSIS Diabetic neuropathy is suspected in any person with insulin-dependent diabetes mellitus (IDDM) of more than five years duration and in all patients with NIDDM. At a minimum, such patients should annually undergo a complete neurological history and physical examination focus­ ing on symptoms of distal symmetric and autonomic neuropathy, a com­ plete sensory examination of the upper and lower extremities and testing of deep tendon reflexes, and an orthostatic blood pressure test and pulse rate test by the Valsalva maneuver. More cursory sensory testing and examination of the feet for neuropathic deformities and/or ulceration should be performed on each office visit (at least quarterly). Positive findings should be pursued with appropriate quantitative electrodiagnostic tests to confirm the presence of a neuropathy consistent with the suspected

311

DIABETIC NEUROPATHY

form of diabetic neuropathy (Table 2) and appropriate laboratory tests to exclude other known causes of or conditions that mimic peripheral neuropathy (Table 3). Some, but not all, authors suggest periodic screening for subclinical neuropathy with electrodiagnostic, autonomic, and/or quantitative cutaneous sensory tests (Table 1) (47). Specific neuropathic syndromes entail additional differential diagnoses; e.g. vascular, hormonal, iatrogenic, and psychogenic causes of impotence must be excluded before it is attributed to diabetic autonomic neuropathy.

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MANAGEMENT OF CLINICAL SYNDROMES

-

Therapy for diabetic distal symmetric polyneuropathy is symptomatic, palliative, supportive, and prophylactic. Sensory deficits are asymptomatic Hyperglycemia

r

��ent

� Gra



tPolyol Pathway .Na-dependent �MIUPtake,'"

J] �t; ';1I": J ��t"," ' l' � t. tNa

".NaIK-ATPase Activity

.MI Content

t

�Ne�e Conduction

�Ca + IProtein Kinase C AC Ii

Paran�dal ng s

""o-gllal Dysjunction

Pe '

!:.

bIl

Rei. ... of Neurotrophic Facto�

Blunted Regenerative Response

..

Synaptic Block.de

Musca,;nIC Agonists

_

FI""' _ .'.no'" """"" DenervatIon Demyelination -tI"" L oss Figure 2

Proposed pathogenetic scheme linking disturbances in nerve myoinositol metab­ olism to slowing of nerve conduction; nerve fiber damage, demyelination, and degeneration; impaired synaptic transmission; and blunted nerve fiber repair and regeneration. The identity of neurotrophic factors is unknown, but they may include insulinlike growth factors or nerve growth factor. MI, myoinositol; DG, diacylglycerol. (From Greene, D. A., et al. 1988.

Diabetes

37: 688-93.)

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312

GREENE ET

It

AL

Nerve sorbitol

J,

T'" Nerve.nositol l Figure 3

Suggested pathogenesis of diabetic neuropathy. (From Ref. 35.)

(unless secondary complications develop), so that early diagnosis requires careful sensory examination, at which point aggressive patient education and foot hygiene and surveillance are begun. Accompanying dyscsthesias or paresthesias, often unnoticed or well tolerated by the patient, usually remit within a few months (5, 20), although this view is disputed (48). Severe and intractable pain in a small subset of patients has been managed by administration of standard nonaddicting analgesics, carbamazine (49, 50), phenytoin (51), or intravenous lidocaine (52) or its orally administered derivative mexiletinc (53), by transcutaneous nerve stimulation (54), or by the use of amitriptyline and related compounds in a stepwise trea tmen t protocol (55) or in combination with fl uphenazine (56). Others recommend 0.1 mg of clonidine at bedtime, although its efficacy has not been reported in the literature. Management of autonomic neuropathy is also palliative and syndrome specific (47). Postural hypotension is managcd by the use of body stockings, plasma volume expanders such as a high-saIt diet and fiudrocortisone, or autonomic drugs such as clonidine and phenylephrine nasal spray, after volume depletion, anemia, hypothyroidism, and adrenal insufficiency have been ruled out (57,58). Patients with cardiac denervation syndrome (80-90 beats per min fixed heart rate) should be evaluated for painless myocardial ischemia before an exercise program is instituted. Gastric atony, gallbladder dysfunction, and diabetic diarrhea and constipation all have

DIABETIC NEUROPATHY

Table 2

Polyneuropathy protocol

I.

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313

Conduction studies' A. General I. Test most-involved site if mild or moderate, least-involved site if severe. 2. Warm limb if temperature is < 32°C; monitor and maintain temperature through­ out study. 3. Use reproducible recording and stimulation sites (either fi xed distances or standard landmarks). 4. Use supramaximal percutaneous stimulation. B. Motor studies I. Peroneal motor (extensor digitorum brevis); stimulate at ankle and knee. Record F response latency following distal antidromic stimulation. 2. If abnormal, tibial motor (abductor hallucis); stimulate at ankle. Record F response latency. 3. If no responses: peroneal motor (anterior tibial); stimulate at fibula. 4. Ulnar motor (hypothenar); stimulate below wrist and elbow. Record F response latency. 5. Median motor (thenar); stimulate wrist and anticubital fossa. Record F response latency. C. Sensory studies I. Sural sensory (ankle); may occasionally require: a. Needle recording. b. Response averaging. 2. Median sensory (index); stimulate wrist and elbow. If antidromic response absent or focal entrapment suspected, record (wrist) stimulating palm. 3. Ulnar sensory (5th digit); stimulate wrist. If antidromic response absent or super­ imposed upon motor artifact, perform orthodromic study. D. Autonomic studies I. Skin potential responses (palmar and plantar surfaces of hand and foot, respec­ tively); stimulate contralateral median nerve . E. Additional I. Additional motor or sensory nerves can be evaluated if findings equivocal. Definite abnormalities should result in: a. Evaluation of opposite extremity. b. Proceed to evaluation of specific suspected abnormality. II. Needle examination A. Representative muscles I. Anterior tibial, medial gastrocnemius, first dorsal interosseous (hand), and lumbar paraspinal muscles. 2. If normal, intrinsic foot muscles should be examined. 3. Any abnormalities should be confirmed by examination of at least one contra­ lateral muscle. B. Grading I. Abnormal spontaneous activity should be graded subjectively (0 to 4+) by using conventional criteria. 2. Motor unit action potential amplitude, duration, configuration, and recruitment graded subjectively. a

Recording sites listed in parentheses_

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GREENE ET AL

Table 3

Differential diagnosis of diabetic neuropathy

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I.

II.

Distal symmetrical polyneuropathy A. Metabolic I. Diabetes mellitus 2. Uremia 3. Folic acid/cyanocobalamin deficiency 4. Hypothyroidism 5. Acute intermittent porphyria B. Toxic 1. Alcohol 2. Heavy metals (lead, mercury, arsenic) 3. Industrial hydrocarbons 4. Various drugs C. Infectious or inflammatory 1. Sarcoidosis 2. Leprosy 3. Periarteritis nodosa 4. Other connective-tissue diseases (e.g. systemic lupus erythematosus) D. Other I. Dysproteinemias and paraproteinemias 2. Paraneoplastic syndrome 3. Leukemias and lymphomas 4. Amyloidosis 5. Hereditary neuropathies Pains and paresthesias without neurologic deficit

A. Early small-fiber sensory neuropathy B. Psychophysiologic disorder (e.g. severe depression, hysteria) III. Autonomic neuropathy without somatic component A. Shy-Drager syndrome (progressive autonomic failure) B. Diabetic neuropathy with mild somatic involvement C. Riley-Day syndrome D. Idiopathic ort hostatic hypot ension IV. Diffuse motor neuropathy without sensory deficit A. Guillain-Barre syndrome B. Primary myopathies C. Myasthenia gravis D. Heavy-metal toxicity V. Femoral neuropathy (sacral plexopathy) A. Degenerative spinal-disk disease (e.g. Paget's disease of the spine) B. Intrinsic spinal-cord-mass lesion C. Equina cauda lesions D. Coagulopathies VI. Cranial neuropathy A. Carotid aneurysm B. Intracranial mass C. Elevated intracranial pressure VII. Mononeuropathy multiplex A. Vasculitides B. Amyloidosis C. Hypothyroidism D. Acromegaly E. Coagulopathies

DIABETIC NEUROPATHY

315

specific pharmacological or dietary interventions (47). Bladder dysfunction is suspected in cases of recurrent urinary tract infection; it is diagn osed by appropriate urological and/or radiographic procedures and managed by programmed frequent voiding with a Crude maneuver, bethanechol (1030 mg three times daily), internal sphincter resection, or chronic suprapubic catheterization (47), etc. Pathogenetically specific forms of therapy such as aldose reductase inhibitors (14) are presently experimental.

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1. Rollo,

J. 1798. Cases of Diabetes Mellitus. London: C. Dilly

2. Johnson, P. c., Doll, S. C., Cromey, D. W. 1986. Pathogenesis of diabetic neu­ ropathy. Ann. Neurol. 19: 450-57 3. Melton, L. J., Dyck, P. J. 1987. Epi­ demiology. In Diabetic Neuropathy, ed. P. J. Dyck, P. K. Thomas, A. K. Asbury, A. I. Winegrad, D. Porte, pp. 27-35. Philadelphia: Saunders 4. Dyck, P. J., Karnes, J., O'Brien, P. C. 1987. Diagnosis, staging, and classi­ fication of diabetic neuropathy and associations with other complications. See Ref. 3, p. 36 5. Brown, M. J., Greene, D. A. 1984. Dia­ betic neuropathy: pathophysiology and management. In Neurology, Peripheral

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spray. Clin. Res. 92: 30R

Diabetic neuropathy.

Diabetic neuropathy, the most common peripheral neuropathy in the Western world, is responsible for most limb amputations and considerable morbidity i...
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