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Diabetic neuropathies are the most prevalent chronic complications of diabetes. This heterogeneous group of conditions affects different parts of the nervous system and presents with diverse clinical manifestations. The early recognition and appropriate management of neuropathy in the patient with diabetes is important for a number of reasons: 1. Diabetic neuropathy is a diagnosis of exclusion. Nondiabetic neuropathies may be present in patients with diabetes and may be treatable by specific measures. 2. A number of treatment options exist for symptomatic diabetic neuropathy. 3. Up to 50% of diabetic peripheral neuropathies may be asymptomatic. If not recognized and if preventive foot care is not implemented, patients are at risk for injuries to their insensate feet. 4. Recognition and treatment of autonomic neuropathy may improve symptoms, reduce sequelae, and improve quality of life. Among the various forms of diabetic neuropathy, distal symmetric polyneuropathy (DSPN) and diabetic autonomic neuropathies, particularly cardiovascular autonomic neuropathy (CAN), are by far the most studied (1–4). There are several atypical forms of diabetic neuropathy as well (1–4). Patients with prediabetes may also develop neuropathies that are similar to diabetic neuropathies (5–10). Table 1 provides a comprehensive classification scheme for the diabetic neuropathies. View this table: Table 1 Classification for diabetic neuropathies Due to a lack of treatments that target the underlying nerve damage, prevention is the key component of diabetes care. Screening for symptoms and signs of diabetic neuropathy is also critical in clinical practice, as it may detect the earliest stages of neuropathy, enabling early intervention. Although screening for rarer atypical forms of diabetic neuropathy may be warranted, DSPN and autonomic neuropathy are the most common forms encountered in practice. The strongest available evidence regarding treatment pertains to these forms. This Position Statement is based on several recent technical reviews, to which the reader is referred for detailed discussion …

OBJECTIVE To evaluate the efficacy and safety of α-lipoic acid (ALA) over 4 years in mild-to-moderate diabetic distal symmetric sensorimotor polyneuropathy (DSPN). RESEARCH DESIGN AND METHODS In a multicenter randomized double-blind parallel-group trial, 460 diabetic patients with mild-to-moderate DSPN were randomly assigned to oral treatment with 600 mg ALA once daily (n = 233) or placebo (n = 227) for 4 years. Primary end point was a composite score (Neuropathy Impairment Score [NIS]–Lower Limbs [NIS-LL] and seven neurophysiologic tests). Secondary outcome measures included NIS, NIS-LL, nerve conduction, and quantitative sensory tests (QSTs). RESULTS Change in primary end point from baseline to 4 years showed no significant difference between treatment groups (P = 0.105). Change from baseline was significantly better with ALA than placebo for NIS (P = 0.028), NIS-LL (P = 0.05), and NIS-LL muscular weakness subscore (P = 0.045). More patients showed a clinically meaningful improvement and fewer showed progression of NIS (P = 0.013) and NIS-LL (P = 0.025) with ALA than with placebo. Nerve conduction and QST results did not significantly worsen with placebo. Global assessment of treatment tolerability and discontinuations due to lack of tolerability did not differ between the groups. The rates of serious adverse events were higher on ALA (38.1%) than on placebo (28.0%). CONCLUSIONS Four-year treatment with ALA in mild-to-moderate DSPN did not influence the primary composite end point but resulted in a clinically meaningful improvement and prevention of progression of neuropathic impairments and was well tolerated. Because the primary composite end point did not deteriorate significantly in placebo-treated subjects, secondary prevention of its progression by ALA according to the trial design was not feasible.

OBJECTIVE To determine the relationships among large, small, and autonomic fiber neurophysiological measures in a cross-sectional study of patients with diabetes. RESEARCH DESIGN AND METHODS We assessed 130 individuals: 25 healthy subjects and 105 subjects with diabetes. Subjects were classified by the presence or absence of neuropathy by physical examination. All subjects underwent autonomic testing, nerve conduction studies, quantitative sensory testing, and nerve-axon reflex vasodilation in addition to quantifiable neurological examination and symptom scores. Correlation and cluster analysis were used to determine relationships between and among different neurophysiological testing parameters. RESULTS Results of neurophysiological tests were abnormal in patients with clinical evidence of diabetic neuropathy compared with results in healthy control subjects and in those without neuropathy (P < 0.01, all tests). The correlations among individual tests varied widely, both within (r range 0.9, NS to 0.5, NS to CONCLUSIONS The modest correlation coefficients seen between the different testing modalities suggest that these techniques measure different neurophysiological parameters and are therefore not interchangeable. However, the data suggest that only a small number of neurophysiological tests are actually required to clinically differentiate individuals with neuropathy from those without. The natural clustering of both patients and healthy control subjects suggests that variations in the population will need to be considered in future studies of diabetic neuropathy.

OBJECTIVE—To evaluate the efficacy, safety, and tolerability of pregabalin across the effective dosing range, to determine differences in the efficacy of three times daily (TID) versus twice daily (BID) dosage schedules, and to use time-to-event analysis to determine the time to onset of a sustained therapeutic effect using data from seven trials of pregabalin in painful diabetic peripheral neuropathy (DPN). RESEARCH DESIGN AND METHODS—Data were pooled across seven double-blind, randomized, placebo-controlled trials using pregabalin to treat painful DPN with dosages of 150, 300, and 600 mg/day administered TID or BID. Only one trial included all three of these dosages, and TID dosing was used in four. All studies shared fundamental selection criteria, and treatment durations ranged from 5 to 13 weeks. RESULTS—Pooled analysis showed that pregabalin significantly reduced pain and pain-related sleep interference associated with DPN (150, 300, and 600 mg/day administered TID vs. placebo, all P ≤ 0.007). Only the 600 mg/day dosage showed efficacy when administered BID (P ≤ 0.001). Pain and sleep interference reductions associated with pregabalin appear to be positively correlated with dosage; the greatest effect was observed in patients treated with 600 mg/day. Kaplan-Meier analysis revealed that the median time to onset of a sustained (≥30% at end point) 1-point improvement was 4 days in patients treated with pregabalin at 600 mg/day, 5 days in patients treated with pregabalin at 300 mg/day, 13 days in patients treated with pregabalin at 150 mg/day, and 60 days in patients receiving placebo. The most common treatment-emergent adverse events were dizziness, somnolence, and peripheral edema. CONCLUSIONS—Treatment with pregabalin across its effective dosing range is associated with significant, dose-related improvement in pain in patients with DPN.

The diabetic neuropathies are heterogeneous, affecting different parts of the nervous system that present with diverse clinical manifestations. They may be focal or diffuse. Most common among the neuropathies are chronic sensorimotor distal symmetric polyneuropathy (DPN) and the autonomic neuropathies. DPN is a diagnosis of exclusion. The early recognition and appropriate management of neuropathy in the patient with diabetes is important for a number of reasons. 1 ) Nondiabetic neuropathies may be present in patients with diabetes. 2 ) A number of treatment options exist for symptomatic diabetic neuropathy. 3 ) Up to 50% of DPN may be asymptomatic, and patients are at risk of insensate injury to their feet. As >80% of amputations follow a foot ulcer or injury, early recognition of at-risk individuals, provision of education, and appropriate foot care may result in a reduced incidence of ulceration and consequently amputation. 4 ) Autonomic neuropathy may involve every system in the body. 5 ) Autonomic neuropathy causes substantial morbidity and increased mortality, particularly if cardiovascular autonomic neuropathy (CAN) is present. Treatment should be directed at underlying pathogenesis. Effective symptomatic treatments are available for the manifestations of DPN and autonomic neuropathy. This statement is based on two recent technical reviews (1,2), to which the reader is referred for detailed discussion and relevant references to the literature. An internationally agreed simple definition of DPN for clinical practice is “the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after the exclusion of other causes” (3). However, the diagnosis cannot be made without a careful clinical examination of the lower limbs, as absence of symptoms should never be assumed to indicate an absence of signs. This definition conveys the important message that not all patients with peripheral nerve dysfunction have a neuropathy caused by diabetes. Confirmation can be established with …

OBJECTIVE—To examine by meta-analysis the relationship between cardiovascular autonomic neuropathy (CAN) and risk of mortality in individuals with diabetes. RESEARCH DESIGN AND METHODS—We searched Medline for English-language articles published from 1966 to 2001. Fifteen studies having a baseline assessment of cardiovascular autonomic function and mortality follow-up were identified. The analyses were stratified according to whether a single abnormality or two or more measures of cardiovascular autonomic function were used to define CAN. A global measure of association (i.e., relative risk) was generated for each group by pooling estimates across the studies using the Mantel-Haenszel procedure. RESULTS—CAN was significantly associated with subsequent mortality in both groups, although the magnitude of the association was stronger for those studies for which two or more measures were used to define CAN. The pooled relative risk for studies that defined CAN with the presence of two or more abnormalities was 3.45 (95% CI 2.66–4.47; P < 0.001) compared with 1.20 (1.02–1.41; P = 0.03) for studies that used one measure. CONCLUSIONS—These results support an association between CAN and increased risk of mortality. The stronger association observed in studies defining CAN by the presence of two or more abnormalities may be due to more severe autonomic dysfunction in these subjects or a higher frequency of other comorbid complications that contributed to their higher mortality risk. Future studies should evaluate whether early identification of subjects with CAN can lead to a reduction in mortality.

Diabetic autonomic neuropathy (DAN) is a serious and common complication of diabetes. Despite its relationship to an increased risk of cardiovascular mortality and its association with multiple symptoms and impairments, the significance of DAN has not been fully appreciated. The reported prevalence of DAN varies widely depending on the cohort studied and the methods of assessment. In randomly selected cohorts of asymptomatic individuals with diabetes, 20% had abnormal cardiovascular autonomic function. DAN frequently coexists with other peripheral neuropathies and other diabetic complications, but DAN may be isolated, frequently preceding the detection of other complications. Major clinical manifestations of DAN include resting tachycardia, exercise intolerance, orthostatic hypotension, constipation, gastro- paresis, erectile dysfunction, sudomotor dysfunction, impaired neurovascular function, "brit- tle diabetes," and hypoglycemic autonomic failure. DAN may affect many organ systems throughout the body (e.g., gastrointestinal (GI), genitourinary, and cardiovascular). GI distur- bances (e.g., esophageal enteropathy, gastroparesis, constipation, diarrhea, and fecal inconti- nence) are common, and any section of the GI tract may be affected. Gastroparesis should be suspected in individuals with erratic glucose control. Upper-GI symptoms should lead to con- sideration of all possible causes, including autonomic dysfunction. Whereas a radiographic gastric emptying study can definitively establish the diagnosis of gastroparesis, a reasonable approach is to exclude autonomic dysfunction and other known causes of these upper-GI symptoms. Constipation is the most common lower-GI symptom but can alternate with episodes of diarrhea. Diagnostic approaches should rule out autonomic dysfunction and the well-known causes such as neoplasia. Occasionally, anorectal manometry and other specialized tests typically performed by the gastroenterologist may be helpful. DAN is also associated with genitourinary tract disturbances including bladder and/or sexual dysfunction. Evaluation of bladder dysfunc- tion should be performed for individuals with diabetes who have recurrent urinary tract infec- tions, pyelonephritis, incontinence, or a palpable bladder. Specialized assessment of bladder dysfunction will typically be performed by a urologist. In men, DAN may cause loss of penile erection and/or retrograde ejaculation. A complete workup for erectile dysfunction in men should include history (medical and sexual); psychological evaluation; hormone levels; mea- surement of nocturnal penile tumescence; tests to assess penile, pelvic, and spinal nerve func- tion; cardiovascular autonomic function tests; and measurement of penile and brachial blood pressure. Neurovascular dysfunction resulting from DAN contributes to a wide spectrum of clinical disorders including erectile dysfunction, loss of skin integrity, and abnormal vascular reflexes. Disruption of microvascular skin blood flow and sudomotor function may be among the earliest manifestations of DAN and lead to dry skin, loss of sweating, and the development of fissures and cracks that allow microorganisms to enter. These changes ultimately contribute to the development of ulcers, gangrene, and limb loss. Various aspects of neurovascular function can be evaluated with specialized tests, but generally these have not been well standardized and have limited clinical utility. Cardiovascular autonomic neuropathy (CAN) is the most studied and clinically important form of DAN. Meta-analyses of published data demonstrate that reduced cardiovascular autonomic function as measured by heart rate variability (HRV) is strongly (i.e., relative risk is doubled) associated with an in- creased risk of silent myocardial ischemia and mortality. The determination of the presence of CAN is usually based on a battery of auto- nomic function tests rather than just on one test. Proceedings from a consensus conference in 1992 recommended that three tests (R-R variation, Valsalva maneuver, and postural blood pressure testing) be used for longitudi- nal testing of the cardiovascular autonomic system. Other forms of autonomic neuropathy can be evaluated with specialized tests, but these are less standardized and less available than commonly used tests of cardiovascular autonomic function, which quantify loss of HRV. Interpretability of serial HRV testing re- quires accurate, precise, and reproducible procedures that use established physiological maneuvers. The battery of three recom- mended tests for assessing CAN is readily per- formed in the average clinic, hospital, or diagnostic center with the use of available technology. Measurement of HRV at the time of diagnosis of type 2 diabetes and within 5 years after diagnosis of type 1 diabetes (unless an individual has symptoms suggestive of au- tonomic dysfunction earlier) serves to estab- lish a baseline, with which 1-year interval tests can be compared. Regular HRV testing pro- vides early detection and thereby promotes timely diagnostic and therapeutic interven- tions. HRV testing may also facilitate differen- tial diagnosis and the attribution of symptoms (e.g., erectile dysfunction, dyspepsia, and diz- ziness) to autonomic dysfunction. Finally, knowledge of early autonomic dysfunction can encourage patient and physician to im- prove metabolic control and to use therapies such as ACE inhibitors and -blockers, proven to be effective for patients with CAN. Diabetes Care 26:1553-1579, 2003

OBJECTIVE To evaluate the efficacy and safety of α-lipoic acid (ALA) over 4 years in mild-to-moderate diabetic distal symmetric sensorimotor polyneuropathy (DSPN). RESEARCH DESIGN AND METHODS In a multicenter randomized double-blind parallel-group trial, 460 diabetic patients with mild-to-moderate DSPN were randomly assigned to oral treatment with 600 mg ALA once daily (n = 233) or placebo (n = 227) for 4 years. Primary end point was a composite score (Neuropathy Impairment Score [NIS]–Lower Limbs [NIS-LL] and seven neurophysiologic tests). Secondary outcome measures included NIS, NIS-LL, nerve conduction, and quantitative sensory tests (QSTs). RESULTS Change in primary end point from baseline to 4 years showed no significant difference between treatment groups (P = 0.105). Change from baseline was significantly better with ALA than placebo for NIS (P = 0.028), NIS-LL (P = 0.05), and NIS-LL muscular weakness subscore (P = 0.045). More patients showed a clinically meaningful improvement and fewer showed progression of NIS (P = 0.013) and NIS-LL (P = 0.025) with ALA than with placebo. Nerve conduction and QST results did not significantly worsen with placebo. Global assessment of treatment tolerability and discontinuations due to lack of tolerability did not differ between the groups. The rates of serious adverse events were higher on ALA (38.1%) than on placebo (28.0%). CONCLUSIONS Four-year treatment with ALA in mild-to-moderate DSPN did not influence the primary composite end point but resulted in a clinically meaningful improvement and prevention of progression of neuropathic impairments and was well tolerated. Because the primary composite end point did not deteriorate significantly in placebo-treated subjects, secondary prevention of its progression by ALA according to the trial design was not feasible.

OBJECTIVE To determine the relationships among large, small, and autonomic fiber neurophysiological measures in a cross-sectional study of patients with diabetes. RESEARCH DESIGN AND METHODS We assessed 130 individuals: 25 healthy subjects and 105 subjects with diabetes. Subjects were classified by the presence or absence of neuropathy by physical examination. All subjects underwent autonomic testing, nerve conduction studies, quantitative sensory testing, and nerve-axon reflex vasodilation in addition to quantifiable neurological examination and symptom scores. Correlation and cluster analysis were used to determine relationships between and among different neurophysiological testing parameters. RESULTS Results of neurophysiological tests were abnormal in patients with clinical evidence of diabetic neuropathy compared with results in healthy control subjects and in those without neuropathy (P < 0.01, all tests). The correlations among individual tests varied widely, both within (r range 0.9, NS to 0.5, NS to

To evaluate the efficacy, safety, and tolerability of pregabalin across the effective dosing range, to determine differences in the efficacy of three times daily (TID) versus twice daily (BID) dosage schedules, and to use time-to-event analysis to determine the time to onset of a sustained therapeutic effect using data from seven trials of pregabalin in painful diabetic peripheral neuropathy (DPN).Data were pooled across seven double-blind, randomized, placebo-controlled trials using pregabalin to treat painful DPN with dosages of 150, 300, and 600 mg/day administered TID or BID. Only one trial included all three of these dosages, and TID dosing was used in four. All studies shared fundamental selection criteria, and treatment durations ranged from 5 to 13 weeks.Pooled analysis showed that pregabalin significantly reduced pain and pain-related sleep interference associated with DPN (150, 300, and 600 mg/day administered TID vs. placebo, all Por = 0.007). Only the 600 mg/day dosage showed efficacy when administered BID (Por = 0.001). Pain and sleep interference reductions associated with pregabalin appear to be positively correlated with dosage; the greatest effect was observed in patients treated with 600 mg/day. Kaplan-Meier analysis revealed that the median time to onset of a sustained (or =30% at end point) 1-point improvement was 4 days in patients treated with pregabalin at 600 mg/day, 5 days in patients treated with pregabalin at 300 mg/day, 13 days in patients treated with pregabalin at 150 mg/day, and 60 days in patients receiving placebo. The most common treatment-emergent adverse events were dizziness, somnolence, and peripheral edema.Treatment with pregabalin across its effective dosing range is associated with significant, dose-related improvement in pain in patients with DPN.

OBJECTIVE—Inflammation may have a major role in the pathogenesis and prognosis of critical illness. Hyperglycemia increases levels of the inflammatory cytokine interleukin-6 (IL-6) and is associated with increased risks of morbidity and mortality. Because hypoglycemia is also associated with adverse outcomes, we tested the hypothesis that hypoglycemia increases IL-6. RESEARCH DESIGN AND METHODS—Seventeen healthy men and women participated in hypoglycemic and euglycemic-hyperinsulinemic clamp studies (target blood glucose levels 2.7 and 5.0 mmol/l, respectively), separated by 1–3 months. IL-6, ACTH, and cortisol were measured at baseline and at 45, 75, 105, and 135 min after initiation of the insulin infusion. RESULTS—IL-6, ACTH, and cortisol levels increased significantly (P < 0.0001) during hypoglycemia but not euglycemia. IL-6 increased from mean ± SEM 1.0 ± 0.2 pg/ml at baseline to 2.6 ± 0.2 pg/ml after 135 min of hypoglycemia, whereas IL-6 levels were unchanged during euglycemia. CONCLUSIONS—Hypoglycemia increases IL-6 levels in healthy individuals.

To examine by meta-analysis the relationship between cardiovascular autonomic neuropathy (CAN) and risk of mortality in individuals with diabetes.We searched Medline for English-language articles published from 1966 to 2001. Fifteen studies having a baseline assessment of cardiovascular autonomic function and mortality follow-up were identified. The analyses were stratified according to whether a single abnormality or two or more measures of cardiovascular autonomic function were used to define CAN. A global measure of association (i.e., relative risk) was generated for each group by pooling estimates across the studies using the Mantel-Haenszel procedure.CAN was significantly associated with subsequent mortality in both groups, although the magnitude of the association was stronger for those studies for which two or more measures were used to define CAN. The pooled relative risk for studies that defined CAN with the presence of two or more abnormalities was 3.45 (95% CI 2.66-4.47; P0.001) compared with 1.20 (1.02-1.41; P = 0.03) for studies that used one measure.These results support an association between CAN and increased risk of mortality. The stronger association observed in studies defining CAN by the presence of two or more abnormalities may be due to more severe autonomic dysfunction in these subjects or a higher frequency of other comorbid complications that contributed to their higher mortality risk. Future studies should evaluate whether early identification of subjects with CAN can lead to a reduction in mortality.

Diabetic neuropathy remains an unmet medical need. While scientific advances (1,2) have been made in understanding pathophysiology, the impact on the clinical care of patients has been minimal, aside from symptomatic treatments for the pain that may accompany diabetic sensorimotor polyneuropathy (DPN) (3). Improved glucose control is still the main recommendation for the prevention and treatment of DPN, based on studies conducted over 10 years ago. Recently, two evidence-based reviews (4,5) for the treatment of diabetic neuropathy have been published, which form the basis of the subsequent American Diabetes Association position statement (6) on the topic. Into the apparent void of therapy for DPN, surgical decompression of multiple lower or upper limb nerves is being advocated as the treatment (7). The procedure is being utilized to treat symptomatic and generalized DPN. This approach is based on a series of hypotheses. First, the signs and symptoms of DPN are due to multiple nerve entrapments. In the lower limb, foot numbness is ascribed to “entrapment” of the peroneal nerve at both the fibular head and the anterior tarsal tunnel, the tibial nerve in the tarsal tunnel, and the sural nerve in the distal posterior calf. In …

OBJECTIVE We have compared the hyperemic response to heat and the endothelium-dependent and endothelium-independent vasodilatation between the dorsum of the foot and the forearm in diabetic neuropathic and non-neuropathic patients and healthy control subjects. RESEARCH DESIGN AND METHODS We studied the cutaneous microcirculation in the forearm and foot in 15 diabetic patients with neuropathy, in 14 diabetic patients without neuropathy, and in 15 control subjects matched for age, sex, BMI, and in the case of diabetic patients, for the duration of diabetes. Patients with peripheral vascular disease and/or renal impairment were excluded. The cutaneous microcirculation of the dorsum of the foot and the flexor aspect of the forearm was tested in all subjects. Single-point laser Doppler was employed to measure the maximal hyperemic response to heating of the skin to 44°C and laser Doppler imaging scanner was used to evaluate the response to iontophoresis of 1% acetylcholine chloride (Ach) (endothelium-dependent response) and 1% sodium nitroprusside (NaNP) (endothelium-independent response). RESULTS The transcutaneous oxygen tension was lower in the neuropathic group at both foot and forearm level, while the maximal hyperemic response to heat was similar at the foot and forearm level in all three groups. The endothelium-dependent vasodilation (percent increase over baseline) was lower in the foot compared to the forearm in the neuropathic group (23 ± 4 vs. 55 ± 10 [mean ± SEM] P < 0.01)], the non-neuropathic group (33 ± 6 vs. 88 ± 14; P < 0.01), and the control subjects (43 ± 6 vs. 93 ± 13; P < 0.001). Similar results were observed during the iontophoresis of NaNP (P < 0.05). No differences were found among the three groups when the ratio of the forearm:foot response was calculated for both the endothelium-dependent (neuropathic group, 2.25 ± 0.24; non-neuropathic group, 2.55 ± 0.35; and control subjects, 2.11 ± 0.26; P = NS) and endothelium-independent vasodilation (neuropathic group, 1.54 ± 0.27; non-neuropathic group, 2.08 ± 0.33; and control subjects, 2.77 ± 1.03; P = NS). The vasodilatory response, which is related to the C nociceptive fiber action, was reduced at the foot level during iontophoresis of Ach in the neuropathic group. In contrast, no difference was found during the iontophoresis of NaNP at the foot and forearm level and of Ach at the forearm level among all three groups. CONCLUSIONS In healthy subjects, the endothelial-dependent and endothelial-independent vasodilatation is lower at the foot level when compared to the forearm, and a generalized impairment of the microcirculation in diabetic patients with neuropathy preserves this forearm-foot gradient. These changes may be a contributing factor for the early involvement of the foot with neuropathy when compared to the forearm.