P. Kempler

Diabetic neuropathies: Update on definitions, diagnostic criteria, estimation of severity, and treatments

Preceding the joint meeting of the 19th annual Diabetic Neuropathy Study Group of the European Association for the Study of Diabetes (NEURODIAB) and the 8th International Symposium on Diabetic Neuropathy in Toronto, Canada, 13–18 October 2009, expert panels were convened to provide updates on classification, definitions, diagnostic criteria, and treatments of diabetic peripheral neuropathies (DPNs), autonomic neuropathy, painful DPNs, and structural alterations in DPNs.

Treatment of symptomatic diabetic polyneuropathy with the antioxidant α‐lipoic acid: a meta‐analysis

Aims  To determine the efficacy and safety of 600 mg of α‐lipoic acid given intravenously over 3 weeks in diabetic patients with symptomatic polyneuropathy.

Cardiovascular autonomic neuropathy in diabetes: clinical impact, assessment, diagnosis, and management

The Cardiovascular Autonomic Neuropathy (CAN) Subcommittee of the Toronto Consensus Panel on Diabetic Neuropathy worked to update CAN guidelines, with regard to epidemiology, clinical impact, diagnosis, usefulness of CAN testing, and management. CAN is the impairment of cardiovascular autonomic control in the setting of diabetes after exclusion of other causes. The prevalence of confirmed CAN is around 20%, and increases up to 65% with age and diabetes duration. Established risk factors for CAN are glycaemic control in type 1 and a combination of hypertension, dyslipidaemia, obesity, and glycaemic control in type 2 diabetes. CAN is a risk marker of mortality and cardiovascular morbidity, and possibly a progression promoter of diabetic nephropathy. Criteria for CAN diagnosis and staging are: (1) one abnormal cardiovagal test result identifies possible or early CAN; (2) at least two abnormal cardiovagal test results are required for definite or confirmed CAN; and (3) the presence of orthostatic hypotension in addition to abnormal heart rate test results identifies severe or advanced CAN. Progressive stages of CAN are associated with increasingly worse prognosis. CAN assessment is relevant in clinical practice for (1) diagnosis of CAN clinical forms, (2) detection and tailored treatment of CAN clinical correlates (e.g. tachycardia, orthostatic hypotension, non‐dipping, QT interval prolongation), (3) risk stratification for diabetic complications and cardiovascular morbidity and mortality, and (4) modulation of targets of diabetes therapy. Evidence on the cost‐effectiveness of CAN testing is lacking. Apart from the preventive role of intensive glycaemic control in type 1 diabetes, recommendations cannot be made for most therapeutic approaches to CAN. Copyright

Autonomic neuropathy is associated with increased cardiovascular risk factors: the EURODIAB IDDM Complications Study.

Aims To assess the prevalence of and risk factors for autonomic neuropathy in the EURODIAB IDDM Complications Study.

Methods of investigation for cardiac autonomic dysfunction in human research studies

This consensus document provides evidence‐based guidelines regarding the evaluation of diabetic cardiovascular autonomic neuropathy (CAN) for human research studies; the guidelines are the result of the work of the CAN Subcommittee of the Toronto Diabetic Neuropathy Expert Group. The subcommittee critically reviewed the limitations and strengths of the available diagnostic approaches for CAN and the need for developing new tests for autonomic function.

Painful Diabetic Neuropathy

Pain is probably the most distressing symptom of diabetic neuropathy (1). The features of pain in diabetic neuropathy were clearly documented by Pavy (2), who observed, that it was of burning and unremitting quality often with a nocturnal exacerbation. Indeed the quality of neuropathic pain has been described as burning, shooting, lancinating, prickling, and aching in character, often with many of these symptoms manifesting in the same patient (3). Some patients describe these symptoms as the feeling of walking barefoot on hot sand or pebbles. Others describe an odd sensation of their legs feeling swollen. The intensity of neuropathic pain is also variable among different individuals and often varies with time in the same individual. Some patients may have mild paresthesia in one or two toes; others may have intolerable unremitting pain involving both legs (4). Most patients with chronic, painful neuropathy have a moderate background pain with relatively short intervals of peak neuropathic pain. Sleep is often disturbed because of the nocturnal exacerbation of these symptoms, in addition to allodynia (contact hypersensitivity to bed clothes) (4). In some patients, neuropathic pain can be so disabling as to lead to loss of employment, reduction in exercise tolerance, and hence interference with daily activities, a reduction in recreational activities, and depression (4,5).

Diabetic neuropathy: new strategies for treatment

Current therapeutic possibilities can be divided into two groups: the pathogenetically oriented and the symptomatic therapy. One of the most important component of etiology‐based treatment is the stabilization of glycemic control. Based on efficacy and safety data benfotiamine and alpha‐lipoic acid should be considered as first choices among pathogenetically oriented treatments of diabetic neuropathy. Promising data were published about the aldose reductase inhibitor ranirestat. The symptomatic effect of antiepileptic drugs in diabetic painful neuropathy (DPN) is originated from several possible pharmacological properties. Pregabalin and gabapentin have the highest efficacy and the lowest frequency of adverse events among these drugs. Antidepressants also extensively used for symptomatic treatment in DPN. In the last years several studies were published about the benefial effect of duloxetine. Most likely combination therapy will be frequently applied in the future for the treatment of DPN, the optimal choice could be to combine pathogenetically oriented and symptomatic treatment.

Noninvasive Evaluation of Neural Impairment in Subjects With Impaired Glucose Tolerance

OBJECTIVE—To evaluate neural dysfunction in subjects with impaired glucose tolerance (IGT). RESEARCH DESIGN AND METHODS—For this study, 46 subjects with IGT and 45 healthy volunteers underwent detailed neurological assessment. Cardiovascular autonomic function was assessed by standard cardiovascular reflex tests, and heart rate variability was characterized by the triangle index. Sensory nerve function was assessed using Neurometer (for current perception threshold) and Medoc devices. Peak plantar pressure was measured by dynamic pedobarography, and symptoms were graded using the neuropathy total symptom score. RESULTS—Subjects with IGT had significantly greater abnormalities detected by four of five cardiovascular reflex tests and greater heart rate variability characterized by the triangle index. They had a higher frequency of both hyperesthesia and hypoesthesia as detected by current perception threshold testing at 5 Hz, as well as increased heat detection thresholds. CONCLUSIONS—This study provides evidence that subclinical neural dysfunction is present in subjects with IGT and can be detected noninvasively. Cardiovascular autonomic neuropathy may contribute to increased cardiovascular risk in IGT subjects.

Prevalence and management of hypertension in Type 1 diabetes mellitus in Europe: The Eurodiab IDDM Complications Study

Aim To examine the prevalence of hypertension and the rates of hypertension awareness by investigating treatment and control among respondents to the EURODIAB IDDM Complications Study, and to explore the variation in hypertension management by age, sex and end‐organ damage.

Is autonomic neuropathy a risk factor for severe hypoglycaemia ? The EURODIAB IDDM Complications Study

Summary The hypothesis that diabetic patients with autonomic neuropathy are at increased risk of severe hypoglycaemia was examined in an epidemiological study of over 3000 IDDM patients in Europe (EURODIAB IDDM Complications Study). Autonomic function was assessed by two standard cardiovascular tests: change in heart rate and systolic blood pressure on standing. Severe hypoglycaemia was defined as an attack serious enough to require the help of another person. Compared to patients (68 %) reporting no attacks in the last year, those reporting one or more attacks were older (34.0 ± 10.7 vs 32.1 ± 9.9 years, mean ± SD, p < 0.0001), had had diabetes for a longer period (16.6 ± 9.5 vs 13.8 ± 9.1 years, p < 0.0001), had better glycaemic control (HbA1c 6.4 ± 1.8 vs 6.9 ± 1.9 %, p < 0.0001) and were more likely (p = 0.002) to have abnormal responses to both autonomic tests (13.0 vs 7.7 %). A single abnormal autonomic response was not associated with an increased risk of severe hypoglycaemia. The odds ratio for severe hypoglycaemia in people with abnormal responses to both autonomic tests, compared to those with normal responses, was 1.7 (95 % confidence interval 1.3, 2.2) after controlling for age, duration of diabetes, glycaemic control and study centre. In conclusion, a combined autonomic deficit in heart rate and blood pressure responses to standing is associated with only a modest increase in the risk of severe spontaneous hypoglycaemia. Although the increase in risk is not large, severe hypoglycaemia was a frequently reported event in this study. IDDM patients with deficient autonomic responses who strive for tight glycaemic control may therefore be at particular risk of severe hypoglycaemia. [Diabetologia (1996) 39: 1372–1376]