subjects who died suddenly. 9.3% were diabetic, whereas only 3.5% of the patients who survived had diabetes [137]. The Zutphen Study [138] recently showed that low HRV predicts mortality from all causes in the general population. The population-based Honolulu Heart Program demonstrated that orthostatic hypotension defined as a drop in systolic blood pressure of at least 20 mmHg or in diastolic blood pressure of at least 10 mmHg predicts four-year all-cause mortality in a cohort of 3522 elderly Japanese-American men aged 71-93. Four-year age-adjusted mortality rates were 57 and 39 per 1000 person-years in men with and without orthostatic hypotension, respectively [139].
The second hypothesis for the explanation of the increased mortality in CAN suggests that impaired central control of respiration rather than abnormal cardiovascular reflexes contributes to the poor prognosis [131]. This view is supported by studies reporting an increased prevalence of sleep apnea and nocturnal oxygen desaturation in diabetic patients with CAN [140,141]. Several studies have demonstrated impaired ventilatory responses to progressive hypercapnia or hypoxemia in CAN [142–144]. This impairment is not due to peripheral factors such as abnormal lung function or diaphragmatic muscle alterations, but to defective central control of respiration. This last suggestion is supported by the finding that naloxone, a specific opioid antagonist, produced no increase in CO2 response in diabetic patients with CAN, in contrast to healthy subjects. However, a lack of effect of naloxone on CO2 response was also observed in diabetic patients without CAN [143]. Hence, the question remains open as to whether the altered central control of respiration is specific to CAN or is rather a feature of diabetes itself. To complicate matters even more, an increased hypercapnic drive, indicating an exaggerated response of the central drive due to removal of the sympathetic inhibition, was recently found in patients with CAN and orthostatic hypotension [144].
There is little information available on the prognostic significance of the other manifestations of autonomic neuropathy. Diabetic gastroparesis diagnosed by scintigraphy was not associated with a poor prognosis in two studies performed over 3-5 and 9-14 years, respectively [145,146].
Conclusions
The study of the epidemiology of diabetic neuropathy remains clouded by lack of agreement over diagnostic criteria and variation in subject selection methods. It is essential that agreement is reached over diagnosis, although it is hard at the present time to see how this is going to come about. One issue that may be relevant in this context is the basis on which the diagnosis should be made. Is diabetic neuropathy a condition which predisposes to clinical endpoints such as foot ulceration and amputation, in which case quantitative sensory testing should suffice, or is it a condition in which neurological function differs from that in a healthy population, in which case diagnosis may require a more detailed assessment?
The available data indicate that DSP is present in approximately 30% of hospital clinic patients, 20% of patients in primary care, and 10% of the total diabetic population, including both diagnosed and undiagnosed diabetes. The major confirmed risk factors are poor glycemic control, diabetes duration and height, with possible roles for hypertension (probably only in type 1 diabetes), age, smoking, hypoinsulinemia, and dyslipidemia.
There are as yet relatively few epidemiological data on the various manifestations of autonomic neuropathy from representative cohorts of diabetic patients, except for erectile dysfunction. Estimates from the available studies suggest that CAN is encountered one of every 4-6 men and ED is observed in one of every 2-3 men. Symptomatic orthostatic hypotension is relatively uncommon. Gastrointestinal symptoms are common in both diabetic and nondiabetic subjects, suggesting that a considerable proportion of these symptoms in diabetic patients is due to causes other than autonomic neuropathy
Clinic-based data suggest that particularly CAN but possibly also DSP are associated with increased mortality in diabetic patients, but prospective population-based studies are required to confirm these findings.
References
[1] Statement C. Report and recommendations of the San Antonio Conference on diabetic neuropathy. Diabetes Care 1988; 37: 1000-4.
[2] The Diabetes Control and Complications Trial Research Group. The effect of intensive diabetes therapy on the development and progression of diabetic neuropathy. Ann Intern Med 1995; 122: 561-8.
[3] Delcourt C, Vauzelle-Kervroedan F, Cathelineau G, Papoz L. Low prevalence of long-term complications in non-insulin-dependent diabetes mellitus in France: a multicenter study. J Diabetes Complications 1998; 12: 88-95.
[4] Nelson RG, Gohdes DM, Everhart JE, Hartner JA, Zwemer FL, Pettitt DJ, Knowler WC. Lower-extremity amputations in NIDDM; 12-yr follow-up study in Pima Indians. Diabetes Care 1988; 11:8-16.
[5] Shaw JE, Hodge AM, Courten M de, Dowse GK, Gareeboo H, Tuomilehto J, Alberti KGMM, Zimmet PZ. Diabetic neuropathy in Mauritius: prevalence and risk factors. Diabetes Res Clin Pract 1998; 42: 131-9.
[6] Herman WH, Aubert RE, Engelgau MM, Thompson TJ, Ali MA, Sous ES, Hegazy M, Badran A, Kenny SJ, Gunter EW, Malarcher AM, Brechner RJ, Wetterhall SF, DeStefano F, Smith PJ, Habib M, abd el Shakour S, Ibrahim AS, el Behairy EM. Diabetes mellitus in Egypt: glycaemic control and microvascular and neuropathic complications. Diabet Med 1998; 15: 1045-51.
[7] Dyck PJ, Dyck PJB, Velosa JA, Larson TS, O'Bnen PC, the Nerve Growth Factor Study Group. Patterns of quantitative sensation testing of hypoesthesia and hyperalgesia are predictive of diabetic polyneuropathy. A study of three cohorts. Diabetes Care 2000; 23: 510-7.
[8] Young MJ, Breddy JL, Veves A, Boulton AJM. The prediction of diabetic neuropathic foot ulceration using vibration perception thresholds. A prospective study. Diabetes Care 1994; 17: 557-60.
[9] Rith-Najarian SJ, Stolusky T, Gohdes DM. Identifying diabetic patients at high risk for lower-extremity amputation in a primary health care setting. A prospective evaluation of simple screening criteria. Diabetes Care 1992; 15: 1386-9.
[10] Young MJ, Boulton AJ, MacLeod AF, Williams DR, Sonksen PH. A multicentre study of the prevalence of diabetic peripheral neuropathy in the United Kingdom hospital clinic population. Diabetologia 1993; 36: 150-4.
[11] Walters DP, Gatting W, Mullee MA, Hill RD. The prevalence of diabetic distal sensory neuropathy in an English community. Diabet Med 1992; 9: 349-53.
[12] Harris MI. Classification, diagnostic criteria, and screening for diabetes. In: National Diabetes Data Group, editors. Diabetes in America. 2nd ed. Bethesda Md: National Institutes of Health and Digestive and Kidney Diseases; 199NIH publ 1995; 95-1468: 15-36.
[13] American Diabetes Association. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 1997; 20: 1183-97.
[14] Tesfaye S, Stevens LK, Stephenson JM, Fuller JH, Plater M, lonescu-Tirgoviste C, Nuber A, Pozza G, Ward JD. Prevalence of diabetic peripheral neuropathy and its relation to glycaemic control and potential risk factors: the EURODIAB IDDM Complications Study. Diabetologia
