• Aaron I Vinik, Raelene E Maser, Braxton D Mitchell, and Roy Freeman.
• Strelitz Diabetes Research Institutes, Eastern Virginia Medical School, Norfolk 23510, USA. vinikai@evms.edu
• Diabetes Care. 2003 May 1;26(5):1553-79.

AbstractDiabetic 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, approximately 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, gastroparesis, erectile dysfunction, sudomotor dysfunction, impaired neurovascular function, "brittle diabetes," and hypoglycemic autonomic failure. DAN may affect many organ systems throughout the body (e.g., gastrointestinal [GI], genitourinary, and cardiovascular). GI disturbances (e.g., esophageal enteropathy, gastroparesis, constipation, diarrhea, and fecal incontinence) 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 consideration 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 dysfunction should be performed for individuals with diabetes who have recurrent urinary tract infections, 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; measurement of nocturnal penile tumescence; tests to assess penile, pelvic, and spinal nerve function; 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 increased risk of silent myocardial ischemia and mortality. The determination of the presence of CAN is usually based on a battery of autonomic 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)or longitudinal 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 requires accurate, precise, and reproducible procedures that use established physiological maneuvers. The battery of three recommended tests for assessing CAN is readily performed 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 autonomic dysfunction earlier) serves to establish a baseline, with which 1-year interval tests can be compared. Regular HRV testing provides early detection and thereby promotes timely diagnostic and therapeutic interventions. HRV testing may also facilitate differential diagnosis and the attribution of symptoms (e.g., erectile dysfunction, dyspepsia, and dizziness) to autonomic dysfunction. Finally, knowledge of early autonomic dysfunction can encourage patient and physician to improve metabolic control and to use therapies such as ACE inhibitors and beta-blockers, proven to be effective for patients with CAN.

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