TECHNICAL REVIEW: Standard of Care - Diabetic Autonomic Neuropathy

Aaron I. Vinik, MD, PHD; Braxton D. Mitchell, PHD
Raelene £. Maser, PHD; Roy Freeman, MD

Key Points: "Given the clinical and economic impact of this complication, testing of diabetic individuals for cardiovascular autonomic dysfunction should be part of their standard of care."

Supporting Statements:

Page 1553: DAN: "Diabetic autonomic neuropathy (DAN) is a serious and common complication of diabetes. ..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 failure."

Page 1556: CAN: "Cardiovascular autonomic neuropathy (CAN) is the most prominent focus because of the life-threatening consequences and the availability of direct tests of cardiovascular autonomic function.. .CAN results from damage due to the autonomic nerve fibers that innervate the heart and blood vessels and results in abnormalities in heart rate control and vascular dynamics. Reduced heart variation is the earliest indicator of CAN."

Page 1553: "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 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..."

Page 1570: "The consensus statement sponsored by the ADA and AAN was a synthesis of reviewed research efforts to date in the clinical assessment of neuropathies and offered recommendations for the testing of diabetic neuropathy (including autonomic neuropathy)... Specifically concerning the assessment of CAN, the panel recognized strong evidence for the three tests of heart rate control. The three tests recommended were heart rate response to: 1) deep breathing, 2) standing, and 3) the Valsalva maneuver... These tests were judged suitable for both routine screening and monitoring the progress of autonomic neuropathy."

Page 1573: "The economic impact of the recommendation to use autonomic function testing is minimal compared with the economic impact of the catastrophic events related to advanced cardiovascular, cerebrovascular, and renal complications. The relative cost of testing will always be less than the incremental costs of treating either a detected complication or the more catastrophic event that could eventually occur."

Summary Statement:

Autonomic dysfunction is a prevalent and serious complication for individuals with diabetes. The clinical manifestations of autonomic dysfunction can affect daily activities (e.g., exercise), produce troubling symptoms (e.g., syncope), and cause lethal outcomes. The patient's history and physical examination are ineffective for early indications of autonomic nerve dysfunction, and thus recommendations for the use of noninvasive tests that have demonstrated efficacy are warranted.

Diabetic Autonomic Neuropathy Abstract

Aaron I. Vinik, MD, PHD(*1); Braxton D. Mitchell, PHD(*2)
Raelene £. Maser, PHD(*3); Roy Freeman, MD(*4)

Abstract: 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, "brittle diabetes,* and hypoglycemic autonomic failure. DAN may affect many organ systems throughout the body (e.g., gastrointestinal [Gl], 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-Gl symptoms. Constipation is the most common lower-Gl 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 manomeiry 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 :Iinical disorders including erectile dysfunction, loss of skin integrity, and abnormal vascular T flexes. Disruption of rnicrovascular 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 issures and cracks that allow microorganisms to enter. These changes ultimately contribute to he development of ulcers, gangrene, and limb loss. Various aspects of neurovascular function an be evaluated with specialized tests, but generally these have not been well standardized and tave limited clinical utility. Cardiovascular autonomic neuropathy (CAN) is the most studied ind clinically important form of DAN. Meta-anaryses 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) be used for 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 toss 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 pblockers, proven to be effective for patients with CAN.

Diabetes Care 26:1553-1579,2003