Aaron I. Vinik, Raelene E. Maser, Braxton D. Diabetes Care 1 May ; 26 5 : — 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. DAN frequently coexists with other peripheral neuropathies and other diabetic complications, but DAN may be isolated, frequently preceding the detection of other complications.

DAN may affect many organ systems throughout the body e. GI disturbances e. 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.

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. 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. Meta-analyses of published data demonstrate that reduced cardiovascular autonomic function as measured by heart rate variability HRV is strongly i.

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 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 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. Diabetic autonomic neuropathy DAN is among the least recognized and understood complications of diabetes despite its significant negative impact on survival and quality of life in people with diabetes 1 , 2.

A subtype of the peripheral polyneuropathies that accompany diabetes, DAN can involve the entire autonomic nervous system ANS. ANS vasomotor, visceromotor, and sensory fibers innervate every organ. DAN may be either clinically evident or subclinical. It is manifested by dysfunction of one or more organ systems e. Many organs are dually innervated, receiving fibers from the parasympathetic and sympathetic divisions of the ANS. Clinical symptoms of autonomic neuropathy generally do not occur until long after the onset of diabetes.

Whereas symptoms suggestive of autonomic dysfunction may be common they may frequently be due to other causes rather than to true autonomic neuropathy.

Subclinical autonomic dysfunction can, however, occur within a year of diagnosis in type 2 diabetes patients and within two years in type 1diabetes patients 5. Because of its association with a variety of adverse outcomes including cardiovascular deaths, cardiovascular autonomic neuropathy CAN is the most clinically important and well-studied form of DAN.

The introduction over 20 years ago of simple, noninvasive tests of cardiovascular autonomic function has supported extensive clinical and epidemiologic investigation of CAN. These data form the strongest body of evidence for the importance of detecting and monitoring impaired autonomic function in patients with diabetes 6 , 7.

Hypotheses concerning the multiple etiologies of diabetic neuropathy include a metabolic insult to nerve fibers, neurovascular insufficiency, autoimmune damage, and neurohormonal growth factor deficiency 8.

Several different factors have been implicated in this pathogenic process. Activation of protein kinase C induces vasoconstriction and reduces neuronal blood flow Increased oxidative stress, with increased free radical production, causes vascular endothelium damage and reduces nitric oxide bioavailability 12 , Alternately, excess nitric oxide production may result in formation of peroxynitrite and damage endothelium and neurons, a process referred to as nitrosative stress 14 , In a subpopulation of individuals with neuropathy, immune mechanisms may also be involved 16 — Reduction in neurotrophic growth factors 19 , deficiency of essential fatty acids 20 , and formation of advanced glycosylation end products localized in endoneurial blood vessels 21 also result in reduced endoneurial blood flow and nerve hypoxia with altered nerve function 8 , 11 , The result of this multifactorial process may be activation of polyADP ribosylation depletion of ATP, resulting in cell necrosis and activation of genes involved in neuronal damage 22 , The reported prevalence of DAN varies, depending on whether studies have been carried out in the community, clinic, or tertiary referral center.

The variance among prevalence studies also reflects the type and number of tests performed and the presence or absence of signs and symptoms of autonomic neuropathy. Other factors that account for the marked variability in reported prevalence rates include the lack of a standard accepted definition of DAN, different diagnostic methods, variable study selection criteria, and referral bias Additional complicating factors include the wide variety of clinical syndromes and confounding variables such as age, sex, duration of diabetes, glycemic control, diabetes type, height, and other factors.

Table 1 reveals the prevalence rates of CAN for several different studies, again indicating the dramatic variability from a low of 7. To address issues in comparing data from different sources, the San Antonio Conference on Diabetic Neuropathy recommended that each laboratory should standardize the objective measures using their own population norms, reporting both absolute data and the relationship of the data to the appropriate normative control population.

Subsequently, a number of studies have been conducted to assess the prevalence of DAN in defined populations. For example, in a community-based population study of diabetic neuropathy in Oxford, England, the prevalence of autonomic neuropathy as defined by one or more abnormal heart rate variability HRV test results was In a further study, Ziegler et al.

The study found that If more strict criteria were used i. Another study group observed nearly an identical prevalence rate Additional studies suggest that the prevalence of DAN may be even more common than these studies report.

For example, using a variety of simple, validated, and noninvasive tests e. These results, however, recapitulate that prevalence rates will vary depending on 1 different patient cohorts studied, 2 varied testing modalities utilized, and 3 different criteria used to define autonomic dysfunction. The metabolic disorders of diabetes lead to diffuse and widespread damage of peripheral nerves and small vessels.

Clinical manifestations of autonomic dysfunction and other microvascular complications frequently occur concurrently but in inconsistent patterns The ubiquitous distribution of the ANS renders virtually all organs susceptible to autonomic dysfunction.

Therefore, a patient diagnosed with diabetes should be suspected of having at least subclinical disturbances of the ANS. Overt signs and symptoms of autonomic disease fall into one or more of the following categories.

Medications, with anticholinergic or sympatholytic effects insulin, vasodilators, sympathetic blockers. DAN is typically assessed by focusing on symptoms or dysfunction attributable to a specific organ system. CAN is the most prominent focus because of the life-threatening consequences of this complication and the availability of direct tests of cardiovascular autonomic function. However, neuropathies involving other organ systems should also be considered in the optimal care of patients with diabetes.

Perhaps one of the most overlooked of all serious complications of diabetes is CAN CAN results from damage 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 rate variation is the earliest indicator of CAN In a review of several epidemiological studies among individuals diagnosed with diabetes, it was shown that the 5-year mortality rate from this serious complication is five times higher for individuals with CAN than for individuals without cardiovascular autonomic involvement 4.

In this report, the clinical manifestations e. It will also be shown that autonomic dysfunction can affect daily activities of individuals with diabetes and may invoke potentially life-threatening outcomes. Advances in technology, built on decades of research and clinical testing, now make it possible to objectively identify early stages of CAN with the use of careful measurement of autonomic function.

Autonomic dysfunction can impair exercise tolerance In a study of individuals with and without CAN, Kahn et al. Roy et al. The severity of CAN has also been shown to correlate inversely with an increase in heart rate at any time during exercise and with the maximal increase in heart rate.

It should also be noted that decreased ejection fraction, systolic dysfunction, and diastolic filling limit exercise tolerance 1. Given the potential for impaired exercise tolerance, it has been suggested that diabetic patients who are likely to have CAN have cardiac stress testing before undertaking an exercise program Hemodynamic changes occur during surgery for individuals with and without diabetes.

Burgos et al. The normal autonomic response of vasoconstriction and tachycardia did not completely compensate for the vasodilating effects of anesthesia. Kitamura et al. Complications arising from intraoperative hypothermia include decreased drug metabolism and impaired wound healing. Sobotka et al. These data suggest that preoperative cardiovascular autonomic screening may provide useful information for anesthesiologists planning the anesthetic management of diabetic patients and identify those at greater risk for intraoperative complications.

Orthostatic hypotension is defined as a fall in blood pressure i. In patients with diabetes, orthostatic hypotension is usually due to damage to the efferent sympathetic vasomotor fibers, particularly in the splanchnic vasculature In addition, there is a decrease in cutaneous, splanchnic, and total vascular resistance that occurs in the pathogenesis of this disorder.

 
 

 

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