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Recognizing and Treating Diabetic Autonomic Neuropathy

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Recognizing and Treating Diabetic Autonomic Neuropathy REVIEW AARON I. VINIK, MD, PhD* TOMRIS ERBAS, MD The Strelitz Diabetes Research Institutes, Department of The Strelitz Diabetes Research Institutes, Department of Internal Medicine and Anatomy/Neurobiology, Eastern Internal Medicine and Anatomy/Neurobiology, Eastern Virginia Medical School, Norfolk, Virginia Virginia Medical School, Norfolk, Virginia Recognizing and treating diabetic autonomic neuropathy ■ ABSTRACT IABETIC AUTONOMIC NEUROPATHY is a D stealthy complication of diabetes, devel- Diabetic autonomic neuropathy can cause heart disease, oping slowly over the years and quietly robbing gastrointestinal symptoms, genitourinary disorders, and diabetic patients of their ability to sense when metabolic disease. Strict glycemic control can slow the they are becoming hypoglycemic or having a onset of diabetic autonomic neuropathy and sometimes heart attack. reverse it. Pharmacologic and nonpharmacologic therapies It can affect any organ of the body, from are available to treat symptoms. the gastrointestinal system to the skin, and its appearance portends a marked increase in the mortality risk of diabetic patients. ■ KEY POINTS Intensive glycemic control is critical in pre- venting the onset and slowing the progression of The diagnosis of autonomic neuropathy is one of exclusion. diabetic autonomic neuropathy. The Diabetes Complications and Control Trial (DCCT) Cardiovascular complications include abnormal heart-rate showed that intensive glycemic control reduced control and orthostatic hypotension, with an increased risk the prevalence of autonomic dysfunction by of death. 53%.1 It is also the first therapy to be considered when diabetic autonomic neuropathy is diag- Gastrointestinal symptoms include dysphagia, abdominal nosed. In addition, a variety of pharmacologic pain, nausea, vomiting, malabsorption, fecal incontinence, and nonpharmacologic therapies are available to diarrhea, and constipation. treat the symptoms of autonomic neuropathy. ■ MANIFESTATIONS ARE VARIED AND SERIOUS Erectile dysfunction is an early genitourinary symptom that may also signal cardiovascular problems. Neuropathy is one of the most common com- plications of diabetes. When it affects the auto- Unawareness of hypoglycemia and unresponsiveness to it nomic nervous system, it can damage the car- are the most troublesome metabolic complications because diovascular, gastrointestinal, and genitourinary they impair the patient’s ability to manage the disease. systems and impair metabolic functions such as glucose counterregulation (FIGURE 1). Diabetic autonomic neuropathy impairs the ability to conduct activities of daily living, lowers quality of life, and increases the risk of death. It also accounts for a large portion of the cost of care.2 The autonomic nervous system is primari- ly efferent, transmitting impulses from the central nervous system to peripheral organs. However, it also has an afferent component. *This author has indicated that he has received grant or research support from multiple Its two divisions—the parasympathetic and pharmaceutical corporations and serves as a consultant on the speakers bureaus of multiple pharmaceutical corporations. the sympathetic nervous systems—work in 928 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 68 • NUMBER 11 NOVEMBER 2001 Downloaded from www.ccjm.org on September 29, 2021. For personal use only. All other uses require permission. balanced opposition to control the heart rate, tribute to the pathogenesis of diabetic the force of cardiac contraction, the dilatation nephropathy and cardiovascular disease. and constriction of blood vessels, the contrac- Autonomic neuropathy is also an independent tion and relaxation of smooth muscle in the risk factor for stroke.10 digestive and urogenital systems, the secre- tions of glands, and pupillary size. ■ A DIAGNOSIS OF EXCLUSION Diabetes can cause dysfunction of any or every part of the autonomic nervous system, The diagnosis of diabetic autonomic neuropa- leading to a wide range of disorders. And these thy is one of exclusion, and many other caus- are serious: among the most troublesome and es of autonomic dysfunction should first be dangerous of the conditions linked to auto- ruled out (TABLE 1). The clinician should take a nomic neuropathy are known or silent careful history, asking about diabetes, cancer, myocardial infarction (MI), cardiac arrhyth- drug use, alcohol use, HIV exposure, and fam- mias, ulceration, gangrene, and nephropathy. ily history of familial amyloidosis. Autonomic neuropathy is also associated with Patients should be asked whether they an increased risk of sudden death. have traveled to South America, where they might have been exposed to Trypanosoma cruzi, ■ NEUROPATHY IS COMMON the cause of Chagas disease. Serologic testing AND BEGINS EARLY for antibodies to this organism may be valuable. Testing the norepinephrine response to The reported prevalence of diabetic autonom- standing may help identify the cause of idio- ic neuropathy varies, with community-based pathic orthostatic hypotension. Basal values studies finding lower rates than clinic-based and the response to standing are normal in and hospital-based studies, in which the diabetic autonomic neuropathy, severely prevalence may be as high as 100%.3 reduced in multiple system atrophy or idio- Clinical symptoms generally do not devel- pathic orthostatic hypotension, and impaired op for many years after the onset of diabetes. in Shy-Drager syndrome. However, subclinical autonomic neuropathy First, rule ■ can often be identified by quantitative func- GLYCEMIC CONTROL IS IMPORTANT out other tional testing within 1 year of diagnosis in patients with type 2 diabetes and within 2 For patients with either type 1 or type 2 dia- causes of years in those with type 1 diabetes.4 betes, glycemic control is important, although autonomic The most important causative factors are methods to achieve target levels may differ. The poor glycemic control, long duration of dia- methods for achieving euglycemia and the tar- dysfunction betes, increasing age, female sex, and higher get blood glucose and hemoglobin A1c levels are body mass index. given in a position statement from the Amrican Diabetes Association available online at ■ MORTALITY IS HIGH www.diabetes.org/clinicalrecommendations/ CareSup1Jan01.htm and in supplement 1 of Of patients with symptomatic autonomic dys- Diabetes Care 2001, volume 24. function, 25% to 50% die within 5 to 10 years of diagnosis.5,6 The 5-year mortality rate in ■ CARDIOVASCULAR AUTONOMIC patients with diabetic autonomic neuropathy NEUROPATHY is three times higher than in diabetic patients without autonomic involvement.7 Cardiovascular autonomic neuropathy causes Leading causes of death in diabetic abnormalities of heart-rate control and vascular patients with either symptomatic or asympto- dynamics.11 It has been linked to postural matic autonomic neuropathy are heart disease hypotension, exercise intolerance, enhanced and nephropathy. Increased urinary albumin intraoperative cardiovascular lability, in-creased excretion is related to autonomic neuropathy incidence of asymptomatic ischemia, myocar- in diabetic patients.8,9 Impairments in the dial infarction, and de-creased likelihood of sur- autonomic nervous system may also con- vival after myocardial infarction.12–15 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 68 • NUMBER 11 NOVEMBER 2001 929 Downloaded from www.ccjm.org on September 29, 2021. For personal use only. All other uses require permission. DIABETIC AUTONOMIC NEUROPATHY VINIK AND ERBAS ■ Clinical manifestations of autonomic neuropathy Diabetes can cause dysfunction of any or all parts of the automomic nervous system, leading to a wide range of disorders. (Sympathetic fibers are shown in orange, parasympathetic in blue, preganglionic solid, and postganglionic dashed.) Pupillary Decreased diameter of dark- adapted pupil Argyll-Robertson type pupil Metabolic Hypoglycemia unawareness Hypoglycemia unresponsiveness Cardiovascular Tachycardia, exercise intolerance Cardiac denervation Orthostatic hypotension Heat intolerance Neurovascular Areas of symmetrical anhydrosis Gustatory sweating Hyperhidrosis Alterations in skin blood flow Gastrointestinal Constipation Gastroparesis diabeticorum Diarrhea and fecal incontinence Esophageal dysfunction Genitourinary Erectile dysfunction Retrograde ejaculation Cystopathy Neurogenic bladder Defective vaginal lubrication CCF ©2001 FIGURE 2 930 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 68 • NUMBER 11 NOVEMBER 2001 Downloaded from www.ccjm.org on September 29, 2021. For personal use only. All other uses require permission. DIABETIC AUTONOMIC NEUROPATHY VINIK AND ERBAS T ABLE 1 Differential diagnosis of diabetic autonomic neuropathy Idiopathic orthostatic hypotension Shy-Drager syndrome (orthostatic hypotension, pyramidal and cerebral signs including tremor, rigidity, hyperreflexia, ataxia, and urinary and bowel dysfunction) Panhypopituitarism Pheochromocytoma Chagas disease Amyloidosis Hypovolemia caused by poor glycemic control or diuretics Effects of insulin Complications from vasodilators (nitrates, calcium channel blockers, hydralazine) Complications from sympathetic blockers (methyldopa, clonidine, prazosin, guanethidine, phenothiazine, tricyclic antidepressants) Orthostatic hypotension caused by alcoholic neuropathy Congestive heart failure Other causes of diarrhea, constipation, and gastrointestinal dysfunction Other causes of genitourinary and erectile dysfunction Other causes of pedal edema Hypoglycemia unresponsiveness
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