REVIEW

AARON I. VINIK, MD, PhD* TOMRIS ERBAS, MD The Strelitz 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 , 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 , abdominal nosed. In addition, a variety of pharmacologic pain, , , , , and nonpharmacologic therapies are available to , and . treat the symptoms of autonomic neuropathy. ■ MANIFESTATIONS ARE VARIED AND SERIOUS 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 and unresponsiveness to it nomic , 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 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, (MI), cardiac arrhyth- drug use, alcohol use, HIV exposure, and fam- mias, ulceration, gangrene, and nephropathy. ily history of familial . 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 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

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■ 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 , exercise intolerance Cardiac denervation Orthostatic hypotension Heat intolerance

Neurovascular Areas of symmetrical anhydrosis Gustatory sweating Hyperhidrosis Alterations in skin blood flow

Gastrointestinal Constipation diabeticorum Diarrhea and fecal incontinence Esophageal dysfunction

Genitourinary Erectile dysfunction Retrograde ejaculation Cystopathy Neurogenic bladder Defective vaginal lubrication

CCF ©2001

FIGURE 2

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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 and unawareness occurring with intensive glycemic control The Argyll-Robertson pupil of syphilis

Cardiovascular autonomic neuropathy respond to mild exercise indicates nearly com- occurs in about 17% of patients with type 1 plete cardiac denervation. diabetes and 22% of those with type 2. An Limited exercise tolerance is due to Resting additional 9% of type 1 patients and 12% of impaired sympathetic and parasympathetic tachycardia type 2 patients have borderline dysfunction.16 responses that normally augment cardiac out- The medical consequences of cardiovas- put and redirect peripheral blood flow to is an early sign cular autonomic neuropathy in diabetes are skeletal muscles. Exercise tolerance is also of autonomic dramatic: a meta-analysis of 11 studies con- reduced by a reduced ejection fraction, systolic cluded that the 5.5-year mortality rate was 5% dysfunction, and decreased diastolic filling. neuropathy among patients with diabetes with normal A prolonged corrected QT interval heart-rate variability vs 27% among those (QTc) indicates an imbalance between right with abnormal heart-rate variability.17 and left sympathetic innervation.21 Diabetic patients with a regional sympathetic imbal- Cardiovascular symptoms and signs ance and QTc interval prolongation may be at Lack of heart-rate variability during deep greater risk for arrhythmias. breathing or exercise is a sign of autonomic Abnormal circadian pattern of blood neuropathy and is associated with a high risk pressure. In this condition, blood pressure rises of coronary heart disease in patients with or during the night and falls in the early morning. without diabetes.18 The Diabetes Control and This abnormal pattern has been shown to cor- Complications Trial (DCCT) found that 1.6% relate with postural hypotension due to cardio- of patients with a 5-year history of diabetes vascular autonomic neuropathy.22 had this sign. The rate rose to 6.2% of those Blunted symptoms of coronary artery dis- with a 5-year to 9-year history of diabetes, and ease. Diabetic patients have a high rate of coro- to 12% in those who had had the disease for nary artery disease, which may be asymptomatic more than 9 years.19 owing to subclinical neuropathy.23,24 Indeed, Resting tachycardia is an early sign, as is painless ischemia is significantly more frequent loss of heart-rate variation during deep breath- in patients with autonomic neuropathy than in ing,20 whereas a heart rate that does not those without it (38% vs 5%). The lack of pain

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T ABLE 2 Diagnostic tests for cardiovascular autonomic neuropathy Resting heart rate > 100 beats/minute is abnormal Beat-to-beat heart rate variation The patient should abstain from drinking coffee overnight Test should not be performed after overnight hypoglycemic episodes When the patient lies supine and breathes 6 times per minute, a difference in heart rate of less than 10 beats/minute is abnormal An expiration:inspiration R-R ratio > 1.17 is abnormal Heart rate response to standing The R-R interval is measured at beats 15 and 30 after the patient stands A 30:15 ratio of less than 1.03 is abnormal Heart rate response to Valsalva maneuver The patient forcibly exhales into the mouthpiece of a manometer, exerting a pressure of 40 mm Hg for 15 seconds A ratio of longest to shortest R-R interval of less than 1.2 is abnormal Systolic blood pressure response to standing Systolic blood pressure is measured when the patient is lying down and 2 minutes after the patient stands A fall of more than 30 mm Hg is abnormal A fall of 10 to 29 mm Hg is borderline Diastolic blood pressure response to isometric exercise The patient squeezes a handgrip dynamometer to establish his or her maximum The patient then squeezes the grip at 30% maximum for 5 minutes A rise of less than 16 mm Hg in the contralateral arm is abnormal Painless MI Electrocardiography A QTc of more than 440 ms is abnormal is particularly Depressed very-low frequency peak or low-frequency peak indicate sympathetic dysfunction common Depressed high-frequency peak indicates parasympathetic dysfunction Lowered low-frequency/high-frequency ratio indicates sympathetic imbalance Neurovascular flow Noninvasive laser Doppler measures of peripheral sympathetic responses to nociception

is the result of damaged afferent nerves. In the altered sympathovagal balance and reduced Framingham study, 39% of patients with dia- nocturnal vagal activity in patients with car- betes had had an asymptomatic MI document- diac autonomic neuropathy.27,28 ed by electrocardiography.15 Pain in any part of the chest in a patient Silent ischemia and silent MI are particu- with diabetes should be considered of myocar- larly dangerous because patients cannot sense dial origin until proven otherwise. Other clues the pain and seek help.25 One study26 found a to a possible silent MI include unexplained mortality rate after asymptomatic MI of 47%, fatigue, confusion, edema, hemoptysis, nausea whereas mortality after MI with pain was and vomiting, diaphoresis, arrhythmias, 35%.26 cough, and dyspnea. In nondiabetic patients, the risk of acute MI is highest in the morning. This diurnal Cardiac functional testing variation is altered in diabetic patients, who of the autonomic nervous system have a lower morning peak and a higher fre- Tests of cardiovascular reflexes are sensitive, quency of infarctions during the evening. The reproducible, simple, and noninvasive and blunting in the morning peak is the result of allow extensive evaluation of diabetic cardio-

934 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. vascular autonomic neuropathy. These include measurements of the resting heart rate, beat-to-beat heart-rate variation, blood pressure response to the Valsalva maneuver, heart rate and systolic blood pressure response to standing, diastolic blood pressure response to sustained exercise, and the QT interval (TABLE 2). An increased resting heart rate and loss of heart-rate variation in response to deep breathing are primary indicators of parasympa- thetic dysfunction. Tests for sympathetic dys- function include measurements of heart rate and blood pressure responses to standing, exer- cise, and handgrip. Reduced 24-hour heart-rate variability, a newer test, is believed to be more sensitive than standard reflex tests and can detect car- diac autonomic dysfunction earlier.29 A 24- hour recording of heart-rate variability can reveal abnormal circadian rhythms regulated by sympathovagal activity. In vagal dysfunc- tion, the high-frequency component of heart rate variability is reduced; in sympathetic dys- function, the low-frequency and very low-fre- quency components are reduced. Furthermore, in advanced cardiac autonomic neuropathy all three components are reduced, as is the low- frequency:high-frequency ratio, which repre- sents sympathovagal balance.30 Heart rate variability should be assessed during deep breathing (to calculate the expi- ration:inspiration ratio), the Valsalva maneu- ver, and standing. Abnormalities in two or more of these tests suggest a diagnosis of auto- nomic neuropathy. Patients with type 1 dia- betes should be tested 5 years after diagnosis and yearly thereafter; patients with type 2 dia- betes should be tested at diagnosis and yearly thereafter (TABLE 3).

Nuclear imaging The sympathetic innervation of the heart can be visualized and quantified by single-photon emission computed tomography with iodine 123 metaiodobenzylguanidine (MIBG).

Treating cardiac manifestations of diabetic autonomic neuropathy Intensive glycemic control is critical to preventing the onset of diabetic autonomic neuropathy and slowing its progression.

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T ABLE 3 Screening for and treating diabetic autonomic neuropathy 1. TIGHT GLYCEMIC CONTROL For all diabetic patients: maintain aggressive control of blood glucose, hemoglobin A1c, blood pressure, and lipids with pharmacologic therapy and lifestyle changes 2. SCREENING Begin screening 5 years after diagnosis of type 1 diabetes At the time of diagnosis of type 2 diabetes Ask about symptoms Examine for signs Test for heart-rate variability Expiration:inspiration ratio Response to Valsalva maneuver Response to standing If negative: repeat yearly If positive: apply appropriate diagnostic tests, treat symptoms 3. TREATMENT

SYMPTOMS TESTS TREATMENTS

Cardiac Multigated angiography (MUGA) ACE inhibitors Thallium scan Beta-blockers 123I metaiodobenzylguanidine Antioxidants (MIBG) scan Aldose reductase inhibitors Postural Measure blood pressure Supportive garments hypotension standing and supine Clonidine Measure catecholamines Midodrine Octreotide Orthostatic Gastrointestinal Emptying study Prokinetic agents Barium study Antibiotics hypotension Endoscopy Bulking agents is often Manometry Tricyclic antidepressants Electrogastrogram Pancreatic extracts incorrectly Sexual Penile-brachial pressure index Sex therapy ascribed to dysfunction Nocturnal penile tumescence Psychological counseling Sildenafil hypoglycemia Prostaglandin E1 injection Device or prosthesis Bladder Cystometrogram Bethanechol dysfunction Postvoiding sonography Intermittent catheterization Sudomotor Quantitative sudomotor axon reflex Scopolamine (sweating) Sweat test Glycopyrrolate dysfunction Skin blood flow Vasodilators 4. FOLLOW-UP Monitor every year for response to treatment

Intensive glycemic control substantially deterioration in heart-rate variability in as lit- reduces the prevalence of autonomic dysfunc- tle as 1 year of therapy.32 However, the tion2 and slows the deterioration of R-R vari- response to improved glycemic control ation and Valsalva ratio.31 depends on the degree of autonomic dysfunc- Intensive glycemic control can reverse tion at baseline.

936 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. In a study of diabetic patients with depletion due to diuretics, excessive sweating, microalbuminuria,33 the stepwise implemen- diarrhea, or polyuria. Medications that may tation of intensified multifactorial treatment contribute to the problem include antihyper- slowed the progression to autonomic neuropa- tensives, beta-blockers (which impair heart thy. Reduced heart-rate variation was used to rate responses), and tricyclic antidepressants select high-risk diabetic patients who required and phenothiazines (which impair vasocon- aggressive interventions with beta-blockers. striction by blocking adrenergic action). ACE inhibition increased heart-rate variation Many people with this condition abruptly and decreased mortality in patients with mild become hypotensive when eating or within 10 microalbuminuria. to 15 minutes of an insulin injection. The Beta-blockers that are cardioselective (eg, symptoms are similar to those of hypoglycemia atenolol, metoprolol, acebutolol) or lipophilic (though they occur earlier) and are often (eg, propranolol, metoprolol) might modulate incorrectly ascribed to the hypoglycemic the effects of autonomic dysfunction in diabetes action of insulin. either centrally or peripherally by opposing the Insulin may mediate the hypotension by sympathetic stimulus, and thereby restore the increasing capillary permeability, causing a parasympathetic-sympathetic balance.34 mild intravascular depletion. Insulin may also Alpha-lipoic acid was shown in multicen- directly stimulate endothelial release of nitric ter clinical trials35 to slow or reverse the pro- oxide, a potent vasodilator, and sensitize gression of cardiovascular autonomic neuropa- smooth muscle to the relaxant effects of thy if started early in the disease. The results prostacyclin and nitric oxide, thereby causing of multicenter trials of alpha-lipoic acid vasodilation unopposed by the action of nor- should be available in 2002. epinephrine.37 Impaired vagal heart rate con- Aldose reductase inhibitors may also trol and sympathetic nervous dysfunction, reverse the progression of diabetic autonomic which occur with advanced autonomic neu- neuropathy.36 These drugs reduce the flux of ropathy, exaggerate the hemodynamic effects glucose through the polyol pathway, inhibit- of insulin and worsen insulin-induced ing tissue accumulation of sorbitol and fruc- hypotension.38 Tight glycemic tose. However, they are not currently control is approved for clinical use in the United States; Treating orthostatic hypotension the only patients receiving them are partici- Orthostatic hypotension is difficult to man- critical in pants in clinical trials. age, because the standing blood pressure must preventing be raised without causing hypertension when ■ ORTHOSTATIC HYPOTENSION the patient lies down. diabetic Nonpharmacologic therapy should be autonomic Orthostatic hypotension, another sign of auto- tried first. Patients should be advised to wear nomic neuropathy, is a fall in systolic blood supportive stockings to increase venous neuropathy pressure of more than 30 mm Hg upon stand- return, removing them at bedtime. They ing. The cause is damaged vasoconstrictor should be cautioned to get out of bed slowly, to fibers, impaired baroreceptor function, and avoid hot baths, and to take their insulin poor cardiovascular reactivity. Orthostatic injections while lying down. hypotension may be accompanied by , 9-fluorohydrocortisone and supplemen- weakness, faintness, visual impairment, pain in tary salt may benefit some patients with the back of the head, and loss of consciousness. orthostatic hypotension. Unfortunately, these Two pathophysiologic states cause ortho- agents do not improve symptoms until edema static hypotension: autonomic insufficiency develops, which carries a risk of causing con- and intravascular volume depletion. A physi- gestive heart failure and hypertension. cal examination and history should easily rule Clonidine, an alpha-2 agonist, can treat a out volume depletion. deficiency of alpha-2 adrenergic receptor. Factors that may aggravate orthostatic However, in some patients with diabetic hypotension in diabetic autonomic neuropa- orthostatic hypotension, clonidine can actual- thy and should be looked for include volume ly increase blood pressure. The initial dose

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T ABLE 4 Pharmacologic therapies for diabetic autonomic neuropathy

INDICATION DRUG AND DOSAGE SIDE EFFECTS

Orthostatic 9-Alpha fluorohydrocortisone 0.5–2 mg/day Congestive heart failure, hypertension hypotension Clonidine 0.1–0.5 mg at bedtime Hypotension, sedation, dry mouth Octreotide 0.1–0.5 µg/kg/day Injection site pain, diarrhea Gastroparesis Metoclopramide 10 mg Galactorrhea, extrapyramidal symptoms 30–60 minutes before meals and at bedtime Domperidone 10–20 mg Galactorrhea 30–60 minutes before meals and at bedtime Erythromycin 250 mg 30 minutes before meals Abdominal cramps, nausea, diarrhea, rash Levosulpiride 25 mg three times a day Galactorrhea Diarrhea Metronidazole 250 mg three times a day for at least 3 weeks Clonidine 0.1 mg two or three times a day Orthostatic hypotension Cholestyramine 4 g one to six times a day Loperamide 2 mg four times a day Toxic megacolon Octreotide 50 µg three times a day Aggravation of nutrient malabsorption Cystopathy Bethanechol 10 mg four times a day Doxazosin 1–2 mg two or three times a day Hypotension, headache, palpitations Erectile Sildenafil 50 mg Headache, flushing, nasal congestion, dysfunction 1 hour before sexual activity, dyspepsia, musculoskeletal pain, once only per day blurred vision; interacts with nitrate-containing drugs (hypotension and fatal cardiac events)

should therefore be small and increased grad- interfere with nutrient supply to the skin on ually. the rest of the body, which is called nonapical Midocrine, an alpha-1 adrenergic agonist, or hairy skin. In hairy skin, functional defects might be of benefit if nonpharmacologic mea- in small capillary circulation can be identified sures, cortisone, salt supplementation, and before neuropathy develops.39–41 The result is clonidine fail. dry skin, impaired sweating, and the develop- Octreotide may help some patients who ment of fissures and cracks that are portals for experience particularly refractory orthostatic microorganisms that cause infectious ulcers hypotension after eating (TABLE 4). and gangrene. Microvascular blood flow can be mea- ■ ALTERATIONS IN SKIN BLOOD FLOW sured noninvasively using laser Doppler flowmetry under basal and stimulated condi- Microvascular skin flow is regulated by both tions. the central and peripheral components of the Use of emollients can soften skin and pre- autonomic nervous system and can thus be vent dryness and cracking, reducing entry of deranged by diabetic autonomic neuropathy. microorganisms that cause infection, ulcera- This derangement can disrupt the main- tion, and gangrene. tenance of regional and whole-body tempera- ture through the apical or glabrous skin, ■ GASTROINTESTINAL AUTONOMIC which is the smooth skin on the palm of the NEUROPATHY hand, the sole of the foot, and the face. Apical skin contains a large number of arteriovenous Gastrointestinal disturbances caused by auto- anastomoses or shunts for thermoregulation. nomic neuropathy are common. Some are dis- A disruption to the blood supply can also abling, but many are mild. Gastrointestinal

938 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. disturbances are often overlooked and The typical symptoms of diabetic gastro- untreated.42,43 They appear to be more com- paresis are early satiety, nausea, vomiting, mon in patients with long-standing disease abdominal bloating, epigastric pain, and and poorly controlled blood glucose levels. anorexia. Patients with gastroparesis have These conditions may affect any part of emesis of undigested food consumed many the . The most prevalent hours or even days previously. Episodes of complications are motility disturbances of the nausea and vomiting may last days to months, viscera, which are generally the result of wide- or they may occur in cycles.46 spread autonomic neuropathy. They include Upper gastrointestinal symptoms should dysphagia, , nausea, vomiting, not be attributed to gastroparesis until condi- malabsorption, fecal incontinence, diarrhea, tions such as gastric ulcer, duodenal ulcer, gas- and constipation.44 tritis, and gastric cancer have been excluded. However, gastroparesis should always be sus- Constipation pected in patients with erratic glucose con- Constipation is the most common gastroin- trol. Even when mild, gastroparesis interferes testinal complication, affecting nearly 60% of with nutrient delivery to the small bowel and diabetic patients. It may be associated with therefore disrupts the relationship between atony of the large bowel and rectum and some- glucose absorption and exogenous insulin times with megacolon. Bouts of constipation administration. This may result in wide swings may alternate with episodes of diarrhea.45 of glucose levels, unexpected episodes of post- Evaluating constipation. Before attribut- prandial hypoglycemia, and apparent “brittle ing constipation to diabetic autonomic neu- diabetes.” ropathy, the clinician should rule out other Evaluating gastric dysfunction. Gastric causes such as hypothyroidism, side effects of emptying can be visualized by scintigraphic drugs such as amitriptyline or calcium channel imaging after the patient consumes radionu- blockers, and colonic carcinoma. All patients clide-labeled food, but the scintigraphic should have a careful digital rectal examina- results do not always correlate with the sever- tion, and women should have a bimanual ity of the symptoms. Some diabetic patients Suspect pelvic examination. Three stool specimens with delayed gastric emptying may have no gastroparesis if should be tested for occult blood. Anorectal symptoms, and others with apparently normal manometry may be used to assess the rectal emptying may have severe symptoms. glucose control anal inhibitory reflex, which can distinguish Gastroduodenal manometry may be help- is erratic rectosigmoid dysfunction and outlet-obstruc- ful in patients with symptoms but apparently tive symptoms from colonic hypomotility. normal emptying because it can help identify Treatment for constipation should begin pylorospasm or incoordinate gastric and duo- with emphasis on good bowel habits, which denal motility. Magnetic resonance imaging include regular exercise and maintenance of and percutaneous electrogastrography hold adequate hydration and fiber consumption. promise for future clinical application. Sorbitol and lactulose may be helpful. The However, manometric studies and electrogas- intermittent use of saline or osmotic laxatives trography are generally available only in may be required for patients with more severe research settings. symptoms. Treating diabetic gastroparesis. Initial treatment of diabetic gastroparesis should Gastric dysfunction focus on blood glucose control, which Diabetic autonomic neuropathy can impair improves gastric motor function. In addition, both gastric acid secretion and gastrointesti- patients should be advised to eat multiple nal motility, causing gastroparesis diabetico- small meals (4–6 per day) and to reduce the rum, which can be detected in 25% of fat content of their diet to less than 40 g/day. patients with diabetes. It is most often clini- They should also restrict their fiber intake to cally silent, but the severe form is one of the prevent the formation of bezoars.47 most debilitating gastrointestinal complica- Prokinetic agents used to treat diabetic tions of diabetes. gastropathy are metoclopramide, domperi-

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done, erythromycin, and levosulpiride (TABLE tified cause of diabetic diarrhea. Antidiarrheal 4).48,49 Unfortunately, after the first few doses, agents (eg, loperamide and diphenoxylate) tachyphylaxis develops and these agents can reduce the number of stools, but they may become progressively less effective. Periodic also be associated with toxic megacolon and withdrawal restores responsiveness and should so should be used with extreme care (TABLE 4). be tried in apparently refractory cases. In A broad-spectrum antibiotic such as doxycy- severe cases, jejunostomy may allow the stom- cline or metronidazole is usually the treatment ach to rest until it recovers its function. of choice for bacterial overgrowth. Chelation of bile salts may relieve symptoms. Diabetic diarrhea Clonidine may reverse adrenergic nerve Diarrhea affects 20% of diabetic patients and dysfunction and improve diarrhea. This agent is more frequent in those with known auto- clearly reduces volume of stool in severe cases nomic neuropathy. A characteristic symptom but does not stop diarrhea. High doses of of diabetic diarrhea is an intermittent pattern clonidine may be required for diarrhea of dia- of episodes lasting from several hours to sever- betic enteropathy. Diarrhea resistant to treat- al days. Nocturnal diarrhea and fecal inconti- ment with these agents will respond to nence are common. The patient may have as octreotide (TABLE 4). many as 20 to 30 bowel movements in 24 hours. Diarrhea may result from intestinal Esophageal dysfunction hypermotility caused by diminished sympa- Esophageal motility disorders such as dyspha- thetic inhibition, hypomotility with bacterial gia, retrosternal discomfort, and heartburn are overgrowth, pancreatic insufficiency, steator- uncommon in diabetes.51 Esophageal dysfunc- rhea, or bile-salt malabsorption.50 tion is detectable through esophageal motility Evaluating diabetic diarrhea. Drug-relat- tests and scintigraphy. Clinicians should mon- ed diarrhea from agents such as metformin and itor patients who use drugs associated with acarbose should be excluded, as should lactose esophageal erosion and perforation, such as intolerance. Diarrhea that resolves with fast- the oral bisphosphonates. Erectile ing may be osmotic, caused by ingested sub- ■ dysfunction is a stances. In contrast, diarrhea that continues GENITOURINARY TRACT DISTURBANCES when the patient is not eating, such as noc- coronary turnal diarrhea, suggests that the cause is a Diabetic autonomic neuropathy can be associ- disease marker secretory process, and neuroendocrine causes ated with voiding dysfunction or erectile prob- should be pursued. lems. The latter condition is particularly Common causes of these endocrine diar- important because it may signal cardiovascular rhea syndromes are carcinoid tumors, carcinoid problems. syndrome, calcitonin-secreting tumors, PPomas (pancreatic polypeptide-secreting tumors), Erectile dysfunction somatostatinomas, VIPomas (vasoactive intesti- The prevalence of erectile or sexual dysfunc- nal polypeptide-secreting tumors), and gastrino- tion is about 50% in men with diabetes and mas. Measurement of the fasting concentrations about 30% in women, but limitations in of hormones in serum and the urinary excretion assessing female sexual dysfunction may be the of 5HIAA (5-hydroxyindoleacetic acid) and reason for the apparent sex-related difference. the foregut carcinoid markers substance P and Erectile dysfunction may be the presenting CGRP (calcitonin gene-related peptide) will symptom of diabetes, and more than 50% of usually identify the cause. men with diabetes notice the onset of erectile Treating diabetic diarrhea. Initial therapy dysfunction within 10 years of onset of the of diabetic diarrhea should be directed toward diabetes.48,52 correcting fluid and electrolyte disturbances In men, neuropathy can cause loss of and improving nutrition. As with all types of penile erection, retrograde ejaculation, or diabetic autonomic dysfunction, good control both, without affecting libido, potency, or of glucose levels is also helpful. orgasmic function. Early symptoms include Treatment should be directed at the iden- decreased rigidity and incomplete tumes-

940 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. cence. Morning erections are lost, and impo- T ABLE 5 tence progresses gradually over a period of 6 months to 2 years. In contrast, a sudden loss of Drugs known to cause erections with a particular partner, without an erectile dysfunction that are accompanying loss of morning erections or used by diabetic patients nocturnal penile tumescence, suggests a psy- Antihypertensive agents chological cause. However, psychogenic fac- Beta-blockers tors may be superimposed on organic dysfunc- Thiazide diuretics tion in diabetes. Spironolactone Importantly, erectile dysfunction is a Methyldopa marker for the development of generalized Reserpine vascular disease and for premature death from Agents acting on the central nervous MI. It may also presage future cardiovascular system events. Thus, physicians should perform car- Phenothiazines diovascular evaluations in all diabetic patients Haloperidol with erectile dysfunction. Tricyclic antidepressants Erectile dysfunction is multifactorial. In Drugs acting on the endocrine system addition to neuropathy, contributing factors Estrogens include vascular disease, metabolic control, Antiandrogens nutritional deficiencies, endocrine disorders, Gonadotropin antagonists psychogenic factors, and drugs used in the Spironolactone Cimetidine treatment of diabetes and its complications. Metoclopramide Autonomic neuropathy contributes by Fibric acid derivatives impeding cholinergic activation of the erec- Alcohol tile process, through which, in healthy peo- Marijuana ple, acetylcholine acts upon the vascular endothelium to release nitric oxide and prostacyclin. There is also evidence that non- Sildenafil is adrenergic/noncholinergic nerve function is Stenosis of the internal pudendal artery is contraindicated hampered by decreased levels of VIP (vasoac- another potential cause of impotence. A tive intestinal peptide), substance P, and penile/brachial index of less than 0.7 indi- in those other vasodilatory neurotransmitters. cates diminished blood supply. A venous leak receiving Evaluating erectile dysfunction. A thor- manifests as unresponsiveness to vasodilators ough workup for impotence in men should and must be evaluated by penile Doppler nitrates include a medical and sexual history, physical sonography. and psychological evaluations, a blood test for To distinguish psychogenic from organic diabetes, assays for testosterone, prolactin, and erectile dysfunction, nocturnal penile tumes- thyroid hormones, a test for nocturnal erec- cence may be assessed. Patients with normal tions, tests to assess penile, pelvic, and spinal nocturnal penile tumescence are considered to nerve function, and assessments of penile have psychogenic erectile dysfunction. blood supply and blood pressure. Treating erectile dysfunction. Initially, Physical examination must include an the patient should be urged to forego alcoholic evaluation of the autonomic nervous system, drinks and smoking, cease taking medications vascular supply, and hypothalamic-pituitary- known to cause erectile dysfunction (TABLE 5), gonadal axis. Autonomic neuropathy that and optimize metabolic glucose control. causes erectile dysfunction is almost always Sildenafil (Viagra) may be taken at a dose accompanied by loss of the ankle jerk reflex of 50 mg, or lower for patients with renal fail- and absent or reduced vibration sense over the ure or hepatic dysfunction. It is not recom- large toes. To determine the integrity of sacral mended for patients with ischemic heart dis- parasympathetic divisions, the physician ease and is absolutely contraindicated in should assess perianal sensation, sphincter patients being treated with nitroglycerine or tone, and the bulbocavernosus reflex. other nitrate-containing drugs.53

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For many men, direct injection of prosta- full. If they are unable to start urination, they cyclin into the corpus cavernosum will pro- should massage or press the abdomen just duce satisfactory erections. Surgically implant- above the pubic bone (the Credé maneuver) ed penile prostheses are also available. to start the flow of urine. Pharmacotherapy should be directed at Retrograde ejaculation improving bladder emptying and reducing the Retrograde ejaculation is caused by damage to risk of urinary tract infection. Parasympatho- efferent sympathetic nerves that coordinate mimetics such as bethanechol are sometimes the simultaneous closure of the internal vesi- helpful, although frequently they do not fully cle sphincter and relaxation of the external empty the bladder. Extended sphincter relax- vesicle sphincter during ejaculation. Absence ation can be achieved with an alpha-1 block- of spermatozoa in the semen and presence of er, such as doxazosin (TABLE 4). motile sperm in a postcoital specimen of urine Self-catheterization can be particularly confirm the diagnosis. Clinically, retrograde useful and has a low risk of infection. ejaculation is of little significance unless it prevents a patient from fathering children. In ■ SWEATING DISTURBANCES that case, the patient needs to pursue assisted reproduction whereby the sperm are retrieved Hyperhidrosis of the upper body and anhidro- from the bladder for artificial insemination. sis of the lower body are characteristic features of autonomic neuropathy. Hyperhidrosis asso- Female sexual dysfunction ciated with eating, known as gustatory sweat- Women may experience decreased sexual ing, may be linked with certain foods, partic- arousal or inadequate lubrication and pain ularly spicy foods and cheeses. Patients can during sexual intercourse.54 get relief by avoiding the inciting food. There are no guidelines for diagnosing The loss of lower body sweating can cause female sexual dysfunction, as there are for dry, brittle skin that cracks easily, predisposing diagnosing erectile dysfunction. Some the patient to ulcer formation that can lead to Consider less researchers have used vaginal plethysmogra- loss of the limb. For such patients, special intense glucose phy to measure lubrication and vaginal flush- attention must be paid to foot care. ing, but the technique is not well established. Glycopyrrolate (an antimuscarinic com- control if Treatment usually requires application of pound) may benefit diabetic patients with hypoglycemia vaginal lubricants, including topical estrogen gustatory sweating.56 creams. Current studies are being done on unawareness is transdermal sildenafil to enhance blood flow. ■ METABOLIC DYSFUNCTION: present LACK OF AWARENESS AND RESPONSE Cystopathy TO HYPOGLYCEMIA In diabetic autonomic neuropathy, the motor function of the bladder is unimpaired, but dam- Unawareness of hypoglycemia and unrespon- age to the afferent fibers diminishes bladder siveness to it are serious problems that ham- sensation. The bladder can become enlarged to per the patient’s ability to manage his or her more than three times its normal size, but the diabetes. Both are caused by impairments of loss of sensation means that the distention the sympathetic and parasympathetic ner- causes no discomfort. Voiding frequency is vous system. diminished, and the patient is no longer able to In most diabetic patients, catecholamine void completely. Dribbling and overflow release, triggered by low glucose levels, pro- incontinence are common effects. A postvoid- duces noticeable symptoms such as tremulous- ing residual volume of more than 150 mL is ness and cold sweat, which alert the patient to diagnostic of cystopathy. Cystopathy may put eat and take other measures to prevent coma. the patients at risk for urinary infections.55 Diabetic autonomic neuropathy impairs cate- Treating cystopathy. Patients with cholamine release and prevents the warning cystopathy should be instructed to palpate signs of hypoglycemia, leaving the patient their bladder and to try to urinate when it is unaware of it.

942 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. The related problem of glycemic unre- glycemic unawareness and unresponsive- sponsiveness to hypoglycemia occurs when ness.58 In such patients, lowered glucose levels impaired autonomic responses derange glu- increase the risk of hypoglycemia, and their cose counterregulation during fasting or peri- unawareness and inability to mount a coun- ods of increased insulin activity. In healthy terregulatory response makes hypoglycemia people and in patients with early-stage dia- especially dangerous. betes, these autonomic responses result in the For patients using an insulin pump, we release of glucagon and epinephrine for short- therefore recommend using boluses of less term glucose counterregulation, and of growth than the calculated amount. In intensive hormone and cortisol for long-term regula- glycemic control therapy, we recommend tion. Failure in glucose counterregulation can using very small boluses of long-acting be confirmed by the absence of glucagon and insulin. epinephrine responses to hypoglycemia Unfortunately, intensive insulin treat- induced by a controlled dose of insulin.57 ment may produce a functional autonomic The glucagon response becomes impaired insufficiency that is virtually identical to after 1 to 5 years of type 1 diabetes. After 14 autonomic neuropathy. In patients with this to 31 years, the glucagon response is almost problem, as for patients with bona fide auto- undetectable, and it is absent in patients with nomic neuropathy and hypoglycemic unre- autonomic neuropathy. sponsiveness, therapy should be relaxed so that glucose levels can rise. If hypoglycemia Treating hypoglycemia unawareness occurs in these patients at a certain glucose and unresponsiveness level, it will take a lower glucose level to These conditions are difficult to manage. trigger the same symptoms in the next 24 to Although normalized glucose level is usually 48 hours. Avoiding hypoglycemia for a few the goal of treatment for diabetic patients, it days will allow the adrenergic response to should not be the goal for those with hypo- recover.

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