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Diabetic Autonomic Neuropathy

¹ Strelitz Diabetes Research Institutes, Eastern Virginia Medical School, Norfolk, Virginia
² Department of Medical Technology, University of Delaware, Newark, Delaware
³ Department of Medicine, Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland
⁴ Center for Autonomic and Peripheral Nerve Disorders, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATHOGENESIS OF DAN EPIDEMIOLOGY OF DAN CLINICAL MANIFESTATIONS OF DAN CAN OTHER AUTONOMIC NEUROPATHIES RELATIONSHIP OF AUTONOMIC... RELATIONSHIP OF AUTONOMIC... CLINICAL TESTING OF AUTONOMIC... CURRENT GUIDELINES FOR THE... SAFETY OF TESTING PROCEDURES WHO IS A CANDIDATE... MANAGEMENT IMPLICATIONS OF... SUMMARY GLOSSARY APPENDIX: STANDARDIZED TESTS OF... References

 
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, 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) 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.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 ß-blockers, proven to be effective for patients with CAN.

Abbreviations: AAN, American Academy of Neurology • ANS, autonomic nervous system • CAN, cardiovascular autonomic neuropathy • DAN, diabetic autonomic neuropathy • DCCT, Diabetes Control and Complications Trial • ECG, electrocardiogram • ED, erectile dysfunction • E:I, expiration-to-inspiration • GI, gastrointestinal • HRV, heart rate variability • MI, myocardial infarction • PSA, power spectral analysis • QSART, quantitative sudomotor axon reflex test • TST, thermoregulatory sweat test

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATHOGENESIS OF DAN EPIDEMIOLOGY OF DAN CLINICAL MANIFESTATIONS OF DAN CAN OTHER AUTONOMIC NEUROPATHIES RELATIONSHIP OF AUTONOMIC... RELATIONSHIP OF AUTONOMIC... CLINICAL TESTING OF AUTONOMIC... CURRENT GUIDELINES FOR THE... SAFETY OF TESTING PROCEDURES WHO IS A CANDIDATE... MANAGEMENT IMPLICATIONS OF... SUMMARY GLOSSARY APPENDIX: STANDARDIZED TESTS OF... References

 
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.g., cardiovascular, gastrointestinal [GI], genitourinary, sudomotor, or ocular) (3). Many organs are dually innervated, receiving fibers from the parasympathetic and sympathetic divisions of the ANS. DAN typically occurs as a system-wide disorder affecting all parts of the ANS. Indeed, because the vagus nerve (the longest of the ANS nerves) accounts for 75% of all parasympathetic activity (4), and DAN manifests first in longer nerves, even early effects of DAN are widespread.

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).

	PATHOGENESIS OF DAN

TOP ABSTRACT INTRODUCTION PATHOGENESIS OF DAN EPIDEMIOLOGY OF DAN CLINICAL MANIFESTATIONS OF DAN CAN OTHER AUTONOMIC NEUROPATHIES RELATIONSHIP OF AUTONOMIC... RELATIONSHIP OF AUTONOMIC... CLINICAL TESTING OF AUTONOMIC... CURRENT GUIDELINES FOR THE... SAFETY OF TESTING PROCEDURES WHO IS A CANDIDATE... MANAGEMENT IMPLICATIONS OF... SUMMARY GLOSSARY APPENDIX: STANDARDIZED TESTS OF... References

 
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. Hyperglycemic activation of the polyol pathway leading to accumulation of sorbitol and potential changes in the NAD:NADH ratio may cause direct neuronal damage and/or decreased nerve blood flow (9–11). Activation of protein kinase C induces vasoconstriction and reduces neuronal blood flow (11). Increased oxidative stress, with increased free radical production, causes vascular endothelium damage and reduces nitric oxide bioavailability (12,13). Alternately, excess nitric oxide production may result in formation of peroxynitrite and damage endothelium and neurons, a process referred to as nitrosative stress (14,15). In a subpopulation of individuals with neuropathy, immune mechanisms may also be involved (16–18). 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 (8,11,12). 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 (22,23).

	EPIDEMIOLOGY OF DAN

TOP ABSTRACT INTRODUCTION PATHOGENESIS OF DAN EPIDEMIOLOGY OF DAN CLINICAL MANIFESTATIONS OF DAN CAN OTHER AUTONOMIC NEUROPATHIES RELATIONSHIP OF AUTONOMIC... RELATIONSHIP OF AUTONOMIC... CLINICAL TESTING OF AUTONOMIC... CURRENT GUIDELINES FOR THE... SAFETY OF TESTING PROCEDURES WHO IS A CANDIDATE... MANAGEMENT IMPLICATIONS OF... SUMMARY GLOSSARY APPENDIX: STANDARDIZED TESTS OF... References

 
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 (24). 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 7.7% for newly diagnosed patients with type 1 diabetes, when strict criteria to define CAN were used (24), to a high of 90% in potential recipients of a pancreas transplant (25).

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 16.7% (38). In a further study, Ziegler et al. (24) evaluated the prevalence of CAN in 1,171 diabetic patients (647 type 1 diabetic patients, 524 type 2 diabetic patients) randomly recruited from 22 diabetes centers in Germany, Austria, and Switzerland. The study found that 25.3% of patients with type 1 diabetes and 34.3% of patients with type 2 diabetes had abnormal findings in more than two of six autonomic function tests. If more strict criteria were used (i.e., abnormalities present in least three of six autonomic function tests), the prevalence of CAN was 16.8% for individuals with type 1 diabetes and 22.1% for individuals with type 2 diabetes. Another study group observed nearly an identical prevalence rate (16.6%) for individuals with insulin-dependent diabetes (39).

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.g., fall in systolic blood pressure and heart rate response after standing), Verrotti et al. (40) found that 47 of 110 diabetic children and adolescents showed one or more abnormal tests for cardiovascular autonomic dysfunction. 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.

	CLINICAL MANIFESTATIONS OF DAN

TOP ABSTRACT INTRODUCTION PATHOGENESIS OF DAN EPIDEMIOLOGY OF DAN CLINICAL MANIFESTATIONS OF DAN CAN OTHER AUTONOMIC NEUROPATHIES RELATIONSHIP OF AUTONOMIC... RELATIONSHIP OF AUTONOMIC... CLINICAL TESTING OF AUTONOMIC... CURRENT GUIDELINES FOR THE... SAFETY OF TESTING PROCEDURES WHO IS A CANDIDATE... MANAGEMENT IMPLICATIONS OF... SUMMARY GLOSSARY APPENDIX: STANDARDIZED TESTS OF... References

 
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 (41). 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.

Cardiovascular

• Resting tachycardia
  
• Exercise intolerance
  
• Orthostatic hypotension
  
• Silent myocardial ischemia
  

GI

• Esophageal dysmotility
  
• Gastroparesis diabeticorum
  
• Constipation
  
• Diarrhea
  
• Fecal incontinence
  

Genitourinary

• Neurogenic bladder (diabetic cystopathy)
  
• Erectile dysfunction
  
• Retrograde ejaculation
  
• Female sexual dysfunction (e.g., loss of vaginal lubrication)
  

Metabolic

• Hypoglycemia unawareness
  
• Hypoglycemia-associated autonomic failure
  

Sudomotor

• Anhidrosis
  
• Heat intolerance
  
• Gustatory sweating
  
• Dry skin
  

Pupillary

• Pupillomotor function impairment (e.g., decreased diameter of dark-adapted pupil)
  
• Argyll-Robertson pupil
  

The differential diagnosis of DAN involves excluding the following conditions:

• Pure autonomic failure (formerly called idiopathic orthostatic hypotension)
  
• Multiple system atrophy with autonomic failure (formerly called Shy-Drager syndrome)
  
• Addison’s disease and hypopituitarism
  
• Pheochromocytoma
  
• Hypovolemia
  
• Medications, with anticholinergic or sympatholytic effects (insulin, vasodilators, sympathetic blockers)
  
• Peripheral autonomic neuropathies (e.g., amyloid neuropathy, idiopathic autonomic neuropathy)
  

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.

	CAN

TOP ABSTRACT INTRODUCTION PATHOGENESIS OF DAN EPIDEMIOLOGY OF DAN CLINICAL MANIFESTATIONS OF DAN CAN OTHER AUTONOMIC NEUROPATHIES RELATIONSHIP OF AUTONOMIC... RELATIONSHIP OF AUTONOMIC... CLINICAL TESTING OF AUTONOMIC... CURRENT GUIDELINES FOR THE... SAFETY OF TESTING PROCEDURES WHO IS A CANDIDATE... MANAGEMENT IMPLICATIONS OF... SUMMARY GLOSSARY APPENDIX: STANDARDIZED TESTS OF... References

 
Perhaps one of the most overlooked of all serious complications of diabetes is CAN (42). 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 (43). Reduced heart rate variation is the earliest indicator of CAN (44).

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.g., exercise intolerance, intraoperative cardiovascular lability, orthostatic hypotension, and increased risk of mortality) of the presence of CAN will be discussed. 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.

Clinical manifestations of CAN
Exercise intolerance.
Autonomic dysfunction can impair exercise tolerance (45). In a study of individuals with and without CAN, Kahn et al. (46) showed a reduced response in heart rate and blood pressure during exercise in individuals with CAN. Roy et al. (47) demonstrated a decreased cardiac output in response to exercise in individuals with CAN. 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 (45).

Intraoperative cardiovascular lability.
Hemodynamic changes occur during surgery for individuals with and without diabetes. Burgos et al. (48) found that vasopressor support was needed more often in diabetic individuals with autonomic dysfunction than in those without. The normal autonomic response of vasoconstriction and tachycardia did not completely compensate for the vasodilating effects of anesthesia. Kitamura et al. (49) also recently demonstrated an association between CAN and more severe intraoperative hypothermia. Complications arising from intraoperative hypothermia include decreased drug metabolism and impaired wound healing. Sobotka et al. (50) showed that some diabetic patients with autonomic neuropathy have a reduced hypoxic-induced ventilatory drive. 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.
Orthostatic hypotension is defined as a fall in blood pressure (i.e., >20 mmHg for systolic or >10 mmHg for diastolic blood pressure) in response to postural change, from supine to standing (51). In patients with diabetes, orthostatic hypotension is usually due to damage to the efferent sympathetic vasomotor fibers, particularly in the splanchnic vasculature (52). In addition, there is a decrease in cutaneous, splanchnic, and total vascular resistance that occurs in the pathogenesis of this disorder.

Normally, in response to postural change there is an increase in plasma norepinephrine. For individuals with orthostatic hypotension, there may be a reduction in this response relative to the fall in blood pressure (53). Diminished cardiac acceleration and cardiac output, particularly in association with exercise, may also be important in the presentation of this disorder (53,54). Less frequently, there is a rise in norepinephrine that may be due to low blood volume or reduced red cell mass (55,56). Frequently, there are fluctuations in the degree of orthostatic hypotension. This may reflect postprandial blood pooling, the hypotensive role of insulin, and changing patterns of fluid retention due to renal failure or congestive heart failure (57–59).

Patients with orthostatic hypotension typically present with lightheadedness and presyncopal symptoms. Symptoms such as dizziness, weakness, fatigue, visual blurring, and neck pain also may be due to orthostatic hypotension. Many patients, however, remain asymptomatic despite significant falls in blood pressure (60). If the cause of orthostatic hypotension is CAN, treatment goals should not only consist of therapies to increase the standing blood pressure, balanced against preventing hypertension in the supine position (61), but should also provide education to patients so that they avoid situations (e.g., vasodilation from hot showers) that result in the creation of symptoms (i.e., syncopal episodes). Such symptoms can result in injuries from falling. Cardiovascular autonomic function testing may help differentiate CAN from other causes of weakness, lightheadedness, dizziness, or fatigue and promote appropriate therapeutic intervention (62).

Silent myocardial ischemia/cardiac denervation syndrome.
The cause of silent myocardial ischemia in diabetic patients is controversial. It is clear, however, that a reduced appreciation for ischemic pain can impair timely recognition of myocardial ischemia or infarction and thereby delay appropriate therapy. Table 2 and Fig. 1A summarize the results of 12 cross-sectional studies, comparing the presence of silent myocardial ischemia, generally measured by exercise stress testing between diabetic individuals with and without CAN.

View larger version (30K): [in this window] [in a new window]   Figure 1— Association of CAN and silent myocardial infarction (SMI) in 12 studies. A: +CAN, CAN present; -CAN, no CAN found; +SMI, SMI present. B: Prevalence rate ratios and 95% CIs for association between CAN and SMI from the 12 studies.

There are several additional published studies that have examined the relationship between autonomic dysfunction and silent myocardial ischemia in diabetic individuals but that are not included in the meta-analysis because the raw numbers of case and control subjects among individuals with and without cardiovascular autonomic dysfunction were not presented (75–78). However, virtually all of these studies also provide evidence for an association. For example, Ambepityia et al. (75) measured the anginal perceptual threshold (i.e., the time from onset of 0.1 mV ST depression to the onset of angina pectoris during exercise) in individuals with and without diabetes. The influence of autonomic function was assessed via heart rate variation during deep breathing (beats/min), Valsalva maneuver, 30:15 ratio, and blood pressure response to standing. The perception of angina was severely impaired in the diabetic patients, allowing these individuals to exercise longer after the onset of myocardial ischemia. The delay in perception of angina was associated with the presence of cardiovascular autonomic dysfunction. The investigators suggested that the neuropathic damage to the myocardial sensory afferent fibers in the autonomic nerve supply reduced the diabetic individual’s sensitivity to regional ischemia by interrupting pain transmission (75). A study by Marchant et al. (76) examined 22 diabetic and 30 nondiabetic individuals who had similar left ventricular function and severity of coronary artery disease as assessed by coronary angiography and ventriculography. The following autonomic function tests were included: heart rate variation during deep breathing (beats/min), 30:15 ratio, Valsalva maneuver, blood pressure response to standing, and blood pressure response to sustained handgrip. All 52 individuals manifested ischemia during exercise. A total of 16 individuals did not experience angina, and 10 of these had diabetes. Comparing the silent ischemia group (n = 16) with the group who did experience angina (n = 36) revealed impaired autonomic function in the silent ischemia group, with statistically lower 30:15 ratios. In subgroup analysis, the impaired autonomic function was found to be confined to just the diabetic individuals and not seen in the nondiabetic individuals with silent myocardial ischemia, thus indicating that subclinical autonomic neuropathy is associated with silent ischemia in individuals with diabetes (76). Hikita et al. (77), using 24-h ambulatory electrocardiographic recordings, demonstrated that HRV is reduced in diabetic patients with silent ischemia when compared with nondiabetic individuals with silent or painful ischemia. Some investigators, however, have questioned whether the association between CAN and silent myocardial ischemia is a causal one (79), suggesting instead that underlying coronary artery disease might be a cause of both autonomic dysfunction and silent myocardial ischemia (80).

The presence of CAN does not exclude painful myocardial infarction (MI) among individuals with diabetes (81). Chest pain in any location in a patient with diabetes should be considered to be of myocardial origin until proven otherwise; but, of equal importance, unexplained fatigue, confusion, tiredness, edema, hemoptysis, nausea and vomiting, diaphoresis, arrhythmias, cough, or dyspnea should alert the clinician to the possibility of silent MI (1).

Increased risk of mortality
Table 3 summarizes investigations that have examined the association of autonomic dysfunction and mortality. These studies have consistently provided evidence for an increased mortality risk among diabetic individuals with CAN compared with individuals without CAN (Table 3).

A study by O’Brien (36) reported 5-year mortality rates of 27% in patients having asymptomatic autonomic neuropathy compared with an 8% mortality rate in diabetic subjects with normal autonomic function tests. Among individuals who died, there was no difference in duration of diabetes between those with and without autonomic neuropathy. As was true for the study performed by Ewing et al. (31); a significant number of the deaths (10/23) of the neuropathic patients were attributable to renal failure. O’Brien et al., however, compared the relative importance of various factors associated with mortality by discriminate analysis of survivors and nonsurvivors using Rao’s stepwise selection method and revealed that autonomic neuropathy was more of an independent predictive factor than systolic blood pressure, foot disease, BMI, sensory neuropathy, proteinuria, and macrovascular disease (36) (Table 4).

Two separate population-based studies have also examined the association of CAN and mortality. Orchard et al. (87) studied a population-based sample of individuals with type 1 diabetes. Individuals for this study were identified through a hospital-based registry system and were considered to be representative of all type 1 diabetic patients residing in Allegheny County, Pennsylvania. Initial analyses based on a 2-year follow-up of 487 subjects revealed a fourfold higher mortality rate in individuals with CAN at baseline compared with individuals without. However, after adjusting for baseline differences between individuals with and without CAN for markers related to renal and cardiovascular disease, the relative risk decreased from 4.03 to 1.37 and was no longer statistically significant.

Another population-based study (the Hoorn study) examined 159 individuals with type 2 diabetes (85 had newly diagnosed diabetes) who were followed for an average of nearly 8 years. All-cause as well as cardiovascular mortality were found to be associated with impaired autonomic function in this study. In addition, the investigators suggested that cardiovascular autonomic dysfunction in individuals already at high risk (e.g., those with diabetes, high blood pressure, or a history of cardiovascular disease) may be particularly hazardous (93).

Meta-analysis of the relationship between CAN and mortality
As noted above, the relationship of CAN and mortality in diabetic individuals has been evaluated in a number of studies on an individual basis. Analysis of each of these studies as a single entity, however, only includes a limited number of subjects. Thus, in this section, results were pooled from a number of studies into a meta-analysis for the purpose of obtaining more precise estimates. Studies were included in this meta-analysis if they were based on diabetic individuals, included a baseline assessment of HRV, and included a mortality follow-up (94a).

Table 3 and Fig. 2A summarize the results from 15 different studies that have included a follow-up of mortality. The follow-up intervals in these studies ranged from 1 to 16 years. In all 15 studies, the baseline assessment for cardiovascular autonomic function was made on the basis of one or more of the tests described by Ewing et al. (95). Total mortality rates were higher in subjects with CAN at baseline than in subjects whose baseline assessment was normal, with statistically significant differences in 11 of the studies. The study-specific relative risks ranged from 0.91 for the study by Sawicki et al. (91) to 9.20 for the study by Jermendy et al. (84). Figure 2B shows the relative risks and 95% CIs for each study, as well as the pooled risk estimate estimated by the Mantel-Haenszel procedure. The pooled estimate of the relative risk, based on 2,900 total subjects, was 2.14, with a 95% CI of 1.83–2.51 (P < 0.0001).

View larger version (39K): [in this window] [in a new window]   Figure 2— Relative risks and 95% CIs for association between CAN and mortality in 15 studies. A: Association of CAN and mortality in 15 studies. +CAN, CAN present; -CAN, no CAN found. B: Log relative risks from the 15 studies.

Potential reasons for the increased mortality rate associated with CAN
Despite the increased association with mortality, the causative relationship between CAN and the increased risk of mortality has not been conclusively established. Several mechanisms have been suggested including a relationship with autonomic control of respiratory function. Page and Watkins (96) reported 12 cardiorespiratory arrests in eight diabetic individuals with severe autonomic neuropathy and suggested that diabetic individuals with CAN have impaired respiratory responses to conditions of hypoxia and may be particularly susceptible to medications that depress the respiration system. An impaired ability to recognize hypoglycemia and impaired recovery from hypoglycemic episodes due to defective endocrine counterregulatory mechanisms are also potential reasons for death (36). Other investigators have noted explanations for the high mortality rate as an interaction with other concomitant disorders that also carry high risks of mortality. Clarke et al. (7) speculated that the increased mortality found for patients with clinical symptoms of autonomic neuropathy were due to both a direct effect of the autonomic neuropathy itself and an indirect, but parallel, association with accelerating microvascular complications. O’Brien et al. (36) suggested that the high rate of mortality due to end-stage renal disease among diabetic patients with autonomic neuropathy may have been due to the parallel development of late-stage neuropathy and nephropathy. The presence of autonomic neuropathy may accelerate the rate of progression of diabetic glomerulopathy by mechanisms not completely understood (36). A consequential increase in cardiovascular risk experienced by individuals with nephropathy has also been noted. In one study of type 1 diabetic individuals, hypertension along with LDL and HDL cholesterol concentrations were found to be independent correlates of CAN (97). These results suggested that a disturbed cardiovascular risk profile seen in individuals with nephropathy might lead to both cardiovascular disease and CAN. Other investigators have also shown independent associations of autonomic dysfunction with markers of cardiovascular risk (e.g., elevated blood pressure [98], body weight, glycosylated hemoglobin, and overt albuminuria [99]). Long-term follow-up studies are needed to distinguish the exact roles of cardiovascular risk factors, nephropathy, and CAN in the etiology of cardiovascular disease. Nonetheless, CAN cosegregates with indexes of macrovascular risk, which may contribute to the marked increase in cardiovascular mortality. Diabetic patients with CAN are predisposed to a lack of the normal nighttime decrease in blood pressure because of an increased prevalence of sympathetic activity (100). A disturbed circadian pattern of sympathovagal activity with prevalent nocturnal sympathetic activity combined with higher blood pressure values during the night and increased left ventricular hypertrophy could represent another important link between CAN and an increased risk of mortality.

CAN and sudden death
A number of researchers have reported sudden unexpected deaths among subjects identified with autonomic neuropathy (31,82,85). One potential cause of sudden death may be explained by severe but asymptomatic ischemia, eventually inducing lethal arrhythmias (85). An autonomic imbalance resulting in QT prolongation may also predispose individuals to life-threatening cardiac arrhythmias and sudden death (101). Results from the EURODIAB IDDM Complications Study showed that male patients with impaired HRV had a higher corrected QT prolongation than males without this complication (102). Imaging of myocardial sympathetic innervation with various radiotracers (e.g., meta-iodobenzylguanidine) has shown that predisposition to arrhythmias and an association with mortality may also be related to intracardiac sympathetic imbalance (103,104).

The significance of CAN as an independent cause of sudden death has, however, been recently questioned (105). In the Rochester Diabetic Neuropathy Study, the investigators found that all case subjects (individuals with and without diabetes) with sudden death had severe coronary artery disease or left ventricular dysfunction. Therefore, they suggested that although CAN could be a contributing factor, it was not a significant independent cause of sudden death. Heart failure is, however, common in individuals with diabetes, identified by the presence of neuropathy, even in individuals without evidence of coronary artery disease or left ventricular dysfunction (106). The association of cardiovascular autonomic dysfunction in the absence of coronary disease and cardiomyopathy requires further study.

Increased mortality after an MI
Mortality rates after an MI are also higher for diabetic patients than for nondiabetic patients (107). This may be due to autonomic insufficiency, increasing the tendency for development of ventricular arrhythmia and cardiovascular events after infarction. Fava et al. (108) showed that the presence of autonomic neuropathy contributed to a poor outcome in a study of 196 post-MI diabetic patients. In another study, Katz et al. (109) showed that a simple bedside test that measured 1-min HRV during deep breathing was a good predictor of all-cause mortality for 185 patients (17.8% with diabetes) after a first MI. These investigators also suggested that cardiovascular autonomic function testing provided a predictive value that could be used to identify a subgroup of patients after an MI who are a high risk for cardiovascular death (109).

Dysfunction of the ANS is associated with increased risk of mortality in individuals with diabetes. It is true, however, that at least some of the association between CAN and mortality appears to be due to an increased prevalence of other complications in individuals with CAN. Though the exact pathogenic mechanism is unclear, it is realized that some deaths may be avoidable through early identification of these higher-risk patients and by slowing, with therapy, the progression of autonomic dysfunction and its associated conditions. In addition, it would appear that autonomic function testing is a valuable tool in identifying a subgroup of post-MI patients who are at high risk for death.

Association of cerebrovascular disease and CAN
The frequency of ischemic cerebrovascular events is increased in individuals with type 2 diabetes. The impact of autonomic dysfunction on the risk of the development of strokes was examined by Toyry et al. (110), who followed a group of 133 type 2 diabetic patients for 10 years. During the study period, 19 individuals had one or more strokes. Abnormalities of parasympathetic and sympathetic autonomic function were found to be independent predictors of stroke in this cohort (110).

Progression of CAN
Results of the cardiovascular autonomic function tests that are mediated mainly by the parasympathetic nervous system (e.g., heart rate response to deep breathing) are typically abnormal before those responses that are mediated by the sympathetic nerves. Although one might speculate then that parasympathetic damage occurs before sympathetic damage, this may not always be true. The increased frequency of abnormalities detected via tests of the parasympathetic system may merely be a reflection of the test (e.g., sensitivity) and not of the natural history of nerve fiber damage (111). Thus, it may be better to describe the natural history of autonomic dysfunction as developing from early to more severe involvement rather than to anticipate a sequence of parasympathetic to sympathetic damage (111).

Although much remains to be learned about the natural history of CAN, previous reports can be coalesced into a few observations that provide some insight with regard to progression of autonomic dysfunction:

• It can be detected at the time of diagnosis (24,44,112).
  
• Neither age nor type of diabetes are limiting factors in its emergence, being found in young individuals with newly diagnosed type 1 diabetes and older individuals newly diagnosed with type 2 diabetes (5,24,40,44,113,114).
  
• Poor glycemic control plays a central role in development and progression (44,115–117).
  
• Intensive therapy can slow the progression and delay the appearance of abnormal autonomic function tests (37).
  
• Subclinical autonomic neuropathy can be detected early using autonomic function tests (26,41,44).
  
• Autonomic features that are associated with sympathetic nervous system dysfunction (e.g., orthostatic hypotension) are relatively late complications of diabetes (31,41,116,118–120).
  
• There is an association between CAN and diabetic nephropathy that contributes to high mortality rates (31,44,82).
  

Even with consensus regarding these general observations, much remains unclear:

• Some individuals with symptoms associated with autonomic neuropathy die suddenly and unexpectedly (31,44,82).
  
• Clinical signs and symptoms of autonomic dysfunction do not always progress. This underscores the need for performance of quantitative autonomic function tests to identify individuals at risk for premature death (121).
  
• Type 1 and type 2 diabetes may have different progression paths.
  
• The relationship between autonomic damage and duration of diabetes is not clear although numerous studies support an association (116).
  
• Prevalence and mortality rates may be higher among individuals with type 2 diabetes, potentially due in part to longer duration of glycemic abnormalities before diagnosis.
  

	OTHER AUTONOMIC NEUROPATHIES

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GI autonomic neuropathy
GI symptoms are relatively common among patients with diabetes and often reflect diabetic GI autonomic neuropathy (7,122). It should be noted, however, that although GI symptoms are common, symptoms may be more likely due to other factors than to autonomic dysfunction. GI manifestations of DAN are diverse, and symptoms and pathogenic mechanisms have been categorized according to which section of the GI tract is affected:

• Esophageal enteropathy (disordered peristalsis, abnormal lower esophageal sphincter function)
  
• Gastroparesis diabeticorum (nonobstructive impairment of gastric propulsive activity; brady/tachygastria, pylorospasm)
  
• Diarrhea (impaired motility of the small bowel [bacterial overgrowth syndrome], increased motility and secretory activity [pseudocholeretic diarrhea])
  
• Constipation (dysfunction of intrinsic and extrinsic intestinal neurons, decreased or absent gastrocolic reflex)
  
• Fecal incontinence (abnormal internal anal sphincter tone, impaired rectal sensation, abnormal external sphincter)
  
• Gallbladder atony and enlargement
  

Esophageal dysfunction results at least in part from vagal neuropathy (123); symptoms include heartburn and dysphagia for solids. Via the use of radioisotopic techniques that quantify gastric emptying, it appears that 50% of patients with longstanding diabetes have delayed gastric emptying (gastroparesis) (124). Gastric emptying largely depends on vagus nerve function, which can be severely disrupted in diabetes. Gastroparesis in diabetes is usually clinically silent, although severe diabetic gastroparesis is one of the most debilitating of all diabetic GI complications. Major clinical features of this disorder are early satiety, anorexia, nausea, vomiting, epigastric discomfort, and bloating. Episodes of nausea or vomiting may last days to months or occur in cycles (125).

Diarrhea is evident in 20% of diabetic patients, particularly those with known DAN (1). Diarrhea is typically intermittent, but bowel movements may occur 20 or more times per day with urgency, and the stools are often watery. Bacterial overgrowth due to stasis of the bowel may contribute to diarrhea, in which case broad-spectrum antibiotics (e.g., tetracycline and metronidazole) are useful. Individuals with constipation may have less than three bowel movements per week, and these may alternate with diarrhea. Treatment of diarrhea with or without constipation should always involve the use of a prokinetic agent rather than constipating agents that create vicious cycles of constipation and diarrhea (1). Fecal incontinence due to poor sphincter tone (126) is common for individuals with diabetes (127) and may be associated with severe paroxysmal diarrhea or constitute an independent disorder of anorectal dysfunction.

Genitourinary autonomic neuropathy
The neurogenic bladder, also called cystopathy, may be due to DAN (62). An examination of the neuroanatomy of the genitourinary system provides an insight into the extent to which autonomic fibers are involved with its proper control. Serving as a receptacle for the storage and appropriate evacuation of urine, the urinary bladder comprises three layers of interdigitating smooth muscle (i.e., detrusor muscle). This muscle forms an internal sphincter at the junction of the bladder neck and urethra, and although it is not anatomically discrete, there is localized autonomic innervation so that it functions as a physiological sphincter. Afferent nerve impulses of bladder sensation and reflex bladder contraction are carried by sympathetic, parasympathetic, and somatic nerves to the spinal cord (128). The earliest bladder autonomic dysfunctions are sensory abnormalities that result in impaired bladder sensation, an elevated threshold for initiating the micturition reflex and an asymptomatic increase in bladder capacity and retention.

The parasympathetic nerves that originate in the intermediolateral column of sacral segments S2–S4 provide the major excitatory input to the urinary bladder. Activation of the muscarinic, cholinergic, and postganglionic pelvic nerve fibers result in contraction of the urinary bladder. When there is damage to the efferent parasympathetic fibers to the urinary bladder, symptoms such as hesitancy in micturition, weak stream, and dribbling ensue, with a reduction in detrusor activity (i.e., detrusor areflexia). This leads to incomplete bladder emptying, an increased postvoid residual, decreased peak urinary flow rate, bladder overdistention, and urine retention. Finally, overflow incontinence occurs because of denervation of the external and internal sphincter (129,130). The somatic pudendal nerve innervates the external sphincter, whereas the sympathetic hypogastric nerves innervate the internal sphincter. Individuals with bladder dysfunction are predisposed to the development of urinary tract infections, including pyelonephritis, which may accelerate or exacerbate renal failure (131,132).

Urinary frequency is another commonly associated symptom of autonomic dysfunction of the genitourinary system. Unfortunately, 37–50% of individuals with diabetes have symptoms of bladder dysfunction, and 43–87% of individuals with type 1 diabetes have physiological evidence of bladder dysfunction (129,133,134).

Erectile dysfunction
Erectile dysfunction (ED) is the most common form of organic sexual dysfunction in males with diabetes, with an incidence estimated to be between 35 and 75% (135). ED is defined as the consistent inability to attain and maintain an erection adequate for sexual intercourse, usually qualified by being present for several months and occurring at least half the time. An estimated 20–30 million men in the U.S. have ED (136). In a large cohort study of men 53–90 years old, a significant association between diabetes (and duration of diabetes) and ED was found when comparing diabetic men with nondiabetic men of similar age (137). ED is a marker for the development of generalized vascular disease and for premature demise from a myocardial infarct, and penile failure may be a portent of upcoming, and possible preventable, cardiovascular events (138). ED etiology in diabetes is multifactorial, including neuropathy, vascular disease, metabolic control, nutrition, endocrine disorders, psychogenic factors, and anti-diabetes drugs. Retrograde ejaculation into the bladder also occurs in diabetic males. ED should alert physicians to perform cardiovascular evaluations for these patients.

Sexual dysfunction in women
Females with diabetes may have decreased sexual desire and increased pain during intercourse and are at risk of decreased sexual arousal and inadequate lubrication (139).

Anemia of autonomic dysfunction
It has been shown that type 1 diabetic individuals with early nephropathy and symptomatic autonomic neuropathy have inappropriately low levels of erythropoietin for the severity of their anemia (140). These individuals can, however, mount an appropriate erythropoietin response to moderate hypoxia. The mechanism that underlies the erythropoietin-deficient anemia is unclear. Reduced sympathetic stimulation of erythropoietin production has been previously hypothesized as the cause of ineffective erythropoiesis resulting in anemia (141).

	RELATIONSHIP OF AUTONOMIC NEUROPATHY TO HYPOGLYCEMIA RESPONSIVENESS

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Hypoglycemic unawareness and DAN
DAN plausibly could cause or contribute to hypoglycemia unawareness, but this relationship is complex. Two groups concluded that unawareness of hypoglycemia and inadequate counterregulation occur independently of autonomic neuropathy. Ryder et al. (142) noted "little evidence" of autonomic neuropathy in 12 diabetic patients with a history of unawareness of hypoglycemia and 7 patients with inadequate hypoglycemic counterregulation. They also observed no history of unawareness of hypoglycemia in seven patients with clear evidence of autonomic neuropathy, and in six of the seven, there was adequate hypoglycemic counterregulation. Based on these findings, they suggested that there was no causal relation between DAN and unawareness of hypoglycemia or inadequate hypoglycemic counterregulation (142). Hepburn et al. (143) reported that 7 of 17 patients with absent awareness of hypoglycemia had no evidence of autonomic dysfunction. Based on these data, they suggested that loss of hypoglycemia awareness is not invariably associated with abnormal cardiovascular autonomic function tests.

Careful examination of these studies suggests, however, that the relationship between autonomic neuropathy and hypoglycemic unawareness may be more complex than these reports suggest. Ryder et al. observed that patients with autonomic neuropathy had a negligible plasma pancreatic polypeptide response (3.7 pmol/l), and this response was also blunted in the patients with inadequate hypoglycemic counterregulation (72.4 pmol/l) compared with that of the control subjects (414 pmol/l; P < 0.05) (142). Furthermore, 10 of 17 individuals with hypoglycemia unawareness reported by Hepburn et al. had evidence of autonomic dysfunction (145). Taken together, even these data suggest that there is some overlap between the features of autonomic neuropathy and hypoglycemic unawareness. More recent data suggest that the presence of autonomic neuropathy further attenuates the epinephrine response to hypoglycemia in diabetic individuals after recent hypoglycemic exposure (144–146).

Hypoglycemic autonomic failure
The spectrum of reduced counterregulatory hormone responses (in particular epinephrine) and decreased symptom perception of hypoglycemia due to decreased ANS activation after recent antecedent hypoglycemia has been termed "hypoglycemia-induced autonomic failure" (147–149). Hypoglycemia-induced autonomic failure leads to a vicious cycle of hypoglycemia unawareness that induces a further decrease in counterregulatory hormone responses to hypoglycemia. This vicious cycle occurs commonly in individuals with diabetes who are in strict glycemic control. The reduced epinephrine response to antecedent hypoglycemia occurs in the absence of DAN as measured by standard tests of autonomic function (143,148,150). The presence of autonomic neuropathy, however, further attenuates the epinephrine response to hypoglycemia in diabetic subjects after recent hypoglycemic exposure (144–146) in most, but not all, studies (148). Furthermore, individuals with abnormal autonomic function have a greater risk for severe hypoglycemia (151).

	RELATIONSHIP OF AUTONOMIC NEUROPATHY TO TISSUE PERFUSION

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Microvascular skin flow is under the control of the ANS and is regulated by both the central and peripheral components. In diabetes, the rhythmic contraction of arterioles and small arteries is disordered. Microvascular insufficiency may be a cause of diabetic neuropathy (152). Microvascular blood flow can be accurately measured noninvasively using laser Doppler flowmetry. Defective blood flow in the small capillary circulation is found with decreased responsiveness to mental arithmetic, cold pressor, handgrip, and heating. The defect is associated with a reduction in the amplitude of vasomotion and resembles premature aging (153). There are differences in the glabrous and hairy skin circulations. In hairy skin, a functional defect is found before the development of neuropathy (154). The clinical counterpart is dry skin, loss of sweating, and the development of fissures and cracks that are portals of entry for microorganisms leading to infectious ulcers and ultimately gangrene. A prospective study by Boyko et al. (155) demonstrated the effect of autonomic neuropathy on the risk of developing a foot ulcer independent of other measures of sensory neuropathy. Autonomic neuropathy may also lead to increased osteoclastic activity resulting in reduced bone density. Thus, Young et al. (156) suggested that the significant relationship between reduced bone mineral density and severity of diabetic neuropathy in the lower extremities of individuals with Charcot neuroarthropathy may reflect the severity of autonomic neuropathy.

	CLINICAL TESTING OF AUTONOMIC FUNCTION

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Assessing cardiovascular autonomic function
Quantitative tests of autonomic function have historically lagged behind measures of motor nerve function and sensory nerve function deficits. The lack of interest in the development of such measures was partly due to the erroneous but commonly held view that autonomic neuropathy was only a small and relatively obscure contributor to the peripheral neuropathies affecting individuals with diabetes (116,118,120).

In the early 1970s, Ewing et al. (95) proposed five simple noninvasive cardiovascular reflex tests (i.e., Valsalva maneuver, heart rate response to deep breathing, heart rate response to standing up, blood pressure response to standing up, and blood pressure response to sustained handgrip) that have been applied successfully by many. The clinical literature has consistently identified these five tests as they have been widely used in a variety of studies. The tests are valid as specific markers of autonomic neuropathy if end-organ failure has been carefully ruled out and other potential factors such as concomitant illness, drug use (including antidepressants, over-the-counter antihistamines and cough/cold preparations, diuretics, and aspirin), lifestyle issues (such as exercise, smoking, and caffeine intake), and age are taken into account. A large body of evidence indicates that these factors can, to various degrees, affect the cardiovascular ANS and potentially other autonomic organ systems (157).

Heart rate response to deep breathing is for the most part a function of parasympathetic activity, although the sympathetic nervous system may affect this measure (158). Similarly, it is parasympathetic activity that plays the greatest role in the heart rate regulation for short-term standing, where the act of standing involves low-level exercise and parasympathetic tone is withdrawn to produce a sudden tachycardic response (159). In response to subsequent underlying blood pressure changes while standing, a baroreceptor-mediated reflex involves the sympathetic nerves for further heart rate control (160). Heart rate response to the Valsalva maneuver is influenced by both parasympathetic and sympathetic activity. Measurements of blood pressure response to standing and blood pressure response to sustained handgrip are used to assess sympathetic activity.

Heart rate response to deep breathing (i.e., beat-to-beat heart rate variation, R-R variation).
Beat-to-beat variation in heart rate with respiration depends on parasympathetic innervation. Pharmacological blockade of the vagus nerve with atropine all but abolishes respiratory sinus arrhythmia, whereas sympathetic blockade with the use or pretreatment of propranol