Diabetic autonomic neuropathy

INTRODUCTION — Diabetic autonomic neuropathy (DAN) is a common form of neuropathy in patients with diabetes mellitus characterized by dysfunction due to impairment of peripheral autonomic nerves. A wide spectrum of manifestations can affect many different organ systems, including the cardiovascular, gastrointestinal, genitourinary, sudomotor and vasomotor, and neuroendocrine systems (table 1).

This topic will review the clinical manifestations and management of DAN. Other forms of neuropathy associated with diabetes mellitus are discussed separately. (See "Epidemiology and classification of diabetic neuropathy".)

Hereditary sensory and autonomic neuropathies are discussed elsewhere. (See "Hereditary sensory and autonomic neuropathies".)

EPIDEMIOLOGY — DAN is a common form of neuropathy in patients with diabetes mellitus. The prevalence of DAN increases with the duration of diabetes. It may be identified in patients at the time of diabetes diagnosis in up to 7 percent [1] but can be as high as 50 percent after 15 years [2]. DAN occurs in patients with type 1 or type 2 diabetes mellitus [3].

SCREENING — We recommend assessing all patients with diabetes mellitus for DAN. Some patients with DAN may not have overt symptoms. Early recognition of clinical or subclinical DAN is useful for risk stratification and to guide specific glycemic, lipid, and blood pressure targets. (See "Overview of general medical care in nonpregnant adults with diabetes mellitus".)

We screen for DAN at the time of diagnosis of type 2 diabetes and five years after the diagnosis of type 1 diabetes, in agreement with guidelines from the American Diabetes Association [4]. Screening should include a history and physical examination to assess for symptoms and signs of autonomic dysfunction. Symptoms can include orthostatic dizziness, palpitations, syncope, bloating or early satiety, and/or chronically dry skin. Signs of autonomic neuropathy can include orthostatic hypotension, resting tachycardia, or evidence of dry and cracked skin [5].

If screening is positive, directed testing may be performed to help establish the diagnosis of DAN. (See 'Cardiovascular autonomic neuropathy' below and 'Peripheral sudomotor and vasomotor neuropathy' below and 'Gastrointestinal autonomic neuropathy' below and 'Genitourinary autonomic neuropathy' below.)

If initial screening is negative, a history and physical examination for symptoms and signs of autonomic dysfunction should be repeated annually.

OVERVIEW OF MANAGEMENT — DAN represents a complication of diabetes mellitus. Management to help prevent development or progression of DAN involves optimizing glycemic control, treating comorbid vascular risk factors (eg, hypertension, hyperlipidemia, obesity), and addressing specific autonomic symptoms to provide symptomatic relief and reduce associated morbidity.

Glycemic control — Glycemic control is a key component of the overall management strategy to help prevent and to slow progression of DAN.

●Glycemic targets – The appropriate glycated hemoglobin A1C target for patients with diabetes mellitus (with or without DAN) includes balancing individual benefits of improved glycemic control to reduce risk of complications with risks of treatment-related complications (eg, hypoglycemia, weight gain). These issues are discussed separately. (See "Glycemic control and vascular complications in type 1 diabetes mellitus", section on 'Glycemic targets' and "Glycemic control and vascular complications in type 2 diabetes mellitus", section on 'Choosing a glycemic target'.)

●Rate of glycemic improvement – For individuals with chronic hyperglycemia, our practice is to achieve a target hemoglobin A1C gradually, not exceeding a 3-point change in hemoglobin A1C in three months. Extremely rapid improvements in glycemic control in patients with chronic hyperglycemia may be associated with the development of microvascular complications of diabetes, including DAN and peripheral neuropathy [6]. This phenomenon is called treatment-induced neuropathy of diabetes (TIND). (See "Epidemiology and classification of diabetic neuropathy", section on 'Treatment-induced neuropathy of diabetes'.)

TIND appears to be more common in those with type 1 diabetes, most likely because of the rapid change in glycemic control that can occur with the use of insulin. Based on the limited data available, chronic hyperglycemia of a year or more may be necessary prior to an abrupt decrease in average glucose levels to result in neuropathy development [7].

Not all experts are convinced that overly rapid glycemic control or reduction in hemoglobin A1C can cause neuropathy. An alternative explanation for this finding is that the worsening of neuropathy is an epiphenomenon associated with but not caused by overly rapid glycemic control. The prevalence is unknown and data supporting TIND come from uncontrolled and retrospective studies. No evidence of TIND was observed in data from prospective controlled trials such as the Diabetes Control and Complications Trial (DCCT). However, "early worsening retinopathy" was noted within the DCCT trial, a phenomenon also seen in individuals with TIND [8-11]. The parallel development of retinopathy and neuropathy in acute glycemic control suggests an inflammatory microvascular process.

●Evidence of efficacy – Intensive therapy with insulin in subjects with type 1 diabetes was found to reduce the incidence of cardiovascular autonomic neuropathy (CAN) by 53 percent in the DCCT [12], and the benefit of prior intensive therapy was found to persist for up to 14 years in these subjects [13].

The potential efficacy of intensive therapy in patients with type 2 diabetes and microalbuminuria was examined in the Steno type 2 trial [14]. In this prospective open-label trial, 160 patients were assigned to standard or intensive therapy. The intensive regimen consisted of both behavioral therapy (including advice concerning diet, exercise, and smoking cessation) and pharmacologic intervention (consisting of the administration of multiple agents to attain several aggressive therapeutic goals) (table 2). At a mean follow-up of 7.8 years, progression to autonomic neuropathy occurred in 24 patients assigned to the intensive regimen compared with 43 patients assigned to standard therapy (30 versus 54 percent, relative risk [RR] 0.37, 95% CI 0.18-0.79). This benefit was sustained at a mean of 13.3 years (the trial intervention period plus an additional 5.5 years of observational follow-up) [15]. (See "Overview of general medical care in nonpregnant adults with diabetes mellitus", section on 'Multifactorial risk factor reduction'.)

However, a cautionary note comes from the results of the ACCORD trial, in which intensive glycemic control was linked to increased mortality in type 2 diabetes [16]. The design of the ACCORD trial limited the ability to determine whether the differences in glycemia between the treatment groups or the different profile of the many medications utilized to achieve the glycemic levels was responsible for the excess mortality.

Risk factor management — Modifiable risk factors in addition to hyperglycemia include hypertension, hyperlipidemia, and smoking. Multimodal management of vascular risk factors reduces cardiovascular mortality in patients with diabetes [15,17]. (See "Overview of general medical care in nonpregnant adults with diabetes mellitus", section on 'Multifactorial risk factor reduction'.)

Vascular risk factor management can also reduce the incidence and may help reduce the progression of diabetic neuropathy, including DAN [18-20]. In a prospective, observational study of 1172 patients with type 1 diabetes followed for a mean of 7.3 years, the rate of development of diabetic neuropathy was 24 percent [18]. After adjustment for glycated hemoglobin levels and duration of diabetes, other risk factors associated with the incidence of diabetic neuropathy included:

●History of cardiovascular disease (odds ratio [OR] 2.7, 95% CI 1.7-4.5)

●Hypertension (OR 1.9, 95% CI 1.3-2.8)

●History of smoking (OR 1.6, 95% CI 1.2-2.0)

●Body-mass index (OR 1.4, 95% CI 1.2-1.6)

●Triglycerides (OR 1.4, 95% CI 1.2-1.6)

●Total cholesterol (OR 1.3, 95% CI 1.1-1.5)

While poor glucose control and vascular risk factors appear to be associated with the development of diabetic neuropathy, the effects of these risk factors on DAN progression are less clear and, other than the beneficial effects of glycemic control in type 1 diabetes, high-quality evidence is sparse.

In addition to management of modifiable comorbid conditions, certain medications may cause or worsen neuropathy. These medications should be discontinued if possible (table 3).

Symptomatic treatment — DAN may be detected in the majority of patients with diabetes with neurophysiologic testing but is classified as subclinical or clinical depending upon the presence or absence of symptoms [21]. Symptoms commonly involve the cardiovascular system, but other symptoms involving vasomotor, gastrointestinal, and genitourinary systems may also occur. Specific manifestations and respective management strategies are discussed below.

CARDIOVASCULAR AUTONOMIC NEUROPATHY — Cardiovascular autonomic neuropathy (CAN) is defined as the impairment of autonomic control of the cardiovascular system [22]. It may be associated with several abnormalities in cardiovascular function.

The prevalence of CAN varies considerably, which reflects variability in the sensitivity of diagnostic tests used, diagnostic criteria, and the population studied. In the longitudinal Screen-Detected Diabetes in Primary Care (ADDITION) study that included 443 patients with type 2 diabetes followed for a median of 13 years, the annual incidence of CAN was 1.8 percent in individuals with well-controlled diabetes [23]. This incidence is lower than in other reports, which may reflect improvements in early detection and risk factor reduction.

Clinical manifestations — CAN may be associated with overt clinical symptoms such as palpitations at rest, exercise intolerance, orthostatic hypotension, syncope, intraoperative cardiovascular instability, and silent myocardial infarction and ischemia [24]. In addition, CAN may be identified by cardiovascular reflex testing performed on screening evaluation of asymptomatic individuals.

Resting tachycardia and exercise intolerance — The earliest clinical manifestation of CAN may be a resting tachycardia. The increased resting heart rate is due to unopposed cardiac sympathetic nerve activity.

Exercise intolerance is usually due to impaired augmentation of cardiac output resulting from inadequate sympathetic modulation. Persistent sinus tachycardia can occur and may be associated with minimal or absent variation in heart rate during activities that normally increase heart rate variability, such as deep breathing and the Valsalva maneuver.

As autonomic neuropathy progresses, the resting heart rate gradually slows [25]. Cardiac denervation can occur in diabetic patients with advanced autonomic neuropathy. It is characterized by a fixed heart rate, in the range of 80 to 90 beats per minute, and is associated with an elevated risk of painless myocardial infarction, arrhythmias, and sudden death [26]. (See 'Adverse cardiovascular events' below.)

Orthostatic (postural) symptoms — Clinical features of CAN may be related to posture, provoked by standing and relieved by sitting. Tachycardia or hypotension may occur, causing palpitations, lightheadedness, dizziness, or syncope.

●Postural tachycardia — A posture-induced tachycardia without a fall in blood pressure can result in significant postural symptoms of lightheadedness, dizziness, and presyncope. Postural tachycardia is typically seen in patients with diabetes who have a high resting heart rate due to vagal cardiac neuropathy with an unopposed cardiac sympathetic nerve activity.

Although postural tachycardia may occur both with diabetes and postural tachycardia syndrome (POTS), patients with postural tachycardia and diabetes should be diagnosed with DAN. While both conditions can be due to an underlying neuropathy, treatments may differ, and the role of glycemic control and vascular risk factor management is an additional component of the treatment of DAN. (See 'Overview of management' above.)

The clinical features and management of POTS are discussed separately. (See "Postural tachycardia syndrome".)

●Orthostatic hypotension — Orthostatic hypotension is defined as a fall in blood pressure of ≥20 mmHg systolic or ≥10 mmHg diastolic following a change from a supine to a standing (or upright tilt table test) position [27]. Orthostatic hypotension results from a combination of central and peripheral cardiovascular sympathetic denervation. It reflects failure of vasoconstriction in both the splanchnic and peripheral vascular beds.

Symptoms and presentations may include:

•Intermittent dizziness – Dizziness or lightheadedness may occur spontaneously or may be provoked by dehydration. Symptoms are typically intermittent.

Day-to-day variability of symptoms may also be provoked by insulin therapy, which has provoked hypotension in both diabetic [28] and nondiabetic [29] patients with autonomic failure, although the clinical relevance of this to most patients with diabetes is not known.

•Supine hypertension – A loss of the diurnal variation in blood pressure may lead to supine hypertension occurring at night [30]. This may also occur to a lesser degree in diabetic patients without neuropathy. In addition, ambulatory 24-hour blood pressure monitoring has detected hypertension in over 50 percent of subjects with type 2 diabetes and CAN, despite normal office blood pressure measurements [31]. Medications used to treat orthostatic hypotension may also cause supine hypertension.

•Postprandial hypotension – Supine and standing systolic blood pressures may fall profoundly after meals [32]. The mechanism of postprandial hypotension in DAN is unclear. Both inadequate sympathetic compensation to meal-induced pooling of blood in the splanchnic circulation and vasodilatory gut peptides may contribute to this phenomenon [33,34].

•Syncope – In its most severe form, orthostatic hypotension can cause significant drops in blood pressure resulting in syncope. This severe form of orthostasis is rare, with most patients having milder symptoms that are amenable to therapeutic interventions.

Retrospective data suggest that the presence of orthostatic hypotension is associated with microvascular and macrovascular complications of diabetes [35]. The presence of orthostatic hypotension in diabetes is associated with a significant increase in 10-year mortality [36,37]. (See 'Prognosis' below.)

Adverse cardiovascular events — The presence of CAN is associated with the risk of silent myocardial ischemia. A meta-analysis of 12 cross-sectional studies found that patients with CAN had a higher frequency of silent myocardial ischemia than patients without CAN (pooled prevalence rate ratio 1.96, 95% CI 1.53-2.51) [21]. In a study of 522 patients with type 2 diabetes and no known or suspected coronary artery disease who underwent adenosine stress radionuclide myocardial perfusion imaging studies, silent ischemia was detected in 113 (22 percent) [38].

The mechanisms of silent myocardial ischemia are complex and not completely understood. This issue is discussed separately. (See "Silent myocardial ischemia: Epidemiology, diagnosis, treatment, and prognosis", section on 'Pathophysiology'.)

CAN is also associated with other adverse cardiac outcomes such as cardiac arrhythmia, heart failure, and need for coronary revascularization. A study of 120 patients with type 1 or type 2 diabetes and no history of myocardial infarction or angina but at least two additional cardiovascular risk factors followed for an average of 4.5 years found that a major cardiac event was significantly more common in patients with CAN than in those without CAN (24 versus 7 percent) [39].

CAN is also associated with an increased mortality risk. (See 'Prognosis' below.)

Other vascular complications — The presence of CAN may also be associated with kidney disease and cerebrovascular events.

●Kidney disease – CAN has been associated with the development of chronic kidney disease. In a prospective study of subjects with type 1 diabetes who were followed for over 14 years, CAN and abnormal orthostatic diastolic blood pressure were associated with the subsequent development of kidney complications [40]. In another study including 1523 subjects with diabetes followed for 16 years, both a higher resting heart rate and a lower heart rate variability were associated with an increased risk of developing end-stage kidney disease [41].

●Cerebrovascular disease – CAN may be associated with an increased stroke risk. In patients with type 2 diabetes enrolled in the longitudinal Appropriate Blood Pressure Control in Diabetes trial, CAN was an independent risk factor for the occurrence of stroke [42].

Diagnostic testing — CAN may be diagnosed with cardiovascular reflex testing in both symptomatic patients and asymptomatic patients. Tests of autonomic function may include assessment of heart rate (for resting tachycardia), heart rate variability (including the expiration-to-inspiration ratio), response to the Valsalva maneuver, and assessment of orthostatic hypotension.

Some experts believe that a confident diagnosis of CAN requires abnormalities in two or more cardiac autonomic functions [21,43]. This notion underlies proposed criteria for the diagnosis and staging of CAN [22,44], which specify:

●Possible or early CAN – one abnormal cardiovascular reflex test [45].

●Definite or confirmed CAN – two abnormal cardiovascular reflex tests [46].

●Severe or advanced CAN – definite CAN and the additional presence of orthostatic hypotension [47].

There is no evidence that any one test has diagnostic superiority [22,44,48], although it is rare that a single test would be administered.

●Common diagnostic test options – The selection of specific autonomic tests (table 4) varies according to local protocols and availability but typically includes measures that assess several different components of the autonomic reflex arc [49]:

•Parasympathetic function (eg, heart rate response to Valsalva maneuver)

•Sympathetic adrenergic function (eg, blood pressure change to standing)

•Sympathetic cholinergic function (eg, quantitative sudomotor axon reflex testing)

●Investigational tests – Other tests using radiolabeled analogues of norepinephrine can provide direct assessments of the pattern of cardiac sympathetic innervation and help establish the diagnosis of CAN. However, these have limited clinical utility because they are expensive and not widely available. These include [50-53]:

•123-I-metaiodobenzylguanidine (MIBG; iobenguane I-123)

•11-C-hydroxyephedrine scintigraphy

Scintigraphy has a greater sensitivity to detect more subtle degrees of CAN than is possible by (indirect) cardiovascular reflex testing. Conventional measures of autonomic function use indirect methods relying on cardiovascular reflexes, which can detect early abnormalities in parasympathetic integrity but are relatively insensitive to sympathetic adrenergic deficits [54]. Among patients with type 1 diabetes and no evidence of DAN on cardiovascular reflex testing, abnormalities in cardiac innervation by cardiac MIBG scanning have been noted in some small studies [50,52]. In addition, 11-C-hydroxyephedrine scintography facilitates the quantitative regional characterization of sympathetic neuronal dysfunction and loss [55]. It undergoes highly specific uptake and retention in sympathetic nerve terminals [56,57] and, in comparison with MIBG, the images are less affected by nonneuronal uptake [58] and tissue attenuation [59].

Treatment — The management of CAN involves glycemic control and risk factor reduction in an attempt to reduce disease progression and associated morbidity as well as symptomatic strategies to alleviate symptoms. Symptomatic therapy is administered in a step-wise fashion, to minimize adverse treatment effects.

●General treatment measures for all patients – Glycemic control and risk factor management strategies for all patients with CAN should also incorporate interventions to increase overall cardiovascular fitness and weight control since there is evidence that an exercise program can improve surrogate measures of both early and more advanced CAN [60,61]. In individuals with type 2 diabetes, there is a beneficial effect of weight loss on autonomic function, although it is unclear if this translates into a clinically meaningful outcome [62]. However, the clinical benefits of weight loss across all functional outcomes in type 2 diabetes support this clinical recommendation.

●Nonpharmacologic symptomatic treatment – The initial step in managing CAN symptoms involves several nonpharmacologic strategies that are used for patients with orthostatic hypotension. For some patients with mild symptoms, these measures may be sufficient to achieve symptom control without pharmacologic interventions. Strategies include:

•Detailed review and removal of any medications that may worsen orthostatic hypotension (table 5).

•Increase in fluid intake and liberalize salt intake.

•Modify daily activities (eg, stand upright slowly, elevate head of bed, flex hands and/or feet before standing).

However, we typically avoid measures aimed at increasing peripheral vascular tone (such as body stockings and gravity suits) that may be used for other patients with orthostatic hypotension. They often prove ineffective for patients with CAN since blood pooling probably occurs in the large splanchnic vascular bed [63]. Furthermore, in individuals with diabetic peripheral neuropathy, pressure sores can occur with compression stockings and should be avoided.

Nonpharmacologic measures for patients with orthostatic hypotension are discussed in greater detail separately. (See "Treatment of orthostatic and postprandial hypotension", section on 'Nonpharmacologic measures'.)

●Pharmacologic symptomatic treatment – For patients with CAN whose symptoms do not resolve with nonpharmacologic treatment options, medications used for treatment of orthostatic hypotension may provide additional relief. The selection of agent depends on symptom severity and patient risk factors. Options for patients with CAN include (table 6):

•Fludrocortisone

•Midodrine

•Droxidopa

We typically do not use norepinephrine transporter (NET) inhibitors for patients with CAN as these agents generally require intact peripheral sympathetic functioning.

The approach to the pharmacologic treatment of orthostatic hypotension is discussed in greater detail separately. (See "Treatment of orthostatic and postprandial hypotension", section on 'Pharmacotherapy'.)

●Treatment of supine hypertension – Supine hypertension is a common manifestation of CAN. It may reflect an imbalance in sympathetic and parasympathetic tone. Supine hypertension may accompany and be a treatment-limiting factor for patients with concomitant orthostatic hypotension. Management is challenging, and the approach is primarily guided by indirect evidence, clinical experience, and expert consensus [64].

The management of supine hypertension is discussed separately. (See "Treatment of orthostatic and postprandial hypotension", section on 'Supine hypertension'.)

PERIPHERAL SUDOMOTOR AND VASOMOTOR NEUROPATHY — The peripheral sympathetic cholinergic system controls sweat function and thermoregulation. The relationship between peripheral autonomic denervation and its effects on the peripheral vasculature was recognized as early as 1941 when it was noted that diabetic patients with neuropathy had similar peripheral vasomotor reflexes as nondiabetic patients after sympathectomy [65]. This loss of sympathetic vascular innervation results in high peripheral blood flow through arteriovenous shunting and abnormal local reflex vascular control [24]. Sudomotor and vasomotor neuropathies are common in patients with diabetes mellitus and typically are comorbid complications of diabetic axonal polyneuropathies. (See "Epidemiology and classification of diabetic neuropathy".)

Clinical features — Loss of sudomotor function leads to thermoregulatory impairment and hyperthermia. Loss of sweat function occurs distally in a stocking-and-glove distribution and leads to a compensatory proximal hyperhidrosis [66]. Sudomotor and vasomotor dysfunction may also cause changes in the texture of the skin and/or underlying tissue and joints.

Common features of peripheral autonomic neuropathy include [22,66-68]:

●Proximal hyperhidrosis

●Acral symptoms (hyperthermia, pruritus, aching, cramping)

●Skin changes (dry skin, venous prominence, callus formation, loss of nails)

●Peripheral edema, associated with foot ulceration and/or poor wound healing

●Neuroarthropathy (Charcot arthropathy) (picture 1)

Neuroarthropathy can lead to spontaneous fractures followed by progressive bone disorganization with an increased risk of secondary ulceration. (See "Diabetic neuroarthropathy".)

Diagnostic testing — The clinical diagnosis of peripheral autonomic neuropathy may be confirmed with superficial recording modalities that identify sudomotor or vasomotor dysfunction after chemical or electrical stimulation. These include the following techniques:

●Quantitative sudomotor axon reflex testing (QSART) can be used for the detection of early peripheral sympathetic denervation [69]. QSART involves measuring sweat output both at baseline and following a mild electrical stimulation used to stimulate sweat.

●Galvanic skin response, also referred to as the sympathetic skin response, offers a surrogate measure of sympathetic innervation in the hands and feet [70]. This sympathetic skin response involves measuring changes in skin conductivity due to sweat output. However, it can be an unreliable measure of sudomotor function and is frequently absent in the older population.

●Measurement of vascular responses in the foot is an alternative method to detect peripheral sympathetic denervation. Thermal-induced vasoconstriction (rather than the normal vasodilation) reflects vascular denervation and is present only in those patients with both autonomic and somatic neuropathy [71]. Impairment of local axon reflex dilatation is thought to reflect depletion of local vasoactive neuropeptides.

Peripheral autonomic dysfunction may also be identified during routine nerve conduction studies. Motor nerve conduction velocity is decreased in patients with other evidence of small fiber damage, particularly loss of thermal sensation. However, peripheral autonomic neuropathy correlates poorly with motor nerve dysfunction. (See "Overview of nerve conduction studies", section on 'Motor nerve conduction'.)

Skin biopsy assessment is sometimes used to detect autonomic (small fiber) neuropathy [72]. In addition, the assessment of sweat gland nerve fiber density has been studied as a marker of sudomotor neuropathy [73,74]. However, the diagnostic sensitivity of intraepidermal nerve fiber assessment is suboptimal so its clinical role for the quantitation of DAN remains unclear [75]. (See "Skin biopsy for the evaluation of peripheral nerve disease".)

Treatment — Treatment of peripheral sudomotor and vasomotor neuropathy is generally supportive. Lifestyle modifications such as cooling garments and avoidance of warm environments can improve symptoms. Clinicians should avoid the temptation to treat a proximal compensatory hyperhidrosis because treatment increases the risk of hyperthermia.

Comprehensive foot examination is warranted to optimize foot care and prevent foot infection and/or ulceration. (See "Evaluation of the diabetic foot".)

GASTROINTESTINAL AUTONOMIC NEUROPATHY — DAN that involves autonomic fibers of the enteric nervous system may cause upper and lower gastrointestinal symptoms. These include:

●Gastroesophageal reflux disease (GERD) – The most common symptoms of GERD are heartburn (pyrosis) and regurgitation. Other extraesophageal manifestations of GERD include bronchospasm, laryngitis, and chronic cough. Dysphagia for liquids and/or solids is rarely seen in diabetes mellitus. (See "Diabetic autonomic neuropathy of the gastrointestinal tract", section on 'Gastroesophageal reflux disease'.)

●Gastroparesis – Symptoms of gastroparesis include nausea, vomiting, early satiety, bloating, and/or upper abdominal pain. Patients with diabetic gastroparesis may also present with symptoms that are not directly related to the gastroparesis but are due to complications of poor glycemic control. Gastroparesis may improve with stable glycemic control. (See "Diabetic autonomic neuropathy of the gastrointestinal tract", section on 'Gastroparesis'.)

●Diarrhea – Diarrhea, and rarely steatorrhea, can occur in patients with DAN, particularly those with advanced disease. The diarrhea is watery and painless, occurs at night, and may be associated with fecal incontinence. Bouts of diarrhea can be episodic with intermittent, normal bowel habits or even alternating with periods of constipation. (See "Diabetic autonomic neuropathy of the gastrointestinal tract", section on 'Diabetic diarrhea'.)

The clinical features, diagnosis, and treatment of gastrointestinal complications of DAN are discussed in greater detail separately. (See "Diabetic autonomic neuropathy of the gastrointestinal tract".)

GENITOURINARY AUTONOMIC NEUROPATHY — Diabetic genitourinary autonomic neuropathy is responsible for several syndromes including bladder dysfunction, retrograde ejaculation, erectile dysfunction, and dyspareunia (due to decreased vaginal lubrication) [76]. Symptoms may be present in up to 50 percent of individuals with diabetes mellitus [77].

Bladder dysfunction — Diabetic bladder dysfunction initially presents as a decrease in the ability to sense a full bladder from impaired afferent innervation [78]. Subsequent efferent impairment leads to incomplete emptying. These abnormalities can result in overflow incontinence, poor urinary stream, and recurrent urinary tract infections. Lower urinary tract symptoms (frequency, urgency, nocturia) were present in approximately 20 percent of males with type 1 diabetes at the 10-year follow-up time point after completion of the Diabetes Control and Complications Trial (DCCT) [79] while urinary incontinence was reported in 38 percent of females [80].

The management of chronic urinary incontinence is discussed in greater detail separately. (See "Female urinary incontinence: Treatment" and "Urinary incontinence in men", section on 'Management'.)

Sexual dysfunction — Sexual dysfunction due to autonomic neuropathy may cause several symptoms. However, the evidence for diabetes as an independent risk factor for sexual dysfunction is limited; depression and anxiety may be more important predictors of sexual dysfunction [81,82].

●Male sexual dysfunction – Erectile dysfunction is a common manifestation of DAN and may be associated with the risk of cardiovascular disease [83]. Retrograde ejaculation reflects loss of coordinated internal urethral sphincter closure with external urethral sphincter relaxation during ejaculation. It may be manifest as cloudy urine postcoitally due to the presence of sperm. Impotence due to autonomic neuropathy usually occurs as a severe manifestation along with other features of somatic or autonomic neuropathy.

The evaluation and treatment of male sexual dysfunction is discussed in greater detail separately. (See "Evaluation of male sexual dysfunction" and "Treatment of male sexual dysfunction".)

●Female sexual dysfunction – Genitourinary neuropathy may cause vulvovaginal symptoms, including dryness, dyspareunia, and bleeding. Sexual dysfunction is more common in females with diabetes compared with those without diabetes [81,84].

The evaluation and management of female sexual dysfunction is discussed in greater detail separately. (See "Overview of sexual dysfunction in females: Epidemiology, risk factors, and evaluation" and "Overview of sexual dysfunction in females: Management".)

OTHER MANIFESTATIONS — Other symptoms that may occur with DAN include:

●Difficulty with night driving – Dysfunction in pupillary constrictor muscles may result in failure in dark adaptation [85]. Patients may report difficulty with dark vision or adapting to headlights of facing traffic.

●Hypoglycemic episodes – Alterations in neuroendocrine responses attributed to DAN include a reduction in glucagon and epinephrine secretion in response to hypoglycemia, thereby increasing the likelihood of hypoglycemic episodes, also referred to as hypoglycemia-associated autonomic failure [86-88]. In subjects with DAN, decreased counterregulatory catecholamine responses may increase the risk for severe hypoglycemia [89]. (See "Physiologic response to hypoglycemia in healthy individuals and patients with diabetes mellitus", section on 'Hypoglycemia-associated autonomic failure'.)

In addition, patients with DAN may also have an impaired awareness of hypoglycemia, perhaps related to impaired peripheral nerve signaling [90]. (See "Hypoglycemia in adults with diabetes mellitus", section on 'Impaired awareness of hypoglycemia'.)

PROGNOSIS

Mortality — Longitudinal studies of patients with DAN have typically reported five-year mortality rates ranging between 16 and 53 percent [91-95]. Although the majority of deaths result from associated cardiovascular disease, cardiorespiratory arrest secondary to autonomic denervation has been implicated in some patients [95,96]. Two meta-analyses of diabetic patients have found that cardiovascular autonomic neuropathy (CAN) is associated with an increased risk of mortality [43,97]. In one meta-analysis, the mortality of autonomic neuropathy-free subjects over 5.5 years was approximately 5 percent, but this increased to 27 percent with the onset of abnormal cardiovascular reflex tests [97]. In a subsequent meta-analysis, the magnitude of the association was stronger for studies that required more than one abnormality of cardiovascular function to define CAN [43].

There are several potential mechanisms by which DAN may increase mortality rates:

●Diminished perception of cardiac ischemia among patients with diabetes [98-100].

●Impaired cardiovascular response to physiologic stressors such as surgery or infection [101,102].

●Arrhythmogenicity due to alterations in vagal control of heart rhythm or QT interval [103,104].

●Denervated myocardial tissue that has focal areas of reinnervation at increased risk for arrhythmia [105].

Studies reporting the highest mortality rates have typically enrolled symptomatic patients with abnormalities of both the sympathetic and parasympathetic divisions of the autonomic nervous system. Postural hypotension appears to predict a poor prognosis [35,94].

Role of comorbid risk factors — In addition to the increased risk of cardiac morbidity and mortality from DAN, other conditions also contribute to the mortality risk associated with DAN.

●Atherosclerotic heart disease – DAN is associated with an elevated risk of developing atherosclerotic heart disease. In the Rochester Diabetic Neuropathy Study (RDNS), a prospective, longitudinal, population-based study, 21 cases of sudden cardiac death occurred in 462 patients with diabetes who were followed for over 15 years [106]. All 21 with sudden cardiac death had evidence of preceding severe atherosclerosis and myocardial damage. Autonomic dysfunction was not associated with sudden cardiac death after adjusting for electrocardiogram abnormalities and stage of nephropathy.

●Chronic kidney disease – In a prospective observational study that followed patients with type 1 diabetes who had nephropathy (n = 197) or no nephropathy (n = 191) for 10 years, the presence of CAN (as measured by decreased heart rate variability) in the patients with nephropathy was an independent risk factor for cardiovascular morbidity and mortality [107].

●Obstructive sleep apnea – Sleep apnea is common among patients with DAN [108]. The severity of DAN among patients with obstructive sleep apnea (OSA) correlates with desaturation rates and the risk of respiratory arrest, contributing to an increased mortality risk [109-112].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Neuropathy".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Nerve damage caused by diabetes (The Basics)")

●Beyond the Basics topics (see "Patient education: Diabetic neuropathy (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Definition – DAN is a common form of neuropathy in patients with diabetes mellitus characterized by dysfunction due to impairment of peripheral autonomic nerves. A wide spectrum of manifestations can affect many different organ systems, including the cardiovascular, gastrointestinal, genitourinary, sudomotor and vasomotor, and neuroendocrine systems (table 1). (See 'Introduction' above.)

●Screening – We assess all patients with diabetes mellitus for DAN, typically at the time of diagnosis for patients with type 2 diabetes and five years after the diagnosis for patients with type 1 diabetes, as well as annually thereafter for all patients.

●Management overview – DAN represents a complication of diabetes mellitus. Management to help prevent the development or progression of DAN involves (see 'Overview of management' above):

•Optimizing glycemic control

•Treating comorbid vascular risk factors (eg, hypertension, hyperlipidemia, obesity)

•Addressing specific autonomic symptoms to provide symptomatic relief and reduce associated morbidity

Specific recommendations for optimized glycemic control and treating comorbid vascular risk factors (eg, hypertension, hyperlipidemia, and obesity) are provided separately. (See "Glycemic control and vascular complications in type 1 diabetes mellitus", section on 'Glycemic targets' and "Glycemic control and vascular complications in type 2 diabetes mellitus", section on 'Choosing a glycemic target' and "Overview of general medical care in nonpregnant adults with diabetes mellitus".)

●Clinical manifestations

•Cardiovascular autonomic neuropathy – Cardiovascular autonomic neuropathy (CAN) is defined as the impairment of autonomic control of the cardiovascular system. It may be associated with resting tachycardia, exercise intolerance, orthostatic hypotension, and syncope. It is also associated with elevated risks of myocardial ischemia, kidney disease, and ischemic stroke. (See 'Cardiovascular autonomic neuropathy' above.)

CAN is diagnosed by cardiovascular reflex testing (table 4). Management involves glycemic control and risk factor management as well as symptomatic strategies to alleviate symptoms.

•Peripheral autonomic neuropathy – Peripheral sudomotor and vasomotor dysfunction leads to thermoregulatory impairment, hyperthermia, and changes in the texture of the skin and/or underlying tissue and joints. Advanced features include chronic peripheral edema, neuroarthropathy, and skin ulceration. The clinical diagnosis of peripheral autonomic neuropathy may be confirmed with superficial recording modalities that identify sudomotor or vasomotor dysfunction. Treatment is supportive. (See 'Peripheral sudomotor and vasomotor neuropathy' above.)

•Gastrointestinal autonomic neuropathy – DAN that involves autonomic fibers of the enteric nervous system may cause upper and lower gastrointestinal symptoms such as gastroesophageal reflux disease, gastroparesis, and diarrhea. This is discussed separately. (See "Diabetic autonomic neuropathy of the gastrointestinal tract".)

•Genitourinary autonomic neuropathy – Diabetic genitourinary autonomic neuropathy is responsible for several syndromes including bladder dysfunction, retrograde ejaculation, erectile dysfunction, and dyspareunia. (See 'Genitourinary autonomic neuropathy' above.)

●Prognosis – Five-year mortality rates for patients with DAN range between 16 and 53 percent, mostly due to CAN-related complications. Comorbid risk factors associated with poor prognosis in DAN include atherosclerotic heart disease, chronic kidney disease, and obstructive sleep apnea. (See 'Prognosis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Martin Stevens, MD, who contributed to earlier versions of this topic review.