Diabetic Autonomic Neuropathy - UpToDate

9/28/2020 Diabetic autonomic neuropathy - UpToDate
Author: Christopher H Gibbons, MD, MMSc, FAAN

Section Editors: David M Nathan, MD, Jeremy M Shefner, MD, PhD
Deputy Editor: Richard P Goddeau, Jr, DO, FAHA
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Aug 2020. | This topic last updated: Mar 12, 2019.
INTRODUCTION
Diabetic autonomic neuropathy (DAN) is a common and debilitating form of neuropathy. 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 [1]. A wide
spectrum of manifestations affecting many different organ systems can occur, including the
cardiovascular, gastrointestinal, genitourinary, pupillary, sudomotor, and neuroendocrine systems
(table 1).
GLYCEMIC CONTROL AND RISK FACTOR REDUCTION
The therapy of DAN can be difficult. It is therefore desirable to prevent this complication or, once
established, to slow disease progression.
Poor glucose control and vascular risk factors appear to be associated with the development of
diabetic neuropathy [2]. This observation is supported by the results of the EURODIAB study, which
found that the incidence of neuropathy was associated with poor glucose control, elevated
triglyceride levels, elevated body mass index, smoking, and hypertension [3]. However, the effects
of these risk factors on DAN progression are less clear. (See "Pathogenesis of diabetic
polyneuropathy", section on 'Risk factors'.)
Results from a large prospective observational study suggest that the incidence of DAN is declining
in type 1 diabetes, potentially reflecting improvements in the management of risk factors [4].
Furthermore, results from randomized trials suggest that intensive therapy reduces the onset and
progression of autonomic neuropathy:
● In the Diabetes Control and Complications Trial (DCCT), intensive therapy with insulin in
subjects with type 1 diabetes was found to reduce cardiovascular autonomic neuropathy
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incidence by 53 percent [5], and the benefit of prior intensive therapy was found to persist for
up to 14 years in these subjects [6].
● In individuals with type 2 diabetes, the potential efficacy of intensive combined therapy in
patients with type 2 diabetes and microalbuminuria was examined in the Steno type 2 trial [7].
In this prospective open-label trial, 160 patients were randomly assigned to standard or
multifactorial intensive therapy. The intensive regimen consisted of 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). DAN was present at baseline in 28 percent. At the end of the trial
(mean follow-up of 7.8 years), intensive therapy reduced both microvascular and
macrovascular disease [7]. In addition, intensive therapy reduced the rate of progression to
DAN (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) with a RR of 0.53 (95% CI 0.34-0.81) [8]. By contrast, there was no
slowing of progression of peripheral neuropathy. The details of the protocol and overall results
of this study are discussed elsewhere. (See "Overview of general medical care in nonpregnant
adults with diabetes mellitus", section on 'Multifactorial risk factor reduction'.)
In some cases, extremely rapid improvements in glycemic control may be associated with the
development of both autonomic and peripheral neuropathy in individuals with chronic hyperglycemia
[9]. Described as treatment-induced neuropathy of diabetes (TIND), the severity of neuropathy was
linked to the magnitude of change in the glycated hemoglobin A1C over three months. The risk of
neuropathic complications was approximately 10 percent if the hemoglobin A1C decreased by more
than 3 percentage points in three months, and exceeded 50 percent if the hemoglobin A1C
decreased by 5 or more points in three months. These findings suggest that in individuals with
chronic hyperglycemia, the achievement of a target hemoglobin A1C (as suggested by the DCCT
and Steno 2 trials) should be achieved gradually, and not exceed a 3-point change in hemoglobin
A1C in three months. TIND is 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.
Not all experts are convinced that overly rapid glycemic control or reduction in hemoglobin A1C can
cause neuropathy. The data supporting it come from uncontrolled and retrospective studies. The
prevalence of this problem is unknown, as the most recent data on the subject are from a specialty
tertiary referral center that may not reflect the general population. Although no evidence of the TIND
phenomenon was observed in data from prospective controlled trials such as the DCCT, there was
no measurement of small fiber neuropathy in such trials. Interestingly, "early worsening retinopathy"
was noted within the DCCT trials, a phenomenon also seen in individuals with TIND [10-13]. The
parallel development of retinopathy and neuropathy in acute glycemic control does suggest an
inflammatory microvascular process. An alternative explanation is that the worsening of neuropathy

is an epiphenomenon associated with but not caused by overly rapid glycemic control. To date, the
data have only suggested an association, not causation. Thus, prospective, controlled studies would
be helpful to resolve the relationship between glycemic control and the development of neuropathy.
CARDIOVASCULAR AUTONOMIC NEUROPATHY
Cardiovascular autonomic neuropathy (frequently abbreviated as CAN in the literature) is defined as

the impairment of autonomic control of the cardiovascular system [14]. It is associated with several
abnormalities in autonomic cardiovascular function. Subclinically, the disease is defined by
cardiovascular reflex testing, which may have prognostic implications. Clinically, the impairment in
autonomic function is associated with resting tachycardia, exercise intolerance, orthostatic
hypotension, syncope, intraoperative cardiovascular instability, silent myocardial infarction and
ischemia, and increased mortality [15].
The prevalence of cardiovascular autonomic neuropathy varies considerably, which reflects the
tests used, diagnostic criteria, and the population studied. The Screen-Detected Diabetes in Primary
Care (ADDITION) study reported an annual incidence of cardiovascular autonomic neuropathy of
1.8 percent in individuals with well-controlled diabetes [16]. This incidence is lower than in prior
reports, which may reflect improvements in early detection and risk factor reduction.
Tachycardia and exercise intolerance — The earliest clinical manifestation of cardiac autonomic
neuropathy may be a resting tachycardia. The increased resting heart rate is due to unopposed
cardiac sympathetic nerve activity. As the autonomic neuropathy progresses, the heart rate
gradually slows and in advanced cases will manifest as a fixed heart rate [17].
Exercise intolerance is usually due to impaired augmentation of cardiac output resulting from
inadequate sympathetic modulation. Persistent sinus tachycardia can occur and there may be no
variation in heart rate during activities that normally increase heart rate variability, such as deep
breathing and the Valsalva maneuver.
Considerable interest has centered upon the role of abnormal myocardial electrical activity in
arrhythmogenesis including, for example, QT prolongation and altered ventricular repolarization. In
the EURODIAB Type 1 Complications Study, the prevalence of QT prolongation was 16 percent
overall (11 percent in men, 21 percent in women) [18].
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
painless myocardial infarction and sudden death [19].

Orthostatic (postural) hypotension — Orthostatic hypotension is defined as a fall in blood

pressure of ≥20 mmHg systolic or ≥10 mmHg diastolic within three minutes of moving from a supine
position to an upright tilt table test or standing position [20]. 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. In its most severe disabling
form, orthostatic hypotension can cause significant drops in blood pressure resulting in syncope.
Retrospective data suggest that the presence of orthostatic hypotension is associated with
microvascular and macrovascular complications of diabetes [21]. The presence of orthostatic
hypotension in diabetes is associated with a significant increase in 10-year mortality [22,23].
Fortunately, this severity of orthostasis is rare, with the majority of patients having milder symptoms
that are amenable to therapeutic interventions.
Orthostasis with DAN may have the following hemodynamic characteristics:
● A loss of the diurnal variation in blood pressure, with supine hypertension occurring at night
[24]. 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 cardiovascular autonomic neuropathy, despite normal office
blood pressure measurements [25].
● It is possible that day-to-day variability of symptoms may be exacerbated by insulin therapy,

which has provoked hypotension in both diabetic [26] and nondiabetic [27] patients with
autonomic failure, although the clinical relevance of this to most patients with diabetes is not
known.
● Postprandial hypotension, whereby supine and standing systolic blood pressures may fall
profoundly after meals [28]. 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 [29,30]. A hematocrit should also be
checked, since anemia can result from erythropoietin deficiency secondary to renal
denervation, which may exacerbate orthostatic symptoms [31]. (See "Mechanisms, causes,
and evaluation of orthostatic hypotension".)
Postural tachycardia — A posture-induced tachycardia without a fall in blood pressure can result
in significant postural symptoms of lightheadedness, dizziness, and presyncope. Although postural
tachycardia syndrome (POTS) is a heterogeneous disorder, a diagnosis of POTS should not be
made in individuals with diabetes; a more appropriate diagnosis would be DAN. 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. This is very
different from a diagnosis of POTS. (See "Postural tachycardia syndrome".)
The distinction between POTS and postural tachycardia related to DAN is a critical point for
clinicians to be aware of, because many patients with diabetes are misdiagnosed with POTS. In
such cases, the importance of DAN and its relationship to glycemic control are often dismissed, and
the risks of morbidity and mortality associated with DAN are not typically considered.
Increased mortality — At least two meta-analyses of diabetic patients have found that
cardiovascular autonomic neuropathy is associated with an increased risk of mortality [32,33]. 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 [32]. 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 cardiovascular
autonomic neuropathy [33]. In the ACCORD trial, over a mean follow-up of 3.5 years, subjects with
cardiovascular autonomic neuropathy at baseline had overall mortality and cardiovascular mortality
rates that were approximately 1.6 to 2.1 and 1.9 to 3.0 times higher, respectively, compared with
those who did not have cardiovascular autonomic neuropathy, even after adjusting for baseline
cardiovascular risk factors [34].
Longitudinal studies of patients with DAN have typically found mortality rates over five years ranging
between 16 and 53 percent (mean of approximately 30 percent) [35-39]. Although the majority of
deaths result from associated macrovascular and microvascular disease, cardiorespiratory arrest
secondary to autonomic denervation has been implicated in some diabetic patients [39,40]. In the
EURODIAB Prospective Complications Study of over 2700 subjects with type 1 diabetes, an annual
mortality rate of 5 per 1000 person-years was reported, with peripheral neuropathy (standardized
hazard ratio [SHR] 1.88, 95% CI 1.06-3.35) and autonomic neuropathy (SHR 2.40, 95% CI 1.32-
4.36) being the most important risk markers for mortality [41].
There are several potential mechanisms by which DAN may increase mortality rates. First,
numerous studies have reported diminished perception of cardiac ischemia in individuals with
diabetes [42-44]. Second, there is reduced cardiovascular response to physiologic stressors such
as surgery or infection [45,46]. Third, there is an association between DAN and cardiac arrhythmias
due to alterations in QT interval [47]. Fourth, alterations in the balance between sympathetic and
parasympathetic systems have also been considered to be pro-arrhythmogenic [48]. Finally,
denervated myocardial tissue that has focal areas of reinnervation may be at increased risk for
arrhythmia [49].

Despite the evidence that DAN is associated with increased cardiac morbidity and mortality, sudden
cardiac death in patients with DAN may have a stronger relationship with atherosclerotic heart
disease and nephropathy than with DAN itself. 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 (151 with type 1) who were followed for over 15 years [50].
All 21 with sudden cardiac death had evidence of preceding severe atherosclerosis and myocardial
damage. After adjusting for electrocardiogram (ECG) abnormalities (including evolving or previous
Q wave changes indicative of myocardial infarction, left bundle branch block, or pacing) and stage
of nephropathy, autonomic dysfunction was not significantly associated with sudden cardiac death.
Conversely, 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 cardiovascular
autonomic neuropathy (as measured by decreased heart rate variability) in the patients with
nephropathy was an independent risk factor for cardiovascular morbidity and mortality [51]. Long-
term follow-up data from the DCCT and Epidemiology of Diabetes Interventions and Complications
(DCCT/EDIC) study also found that individuals with type 1 diabetes diagnosed with cardiovascular
autonomic neuropathy had a higher incidence of cardiovascular events over a 20-year period [52].
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 poorer prognosis [38].
Adverse cardiovascular events and silent ischemia — The presence of cardiovascular

autonomic neuropathy is associated with adverse cardiac outcomes and with silent ischemia, as
illustrated by the following studies:
● In the DIAD study, 522 patients with type 2 diabetes and no known or suspected coronary
artery disease at baseline had adenosine stress radionuclide myocardial perfusion imaging
studies, and silent ischemia was detected in 113 (22 percent) [53].
● 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
cardiovascular autonomic neuropathy than in those without cardiovascular autonomic
neuropathy (24 versus 7 percent) [54].
● A meta-analysis of 12 cross-sectional studies found that patients with cardiovascular autonomic

neuropathy had a significantly higher frequency of silent myocardial ischemia than patients
without cardiovascular autonomic neuropathy (pooled prevalence rate ratio 1.96, 95% CI 1.53-
2.51) [1].

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'.)
Adverse renal and cerebrovascular outcomes — The presence of cardiovascular autonomic

neuropathy may be associated with adverse renal and cerebrovascular outcomes, as suggested by
the following studies:
● In a prospective study of subjects with type 1 diabetes who were followed for over 14 years,
cardiovascular autonomic neuropathy and abnormal orthostatic diastolic blood pressure were
associated with the subsequent development of renal complications [55].
● In patients with type 2 diabetes enrolled in the longitudinal Appropriate Blood Pressure Control
in Diabetes (ABCD) trial, cardiovascular autonomic neuropathy was an independent risk factor
for the occurrence of stroke [56].
● In a 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 [57].
Sleep apnea — There is evidence that sleep apnea and respiratory arrest may contribute to the
increased mortality complicating DAN [58].
● Obstructive and/or central sleep apnea have been reported in 26 to 50 percent of subjects with
type 1 diabetes and DAN [59,60].
● The number of oxygen desaturation episodes during sleep correlate with DAN severity [61].
● In nonobese adults with DAN and postural hypotension, the frequency of obstructive sleep
apnea-hypopnea is >30 percent [62].
● In obese subjects, DAN is associated with an increased risk of obstructive sleep apnea
compared with other obese subjects with or without diabetes [63].
Diagnostic testing — Subclinical autonomic neuropathy is often found in association with distal
symmetric polyneuropathy and may only be detected by using cardiovascular reflex tests or tests of
peripheral sympathetic cholinergic function. 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 [64].
The selection of tests to evaluate autonomic function (table 3) has become reasonably standardized
and should include measures of parasympathetic, sympathetic adrenergic, and sympathetic

cholinergic function [65]. There is no evidence that any one test has diagnostic superiority
[14,66,67], although it is rare that a single test would be administered.
Some experts believe, based on data from a meta-analysis, that a confident diagnosis of
cardiovascular autonomic neuropathy requires abnormalities in more than one test, which evaluate
different limbs of the reflex arc [1,33]. This notion underlies proposed criteria for the diagnosis and
staging of cardiovascular autonomic neuropathy [14], which identify possible or early cardiovascular
autonomic neuropathy on the basis of one abnormal cardiovagal test [68], definite or confirmed
cardiovascular autonomic neuropathy on the basis of two abnormal cardiovagal tests [69], and
severe or advanced cardiovascular autonomic neuropathy by the additional presence of orthostatic
hypotension [70], which usually occurs late in the course of diabetes [66].
Direct assessment of cardiac sympathetic integrity is possible with radiolabeled analogues of

norepinephrine, which are actively taken up by the sympathetic nerve terminals of the heart. The
use of either 123-I-metaiodobenzylguanidine (MIBG, iobenguane I-123) or 11-C-hydroxyephedrine
scintigraphy permits noninvasive assessment of the pattern of sympathetic innervation of the heart
[71-74]. These tests have limited clinical utility because they are expensive and not widely available.
They have, however, provided useful information because of their greater sensitivity to detect more
subtle degrees of DAN than is possible by cardiovascular reflex testing:
● 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 [71,73].
● Diabetic patients with confirmed autonomic neuropathy have more pronounced abnormalities,
but the MIBG scans do not differentiate between minimal or severe DAN on reflex testing
[73,74].
● 11-C-hydroxyephedrine undergoes highly specific uptake and retention in sympathetic nerve

terminals [75,76] and, in comparison with MIBG, the images are less affected by non-neuronal
uptake [77] and tissue attenuation [78]. This characteristic facilitates the quantitative regional
characterization of sympathetic neuronal dysfunction and loss [79].
Treatment — Treatment is aimed primarily at prevention of disease progression. Modifiable risk

factors include hyperglycemia, smoking, hypertension, and hyperlipidemia [3,8,80]. There is
evidence that individuals who target these modifiable risk factors have minimal disease progression
over a three-year period of time [81]. 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 [82]. 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 medications utilized to achieve the glycemic
levels was responsible for the excess mortality.
Additional interventions should include a program 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 cardiovascular autonomic neuropathy [83,84]. However, a cardiac
stress study is suggested before this program is initiated. In individuals with type 2 diabetes, there is
a positive effect of weight loss on autonomic function, although it is unclear if this translates into a
clinically meaningful autonomic outcome [85]. However, the clinical benefits of weight loss across all
functional outcomes in type 2 diabetes support this clinical recommendation.
Beyond prevention of disease progression, patients with symptoms associated with DAN may
require additional therapeutic intervention. In those with sympathetic adrenergic dysfunction and
associated postural lightheadedness, the initial evaluation should include a detailed review and
removal of any medications that may worsen orthostatic hypotension (eg, antihypertensive
medications, antidepressant medications) [86]. Fluid intake should be increased and salt intake
liberalized.
Pharmacologic therapy has included:
● Increasing the plasma volume with the mineralocorticoid fludrocortisone (0.1 to 0.4 mg/day)
and a high-salt diet. This regimen may be helpful in more severe cases but can cause
hypertension or peripheral edema. Higher doses of fludrocortisone increase the risk of side
effects without evidence of additional improvement in symptoms, so are not recommended.
(See "Treatment of orthostatic and postprandial hypotension", section on 'Fludrocortisone'.)
● Midodrine, an alpha-adrenoreceptor agonist, has been used to raise blood pressure and reduce
symptoms of orthostatic hypotension [87,88]. Midodrine may cause severe supine
hypertension, so patients should not use midodrine within six hours of bedtime.
● Droxidopa, an orally administered norepinephrine prodrug, has received regulatory approval in

the United States and several Asian countries for treatment of symptoms associated with
neurogenic orthostatic hypotension [89]. There is little published experience with the use of
droxidopa in individuals with DAN and orthostatic hypotension.
● Octreotide (50 mcg three times daily, subcutaneously), a somatostatin analogue, may be
helpful in diabetic patients with refractory and symptomatic postural or postprandial
hypotension [28,30]. It acutely raises the blood pressure only in patients with autonomic failure
but tends to be poorly tolerated because it can exacerbate bowel dysfunction and cause

fluctuations in glycemic control. Treatment of anemia (including the judicious use of

erythropoietin), if present, may also be helpful [90].
Nonpharmacologic therapy includes (see "Treatment of orthostatic and postprandial hypotension",

section on 'Nonpharmacologic measures'):
● Making changes in posture slowly, ie, standing slowly in "stages."
● Elevation of the head of the bed by 10 to 20 degrees.
● Tensing the legs by crossing them while actively standing on both legs. In one report of patients
with autonomic neuropathy, this procedure raised the cardiac output by 16 percent and the
systemic blood pressure by 13 percent [91]. It can therefore minimize postural symptoms.
● Performing dorsiflexion of the feet or handgrip exercise before standing.
Measures aimed at increasing peripheral vascular tone (such as body stockings and gravity suits)
are often tried. They may, however, prove ineffective since blood pooling probably occurs in the
large splanchnic vascular bed [91]. Furthermore, in individuals with diabetic peripheral neuropathy,
pressure sores can occur with compression stockings and should be avoided.
Supine hypertension (usually at night) is characteristic of autonomic neuropathy and may reflect a
sympathetic/parasympathetic imbalance. Occasional patients have severe supine hypertension
combined with orthostatic hypotension. Their management is challenging, and the approach is
primarily guided by indirect evidence, clinical experience, and expert consensus [86]. Because of
safety issues, treatment of the hypotension with volume expansion (eg, fludrocortisone) and
sympathetic stimulation (eg, midodrine) usually takes precedence. However, this approach may
worsen their supine hypertension. In order to minimize daytime hypotension, short-acting
antihypertensive agents such as captopril, diltiazem, or verapamil can be administered before bed,
but patients need to be cautious about getting out of bed at night [86]. (See "Treatment of
orthostatic and postprandial hypotension", section on 'Supine hypertension'.)
PERIPHERAL SUDOMOTOR AND VASOMOTOR NEUROPATHY
The peripheral sympathetic cholinergic system regulates sweat function and thermoregulation. In a
length-dependent peripheral neuropathy there is loss of sweat function in a stocking and glove
distribution. Clinically, this typically manifests as a compensatory proximal hyperhidrosis [92].
Progressive loss of sudomotor function can result in thermoregulatory impairment and
hyperthermia. Peripheral autonomic nerve dysfunction may manifest as changes in the texture of
the skin, itching, edema, venous prominence, callus formation, loss of nails, and sweating
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abnormalities of the feet [14]. The association between peripheral autonomic denervation and the
resultant 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 [93]. This loss of sympathetic vascular innervation results in high
peripheral blood flow through arteriovenous shunts and abnormal local reflex vascular control [15].
Peripheral autonomic neuropathy may be a contributing factor for the development of foot ulceration
[94,95].
Peripheral autonomic neuropathy is thought to contribute to several other abnormalities:
● Symptoms such as aching, pulsation, tightness, cramping, dry skin, and pruritus.
● Peripheral edema, which is often associated with both foot ulceration and poor wound healing.
● The development of Charcot arthropathy (neuroarthropathy). In this condition, fractures can

occur either spontaneously or with minimal stress and are followed by progressive bone
disorganization with an increased risk of secondary ulceration (picture 1). (See "Diabetic
neuropathic arthropathy".)
Diagnostic testing — Quantitative sudomotor axon reflex testing (QSART) can be used for the
detection of early peripheral sympathetic denervation [96]. Galvanic skin response, also referred to
as the sympathetic skin response, offers a surrogate measure of sympathetic innervation in the
hands and feet [97]. This sympathetic skin response, however, is not a reliable measure of
sudomotor function and is frequently absent in the older population.
Skin biopsy assessment has been increasingly utilized as a measure of small fiber neuropathy [98].
In addition, the assessment of sweat gland nerve fiber density has been studied as a marker of
sudomotor neuropathy [99,100]. Despite growing acceptance as a useful marker of small fiber
neuropathy, the clinical role of skin intraepidermal nerve fiber assessment for the quantitation of
DAN remains unclear [101].
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 [102]. Impairment of local axon reflex dilatation is thought to reflect depletion of local
vasoactive neuropeptides. The role of alteration in the skin blood flow regulation in the development
of foot ulceration is being evaluated. Although peripheral autonomic neuropathy correlates poorly
with motor nerve dysfunction, motor nerve conduction velocity is decreased in patients with other
evidence of small fiber damage, particularly loss of thermal sensation.

Treatment — Therapy of peripheral autonomic neuropathy mainly centers on careful foot care to
prevent foot infection and ulceration. (See "Evaluation of the diabetic foot".)
Clinicians should avoid the temptation to treat a proximal compensatory hyperhidrosis because
treatment increases the risk of hyperthermia. Lifestyle modifications such as cooling garments and
avoidance of warm environments can improve symptoms.
GASTROINTESTINAL AUTONOMIC NEUROPATHY
The major gastrointestinal manifestations of DAN include gastroesophageal reflux disease (GERD),
gastroparesis, and chronic diarrhea. This section will briefly review these problems, and they are
discussed in greater detail elsewhere. (See "Diabetic autonomic neuropathy of the gastrointestinal
tract".)
GERD may be caused by autonomic neuropathy with decreased lower esophageal sphincter (LES)
pressure, increased number of transient LES relaxations due to hyperglycemia, impaired clearance
function of the tubular esophagus, or delayed gastric emptying. 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'.)
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. The
diagnosis of diabetic gastroparesis is established by evidence of delayed gastric emptying on
scintigraphy in the absence of an obstructing structural lesion in the stomach or small intestine by
endoscopy or imaging. Primary treatment of diabetic gastroparesis includes improved glycemic
control, dietary modification, and administration of antiemetic and prokinetic agents in symptomatic
patients. (See "Diabetic autonomic neuropathy of the gastrointestinal tract", section on
'Gastroparesis'.)
Diarrhea, and rarely steatorrhea, can occur in diabetics, particularly those with advanced disease.
The pathogenesis of diabetic diarrhea is unclear, but multiple underlying mechanisms may be
involved (table 4). 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. Management of diabetic diarrhea includes general
measures such as hydration and correction of electrolyte and nutrient deficiency, symptomatic
treatment of diarrhea with antidiarrheals, and treatment of the underlying cause (eg, small intestinal
bacterial overgrowth). (See "Diabetic autonomic neuropathy of the gastrointestinal tract", section on
'Diabetic diarrhea'.)
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) [103]. Symptoms may be present in up to 50 percent of individuals with diabetes [104].
Erectile dysfunction is associated with the development of cardiovascular disease [105]. Diabetic
bladder dysfunction initially presents as a decrease in the ability to sense a full bladder, secondary
to loss of autonomic afferent innervation [106]. This abnormality leads to infrequent urination, while
involvement of efferent nerves of the bladder results in incomplete emptying. These abnormalities
can result in recurrent urinary tract infections and overflow incontinence with dribbling and poor
urinary stream. Urinary incontinence is more common in type 1 diabetes. Lower urinary tract
symptoms were present in approximately 20 percent of men with type 1 diabetes at the 10-year
follow-up time point after completion of the Diabetes Control and Complications Trial (DCCT) [107].
In the same cohort, 38 percent of women reported urinary incontinence [108].
Sexual dysfunction is more common in women with diabetes compared with women without
diabetes [109,110]. However, the evidence for diabetes as an independent risk factor for sexual
dysfunction in women is equivocal; depression and anxiety appear to be more important predictors
of sexual dysfunction [109,111]. (See "Overview of sexual dysfunction in women: Epidemiology, risk
factors, and evaluation", section on 'Endocrine disorders'.)
In men, 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 secondary to autonomic neuropathy usually
occurs with other systemic manifestations of either somatic or autonomic neuropathy.
Treatment — Diabetic bladder dysfunction should initially be evaluated by a post-void residual, and
further evaluated by complete urodynamic testing if necessary. The initial treatment consists of
removal of medications that impair detrusor activity (anticholinergic agents, tricyclic antidepressants,
and calcium channel antagonists) or agents that increase urethral sphincter tone (alpha-1
adrenoreceptor agonists). Treatment initially consists of a strict voluntary urination schedule,
frequently coupled with the Crede maneuver. More advanced cases require intermittent
catheterization.
The multiple potential etiologies of erectile impotence make it difficult to treat each patient with a
standard protocol. An attempt should be made to establish the diagnosis. Potential causes include
alcohol consumption, endocrine dysfunction, depression, functional (psychogenic) disorder,

vascular disease, medications (iatrogenic), and autonomic neuropathy. (See "Evaluation of male
sexual dysfunction".)
Phosphodiesterase-5 (PDE-5) inhibitors are first-line therapy for erectile dysfunction in men with
diabetes. PDE-5 inhibitors are contraindicated in patients being treated with nitrates for heart
disease. (See "Treatment of male sexual dysfunction".)
The management of female sexual dysfunction should be tailored to the specific sexual concerns
and to underlying physical, psychological, and relationship factors. (See "Overview of sexual
dysfunction in women: Management".)
OTHER MANIFESTATIONS
A number of other symptoms may occur with DAN, including:
● Pupillary abnormalities may result in failure in dark adaptation and difficulties in night driving.
● 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 [112-
114]. In subjects with DAN, decreased counterregulatory catecholamine responses may
increase the risk for severe hypoglycemia [115]. (See "Physiologic response to hypoglycemia in
normal subjects and patients with diabetes mellitus", section on 'Hypoglycemia-associated
autonomic failure'.)
SCREENING
The American Diabetes Association recommends screening for DAN at the time of diagnosis of type
2 diabetes and five years after the diagnosis of type 1 diabetes [116].
● Screening should include a history and physical examination for signs of autonomic dysfunction
● Tests of heart rate variability may be indicated, including expiration-to-inspiration ratio,

response to the Valsalva maneuver, and response to standing (table 3)
● If initial screening is negative, a history and physical examination for signs of autonomic
dysfunction should be repeated annually

The identification of subclinical DAN is useful for risk stratification and for the individualization of
glycemic, lipid, and blood pressure targets.
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 5th to 6th 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 10th to 12th 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
● Diabetic autonomic neuropathy (DAN) is classified as subclinical or clinical depending upon the
presence or absence of symptoms. A wide spectrum of manifestations can affect many
different organs, including the cardiovascular, gastrointestinal, genitourinary, pupillary,
sudomotor, and neuroendocrine systems (table 1).
● Cardiovascular autonomic neuropathy is defined as the impairment of autonomic control of the

cardiovascular system. The prevalence of cardiovascular autonomic neuropathy varies
considerably, which reflects the tests used, diagnostic criteria, and the population studied.
Subclinically and clinically, the severity of the disease is defined by cardiovascular autonomic
reflex testing to assess parasympathetic and sympathetic adrenergic function. Clinically, the

impairment in autonomic function is associated with resting tachycardia, exercise intolerance,

orthostatic hypotension, intraoperative cardiovascular instability, silent myocardial infarction and
ischemia, and increased mortality. (See 'Cardiovascular autonomic neuropathy' above.)
● Peripheral autonomic nerve dysfunction may be manifest as changes in the texture of the skin,
itching, edema, venous prominence, callus formation, loss of nails, and sweating abnormalities
of the feet. Peripheral autonomic neuropathy may be a contributing factor for the development
of foot ulceration, and may contribute to several other abnormalities such as aching, pulsation,
tightness, cramping, dry skin and pruritus, peripheral edema, and the development of Charcot
arthropathy (neuroarthropathy). (See 'Peripheral sudomotor and vasomotor neuropathy'
above.)
● Gastrointestinal autonomic neuropathy can result in disorders of esophageal motility, gastric

emptying (gastroparesis), and intestinal function. (See 'Gastrointestinal autonomic neuropathy'
above.)
● Diabetic genitourinary autonomic neuropathy is responsible for several syndromes including

bladder dysfunction, retrograde ejaculation, erectile dysfunction, and dyspareunia. (See
'Genitourinary autonomic neuropathy' above.)
● The American Diabetes Association recommends screening for DAN at the time of diagnosis of
type 2 diabetes and five years after the diagnosis of type 1 diabetes. (See 'Screening' above.)
ACKNOWLEDGMENT
The editorial staff at UpToDate would like to acknowledge Martin Stevens, MD, who contributed to
an earlier version of this topic review.
Use of UpToDate is subject to the Subscription and License Agreement.
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9/28/2020 Diabetic autonomic neuropathy - UpToDate

Author: Christopher H Gibbons, MD, MMSc, FAAN

GLYCEMIC CONTROL AND RISK FACTOR REDUCTION

uptodate.searchbox.science/contents/diabetic-autonomic-neuropathy?search=diabetic neuropathy&source=search_result&selectedTitle=4~150&usa… 1/27

inflammatory microvascular process. An alternative explanation is that the worsening of neuropathy

CARDIOVASCULAR AUTONOMIC NEUROPATHY

Cardiovascular autonomic neuropathy (frequently abbreviated as CAN in the literature) is defined as

uptodate.searchbox.science/contents/diabetic-autonomic-neuropathy?search=diabetic neuropathy&source=search_result&selectedTitle=4~150&usa… 3/27

Orthostatic (postural) hypotension — Orthostatic hypotension is defined as a fall in blood

Orthostasis with DAN may have the following hemodynamic characteristics:

● It is possible that day-to-day variability of symptoms may be exacerbated by insulin therapy,

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Adverse cardiovascular events and silent ischemia — The presence of cardiovascular

● A meta-analysis of 12 cross-sectional studies found that patients with cardiovascular autonomic

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Adverse renal and cerebrovascular outcomes — The presence of cardiovascular autonomic

uptodate.searchbox.science/contents/diabetic-autonomic-neuropathy?search=diabetic neuropathy&source=search_result&selectedTitle=4~150&usa… 7/27

Direct assessment of cardiac sympathetic integrity is possible with radiolabeled analogues of

● 11-C-hydroxyephedrine undergoes highly specific uptake and retention in sympathetic nerve

Treatment — Treatment is aimed primarily at prevention of disease progression. Modifiable risk

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Pharmacologic therapy has included:

● Droxidopa, an orally administered norepinephrine prodrug, has received regulatory approval in

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fluctuations in glycemic control. Treatment of anemia (including the judicious use of

Nonpharmacologic therapy includes (see "Treatment of orthostatic and postprandial hypotension",

● Making changes in posture slowly, ie, standing slowly in "stages."

● Elevation of the head of the bed by 10 to 20 degrees.

● Performing dorsiflexion of the feet or handgrip exercise before standing.

PERIPHERAL SUDOMOTOR AND VASOMOTOR NEUROPATHY

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Peripheral autonomic neuropathy is thought to contribute to several other abnormalities:

● The development of Charcot arthropathy (neuroarthropathy). In this condition, fractures can

Measurement of vascular responses in the foot is an alternative method to detect peripheral

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GASTROINTESTINAL AUTONOMIC NEUROPATHY

GENITOURINARY AUTONOMIC NEUROPATHY

alcohol consumption, endocrine dysfunction, depression, functional (psychogenic) disorder,

A number of other symptoms may occur with DAN, including:

● Alterations in neuroendocrine responses attributed to DAN include a reduction in glucagon and

● Tests of heart rate variability may be indicated, including expiration-to-inspiration ratio,

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SOCIETY GUIDELINE LINKS

INFORMATION FOR PATIENTS

● Cardiovascular autonomic neuropathy is defined as the impairment of autonomic control of the

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impairment in autonomic function is associated with resting tachycardia, exercise intolerance,

● Gastrointestinal autonomic neuropathy can result in disorders of esophageal motility, gastric

● Diabetic genitourinary autonomic neuropathy is responsible for several syndromes including

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7. Gaede P, Vedel P, Larsen N, et al. Multifactorial intervention and cardiovascular disease in

8. Gæde P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on

9. Gibbons CH, Freeman R. Treatment-induced neuropathy of diabetes: an acute, iatrogenic

11. Chantelau E, Meyer-Schwickerath R. Reversion of 'early worsening' of diabetic retinopathy by

13. Chantelau E, Meyer-Schwickerath R, Klabe K. Downregulation of serum IGF-1 for treatment of

19. Zander E, Schulz B, Heinke P, et al. Importance of cardiovascular autonomic dysfunction in