Diabetic autonomic neuropathy

Author
Martin J Stevens, MD
Section Editors
Jeremy M Shefner, MD, PhD
David M Nathan, MD
Deputy Editor
John F Dashe, MD, PhD
Disclosures
Last literature review version 19.3: Fri Sep 30 00:00:00 GMT 2011 | This topic last
updated: Wed Oct 12 00:00:00 GMT 2011 (More)
INTRODUCTION Diabetic autonomic neuropathy (DAN) is classified as subclinical or
clinical depending upon the presence or absence of symptoms. A wide spectrum of
symptoms affecting many different organ systems can occur, including the cardiovascular,
gastrointestinal, genitourinary, pupillary, sudomotor and neuroendocrine systems (table 1).
GLYCEMIC CONTROL AND MULTIFACTORIAL RISK FACTOR REDUCTION The
therapy of diabetic autonomic neuropathy (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 [1]. 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
[2]. (See "Pathogenesis and prevention of diabetic polyneuropathy", section on 'Risk
factors'.)
However, 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 [3].
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
incidence by 53 percent [4], and the benefit of prior intensive therapy was found to persist
for up to 14 years in these subjects [5].
The potential efficacy of intensive combined therapy in patients with type 2 diabetes and
microalbuminuria was examined in the Steno type 2 trial [6]. 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 [6]. 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) [7]. In 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 medical care in adults with diabetes mellitus", section on 'Multifactorial
risk factor reduction'.)
CARDIOVASCULAR AUTONOMIC NEUROPATHY Cardiovascular autonomic neuropathy
is defined as the impairment of autonomic control of the cardiovascular system [8]. It is
associated with several abnormalities in autonomic cardiovascular function. The prevalence
of cardiovascular autonomic neuropathy varies considerably, which reflects the tests used,
diagnostic criteria, and the population studied. 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, intraoperative cardiovascular instability, silent
myocardial infarction and ischemia, and increased mortality [9].
Tachycardia and exercise intolerance 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 parasympathetic vagal tone, such as deep breathing and
the Valsalva maneuver. Sympathetic tone may be increased during the day and
parasympathetic tone decreased at night, which may predispose to nocturnal
arrhythmogenesis [10,11].
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) [12].
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 [13].
Postural hypotension Postural hypotension (defined as an orthostatic fall in systolic
blood pressure in excess of 20 mmHg) 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, postural
hypotension can be refractory to treatment and result in the victim becoming wheelchair
bound and unable to stand [14]. Fortunately, this severity of orthostasis is rare, with the
majority of patients having milder symptoms which are amenable to therapeutic
interventions.
Orthostasis with DAN has the following hemodynamic characteristics:

There is a loss of the diurnal variation in blood pressure, with supine hypertension
occurring at night [15]. 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 [16].

There is day-to-day variability of symptoms that may be exacerbated by insulin

therapy, which can provoke hypotension in both diabetic [17] and nondiabetic
[18] patients with autonomic failure.

In occasional patients, supine and standing systolic blood pressures may fall
profoundly after meals [14]. 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 [19,20]. A
hematocrit should also be checked, since anemia can result from erythropoietin
deficiency secondary to renal denervation, which may exacerbate orthostatic
symptoms [21]. (See "Mechanisms, causes, and evaluation of orthostatic and
postprandial hypotension".)

Postural tachycardia syndrome A posture-induced tachycardia without a fall in blood

pressure can result in similar symptoms as are experienced in postural hypotension. The
etiology is poorly understood. This condition is discussed separately. (See "Postural
tachycardia syndrome".)
Increased mortality At least two meta-analyses of diabetic patients have found that
cardiovascular autonomic neuropathy is associated with an increased risk of mortality
[22,23]. 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 [22]. 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 [23]. In the ACCORD
trial, over a mean follow-up of 3.5 years, the mortality rate for subjects with cardiovascular
autonomic neuropathy at baseline was approximately 1.6 to 2.1 times higher compared with
those who did not have cardiovascular autonomic neuropathy [24].
Longitudinal studies of patients with DAN have typically found mortality rates over five years
ranging between 16 and 53 percent (mean about 30 percent) [25-29]. 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 [29,30]. In the EURODIAB Prospective Complications Study of over 2700
subjects with type 1 diabetes, an annual mortality rate of 5 per 1,000 person-years was
reported, with peripheral neuropathy (standardized hazard ratio [SHR] 1.88, 95% CI 1.063.35) and autonomic neuropathy (SHR 2.40, 95% CI 1.32-4.36) being the most important
risk markers for mortality [31].
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 [32]. All 21 with sudden cardiac death had evidence of
preceding severe atherosclerosis and myocardial damage. After adjusting for 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 [33].
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 [28].
Adverse cardiovascular events and silent ischemia The presence of cardiovascular
autonomic neuropathy (CAN) 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)
[34].

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) [35]

A meta-analysis of 12 cross-sectional studies found that patients with CAN had a

significantly higher frequency of silent myocardial ischemia than patients without
CAN (pooled prevalence rate ratio 1.96, 95% CI 1.53-2.51) [36]

The mechanisms of silent myocardial ischemia are complex and not completely understood.
This issue is discussed separately. (See "Silent myocardial ischemia: Epidemiology and
pathogenesis", section on 'Pathophysiology and pathogenesis'.)
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 [37]

In patients with type 2 diabetes patients 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 [38]

In a study including 1523 subjects with diabetes followed for 16 years, higher resting
HR and lower HR variability and a higher resting heart rate increased the risk of
developing end-stage renal disease [39]

Sleep apnea There is evidence that sleep apnea and respiratory arrest may contribute to
the increased mortality complicating DAN [40].

Obstructive and/or central sleep apnea have been reported in 26 to 50 percent of

subjects with type 1 diabetes and DAN [41,42].

The number of oxygen desaturation episodes during sleep correlate with DAN
severity [43].

In nonobese adults with DAN and postural hypotension, the frequency of obstructive
sleep apnea-hypopnea is >30 percent [44]

In obese subjects, DAN is associated with an increased risk of obstructive sleep

apnea compared with other obese subjects with or without diabetes [45].

Diagnostic testing Subclinical autonomic neuropathy is usually found in association with

distal symmetric polyneuropathy and may only be detected by using cardiovascular reflex
tests or tests of peripheral sympathetic 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
deficits [46].
The choice of tests and their mode of analysis remains debatable [18]. Most studies
evaluate vagal regulation of the heart rate as reflected in the RR interval as measured by
determining heart rate variability. In general, for a confident diagnosis of cardiovascular
autonomic neuropathy, the patient should have abnormalities in more than one test, which
evaluate different limbs of the reflex arc [36]. Proposed criteria for the diagnosis and
staging of cardiovascular autonomic neuropathy are as follows [8]:

Possible or early cardiovascular autonomic neuropathy is identified by one abnormal

cardiovagal test

Definite or confirmed cardiovascular autonomic neuropathy requires two abnormal

cardiovagal tests

Severe or advanced cardiovascular autonomic neuropathy is identified by the

additional presence of orthostatic hypotension

The following table lists the techniques most commonly used in the diagnosis of DAN (table
3). The results of all reflex tests need to be interpreted with reference to age-matched
normal subjects [47].
Direct assessment of cardiac sympathetic integrity has become possible with the
introduction of 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) or 11-C-hydroxyephedrine scintigraphy permits noninvasive assessment of the
pattern of sympathetic innervation of the heart [48-51].

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 no evidence of DAN on cardiovascular reflex testing,

abnormalities in cardiac innervation have been found in 40 to 71 percent of patients
[48,50].

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 [50,51].

11-C-hydroxyephedrine undergoes highly specific uptake and retention in

sympathetic nerve terminals [52,53] and, in comparison to MIBG, the images are
less affected by non-neuronal uptake [54] and tissue attenuation [55]. This
characteristic facilitates the quantitative regional characterization of sympathetic
neuronal dysfunction and loss [56].

A statement of the American Diabetes Association in 2005 noted that a patient's history and
physical examination are ineffective for the early detection of cardiovascular autonomic
neuropathy and recommended tests that quantify the loss of heart rate variability be
performed to assess autonomic function (table 3) [57]. These heart rate variability tests are
more widely available than the more specialized tests discussed above. However, heart rate
variability tests do require standardized and accurate procedures to ensure accuracy and
reproducibility of results. (See"Heart rate variability: Technical aspects" and "Heart rate
variability: Uses other than after myocardial infarction" and "Evaluation of parasympathetic
nervous system function".)
Treatment Treatment should aim initially to improve overall cardiovascular fitness, since
there is evidence that an exercise program can improve both early and more advanced
cardiovascular autonomic neuropathy [58,59]. However, a cardiac stress study is suggested
before this program is initiated.
Mild postural symptoms can be treated by discontinuation of aggravating drugs (eg,
tranquilizers, antidepressants, and diuretics) and elevation of the head of the bed by up to
30 cm [60]. There are several other general recommendations that may be helpful:

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

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 [61]. It can therefore
minimize postural symptoms.

Performing dorsiflexion of the feet or handgrip exercise before standing.

The major form of medical therapy consists of 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.
(See "Treatment of orthostatic and postprandial hypotension".)
Other treatments that have been tried with variable success are atrial tachypacing, the
alpha adrenoreceptor agonist midodrine [62,63], the beta-blocker pindolol (which has
intrinsic
sympathomimetic
activity), fluoxetine [64],
or
intranasal
or
oral desmopressin (dDAVP) to reduce nocturnal vasopressin release. One study, for
example, evaluated the effect of fluoxetine (20 mg/day) in five patients with orthostatic
symptoms that were resistant to other treatments [64]. Two had marked and two had
moderate improvement in symptoms.
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 [61].
The somatostatin analogue octreotide (50 mcg three times daily, subcutaneously) may be
helpful in diabetic patients with refractory and symptomatic postural or postprandial
hypotension [14,20]. It acutely raises the blood pressure only in patients with autonomic
failure but tends to be poorly tolerated because it may exacerbate bowel dysfunction and
cause fluctuations in glycemic control. Treatment of anemia (including the judicious use of
EPO), if present, may also be helpful [65].
PERIPHERAL AUTONOMIC DYSFUNCTION 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 [8]. 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 [66]. This loss of sympathetic vascular innervation results in high peripheral
blood flow through arteriovenous shunts [67] and abnormal local reflex vascular control
[68].
Peripheral autonomic neuropathy may be a prerequisite for the development of foot
ulceration [69-71]. Animal studies have suggested that autonomic neuropathy alone can
precipitate plantar ulceration [72]. (See "Evaluation of the diabetic foot".) Diabetic patients
with neuropathic foot ulceration have greater impairment of heart rate variation than
patients with neuropathy with no foot ulcers [73].
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".)

High peripheral blood flow can cause weakening of the bones in the foot, thereby
predisposing to fractures.

Diagnostic testing Quantitative sudomotor axon reflex testing (QSART) is widely

utilized for the detection of early peripheral sympathetic denervation. Galvanic skin
responses offer a simple measure of the presence of sympathetic innervation in the hands
and feet [74]. This technique, however, does not reliably detect more subtle degrees of
sympathetic denervation. Sudomotor dysfunction may also be assessed using the indicator
plaster Neuropad test [8,75]. This test consists of a patch that is applied to the skin in order
to measure sweat production visually by a change in color from blue to pink that occurs with
absorption of water [76].
Despite growing acceptance as a useful marker of small fiber neuropathy, the role of skin
intraepidermal nerve fiber assessment for the quantitation of DAN remains unclear [77].
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 [68]. 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".)
A stepwise approach is indicated once neuropathy occurs that includes the following
measures:

Stop aggravating drugs

Foot elevation when sitting

Support stockings

Diuretics for edema

Screen for cardiovascular disease

Midodrine

Peripheral vascular denervation in diabetic neuropathy results in excess peripheral

circulation and arteriovenous shunting [67,78]. Neuropathic edema is distinguished from
that due to heart or renal failure by the history and by the lack of elevated jugular venous
pressure.

Sympathomimetic drugs, by reducing the shunting, may have a beneficial effect on edema
[79] and also on the high bone blood flow, which has been implicated in the pathogenesis of
Charcot arthropathy. Ephedrine (30 mg, three times a day) is an effective treatment for
neuropathic edema, although side effects (irritability, insomnia, hypertension and
tachycardia) may limit its use [79]. Midodrine (10 mg three times daily) is better tolerated
and is now the preferred choice. Ephedrine is no longer available in the United States but is
still available in Europe; it should not be used in patients with a history of cardiovascular
disease. Bisphosphonates may also be helpful in the acute management of the Charcot foot
[80].
GASTROINTESTINAL AUTONOMIC NEUROPATHY In diabetes, gastrointestinal
autonomic neuropathy can result in disorders of esophageal motility, gastric emptying
(gastroparesis), and intestinal function. This section will briefly review these problems, and
they are discussed in greater detail elsewhere. (See "Diabetic autonomic neuropathy of the
gastrointestinal tract".)
Clinical presentation The symptoms of gastrointestinal autonomic neuropathy vary with
the site of involvement:

Patients with esophageal motility disorders have dysphagia, retrosternal pain and
"heartburn." However, esophageal disease is rarely clinically important in diabetics,
even among those with autonomic neuropathy.

Patients with delayed gastric emptying have anorexia, nausea, vomiting, early
satiety, and postprandial fullness. The diagnosis of delayed gastric emptying is
discussed separately. (See "Etiology and diagnosis of delayed gastric emptying".)

Diabetic enteropathy reflects widespread gastrointestinal autonomic neuropathy.

Affected patients present with constipation, diarrhea, or even incontinence.
(See "Diabetic autonomic neuropathy of the gastrointestinal tract", section on
'Diabetic enteropathy'.)

Diabetic diarrhea is characterized by severe nocturnal exacerbations and may be secondary

to a variety of factors including abnormal intestinal motility; bacterial overgrowth;
pancreatic exocrine insufficiency; fecal incontinence due to anorectal dysfunction;
concurrent celiac disease, which occurs with increased frequency in diabetics; and/or bile
salt malabsorption. Both diarrhea and gastroparesis can adversely affect glycemic control.
Hyperglycemia can further perturb gastrointestinal function and result in dehydration
requiring parenteral fluid therapy. On the other hand, hypoglycemia may result from insulin
administration to a patient with impaired enteral delivery or delayed absorption.
(See "Diabetic autonomic neuropathy of the gastrointestinal tract".)
Treatment of gastroparesis Therapy varies with the type of symptoms that are
present, and there are a number of therapeutic options:

Dietary modifications (eg, hydration and nutrition)

Optimizing glycemic control

Medications

Occasional surgical therapy

The treatment of gastroparesis is discussed in greater detail separately. (See "Treatment of

delayed gastric emptying".) The American Gastroenterological Association (AGA) technical
review for the diagnosis and treatment of gastroparesis [81], as well as other AGA
guidelines,
can
be
accessed
through
the
AGA
web
site
at file://www.gastro.org/practice/medical-position-statements (accessed on September 20,
2010).
Treatment of enteropathy Treatment of diabetic autonomic enteropathy varies with the
causative factors responsible for the diarrhea. This may include loperamide for aberrant
motility, rotating antibiotics for bacterial overgrowth, and biofeedback for anorectal
dysfunction. Stool softeners are effective when constipation is the predominant complaint,
while increased dietary fiber may exacerbate the constipation. Finally, some patients with
intractable diarrhea have been reported to respond to octreotide.
The treatment of diabetic enteropathy is discussed in greater detail separately.
(See "Diabetic autonomic neuropathy of the gastrointestinal tract", section on 'Diabetic
enteropathy'.)
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)
[82]. Erectile dysfunction is associated with the development of cardiovascular disease [83].
Diabetic bladder dysfunction initially presents as a decrease in the ability to sense a full
bladder, secondary to loss of autonomic afferent innervation [84]. 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 presence in
approximately 20 percent of men with type 1 diabetes at the 10 year follow up time point
after DCCT close out [85]. In the same cohort, 38 percent of women reported urinary
incontinence [86].
Sexual problems are common in women with diabetes. In a study of 120 women with
diabetes, 27 percent reported sexual dysfunction compared with 15 percent of 180 agematched control women [87]. Decreased libido and reduced vaginal lubrication were more
common in the diabetic women (17 versus 9 percent for decreased libido; 14 versus 6
percent for reduced vaginal lubrication, respectively). Depression was a significant predictor
of sexual dysfunction in both groups.
In men, retrograde ejaculation reflects loss of coordinated internal sphincter closure with
external vesicle 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 be confirmed by complete urodynamic

testing. Treatment initially consists of a strict voluntary urination schedule, frequently
coupled with the Crede maneuver. Scheduled urinations should be coupled
with bethanechol (10 to 30 mg three times daily). More advanced cases require intermittent
catheterization, and in extreme cases, resection of the internal sphincter at the bladder
neck.
The multiple potential etiologies of erectile impotence make it difficult to treat each patient
with a standard protocol. An attempt should initially be made to establish the diagnosis:
psychogenic, endocrine, vascular, iatrogenic (secondary to drugs), or autonomic neuropathy.
(See"Evaluation of male sexual dysfunction".) Particularly in men with type 2 diabetes,
atherosclerosis with resulting low penile blood flow may be the causative lesion, a lesion
that can be diagnosed by measuring brachial-to-penile Doppler blood pressure ratios. Many
of the men respond to treatment with type 5 phosphodiesterase inhibition [88].
(See "Treatment of male sexual dysfunction".)
Retrograde ejaculation, a cause of infertility, has been treated with an antihistamine [89].
Treatment for female sexual dysfunction involves vaginal lubricants and estrogen creams.
OTHER MANIFESTATIONS A number of other symptoms may occur with DAN,
including:

Sweating abnormalities such as distal anhidrosis with central hyperhidrosis [90]; the
latter can occur in response to foods including cheese.

Pupillary abnormalities may result in failure in dark adaptation and difficulties in

night driving.

Alterations in neuroendocrine responses, which have been attributed to DAN include

a reduction in glucagon and epinephrine secretion in response to hypoglycemia,
thereby increasing the likelihood of hypoglycemic episodes [91]. In subjects with
DAN, decreased counterregulatory catecholamine responses may increase the risk
for severe hypoglycemia [92]. However, autonomic neuropathy does not appear to
be responsible for hypoglycemia unawareness. (See "Physiologic response to
hypoglycemia in normal subjects and patients with diabetes mellitus".)

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
[57].

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, it should be repeated annually

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