Diabetic autonomic neuropathy

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    Diabetic Autonomic Neuropathy


    Key Points

    • Diabetic autonomic neuropathy is dysfunction of the autonomic nervous system (parasympathetic, sympathetic, or both) in a patient with diabetes (type 1 or type 2) in whom other causes of neuropathy have been excluded r1
    • Both sympathetic and parasympathetic pathways may be affected (though not necessarily proportionately), resulting in inadequate and/or imbalanced autonomic control of heart rate, cardiac contractility, vasomotor function, gastrointestinal and genitourinary smooth muscle contractility, sweat gland secretion, and pupillary constriction r2
    • Symptoms vary depending on systems affected, but they may include lightheadedness on standing up or after eating; nausea; early satiety; abdominal pain or bloating; constipation and/or diarrhea; urinary hesitancy, frequency, urgency, incontinence, or retention; erectile dysfunction; and hyper- or hypohidrosis
    • Diagnostic testing depends on system involved
      • Cardiovascular autonomic reflex tests are the gold standard for diagnosing cardiovascular autonomic neuropathy; they consist of recording heart rate variability in response to maneuvers designed to elicit a sympathetic or parasympathetic response (eg, paced breathing, Valsalva maneuver) and measuring orthostatic changes in heart rate and blood pressure r3
      • Gastroparesis may be diagnosed by scintigraphic studies showing delayed gastric emptying r4
      • Bladder dysfunction may be evaluated by measurement of postvoid residual and urodynamic testing to determine whether bladder is hypotonic or overactive r5
      • Initial workup for erectile dysfunction involves distinction of psychogenic from organic causes
    • Treatment involves optimizing glycemic control and weight loss if indicated; otherwise management is symptom focused r4r6
      • Symptoms of orthostatic hypotension may be minimized by physiologic maneuvers; fludrocortisone, midodrine, and droxidopa can be used if conservative measures do not relieve symptoms adequately r1r7
      • Gastroparesis can be treated with metoclopramide or erythromycin, although tachyphylaxis limits efficacy; electrical stimulation is an alternative r8r9
      • Neurogenic (hypotonic) bladder may be treated with scheduled or assisted urination or intermittent catheterization r7
      • Symptoms due to hyperactive bladder (ie, frequency, urgency, incontinence) may respond to bladder training and Kegel exercises; if not, antimuscarinic agents and/or mirabegron may be effective r10r11r12
      • Erectile dysfunction that is organic in origin may respond to phosphodiesterase-5 inhibitors or prostaglandin E₁; these should be prescribed only after cardiovascular status has been evaluated and risk is deemed low r6r13
    • Prevention of diabetic autonomic neuropathy is primarily through optimizing glycemic control; people with type 2 diabetes benefit from additional behavioral and pharmacologic interventions aimed at other cardiovascular risk factors r1


    Clinical Clarification

    • Diabetic autonomic neuropathy is dysfunction of the autonomic nervous system (parasympathetic, sympathetic, or both) in a patient with diabetes (type 1 or type 2) in whom other causes of neuropathy have been excluded r1
    • May affect cardiovascular, gastrointestinal, urogenital, and sudomotor systems; pupillary reflexes; and awareness of hypoglycemia r1
    • May or may not be associated with other forms of diabetic neuropathy (eg, distal symmetrical polyneuropathy, mononeuropathy, radiculoplexopathy) r1
    • May occur as part of syndrome of treatment-induced neuropathy along with acute or subacute painful peripheral sensory neuropathy r14
      • Complication of aggressive glycemic control, particularly with hemoglobin A1C reduction of 1% or more per month


    • Diabetic autonomic neuropathy falls within the following larger classification of diabetic neuropathies: r1r15
      • Diffuse neuropathy
        • Diffuse symmetrical polyneuropathy
          • Small fiber predominant
          • Large fiber predominant
          • Mixed small and large fiber
        • Autonomic r16
          • Cardiovascular
            • Reduced heart rate variability
            • Resting tachycardia
            • Orthostatic hypotension
            • Sudden death
          • Gastrointestinal
            • Gastroparesis
            • Enteropathy
            • Colonic hypomotility
          • Urogenital
            • Cystopathy
            • Erectile dysfunction
            • Female sexual dysfunction
          • Sudomotor dysfunction
            • Distal or generalized hypohidrosis/anhidrosis
            • Gustatory hidrosis
          • Abnormal pupillary function
          • Hypoglycemia unawareness
        • Mononeuropathy
          • Isolated cranial or peripheral nerve
          • Mononeuropathy multiplex
        • Radiculopathy or polyradiculopathy
          • Radiculoplexus neuropathy
          • Thoracoabdominal neuropathy


    Clinical Presentation


    • Symptoms may be present when diabetes is diagnosed or may occur during the course r6
      • Likelihood of autonomic neuropathy increases with disease duration
    • Patients may have symptoms related to 1 system or several
      • Cardiovascular
        • Early stages may be completely asymptomatic and evident only by decreased heart rate variability with deep breathing r17
        • Orthostatic symptoms include lightheadedness, weakness, head and neck discomfort, blurred vision, tunnel vision or syncope after arising from a sitting or supine position or after prolonged standing; a history of falls may be elicited c1c2c3c4c5c6c7
          • Symptomatic episodes may occur more frequently in the morning, after large meals, or with fever r3
        • Poor exercise tolerance c8
      • Gastrointestinal r18
        • Gastroparesis: early satiety, abdominal pain, nausea, postprandial vomiting, bloating c9c10c11c12c13c14
        • Enteropathy or colon hypomotility: profuse watery diarrhea and/or constipation; fecal incontinence c15c16c17
      • Urogenital
        • Bladder dysfunction (hypotonic or overactive): urinary frequency, urgency, nocturia, hesitancy, slow stream or dribbling, incontinence c18c19c20c21c22c23c24c25c26c27
          • Urgency with or without incontinence, frequency, and nocturia suggest overactive rather than hypotonic bladder
        • Male sexual dysfunction: decreased libido, erectile dysfunction, abnormal ejaculation c28c29c30
          • Erectile dysfunction is defined as the inability to achieve or maintain an erection sufficient for satisfactory sexual performance
          • Key elements of history that suggest organic (eg, neuropathic, endocrine, vascular) rather than psychogenic cause are gradual onset over time and the absence of either nocturnal tumescence or morning erection
        • Female sexual dysfunction: decreased libido, inadequate lubrication, dyspareunia c31c32c33
      • Sudomotor
        • Hypo- or anhidrosis, initially in stocking-glove distribution; may progress proximally c34c35
          • Occasionally hyperhidrosis occurs; distribution may be proximal and central to offset distal hypo- or anhidrosis c36
        • Gustatory (postprandial) perspiration over head and upper torso, even after consuming nonspicy foods c37
      • Pupillary
        • Generally asymptomatic; may experience difficulty in accommodating to rapidly changing light c38
    • Other aspects of medical history suggestive of autonomic dysfunction
      • Asymptomatic hypoglycemia c39
        • May not experience or perceive physiologic responses to hypoglycemia (ie, palpitations, tremor, lightheadedness, diaphoresis) c40c41c42c43
      • Silent myocardial ischemia c44
        • Absence of anginal pain during documented ischemia or infarction
      • Abnormal cardiovascular and thermoregulatory effects of general anesthesia
        • Hypotension, hypothermia c45c46
      • Frequent urinary tract infections c47
        • May signal the presence of neurogenic bladder
    • Medication review may identify confounding or exacerbating factors
      • ACE inhibitors, β-blockers, or diuretics may exacerbate orthostatic symptoms
      • Metformin commonly causes diarrhea
      • Anticholinergics, tricyclic antidepressants, opioids, and some hypoglycemic agents can cause constipation
      • Anticholinergics may precipitate bladder symptoms (eg, weak stream, retention)
      • Antihypertensives, antidepressants, and sedatives may contribute to erectile dysfunction

    Physical examination

    • Cardiovascular
      • Resting tachycardia may be present c48
      • Test each patient for orthostatic changes in heart rate and blood pressure by measuring in seated or supine position and repeating immediately and at intervals after patient stands up
        • Orthostatic hypotension c49
          • Decrease in systolic blood pressure of more than 20 mm Hg or decrease in diastolic blood pressure of more than 10 mm Hg, measured 3 minutes after patient stands up from a 5-minute period in seated or supine position r3
          • Compensatory rise in heart rate may be absent r1
        • Rarely, postural orthostatic tachycardia may be observed in the absence of a decrease in blood pressure r19c50
          • Increase in heart rate of 30 beats per minute or more (40 beats per minute or more for patients younger than 19 years) within 10 minutes or more after patient stands up from seated or supine position
      • Hypertension, especially in supine position, is seen in some patients c51
    • Gastrointestinal
      • Abdominal examination findings are usually unremarkable
      • A gastric splash may sometimes be elicited c52
      • Hardened stool may be palpable in colon or on rectal examination c53
      • Poor anal sphincter tone and absent or diminished anal reflexes may be noted c54c55
    • Urogenital
      • Distended bladder may be noted on palpation and/or percussion c56
    • Sudomotor
      • Dry skin in stocking-glove, lower body, or generalized distribution c57
      • Fissures may be seen on plantar surfaces c58
    • Pupillary
      • Sluggish or absent pupillary light reflex c59

    Causes and Risk Factors


    • Causes of diabetic autonomic neuropathy are poorly understood. Hyperglycemia, alterations in insulin signaling, and (when present) dyslipidemia result in direct cellular damage as well as induction of inflammatory cytokines and other secondary agents of cell damage r20c60c61c62c63
      • May occur in type 1 and type 2 diabetes
    • Both sympathetic and parasympathetic pathways may be affected (though not necessarily proportionately), resulting in inadequate and/or imbalanced autonomic control of heart rate, cardiac contractility, vasomotor function, gastrointestinal and genitourinary smooth muscle contractility, sweat gland secretion, and pupillary constriction r2

    Risk factors and/or associations

    • Data are conflicting; may be more common in females r21r22c66c67
    • Various genes have been associated with predisposition to development or progression of diabetic neuropathy; most of these relate to peripheral neuropathy, but preliminary evidence suggests that sequence variation of TCF7L2 and GSTM1/GSTT1 is associated with cardiac autonomic neuropathy r23c68c69
    Other risk factors/associations
    • General
      • Risk increases with duration of diabetes r2c70
      • May be associated with initiation of insulin or oral hypoglycemic agents with abrupt improvement in glycemic control r24c71
        • Particularly with hemoglobin A1C reduction of 1% or more per month r14
        • Typically occurs within 2 to 8 weeks after medication initiation or dietary change r14
      • Tight glycemic control and resulting hypoglycemia may trigger autonomic dysfunction that paradoxically results in hypoglycemia unawareness; if hypoglycemia is unrecognized and repeated, glucose threshold at which symptoms are perceived may lower progressively r24c72c73
    • Cardiovascular autonomic neuropathy
      • Risk increases with older age; longer duration of diabetes; poor or unstable glycemic control; comorbid diabetic polyneuropathy, retinopathy, or nephropathy; hypertension; and other cardiovascular risk factors r25
      • Poor glycemic control is the primary risk factor in patients with type 1 diabetes r25c74
      • Poor glycemic control, hypertension, dyslipidemia, and obesity are risk factors in patients with type 2 diabetes r25c75c76c77c78

    Diagnostic Procedures

    Primary diagnostic tools

    • For a patient with diabetes, the diagnosis may be suggested by history and physical examination findings r6c79
    • There are no laboratory studies for the diagnosis of diabetic autonomic neuropathy per se, but baseline and serial measures of glycemic control (ie, serum glucose level, hemoglobin A1C) are important in optimizing glucose management to prevent development or slow progression of neuropathy r6c80c81
      • Other studies may be recommended to evaluate for complications of neuropathies, for common comorbid factors, and for other causes and types of neuropathy (eg, distal sensory neuropathy of diabetes, nutritional deficiencies)
    • Further testing is available and may be indicated to assess suspected cardiac, gastrointestinal, and genitourinary neuropathies
      • Cardiac autonomic neuropathy r3
        • Cardiovascular autonomic reflex tests are the gold standard for diagnosing cardiovascular autonomic neuropathy; they consist of recording heart rate variability in response to maneuvers designed to elicit a sympathetic or parasympathetic response c82
          • Heart rate variation during deep breathing, Valsalva maneuver, and orthostatic maneuvers is a reflection of parasympathetic activity
            • At least 1 of these is recommended, in addition to orthostatic blood pressure testing on physical examination, for diagnosis and monitoring of cardiac autonomic neuropathy
            • Reduced heart rate variation is the earliest manifestation of cardiac autonomic neuropathy r26
          • Blood pressure response to Valsalva maneuver and to standing or tilt testing is a measure of sympathetic function
        • Ambulatory blood pressure monitoring over a 24-hour period is not routinely recommended but may be helpful in identifying the following other situational manifestations of cardiovascular autonomic dysfunction: r3c83
          • Absence of normal (10% or more) nocturnal decrease in blood pressure r22
          • Supine hypertension r27
          • Postprandial hypotension r27
        • Obtain an ECG to assess QTc interval and signs of cardiac ischemia r3c84
      • Gastrointestinal neuropathy
        • Gastroparesis r28
          • Studies are appropriate for patients with symptoms (ie, bloating, nausea, prolonged postprandial sense of fullness) or patients with unexplained poor or erratic glycemic control
            • Gastroparesis alters timing and extent of carbohydrate and medication absorption
          • Excluding mechanical gastric outlet obstruction and peptic ulcer disease (generally with upper endoscopy and sometimes with imaging studies) is necessary before specific testing for and diagnosis of gastroparesis r17r29
          • Gastric emptying is most commonly measured by scintigraphy, which is considered the gold standard test for gastroparesis r1r29r30c85
          • Gastric emptying (¹³C octanoic acid) breath test assessment is a generally accepted alternative to scintigraphy r17r29r30c86c87
          • Wireless motility capsule is another potential option r30
        • Intestinal motility r28
          • Measurement of transit time may be indicated for patients with diabetes who have chronic constipation
          • A wireless motility capsule provides ongoing information about transit time through the stomach and intestines as well as luminal pressures and pH
      • Genitourinary neuropathy
        • Bladder dysfunction
          • Measure postvoid residual urine volume by either ultrasonography or catheterization r7c88c89
          • Uroflowmetry can be combined with postvoid residual estimation to provide a noninvasive assessment of urine flow rate, voided volume, intermittent flow, hesitancy, and residual urine r5
          • For patients with high postvoid residual volume, invasive urodynamic testing may be indicated to differentiate from bladder outlet obstruction r31
          • Urodynamic testing can also be helpful in evaluating incontinence when clinical information does not clearly distinguish overactive bladder (involuntary micturition due to overactive detrusor muscle) from hypotonic (neurogenic) bladder (overflow incontinence) or when treatment of presumed overactive bladder has failed r7
            • American Urological Association discourages routine urodynamic testing, cystoscopy, and imaging in patients with typical symptoms of overactive bladder (ie, urgency, urgency incontinence, frequency, nocturia) r32
          • Measure creatinine and BUN levels to assess for diabetic nephropathy or effects of chronic retention r7
        • Erectile dysfunction d1
          • For patients with suspected organic (versus psychogenic) condition
            • Because erectile dysfunction is a marker for cardiovascular disease, cardiovascular status must be assessed to determine whether vascular disease may be a contributing factor and to evaluate sexual activity risk and use of phosphodiesterase-5 inhibitors r13
            • Measure morning testosterone levels to identify or rule out hypogonadism as a contributing factor r13c90
      • Sudomotor neuropathy
        • Usually does not require testing in clinical (nonresearch) setting r1
      • Pupillary neuropathy
        • No testing required beyond demonstration of reduced light reflex on physical examination r4


    • Creatinine and BUN levels r7c91c92
      • In patients with neurogenic bladder, elevated levels may reflect complications of urinary retention, with or without associated diabetic nephropathy
    • Serum total testosterone levels r13c93
      • Draw fasting blood sample before 11 AM
      • Normative ranges for testosterone levels vary among laboratories and assays; clinicians should use the lower reference limit for healthy young adult males established in the laboratory used
      • Low levels may indicate hypogonadism as a factor contributing to erectile dysfunction
    • Hemoglobin A1C level c94
      • Key parameter for monitoring overall pattern of glycemic control
      • Optimization may retard or prevent development of autonomic neuropathy r1


    • Gastric scintigraphy r4c95
      • Gold standard for diagnosis of gastroparesis is measurement of gastric emptying with scintigraphy after food intake r17c96
      • Scintigraphic images are taken at 15-minute intervals after consumption of digestible solids labeled with a radioisotope
        • Normal rates of stomach emptying are as follows: r24
          • 37% to 90% of meal remains at 1 hour
          • 30% to 60% remains at 2 hours
          • 0% to 10% remains at 4 hours
      • Fasting glucose level should be less than 275 mg/dL on day of test because hyperglycemia slows gastric emptying r28
      • Patients should avoid taking promotility agents, anticholinergics, and opioids for several days before the procedure and should not smoke or consume alcohol on day of test because these factors will alter results r28

    Functional testing

    • ¹³C breath test r28r33c97
      • Nonradiographic measure of gastric emptying
      • Patient consumes ¹³C radio-labeled meal that is absorbed in the duodenum, converted into ¹³CO₂ in the liver, and released during respiration; end-tidal breath samples are collected and analyzed by mass spectrometry to plot course of gastric emptying
    • Wireless motility capsule r28c98
      • A small device swallowed by the patient that detects and transmits information on pH, temperature, and luminal pressure
      • A decrease in temperature to environmental levels and/or recovery of the device in stool marks total transit time
      • Changes in pH provide adjunctive information on gastric emptying time
      • Number of contractions and other motility indices are reduced in patients with gastrointestinal neuropathy
    • Postvoid residual c99
      • After the patient voids as completely as possible, the remaining urine volume is estimated by ultrasonography, or a bladder catheter is placed and the collected urine is measured
        • A volume of 50 to 100 mL or more is considered abnormal and suggests neurogenic bladder or outlet obstruction r31
      • Can be combined with uroflowmetry to provide a noninvasive assessment of urine flow rate, voided volume, intermittent flow, hesitancy, and residual urine r5


    Cardiovascular autonomic reflex testing r15c100
    General explanation r2
    • Patient is asked to perform various maneuvers designed to elicit a sympathetic or parasympathetic response while being monitored by continuous ECG
      • Deep breathing (6 breaths per minute)
      • Valsalva maneuver by exhalation into a manometer at force to achieve a pressure of 40 mm Hg for 15 seconds
      • Standing from a seated or supine position
    • Variation in heart rate response can be assessed from tracings
    • Patients should refrain from tobacco and caffeine for 2 hours and strenuous physical activity for 24 hours before the test; ideally, drugs that might alter results should also be withheld (eg, vasodilators, diuretics, antihistamines, antidepressants) r27
    • Patients with diabetes who have unexplained tachycardia, orthostatic hypotension, or prolonged QTc interval
    • After myocardial infarction in a patient with diabetes r34
    • Valsalva maneuver is contraindicated for patients with proliferative retinopathy
    Interpretation of results r2
    • Deep breathing
      • A heart rate difference of more than 15 beats per minute between inspiration and expiration is normal; a difference of less than 10 beats per minute is abnormal
        • Specificity of about 80% r34
      • Distance between QRS complexes (R-R interval) is measured during inspiration and expiration, and a ratio is calculated; normal values are those exceeding a threshold defined by age (in years)
        • 20 to 24: 1.17
        • 25 to 29: 1.15
        • 30 to 34: 1.13
        • 35 to 39: 1.12
        • 40 to 44: 1.10
        • 45 to 49: 1.08
        • 50 to 54: 1.07
        • 55 to 59: 1.06
        • 60 to 64: 1.04
        • 65 to 69: 1.03
        • 70 to 75: 1.02
    • Valsalva maneuver c101
      • Ratio of longest to shortest R-R interval is calculated; a value exceeding 1.2 is normal
    • Standing
      • Normal ratio of R-R intervals measured 30 beats (or the longest observed R-R intervalr4) and 15 beats (or the shortest observed R-R intervalr4) after standing exceeds 1.03
    Urodynamic studies c102
    General explanation
    • Videourodynamics is the gold standard procedure for urodynamic investigation of neurourologic dysfunction r5
      • Combines filling cystometry and pressure flow studies to quantify bladder filling function; bladder capacity and compliance; bladder sensation; urine flow rates; and bladder, urethral, and abdominal pressures during micturition r5
      • Bladder is filled naturally or by instillation of saline through a bladder catheter
      • Detrusor muscle activity may be monitored through electromyography c103
    • Symptoms that are bothersome to patient (eg, frequency, incontinence) and unresponsive to conservative measures
    • High postvoid residual
    • Assessment of risk for complications (eg, frequent urinary tract infections, obstructive uropathy)
    Interpretation of results
    • Large bladder capacity, poor detrusor function, and slow flow rates suggest hypotonic (neurogenic) bladder
    • Involuntary detrusor muscle contractions with urgency suggest hyperactive bladder
    • Obstructive patterns can also be detected (eg, prostatic hypertrophy, pelvic organ prolapse) and often coexist with diabetic neuropathy

    Other diagnostic tools

    • ECG c104
      • 12-Lead ECG may show previously unrecognized ischemia, which can be multifactorial in origin; contributing factors may include impaired vasomotor activity due to cardiac autonomic neuropathy as well as atherosclerotic coronary artery disease r35
      • Prolongation of QTc interval may be an indicator of cardiac autonomic neuropathy
        • 460 milliseconds or more in adult females and 450 milliseconds or more in adult males r3

    Differential Diagnosis

    Most common

    • By definition, diabetic autonomic neuropathy occurs in patients with diabetes (or less commonly, prediabetes); differential diagnoses below therefore assume a context of diabetes and the possibility of a second disease that must be differentiated from a neuropathic complication of diabetes
    • For cardiac autonomic neuropathy
      • Hyperthyroidism c105d2
        • Clinical state induced by excessive production and secretion of thyroid hormones by an overactive thyroid gland
        • Like autonomic neuropathy, may result in resting tachycardia and subjective palpitations
        • Patients with hyperthyroidism may experience tremulousness, unusual heat intolerance, and diaphoresis; there may be associated neck pain, sore throat, and, in Graves disease, eye irritation
        • Differentiation can be made based on thyroid examination findings (may be enlarged and/or nodular and may be tender); in Graves disease, eyelid retraction and proptosis are common findings. Definitive diagnosis is based on results of thyroid function test
      • Anemia c106
        • Low circulating RBC mass or hemoglobin level
        • Significant pallor of skin, mucous membranes, and nail beds may suggest anemia rather than (or in addition to) cardiac autonomic neuropathy
        • Anemia is diagnosed by measurement of hemoglobin and hematocrit
      • Tachyarrhythmias
        • Rapid atrial fibrillation or atrial flutter c107c108c109
        • As with cardiac autonomic neuropathy, resting tachycardia is characteristic; orthostatic abnormalities may be present
        • Tachyarrhythmias may be short lived and episodic
        • Distinction is made by ECG
      • Intravascular volume depletion
        • May be caused by dehydration or acute blood loss c110
        • Like cardiac autonomic neuropathy, may be characterized by resting tachycardia and orthostatic hypotension
        • Distinction is usually apparent from history and context
      • Heart failure c111d3
        • Inadequate cardiac pump function
        • Like cardiac autonomic neuropathy, may be characterized by resting tachycardia
        • Physical examination findings of jugular vein distention, auscultatory rales, and a third heart sound suggest heart failure and are not characteristic of diabetic cardiac autonomic neuropathy alone
        • Distinction can be confirmed by imaging (ie, chest radiograph, echocardiogram)
      • Parkinson disease c112d4
        • A progressive neurodegenerative disease caused by inadequate dopamine activity in the basal ganglia
        • As with advanced diabetic autonomic neuropathy, orthostatic hypotension is a common feature
        • Usually evident by distinctive physical examination findings including bradykinesia, rigidity, resting tremor, and gait impairment
    • For gastrointestinal autonomic neuropathy
      • Gastroparesis
        • Gastric outlet obstruction c113
          • May be due to malignant or inflammatory mass
          • Like gastroparesis, may cause early satiety, nausea, bloating, a sense of fullness
          • Unlike gastroparesis, there may be focal tenderness or a palpable mass on examination
          • Differentiation is made by findings on upper endoscopy or imaging
      • Irritable bowel disease c114d5
        • A functional syndrome of abdominal pain, constipation, and/or diarrhea
        • Nocturnal diarrhea may occur in diabetic gastrointestinal neuropathy; it is unusual in irritable bowel disease
        • There is no definitive diagnostic test for irritable bowel disease, which is defined clinically (Rome criteria). In a patient with diabetes, it may be difficult to distinguish irritable bowel from diabetic autonomic neuropathy
        • Abnormal results of intestinal motility studies (eg, wireless motility capsule) may differentiate diabetic gastrointestinal neuropathy from irritable bowel syndrome
      • Inflammatory bowel disease c115c116c117
        • Idiopathic, chronic inflammatory disease
        • As with diabetic autonomic neuropathy, may present with abdominal pain, diarrhea, and fecal incontinence
          • May be limited to the colon (ulcerative colitis) ord6
          • May involve any part of the gastrointestinal tract (Crohn disease) d7
        • Tends to be more episodic than diabetic autonomic neuropathy and is commonly characterized by bloody stool and systemic manifestations (eg, fever, weight loss)
        • Differentiation is based on clinical presentation and characteristic findings on endoscopy and biopsy
    • For genitourinary autonomic neuropathy
      • For bladder dysfunction
        • Bladder outlet obstruction c118
          • Can result from a variety of causes, including bladder or prostate tumors, bladder stones, benign prostatic hypertrophy, sphincter dysfunction, and urethral stricture d8
          • Like neurogenic bladder, these may cause symptoms of frequency, urgency, decreased flow, and small volume void
          • In patients with diabetes, may be clinically indistinguishable from neurogenic bladder
          • Differentiation can be made through cystoscopy and urodynamic testing
        • Urinary tract infection c119d9
          • Common symptoms of both urinary tract infection and neurogenic bladder can include urinary frequency, urgency, altered flow, and incontinence
          • Unlike uncomplicated neurogenic bladder, urinary tract infection symptoms may include fever, hematuria, and dysuria
          • Urinary tract infection is diagnosed based on urine dipstick result indicating leukocyte esterase and nitrite positivity, microscopic urinalysis indicating presence of WBCs and bacteria, and urine culture showing bacterial growth
          • Urinary tract infection may complicate neurogenic bladder
        • Medication effect c120
          • Anticholinergic medications can cause urinary retention, which may be mistaken for neurogenic bladder
          • Sympathomimetic medications can cause urinary frequency and retention, which may be mistaken for neurogenic bladder
          • Diagnosis can be differentiated by a period of drug abstinence
      • For erectile dysfunction c121d1
        • Erectile dysfunction is defined as the inability to maintain an erection sufficient for intercourse; there is no true differential diagnosis, although there are many possible causes
        • Evaluation focuses on defining the underlying cause of patient's erectile dysfunction, primarily determining whether it is due to organic or psychogenic causes
          • Psychogenic erectile dysfunction is suspected based on historical features and the absence of an organic cause; supported by the presence of nocturnal and spontaneous morning erection
          • Organic erectile dysfunction is suspected based on risk factors, history, and results of physical examination; it may be due to vascular disease, hormonal imbalance, and/or neuropathy or to other physical abnormalities (eg, Peyronie disease, penile malignancy)
    • For sudomotor dysfunction
      • Defined as abnormality in sweating, resulting in hyper- or hypohidrosis; either or both can be seen in patients with diabetic autonomic neuropathy, albeit in different distributions
      • Does not, therefore, have a differential diagnosis but may present as a manifestation of a number of syndromes associated with autonomic dysfunction
      • Usually not the predominant presenting symptom and usually noted secondarily in association with a constellation of dominant findings that define the syndrome



    • Maintain optimal glycemic control to slow further progression r4
    • Management of focal symptoms through lifestyle changes, mechanical or physiologic measures, and pharmacologic intervention r6


    Admission criteria

    • Diagnosis and management of diabetic autonomic neuropathy occur primarily in an outpatient setting
    • Occasionally, severe complications stemming from autonomic neuropathy (eg, syncope, falls, labile glucose levels due to erratic gastrointestinal function, urosepsis) may warrant admission

    Recommendations for specialist referral r36

    • Referral to a neurologist for aid in diagnostic testing and optimal management is appropriate for all patients with suspected diabetic autonomic neuropathy
    • Although routine cardiac autonomic reflex tests can be done by a primary care practitioner, patients are commonly referred to a cardiologist or neurologist for testing
      • If testing is done in the primary care setting, refer patients with abnormal results to a cardiologist for assessment of cardiovascular disease and exercise tolerance and for optimal management of cardiovascular risk factors
        • After approval by a cardiology consultant, refer to a physiatrist for appropriate exercise program
      • Refer patients with erectile dysfunction to a cardiologist for cardiovascular status evaluation, assessment of fitness for sexual activity, and safety of phosphodiesterase-5 inhibitors
    • Refer patients with gastroparesis or severe constipation to a gastroenterologist for upper or lower endoscopy, as indicated, to coordinate gastric emptying studies and aid in management
    • Refer patients with significant bladder symptoms to a urologist to consider cystoscopy and urodynamic studies
    • Patients with erectile dysfunction may require referral to a urologist if further testing is needed to determine cause or if first line treatment efforts are unsuccessful or contraindicated
    • All patients with autonomic diabetic neuropathy should be managed in conjunction with an endocrinologist to optimize glycemic control

    Treatment Options

    Maintain optimal glycemic control; minimize cardiovascular risk factors

    • American Diabetes Association recommends a target hemoglobin A1C of less than 7% as appropriate for most nonpregnant adults; a lower level may be acceptable if it can be safely achieved without significant hypoglycemia r37
    • Maintaining near-normal glycemic control from early in the course of diabetes has been shown to delay or prevent the development of diabetic cardiac autonomic neuropathy in patients with type 1 diabetes and may modestly slow progression in those with type 2 diabetes r17
      • Diabetes Control and Complications Trial followed up 1441 people with insulin-dependent diabetes managed on either a conventional regimen or an intensive glycemic control program; over the 9-year trial, fewer cardiac reflex abnormalities developed in patients in intensive glycemic control arm. Incomplete bladder emptying was also less common in the intensive glycemic control arm r38
      • During follow-up for an additional 13 to 14 years, the frequency of cardiac reflex abnormalities grew in each group, but differences between the groups persisted, with lower rates in the intensive treatment group r39
      • Intensive glycemic control may be more effective in type 1 than type 2 diabetes regarding development and/or progression of neuropathy r2
      • Among patients with type 2 diabetes participating in the Action to Control Cardiovascular Risk in Diabetes trial, those who received intensive glycemic therapy had substantially reduced risk of cardiovascular autonomic neuropathy; this was especially true among those without a history of cardiovascular disease at baseline r40r41

    System-specific management

    • In most cases, there are no guideline-driven, stepwise treatment regimens; rather, approach should be individualized, generally beginning with most conservative measures and adding or modifying therapy as needed
    • Cardiac
      • General
        • Weight loss if indicated
          • Several studies have shown improvement in cardiac autonomic function in people with obesity both with and without diabetes after significant weight loss r42r43
        • Manage cardiovascular risk factors r41
          • Intensive blood pressure control substantially reduced risk of cardiovascular autonomic neuropathy for patients with type 2 diabetes r40
        • Moderate-intensity aerobic exercise training
          • Several systematic reviews have shown beneficial effects on functional capacity, metabolic control, circulating inflammatory markers, and cardiac autonomic activity r44r45r46
        • Pharmacologic agents
          • ACE inhibitors,r48angiotensin receptor blockers,r49 and cardioselective β-blockersr50 have all been shown to improve cardiac reflex parameters in patients with diabetic autonomic neuropathy and have been used alone or in various combinations r34r47
          • There is evidence that sodium-glucose transporter 2 inhibitors exert a modulatory effect on cardiovascular autonomic function; however, these do not have an established role in management r25
          • Avoid use of β-adrenergic blocking agents that have intrinsic sympathomimetic activity (eg, pindolol) and tricyclic antidepressants due to their risk of cardiac arrhythmias r36
      • Orthostatic hypotension r17r51
        • Mechanical and physiologic measures to prevent or counteract decrease in blood pressure r3
          • For patients whose orthostatic symptoms occur in association with a meal, advise smaller, more frequent meals
        • Maintenance of intravascular volume through increased intake of fluid and salt (if not contraindicated) r1
        • Physical conditioning
        • Avoid elevation in body temperature
        • Head-up position while sleeping
        • Compression garments
        • Pharmaceutical support (eg, mineralocorticoids, oral vasopressors) may be necessary for patients with symptoms who do not respond to conservative measures. Care must be taken to avoid supine hypertension; instruct patients to take these medications only when upright position is intended (eg, daytime) r1
          • Fludrocortisone may aid in maintaining intravascular volume, although efficacy data are lacking; according to a recent Cochrane review, evidence of effects of fludrocortisone on blood pressure, orthostatic symptoms, or unfavorable occurrences in people with orthostatic hypotension and diabetes is of very limited certainty r52
          • Midodrine increases peripheral vascular tone through adrenergic stimulation; concomitant use of fludrocortisone increases the effect r53
          • Droxidopa is metabolized to norepinephrine with resulting increase in vascular tone r54
          • Pyridostigmine has been used off-label r51
          • Octreotide may be helpful for patients with postprandial orthostatic hypotension r55
    • Gastrointestinal
      • Gastroparesis r9r17
        • Frequent, small meals, rather than a conventional meal schedule, may prevent sensation of fullness and bloating
        • Promotility drugs may improve transit time and reduce symptoms; these include dopamine antagonists (eg, metoclopramide, domperidone) and erythromycin
          • Metoclopramide is the only agent approved by the FDA for treatment of gastroparesis r56
            • Should be used only for severe cases and not for more than 12 weeks owing to potential for serious adverse effects r17
          • Domperidone is available in the United States as an investigational drug per the FDA; commercially available in Canada, Europe, Australia, and other countries
            • Recommended for symptom management in patients with gastroparesis, if domperidone is approved r30
            • Associated with increased risk of sudden cardiac death; avoid concurrent use with medicines that prolong QTc interval r57
          • Erythromycin: can be used off-label but is effective only for short-term treatment owing to tachyphylaxis r17
        • Avoidance and/or discontinuation of drugs with antimotility effects, such as opioids, anticholinergic agents, tricyclic antidepressants, GLP-1RAs, pramlintide, and marijuana may also enhance intestinal motility r17r26
        • Gastric electrical stimulation via a surgically implanted device has FDA approval, but the limited data available do not support it as an effective therapy for diabetic gastroparesis r17
          • More effective for relief of nausea and vomiting than for other symptoms r58
        • Patients with severe, refractory symptoms may require placement of gastrostomy or jejunostomy or procedures such as partial gastrectomy, pyloroplasty, gastrojejunostomy, or gastric peroral endoscopic myotomy r56
      • Diarrhea
        • Trial of dietary restriction, avoiding soluble fiber, lactose, and glutenr6
        • Loperamide: avoid opiates or other constipating agents r9
        • Because stasis-induced bacterial overgrowth has been postulated as a cause, some authorities recommend antibiotics (eg, metronidazole)r59
        • Clonidine may slow colonic transit time by opposing adrenergic stimulation r55
        • Cholestyramine or octreotide may be effective in patients who do not respond to other measures r55
      • Constipation
        • High-fiber diet with addition of bulking agents (eg, psyllium) r6
        • Osmotic laxatives (eg, milk of magnesia) r6
    • Genitourinary
      • Treatment of urinary symptoms depends on suspected mechanism
        • If possible, discontinue any medications that contribute to genitourinary dysfunction such as anticholinergic agents and tricyclic antidepressants r60
        • Neurogenic (hypotonic) bladder r7
          • Recommend techniques such as scheduled voiding and triggered voiding r5
          • Assisted bladder emptying using Valsalva maneuver or manual pressure over bladder (Credé maneuver) is not recommended unless urodynamic studies show that intravesical pressure remains within safe limits r5
            • Valsalva and Credé maneuvers cause increased intravesical pressure and reflex sphincter contraction; resulting high pressures further damage the lower urinary tract r5
          • Intermittent catheterization may be necessary if other measures are ineffective
          • Bethanechol may be considered in some cases of overflow incontinence r60
        • Overactive bladder r32
          • Lifestyle modifications include attention to timing of fluid intake and avoidance of bladder irritants
          • Weight reduction, if indicated, can reduce stress and urgency incontinence
          • Bladder training to increase time between voids
          • Pelvic floor (Kegel) exercises
            • With or without additional bladder training, shown to improve symptoms in females with incontinence r11
          • Pharmacologic agents may be added if conservative measures are not sufficient
            • Antimuscarinic agents such as oxybutynin, tolterodine, trospium chloride, fesoterodine, solifenacin, and darifenacin are first line pharmacologic agents; they do not appear to differ in efficacy
              • Note that these drugs may cause or exacerbate constipation and gastroparesis
              • Antimuscarinic agents are contraindicated for patients with narrow-angle glaucoma
            • Mirabegron, a β-3 agonist, is also effective in reducing incontinence and frequency of voiding and is recommended as another first line option; evidence suggests efficacy similar to that of antimuscarinic agents r10
          • Botulinum toxin, electrical stimulation of posterior tibial nerve, and various surgical procedures may be options for patients who do not respond to other measures r32
            • Although the mechanism is unclear, electrical stimulation of the posterior tibial nerve appears to achieve durable success in most patients who meet criteria (ie, failure of noninvasive measures, ability to comply with treatment and follow-up schedule) r32
            • Injection of bladder with botulinum toxin reduces incontinence symptoms due to overactive bladder in more than 50% of treated patients with diabetes, and improvement typically lasts for more than 6 months r32
              • Patients require regular postvoid residual evaluation and must be able to perform self-catheterization if needed
      • Erectile dysfunction r6r17
        • If psychogenic factors and hypogonadism have been excluded and if cardiovascular risk is deemed acceptable, pharmacotherapy with oral phosphodiesterase-5 inhibitors or intraurethral or intracorporeal prostaglandin E₁ is recommended
        • When medication is ineffective, vacuum devices and penile prostheses are alternative options
    • Sudomotor dysfunction does not usually require treatment, although associated skin dryness should be treated with emollients to avoid fissuring

    Drug therapy

    • For cardiac autonomic neuropathy
      • General
        • ACE inhibitor
          • Quinapril c122
            • Quinapril Hydrochloride Oral tablet; Adults: 20 mg PO once daily.
        • Angiotensin receptor blocker
          • Losartan c123
            • Losartan Potassium Oral tablet; Adults: 100 mg PO once daily.
        • Cardioselective β-blockers
          • Bisoprolol c124
            • Bisoprolol Fumarate Oral tablet; Adults: 5 mg PO once daily.
          • Metoprolol c125
            • Metoprolol Succinate Oral tablet, extended-release; Adults: 100 mg PO once daily.
      • For orthostatic hypotension
        • Mineralocorticoid
          • Fludrocortisone c126
            • Fludrocortisone Acetate Oral tablet; Adults: 0.05 or 0.1 mg PO once daily, initially. Usual dose: 0.05 to 0.2 mg/day.
        • Sympathomimetic
          • Midodrine c127
            • Midodrine Hydrochloride Oral tablet; Adults: 10 mg PO 3 times daily, every 3 to 4 hours during daytime hours. Max single dose: 20 mg/dose. Usual Max: 30 mg/day.
        • Vasopressor
          • Droxidopa c128
            • Droxidopa Oral capsule; Adults: 100 mg PO 3 times daily, initially. Titrate dose by 100 mg 3 times daily every 24 to 48 hours to symptomatic response. Max: 1,800 mg/day.
        • Somatostatin analogue
          • Octreotide c129
            • Octreotide Acetate Solution for injection; Adults: 12.5 to 25 mcg subcutaneously 3 times daily, initially. Titrate dose to symptomatic response. Dose range: 0.2 to 1.6 mcg/kg/dose.
    • For gastrointestinal neuropathy
      • Gastroparesis
        • Dopamine antagonists
          • Metoclopramide c130
            • Oral
              • Metoclopramide Hydrochloride Oral tablet; Adults: 5 to 10 mg PO 2 to 4 times daily for 2 to 8 weeks. Max: 40 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
            • Intranasal
              • Metoclopramide Nasal spray, solution; Adults: 15 mg in 1 nostril 4 times daily for 2 to 8 weeks.
          • Domperidone c131
            • Domperidone Oral tablet; Adults: 10 mg PO 4 times daily, initially. Dose range: 10 to 30 mg PO 4 times daily. r30r61
        • Motilin receptor agonist
          • Erythromycin c132
            • Erythromycin Ethylsuccinate Oral suspension; Adults: 250 to 500 mg PO 3 times daily, 30 minutes before meals.
      • Diarrhea
        • Antidiarrheal agent
          • Loperamide c133
            • Loperamide Hydrochloride Oral tablet; Adults: 4 mg PO once, then 2 mg PO after each subsequent unformed stool; then reduce to meet individual requirements. Usual dose: 4 to 8 mg/day. Max: 16 mg/day.
        • Polymeric resin
          • Cholestyramine c134
            • Cholestyramine Powder for Oral suspension; Adults: 2 to 4 g PO 2 to 4 times daily.
        • Centrally acting α-1 agonist
          • Clonidine c135
            • Clonidine Hydrochloride Oral tablet; Adults: 0.1 mg PO every 12 hours, initially. Increase dose over 3 days up to 0.5 to 0.6 mg PO every 12 hours.
        • Somatostatin analogue
          • Octreotide c136
            • Octreotide Acetate Solution for injection; Adults: 50 to 100 mcg subcutaneously every 8 to 12 hours.
        • Antibiotics
          • Metronidazole c137
            • Metronidazole Oral tablet; Adults: 250 mg PO 3 times daily for 7 to 10 days.
    • Urogenital neuropathy
      • Hypotonic bladder
        • Parasympathomimetic
          • Bethanechol c138
            • Bethanechol Chloride Oral tablet; Adults: 5 to 10 mg PO every hour, initially, until satisfactory response occurs or a maximum of 50 mg has been given. Usual dose: 10 to 50 mg PO 3 to 4 times daily.
      • Overactive bladder
        • Antimuscarinic agents
          • Darifenacin c139
            • Darifenacin Oral tablet, extended-release; Adults: 7.5 mg PO once daily, initially. May increase the dose to 15 mg PO once daily after 2 weeks based on clinical response. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
          • Fesoterodine c140
            • Fesoterodine fumarate Oral tablet, extended-release; Adults: 4 mg PO once daily, initially. May increase the dose to 8 mg PO once daily based on clinical response and tolerability. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
          • Oxybutynin c141
            • Oxybutynin Chloride Oral tablet; Adults: 5 mg PO 2 to 3 times daily. Max: 5 mg PO 4 times daily.
            • Oxybutynin Chloride Oral tablet; Older Adults: 2.5 mg PO 2 to 3 times daily, initially. Usual dose: 5 mg PO 2 to 3 times daily. Max: 5 mg PO 4 times daily.
          • Solifenacin c142
            • Solifenacin Succinate Oral tablet; Adults: 5 mg PO once daily, initially. May increase the dose to 10 mg PO once daily based on tolerability. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
          • Tolterodine c143
            • Tolterodine Tartrate Oral tablet; Adults: 2 mg PO twice daily. May decrease dose to 1 mg PO twice daily based on clinical response and tolerability. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
          • Trospium chloride c144
            • Trospium Chloride Oral tablet; Adults 18 to 74 years: 20 mg PO twice daily.
            • Trospium Chloride Oral tablet; Adults 75 years and older: 20 mg PO twice daily. May decrease dose to 20 mg PO once daily based on tolerability.
        • β-3 agonist
          • Mirabegron c145c146
            • Mirabegron Oral tablet, extended-release; Adults: 25 mg PO once daily, initially. May increase the dose to 50 mg PO once daily after 4 to 8 weeks if needed.
      • Erectile dysfunction
        • Phosphodiesterase-5 inhibitors
          • Avanafil c147
            • Avanafil Oral tablet; Adults: 100 mg PO as needed as early as 15 minutes before anticipated sexual activity. May decrease the dose to 50 mg or increase the dose to 200 mg PO as needed as early as 15 minutes before sexual activity. Max: 1 dose/day and 200 mg/dose. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
          • Sildenafil c148
            • Sildenafil Citrate Oral tablet; Adults: 50 mg PO as needed approximately 1 hour before anticipated sexual activity. May decrease the dose to 25 mg or increase the dose to 100 mg PO as needed approximately 1 hour before sexual activity. The dose may be taken from 30 minutes to 4 hours before sexual activity. Max: 1 dose/day and 100 mg/dose. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
            • Sildenafil Citrate Oral tablet; Older Adults: 25 mg PO as needed approximately 1 hour before anticipated sexual activity. May increase the dose up to 100 mg PO as needed approximately 1 hour before sexual activity. The dose may be taken from 30 minutes to 4 hours before sexual activity. Max: 1 dose/day and 100 mg/dose. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
          • Tadalafil c149
            • Tadalafil Oral tablet; Adults: 10 mg PO as needed before anticipated sexual activity. May reduce dose to 5 mg or increase the dose to 20 mg PO as needed before anticipated sexual activity. Max: 1 dose/day and 20 mg/dose. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
          • Vardenafil c150
            • Vardenafil Hydrochloride Oral tablet; Adults: 10 mg PO as needed approximately 60 minutes before anticipated sexual activity. May decrease dose to 5 mg or increase dose to 20 mg PO as needed approximately 60 minutes before anticipated sexual activity. Max: 1 dose/day and 20 mg/dose. Coadministration of certain drugs may need to be avoided or vardenafil dosage adjustments may be necessary; review drug interactions.
            • Vardenafil Hydrochloride Oral tablet; Older Adults: 5 mg PO as needed approximately 60 minutes before anticipated sexual activity. May increase dose up to 20 mg PO as needed approximately 60 minutes before anticipated sexual activity. Max: 1 dose/day and 20 mg/dose. Coadministration of certain drugs may need to be avoided or vardenafil dosage adjustments may be necessary; review drug interactions.
        • Prostaglandin E
          • Alprostadil c151
            • Alprostadil Urethral suppository; Adults: 125 or 250 mcg by intraurethral insertion, initially, as a single dose as needed. Adjust the dose on separate occasions in a stepwise manner until an erection that is sufficient for sexual intercourse is achieved. Dose range: 125 to 1,000 mcg/dose. Max: 2 doses/24 hours.

    Nondrug and supportive care

    For patients with obesity, weight loss is beneficial for overall diabetes management and has been shown to reverse progression of cardiac autonomic neuropathyr62r63 as well as incontinence associated with overactive bladderr32

    • May be achieved through conventional means (ie, calorie restriction, increased physical activity) or bariatric surgery r64c152c153c154c155

    Exercise training r6c156c157

    • Graded exercise program designed and supervised by a physiatrist

    Physiologic maneuvers to mitigate effects of orthostatic hypotension

    • Use of support garments (ie, legs, abdomen), dorsiflexion leg exercises to enhance muscle pump activity, avoidance of sudden postural changes or prolonged standing, and raising head of bed r3c158c159c160c161c162
    • Maintain fluid intake of 2 to 3 L/day if not contraindicated r27c163

    Dietary modification including frequent small meals, low in fat (less than 40 g/day)r55 and fiber, may relieve symptoms of gastroparesis r9c164c165c166

    Behavioral modifications may be helpful for patients with bladder dysfunction, including the following: r7

    • Minimize fluid intake late in the day and before bedtime c167c168
    • Avoid alcohol (a diuretic) and caffeine (an irritant) c169c170
    • Scheduled voiding (eg, every few hours) c171

    Other bladder management techniques r7

    • Pelvic muscle (Kegel) exercises c172
      • Instruction and supervision should be provided by a practitioner trained to teach the method
    • Bladder training r12c173
      • Establish schedule of initial intervals based on bladder diary
      • Increase interval by 15 to 30 minutes per week until desired/convenient schedule is achieved
      • Relaxation and distraction techniques are used to relieve urgency
    • Intermittent straight catheterization c174

    Vacuum devices for erectile dysfunction r65

    • Consist of a closed-end cylinder, vacuum pump, and constriction ring c175
    • Vacuum chamber generates negative pressure within the penis, increasing blood flow and resulting in sinusoidal distention
    • Constriction rings are then applied to maintain the erection

    Patients with extensive anhidrosis should be educated about risks of hyperthermia and heat stroke r55c176

    Gastric electrical stimulation c177
    General explanation
    • Battery-driven pulse generator is implanted in abdominal wall to deliver electrical stimulation to smooth muscle of stomach via electrodes implanted in gastric wall
    • Nausea and vomiting associated with diabetic gastroparesis that is refractory to other measures
    Intravesical injection of botulinum toxin r66c178
    General explanation
    • Botulinum toxin (usually onabotulinumtoxin A) is injected at various points in the bladder, most commonly the detrusor muscle
    • Persistent incontinence due to overactive bladder despite behavioral and pharmacologic treatment
    • Acute urinary tract infection
    • Patients with chronic urinary retention who are not catheterized
    • Urinary retention requiring intermittent straight catheterization
    • Systemic effects of the toxin (ie, dysphagia, eyelid weakness, visual impairment, limb and/or trunk weakness)
    Interpretation of results
    • Maximum effects are not seen for 7 to 10 days; patients taking anticholinergic medications should continue those drugs for 5 days following the procedure
    • Pooled data showed achievement of complete continence in 42% to 87% of patients, a decrease in urinary incontinence in 60% to 80%, a 40% to 60% decrease in urinary frequency, and a 35% to 65% increase in quality of life measures
    • Results last 6 to 12 months, depending on dosage used
    Electrical stimulation of posterior tibial nerve c179
    General explanation
    • Application of low-level electrical current applied to posterior tibial nerve via needle electrode r12
    • Treatment consists of 30 minutes weekly for 12 weeks or more; some protocols involve periodic follow-up maintenance treatments r32
    • Persistent incontinence due to overactive bladder despite behavioral and pharmacologic treatment
    Implantation of penile prosthesis c180
    General explanation
    • Surgical implantation of a semirigid or hydraulic (inflatable) device
    • Organic erectile dysfunction refractory to medical therapy
    • Cardiac function inadequate for safe sexual activity

    Special populations

    • Pregnant patients should avoid or discontinue ACE inhibitors and angiotensin receptor blockers
    • Diabetic cardiac autonomic neuropathy is associated with increased perioperative morbidity and mortality; screen for this in patients with diabetes undergoing elective surgery r36


    • No specific guidelines exist for frequency of monitoring established diabetic autonomic neuropathy; in view of its negative effect on prognosis, it is prudent to inquire about existing and potential symptoms at each follow-up visit c181

    Complications and Prognosis


    • Autonomic neuropathy is a complication of diabetes; further complications are sometimes difficult to attribute solely to the neuropathy, but there are some characteristic associations for which the presence of autonomic neuropathy appears to be an independent risk factor
      • Cardiovascular complications r67r68
        • Labile blood pressure c182
          • Normal diurnal variation in blood pressure may be disrupted in cardiac autonomic neuropathy, resulting in the absence of a normal dip in nocturnal blood pressure
            • Associated with left ventricular hypertrophy r3
          • Some patients experience blood pressure elevations in the supine position at any time of day (supine hypertension)
            • Management of supine hypertension and orthostatic hypotension can be challenging; scheduled use of short-acting antihypertensives (eg, captopril) at night coupled with daytime use of short-acting sympathomimetics or vasopressors may be reasonable r27
          • Lack of normal hemodynamic response increases risk of profound and refractory hypotension during anesthesia r27
        • Cardiomyopathy c183
          • Systolic and diastolic dysfunction have been associated with cardiac autonomic neuropathy even in the absence of atherosclerotic coronary disease r2
        • Silent myocardial infarction r3c184
          • Absence of pain with myocardial ischemia may be multifactorial but is associated with the presence of cardiac autonomic neuropathy
          • May delay recognition and treatment, contributing to worse prognosis of myocardial infarction for patients with diabetes
        • Increased mortality after myocardial infarction c185
          • Decreased heart rate variability is a marker of mortality risk r2
        • Sudden death r2c186
          • Cardiac autonomic neuropathy is associated with prolonged QTc interval and malignant arrhythmias
        • Stroke c187
          • Presence of cardiac autonomic neuropathy has been correlated with increased risk of ischemic stroke r4r27
      • Gastrointestinal complications r19
        • Bezoars may form as a result of poor gastrointestinal motility c188
        • Gastritis and/or gastric ulcers may result from gastroparesis c189c190
        • Poor gastrointestinal motility alters the dynamics of food absorption, complicating glycemic control; absorption of oral medication may also be affected
      • Urogenital complications
        • Urinary retention owing to neurogenic bladder predisposes to urinary tract infection, including pyelonephritis r4c191c192c193c194
        • Frequent infections as well as urodynamic abnormalities may contribute to renal dysfunction
        • Presence of autonomic neuropathy—specifically cardiac and pupillary—appears to be an independent predictor of progressive diabetic nephropathy r3
      • Sudomotor complications
        • Anhidrosis involving extensive body surface may predispose to heat stroke r55c195
      • Other complications r68
        • Cardiac autonomic neuropathy may accelerate other diabetic complications such as medial artery calcinosis, foot ulcers, and Charcot joints


    • Symptomatic autonomic dysfunction is an indicator of poor prognosis r2
      • 25% to 50% mortality within 5 to 10 years of diagnosis
      • 5-year mortality is approximately 3 times higher than in people with diabetes who do not have autonomic dysfunction r69
    • Cardiac autonomic neuropathy, in particular, is associated with increased risk for cardiovascular events and increased all-cause mortality r70

    Screening and Prevention


    At-risk populations

    • Screen annually for symptoms and signs of autonomic neuropathy, starting at time of diagnosis of type 2 diabetes and 5 years after the diagnosis of type 1 diabetes r6r17
      • Relevant symptoms and signs include orthostatic dizziness, syncope, orthostatic hypotension, resting tachycardia, and peripheral dryness or cracking of skin
    • Evaluate for symptoms and signs of autonomic neuropathy in patients with other microvascular complications, particularly kidney disease and diabetic peripheral neuropathy r17r51
    • Consider screening for cardiovascular autonomic neuropathy in patients with diabetic kidney disease, diabetic peripheral neuropathy, 2 or more cardiovascular risk factors, hypoglycemia unawareness, high glucose variability, heart failure, or autonomic symptoms r71
      • Also recommended for patients undergoing surgery or before starting a new physical fitness program r27

    Screening tests r6r34

    • Clinical history
    • Cardiac reflex tests
      • Heart rate variability with deep breathing c196
      • Heart rate response to Valsalva maneuver c197
      • Orthostatic blood pressure and heart rate measurements c198


    • American Diabetes Association recommends optimizing glycemic control as early as possible for patients with type 1 diabetes and adopting a multifactorial approach that includes aggressive management of cardiovascular risks as well as good glycemic control for patients with type 2 diabetes r1
      • Intensive glucose control resulted in a 45% reduction in the development of cardiac autonomic neuropathy in patients with type 1 diabetes in the Diabetes Control and Complications Trial r38
      • Intensive glycemic control alone is less effective in preventing neuropathy in type 2 diabetes; the Steno-2 Study showed a near 60% reduction in risk for cardiac autonomic neuropathy through a multipronged program of good glycemic control and specific measures aimed at reducing other cardiac risk factors over a period of almost 8 years. These measures include the following: r41c199
        • Low-fat diet (less than 30% daily calorie intake from fat, less than 10% of daily calorie intake from fatty acids) c200
        • Light to moderate exercise (30 minutes 3-5 times per week) c201c202
        • ACE inhibitor or angiotensin receptor blocker (regardless of blood pressure) c203c204
        • Daily low-dose aspirin c205
        • Treatment of dyslipidemia c206
        • Smoking cessation if applicable c207
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