History

• 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
    • Orthostatic symptoms: 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 ^r17
    • Gastroparesis: early satiety, abdominal pain, nausea, postprandial vomiting, bloating ^{c9c10c11c12c13c14}
    • Enteropathy/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 suggests 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 all patients for orthostatic changes in heart rate and blood pressure by measuring in seated or supine position and repeating immediately and at intervals after standing up
    • Orthostatic hypotension ^c49
      • Drop in systolic blood pressure of more than 20 mm Hg or drop in diastolic blood pressure of more than 10 mm Hg, measured 3 minutes after standing 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 drop in blood pressure ^r18c50
      • Increase in heart rate of 30 beats per minute or more (40 beats per minute or more for age younger than 19 years) within 10 minutes or more after standing 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 in plantar surfaces ^c58
• Pupillary
  • Sluggish or absent pupillary light reflex ^c59

Causes

• 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 ^{r19c60c61c62c63}
  • 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

Primary diagnostic tools

• In 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 one 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 may be the earliest manifestation of cardiac autonomic neuropathy ^r4
      • 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 drop in blood pressure ^r21
      • Supine hypertension ^r25
      • Postprandial hypotension ^r25
    • Obtain an ECG to assess QTc interval and signs of cardiac ischemia ^r3c84
  • Gastrointestinal neuropathy
    • Gastroparesis ^r26
      • Studies are appropriate in symptomatic patients (ie, those with bloating, nausea, prolonged postprandial sense of fullness) or in 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 ^r27r28
      • Gastric emptying is most commonly measured by scintigraphy, which is considered the gold standard test for gastroparesis ^r1r27r29c85
      • Gastric emptying (¹³C octanoic acid) breath test assessment is a generally accepted alternative to scintigraphy ^{r27r28r29c86c87}
      • Wireless motility capsule and gastric ultrasonography have been used, but most recent guidelines do not endorse these modalities for assessing gastric emptying ^r27r29
    • Intestinal motility ^r26
      • Measurement of transit time may be indicated in 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
      • In patients with high postvoid residual volume, invasive urodynamic testing may be indicated to differentiate from bladder outlet obstruction ^r30
      • 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) ^r31
      • 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

Laboratory

• 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 men established in the laboratory used
  • Low levels may indicate hypogonadism as a contributing factor in 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

Imaging

• Gastric scintigraphy ^r4c95
  • Gold standard for diagnosis of gastroparesis is measurement of gastric emptying with scintigraphy after food intake ^r28c96
  • 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: ^r23
      • 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 ^r26
  • 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 ^r26

Functional testing

• ¹³C breath test ^r26r32c97
  • 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 ^r26c98
  • A small device swallowed by the patient that detects and transmits information on pH, temperature, and luminal pressure
  • A drop 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 ^r30
  • Can be combined with uroflowmetry to provide a noninvasive assessment of urine flow rate, voided volume, intermittent flow, hesitancy, and residual urine ^r5

Procedures

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 ^r34
  • Prolongation of QTc interval may be an indicator of cardiac autonomic neuropathy
    • 460 milliseconds or more in women and 450 milliseconds or more in men ^r3

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 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), or^d6
      • 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 finding indicating leukocyte esterase and nitrite positivity, microscopic urinalysis indicating WBC and bacteria, and urine culture showing bacterial growth
      • Urinary tract infection may complicate neurogenic bladder
    • Medication effect ^c120
      • Anticholinergic medications can cause urinary retention that may be mistaken for neurogenic bladder
      • Sympathomimetic medications can cause urinary frequency and retention that 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

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

• 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 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

Drug therapy

• For cardiac autonomic neuropathy
  • General
    • ACE inhibitor
      • Quinapril ^c122
        • Quinapril Hydrochloride Oral tablet; Adults: 20 mg PO once daily. ^r46
    • Angiotensin receptor blocker
      • Losartan ^c123
        • Losartan Potassium Oral tablet; Adults: 100 mg PO once daily. ^r47
    • Cardioselective β-blockers
      • Metoprolol ^r48c124
        • Metoprolol Succinate Oral tablet, extended-release; Adults: 100 mg PO once daily.
      • Bisoprolol ^c125
        • Bisoprolol Fumarate Oral tablet; Adults: 5 mg PO once daily. ^r57
  • For orthostatic hypotension
    • Mineralocorticoid
      • Fludrocortisone ^r1c126
        • Fludrocortisone Acetate Oral tablet; Adults: initially 0.1 mg PO once daily in the morning, increasing weekly as needed to maximum 0.3 mg daily.
    • Sympathomimetic
      • Midodrine ^c127
        • Midodrine Hydrochloride Oral tablet; Adults: 10 mg PO tid. A suggested 4-hour dosing interval schedule is as follows: shortly before or upon rising qAM, midday, and late afternoon (not later than 6 PM).
    • Vasopressor
      • Droxidopa ^c128
        • Droxidopa Oral capsule; Adults: 100 mg PO 3 times daily, upon arising in AM, midday, and late afternoon at least 3 hours prior to bedtime. Titrate to symptomatic response, in increments of 100 mg 3 times daily every 24 to 48 hours up to a dose of 600 mg PO 3 times daily (Max: 1,800 mg/day PO). Monitor supine blood pressure prior to initiating droxidopa and at every dosage increase. Assess efficacy periodically.
    • Somatostatin analogue
      • Octreotide ^c129
        • Octreotide Acetate Solution for injection; Adults: Optimal dose not established. A usual starting dose is 12.5 mcg to 25 mcg subcutaneously 3 times per day, then titrated to effect. Usually reserved for patients not responsive to standard therapies due to limited data. One study has used 100 mcg subcutaneously as a single dose acutely. Low doses (0.2 to 0.4 mcg/kg subcutaneously) and high doses (up to 1.6 mcg/kg subcutaneously) have also been studied.
• For gastrointestinal neuropathy
  • Gastroparesis
    • Dopamine antagonists
      • Metoclopramide ^c130
        • Metoclopramide Hydrochloride Oral tablet; Adults: 10 mg PO, IV, or IM 4 times daily, 30 minutes before meals and at bedtime. Max: 40 mg/day PO. If a CYP2D6 poor metabolizer: 5 mg PO, IV or IM 4 times daily (Max: 20 mg). Consider a similar lower initial dosage for geriatric patients. Avoid treatment with metoclopramide (all dosage forms and routes of administration) for more than 12 weeks because of the increased risk of tardive dyskinesia (TD) with longer-term use. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
      • Domperidone ^c131
        • Available in the United States as an investigational new drug per FDA; commercially available in Canada, Europe, Australia, and other countries
        • Recommended for patients with gastroparesis unresponsive to or with adverse effects from metoclopramide ^r29
        • Domperidone Oral tablets; Adults: initially, 10 mg PO 3 times daily, before meals, increasing to 20 mg 4 times daily, before meals and at bedtime. (Note that this exceeds maximum dose recommended in package insert.^r59) ^r29r58
        • Domperidone carries the risk of QT prolongation and torsades de pointes. A baseline ECG is recommended; withhold treatment if the corrected QT interval is more than 470 milliseconds in male patients and 450 milliseconds in female patients. A follow-up ECG during therapy is advised. ^r29
    • Motilin receptor agonist
      • Erythromycin ^c132
        • Erythromycin Oral tablet; Infants, Children, and Adolescents: 3 mg/kg/dose PO 4 times daily; up to 10 mg/kg/dose (Max: 250 mg/dose) PO 4 times daily has been used; however, data are limited. Long-term use limited by tachyphylaxis.
        • Erythromycin Oral tablet; Adults: 250 to 500 mg PO 3 times daily, 30 minutes before meals, is recommend in guidelines for patients with persistent symptoms following trials of standard prokinetic therapy (e.g., metoclopramide). The oral suspension is often utilized due to rapid absorption and to facilitate dose modifications. Clinical responsiveness to oral erythromycin declines after 4 weeks.
  • Diarrhea
    • Antidiarrheal agent
      • Loperamide ^c133
        • Loperamide Hydrochloride Oral tablet; Adults: 4 mg PO initially, then 2 mg after each subsequent unformed stool until diarrhea is controlled. Then, reduce to meet individual requirements. Average daily maintenance dosage: 4 to 8 mg/day. Max: 16 mg/day PO.
    • 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: Initially, 0.1 mg PO q12h and increased over a period of 3 days up to 0.5—0.6 mg PO q12h.
    • Somatostatin analogue
      • Octreotide ^c136
        • Octreotide Acetate Solution for injection; Adults: Varying doses reported. 50 to 100 mcg subcutaneously every 8 to 12 hours.
    • Antibiotics
      • Metronidazole ^c137
        • Metronidazole Oral tablet; Adults: 250 mg PO 3 times daily for 3 weeks or longer. ^r53
• Urogenital neuropathy
  • Hypotonic bladder
    • Parasympathomimetic
      • Bethanechol ^c138
        • Bethanechol Chloride Oral tablet; Adults: Determine minimal effective dose initially by giving 5—10 mg, repeating at hourly intervals until therapeutic goals attained or up to max 50 mg PO total dose. Usual dosage: 10—50 mg PO, given 3—4 times per day.
  • Overactive bladder
    • Antimuscarinic agents
      • Note that these drugs may cause or exacerbate constipation and gastroparesis
      • Antimuscarinic agents are contraindicated in patients with narrow-angle glaucoma
      • Oxybutynin ^c139
        • Oxybutynin Chloride Oral tablet; Adults: 5 mg PO 2 to 3 times daily. Max: 5 mg PO 4 times daily.
        • Oxybutynin Chloride Oral tablet; Geriatric: 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.
      • Tolterodine ^c140
        • Tolterodine Tartrate Oral tablet; Adults: 2 mg PO twice daily; some patients may respond to 1 mg PO twice daily. If concurrently taking CYP3A4-inhibiting drugs, reduce to 1 mg PO twice daily.
      • Trospium chloride ^c141
        • Trospium Chloride Oral tablet; Adults: 20 mg PO twice daily.
        • Trospium Chloride Oral tablet; Geriatric Adults: Initially, 20 mg PO twice daily. May adjust downward to 20 mg PO once daily at bedtime if anticholinergic side effects are intolerable.
      • Fesoterodine ^c142
        • Fesoterodine fumarate Oral tablet, extended-release; Adults: 4 mg PO once daily initially; may increase to 8 mg PO once daily based upon response and tolerability. Max: 8 mg/day PO. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
      • Solifenacin ^c143
        • Solifenacin Succinate Oral tablet; Adults: 5 mg PO once daily. May increase to 10 mg PO once daily if needed/tolerated. Max: 10 mg/day; in patients taking potent inhibitors of CYP3A4, do not exceed 5 mg/day. USE WITH MIRABEGRON: The FDA-approved dose for solifenacin is 5 mg PO once daily when given with mirabegron.
      • Darifenacin ^c144
        • Darifenacin Oral tablet, extended-release; Adults: 7.5 mg PO once daily. May increase to 15 mg PO once daily after 2 weeks based on response. Max: 15 mg/day PO; do not exceed 7.5 mg/day PO in patients taking potent CYP3A4 inhibitors.
    • β-agonist
      • Mirabegron ^c145c146
        • Mirabegron Oral tablet, extended-release; Adults: 25 mg PO once daily. Based on efficacy and tolerability, may increase to 50 mg PO once daily after 4 to 8 weeks. USE WITH SOLIFENACIN: 25 mg PO once daily with solifenacin (5 mg/day PO). Based on efficacy and tolerability, may increase mirabegron to 50 mg PO once daily if needed after 4 to 8 weeks.
  • Erectile dysfunction
    • Phosphodiesterase-5 inhibitors
      • Note that these medications have interactions with a wide range of other drugs; check specific drug-drug interactions before prescribing
      • Sildenafil ^c147
        • Sildenafil Citrate Oral tablet; Adult Males: 50 mg PO, approximately 1 hour prior to sexual activity, up to once daily. Increase to 100 mg or decrease to 25 mg based on response. Max: 1 dose/day.
        • Sildenafil Citrate Oral tablet; Geriatric Males: 25 mg PO, approximately 1 hour prior to sexual activity, up to once daily.
      • Tadalafil ^c148
        • Tadalafil Oral tablet; Adult males: 10 mg PO before anticipated sexual activity; increase to 20 mg or decrease to 5 mg based on efficacy and tolerability; max dosing frequency is once daily in most patients.Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
      • Vardenafil ^c149
        • Vardenafil Hydrochloride Oral tablet; Adult males: Initially, 10 mg PO approximately 60 minutes before sexual activity. For males 65 years of age or older, consider a lower starting dose of 5 mg PO. The maximum dosing frequency is once per day. May titrate based on efficacy and side effects. Max: 20 mg/day PO. ADJUSTMENTS: Review drug interactions. Vardenafil dosage reductions are required in patients taking moderate or potent CYP3A4 inhibitors. If coadministering with an alpha-blocker, patients should be stable on alpha blocker therapy before starting vardenafil, and the initial vardenafil dose should be reduced to 5 mg (or 2.5 mg if given with certain CYP3A4 inhibitors).
      • Avanafil ^c150
        • Avanafil Oral tablet; Adults: 100 mg PO once daily, approximately 15 minutes before sexual activity. Increase up to 200 mg PO, approximately 15 minutes before sexual activity or decrease to 50 mg PO, approximately 30 minutes before sexual activity, based on clinical response. Maximum dosing frequency is once daily.
    • Prostaglandin E
      • Alprostadil ^c151
        • Alprostadil Urethral suppository; Adult males: 125 mcg or 250 mcg into the urethra as directed. Max: 2 doses per 24-hour period.

Nondrug and supportive care

For obese patients, weight loss is beneficial for overall diabetes management and has been shown to reverse progression of cardiac autonomic neuropathy^r60r61 as well as incontinence associated with overactive bladder^r31

• May be achieved through conventional means (ie, calorie restriction, increased physical activity) or bariatric surgery ^{r62c152c153c154c155}

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 ^r25c163

Dietary modification including frequent small meals, low in fat (less than 40 g/day)^r53 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 ^r63

• 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 ^r53c176

Special populations

• Pregnant patients should avoid or discontinue ACE inhibitors and angiotensin receptor blockers

At-risk populations

• Yearly screening for diabetic autonomic neuropathy is recommended as follows: ^r3r6
  • Asymptomatic patients with type 2 diabetes at time of diagnosis
  • Patients with type 1 diabetes 5 years after diagnosis
• Also recommended under the following circumstances: ^r25
  • Asymptomatic patients with diabetes during preoperative evaluation
  • Before starting a new physical fitness program
• Regular screening for neurogenic orthostatic hypotension is recommended for patients known to have diabetic peripheral neuropathy ^r49

Screening tests ^r6r33

• 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