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Apr.08.2020

Diabetic autonomic neuropathy

Synopsis

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 of 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 work-up 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 bethanechol 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

Terminology

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

Classification

  • Diabetic autonomic neuropathy falls within the following larger classification of diabetic neuropathies: r1r14
    • Diffuse neuropathy
      • Diffuse symmetrical polyneuropathy
        • Small fiber predominant
        • Large fiber predominant
        • Mixed small and large fiber
      • Autonomic
        • 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
        • Hypoglycemia unawareness
        • Abnormal pupillary function
      • Mononeuropathy
        • Isolated cranial or peripheral nerve
        • Mononeuropathy multiplex
      • Radiculopathy or polyradiculopathy
        • Radiculoplexus neuropathy
        • Thoracoabdominal neuropathy

Diagnosis

Clinical Presentation

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 r15
      • 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 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 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)
    • Silent myocardial ischemia c40
      • Absence of anginal pain during documented ischemia or infarction
    • Abnormal cardiovascular and thermoregulatory effects of general anesthesia
      • Hypotension, hypothermia c41c42
    • Frequent urinary tract infections c43
      • May signal 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 c44
    • 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 c45
        • 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 r16c46
        • 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 c47
  • Gastrointestinal
    • Abdominal examination findings are usually unremarkable
    • A gastric splash may sometimes be elicited c48
    • Hardened stool may be palpable in colon or on rectal examination c49
    • Poor anal sphincter tone and absent or diminished anal reflexes may be noted c50c51
  • Urogenital
    • Distended bladder may be noted on palpation and/or percussion c52
  • Sudomotor
    • Dry skin in stocking-glove, lower body, or generalized distribution c53
    • Fissures may be seen in the plantar surfaces c54
  • Pupillary
    • Sluggish or absent pupillary light reflex c55

Causes and Risk Factors

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 r17c56c57c58c59
    • 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

Age
Sex
  • Data are conflicting; may be more common in females r18r19c62c63
Genetics
  • 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 r20c64c65
Other risk factors/associations
  • General
    • Risk increases with duration of diabetes r2
    • Rarely, may be associated with initiation of insulin or oral hypoglycemic agents r21c66
    • 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 r21c67c68
  • Type-specific r3
    • Type 1: glycemic control c69
    • Type 2: glycemic control, hypertension, dyslipidemia, obesity c70c71c72c73

Diagnostic Procedures

Primary diagnostic tools

  • In a patient with diabetes, the diagnosis may be suggested by history and physical examination findings r6c74
  • 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 r6
    • 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
        • 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: r3
        • Absence of normal (10% or more) nocturnal drop in blood pressure r19
        • Supine hypertension r22
        • Postprandial hypotension r22
      • Obtain an ECG to assess QTc interval and signs of cardiac ischemia r3
    • Gastrointestinal neuropathy
      • Gastroparesis r23
        • 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
        • Gastric emptying is most commonly measured by scintigraphy, which is considered the gold standard test for gastroparesis; gastric outlet obstruction should be ruled out before proceeding r1
        • An alternative method is the ¹³C breath test
      • Intestinal motility r23
        • 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 r7
        • In patients with high postvoid residual volume, urodynamic testing may be indicated to differentiate from outlet obstruction r5
        • 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) r24
        • 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 r13
    • 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 r7c75c76
    • In patients with neurogenic bladder, elevated levels may reflect complications of urinary retention, with or without associated diabetic nephropathy
  • Serum total testosterone levels r13c77
    • 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 c78
    • Key parameter for monitoring overall pattern of glycemic control
    • Optimization may retard or prevent development of autonomic neuropathy r1

Imaging

  • Gastric scintigraphy r4c79
    • Gold standard for diagnosis of gastroparesis is measurement of gastric emptying with scintigraphy after food intake r25
    • 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: r21
        • 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 r23
    • 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 r23

Functional testing

  • ¹³C breath test r23r25r26c80
    • Nonradiographic measure of gastric emptying
    • Patient consumes a meal containing ¹³C, which 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 r23c81
    • 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 c82
    • After the patient voids as completely as possible, remaining urine volume is estimated by ultrasonography, or a bladder catheter is placed and collected urine is measured
      • A volume of 50 to 100 mL or more is considered abnormal and suggests neurogenic bladder or outlet obstruction r27

Procedures

Cardiovascular autonomic reflex testing r14c83c84c85c86
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/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 the 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) r22
Indication
  • Patients with diabetes who have unexplained tachycardia, orthostatic hypotension, or prolonged QTc interval
  • After myocardial infarction in a patient with diabetes r28
Contraindications
  • Valsalva maneuver is contraindicated in 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% r28
    • Distance between QRS complexes (R-R interval) is measured during inspiration and expiration and a ratio 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
    • 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 r29c87c88c89c90c91
General explanation
  • Noninvasive and minimally invasive evaluation of bladder filling, storage, and emptying
  • Patient is asked to report bladder sensations during the process (ie, fullness, need to void, urgency)
  • Bladder is filled naturally or by instillation of saline through a bladder catheter
  • Bladder capacity is measured
  • Bladder, urethral, and abdominal pressures are measured manometrically
  • Detrusor muscle activity may be monitored through electromyography
  • Urine flow rate is monitored during micturition
Indication
  • 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 infection, 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 c92
    • 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 r30
    • 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

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 c93d2
      • 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 c94
      • 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 c95c96c97
      • 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 c98c99
      • Like cardiac autonomic neuropathy, may be characterized by resting tachycardia and orthostatic hypotension
      • Distinction is usually apparent from history and context
    • Heart failure c100d3
      • 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 c101d4
      • 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
      • Parkinson disease is usually evident by distinctive physical findings including bradykinesia, rigidity, resting tremor, and gait impairment
  • For gastrointestinal autonomic neuropathy
    • Gastroparesis
      • Gastric outlet obstruction c102
        • 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 c103d5
      • 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 c104c105c106
      • 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 c107
        • 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 c108d9
        • 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 c109
        • 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 c110d1
      • Erectile dysfunction is defined as 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 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

Treatment

Goals

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

Disposition

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

Treatment Options

Maintain optimal glycemic control; minimize cardiovascular risk factors

  • Dietary and pharmacologic management to attain individualized hemoglobin A1C goal based on life expectancy, disease duration, presence or absence of micro- and macrovascular complications, cardiovascular risk factors, comorbid conditions, and risk for hypoglycemia r31
    • Diabetes Control and Complications Trial followed 1441 insulin-dependent people with diabetes managed on either a conventional regimen or an intensive glycemic control program; over the 9 years of the trial, fewer cardiac reflex abnormalities developed in patients in the intensive glycemic control arm. Incomplete bladder emptying was also less common in the intensive control group r32
    • During follow-up for an additional 13 to 14 years, frequency of cardiac reflex abnormalities grew in each group but differences between the groups persisted, with lower rates in the intensive treatment group r33
    • Intensive glycemic control may be more effective in type 1 than type 2 diabetes with respect to development and/or progression of neuropathy r2
    • For patients with type 2 diabetes in particular, control of cardiovascular risk factors (eg, dyslipidemia, hypertension) may mitigate progression of diabetic autonomic neuropathy r34

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 obese people both with and without diabetes after significant weight loss r35r36
      • Moderate intensity aerobic exercise training
        • Several systematic reviews have shown beneficial effects on functional capacity, metabolic control, circulating inflammatory markers, and cardiac autonomic activity r37r38
      • Pharmacologic agents
        • ACE inhibitors,r40angiotensin receptor blockers,r41 and cardioselective β-blockersr42 have all been shown to improve cardiac reflex parameters in patients with diabetic autonomic neuropathy and have been used alone or in various combinations r28r39
    • Orthostatic hypotension r25r43
      • Mechanical and physiologic measures to prevent or counteract drop 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 symptomatic patients who do not respond to conservative measures. Care must be taken to avoid supine hypertension; educate patients to take these medications only when upright position is intended (eg, daytime) r1
        • Fludrocortisone may aid in maintaining intravascular volume
        • Midodrine increases peripheral vascular tone through adrenergic stimulation; concomitant fludrocortisone increases the effect r44
        • Droxidopa is metabolized to norepinephrine with resulting increase in vascular tone r45
        • Pyridostigmine has been used off-label r43
        • Octreotide may be helpful in patients with postprandial orthostatic hypotension r46
  • Gastrointestinal
    • Gastroparesis r9r25
      • Frequent, small meals rather than conventional meal schedule may prevent sensation of fullness and bloating
      • Promotility drugs may improve transit time and symptoms; these include dopamine antagonists (eg, metoclopramide) and erythromycin
        • Only metoclopramide is approved by FDA for treatment of gastroparesis
          • Should be used only for severe cases and not for more than 12 weeks owing to potential for serious adverse effects r25
        • Erythromycin: can be used off-label but is effective only for short-term use owing to tachyphylaxis r25
      • Gastric electrical stimulation has been effective in improving symptoms, gastric emptying time, and nutritional statusr47 in patients with severe refractory diabetic gastroparesis r8
        • More effective for nausea and vomiting than for other symptoms r47
    • 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)r2
      • Clonidine may slow colonic transit time by opposing adrenergic stimulation r46
      • Cholestyramine or octreotide may be effective in patients who do not respond to other measures r46
    • 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
      • Neurogenic (hypotonic) bladder r7
        • Techniques such as Valsalva maneuver, manual pressure over bladder (Credé maneuver), and double voiding have been recommended by some authorities
          • Guidelines from the European Association of Urologyr48 recommend against Valsalva and Credé maneuvers because of concerns that increased intravesical pressure may lead to reflex sphincter tightening and also inflict further damage on lower urinary tract r48
        • Bethanechol, a parasympathomimetic drug that stimulates the detrusor muscle, may improve bladder emptying; it is commonly prescribed in the United States, but European Association of Urology guidelinesr48 recommend against use of parasympathomimetic agents for hypotonic bladder
        • Intermittent catheterization may be necessary if other measures are ineffective
      • Overactive bladder r24
        • 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 women with incontinence r11
        • Pharmacologic agents may be added if conservative measures are not sufficient
          • Antimuscarinic agents such as oxybutynin, tolterodine, trospium chloride, fesoterodine, solifenacin, darifenacin are first line pharmacologic agents; they do not appear to differ in efficacy
          • Mirabegron, a β-agonist, is also effective in reducing incontinence and frequency of voiding, and is recommended as another first line option; evidence suggests efficacy similar to the antimuscarinic agents r12
        • Botulinum toxin, electrical stimulation of posterior tibial nerve, and various surgical procedures may be options for patients who do not respond to other measures r24r48
          • Although the mechanism is unclear, electrical stimulation of 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 with follow-up schedule) r24
          • Injection of bladder with botulinum toxin improves incontinence symptoms due to overactive bladder in more than 50% of diabetic patients treated, and improvement typically lasts for more than 6 months r24
            • Patients require regular postvoid residual evaluation and must able to perform self-catheterization if needed
    • Erectile dysfunction r6r25
      • If psychogenic factors and hypogonadism have been excluded and if cardiovascular risk is deemed acceptable, pharmacotherapy with phosphodiesterase-5 inhibitors or prostaglandin E₁ is recommended
      • When medication is ineffective, constriction device and surgical prosthesis 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 c111
          • Quinapril Hydrochloride Oral tablet; Adults: 20 mg PO once daily. r40
      • Angiotensin receptor blocker
        • Losartan c112
          • Losartan Potassium Oral tablet; Adults: 100 mg PO once daily. r41
      • Cardioselective β-blockers
        • Metoprolol r42c113
          • Metoprolol Succinate Oral tablet, extended-release; Adults: 100 mg PO once daily.
        • Bisoprolol c114
          • Bisoprolol Fumarate Oral tablet; Adults: 5 mg PO once daily. r49
    • For orthostatic hypotension
      • Mineralocorticoid
        • Fludrocortisone r1c115
          • 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 c116
          • 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 c117
          • 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 c118
          • 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 c119
          • Metoclopramide Hydrochloride Oral tablet; Adults: 10 mg PO, IV, or IM 4 times daily, 30 minutes before meals and at bedtime is FDA-approved for diabetic gastroparesis. If the patient is a poor metabolizer of CYP2D6, the oral dose is 5 mg PO 4 times daily (Max: 20 mg). Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. According to gastroparesis guidelines, initiate at 5 to 10 mg PO 2 to 3 times daily, before meals; Max: 40 mg/day is advocated along with “drug holidays” or dose reductions (e.g., 5 mg, before 2 main meals of the day) whenever clinically possible; continuous use longer than 12 weeks is not recommended.
        • Domperidone c120
          • 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 r50
          • 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.r52) r50r51
          • Domperidone carries a 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 and 450 milliseconds in female patients. Follow-up ECG during therapy is advised. r50
      • Motilin receptor agonist
        • Erythromycin c121
          • 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 c122
          • 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 c123
          • Cholestyramine Powder for Oral suspension; Adults: 2 to 4 g PO 2 to 4 times daily.
      • Centrally acting α-1 agonist
        • Clonidine c124
          • 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 c125
          • Octreotide Acetate Solution for injection; Adults: Varying doses reported. 50 to 100 mcg subcutaneously every 8 to 12 hours.
      • Antibiotics
        • Metronidazole c126
          • Metronidazole Oral tablet; Adults: 250 mg PO 3 times daily for 3 weeks or longer. r46
  • Urogenital neuropathy
    • Hypotonic bladder
      • Parasympathomimetic
        • Bethanechol c127
          • 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 c128
          • Oxybutynin Chloride Oral tablet; Adults: Usual: 5 mg PO 2—3 times per day. Max: 5 mg PO 4 times per day.
          • Oxybutynin Chloride Oral tablet; Geriatric: See adult dose. Initiate with 2.5 mg PO 2—3 times per day in frail geriatric patients.
        • Tolterodine c129
          • Tolterodine Tartrate Oral tablet; Adults: 2 mg PO bid. If significant renal or hepatic disease is present or if concurrently taking CYP3A4-inhibiting drugs, reduce to 1 mg PO bid.
        • Trospium chloride c130
          • Trospium Chloride Oral tablet; Adults: 20 mg PO twice daily.
          • Trospium Chloride Oral tablet; Geriatric: Initially, 20 mg PO twice daily. May adjust downward to 20 mg PO once daily at bedtime if anticholinergic side effects are intolerable.
        • Fesoterodine c131
          • Fesoterodine fumarate Oral tablet, extended-release; Adults, including Geriatric Adults: Initially, 4 mg PO once daily. May increase to 8 mg PO once daily based upon response and tolerability. Max: 8 mg/day PO, do not exceed 4 mg/day PO in patients taking potent CYP3A4 inhibitors.
        • Solifenacin c132
          • Solifenacin Succinate Oral tablet; Adults: 5 mg PO once daily. The dose may be increased to 10 mg PO once daily if needed and tolerated. In patients receiving drugs that are potent inhibitors of CYP3A4, do not exceed 5 mg PO once daily. USE WITH MIRABEGRON: The FDA-approved dose for solifenacin is 5 mg PO once daily when given with mirabegron.
        • Darifenacin c133
          • 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 individual response. Max: 15 mg/day PO. If receiving potent CYP3A4 inhibitors, do not exceed 7.5 mg/day PO.
      • β-agonist
        • Mirabegron c134
          • Mirabegron Oral tablet, extended-release; Adults: 25 mg PO once daily; this dose is effective within 8 weeks. Based on efficacy and tolerability, then may increase to 50 mg PO once daily. 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 c135
          • 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 c136
          • 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 c137
          • 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 c138
          • 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 c139
          • 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 neuropathyr53 as well as incontinence associated with overactive bladderr24

  • May be achieved through conventional means (ie, calorie restriction, increased physical activity) or bariatric surgery r54c140c141c142c143

Exercise training r6c144c145

  • 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 r3c146c147c148c149c150
  • Maintain fluid intake of 2 to 3 liters a day if not contraindicated r22c151

Dietary modification including frequent small meals, low in fat (less than 40 g/day)r46 and fiber, may relieve symptoms of gastroparesis r9c152c153c154

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

  • Minimize fluid intake late in the day and before bedtime c155c156
  • Avoid alcohol (a diuretic) and caffeine (an irritant) c157c158
  • Scheduled voiding (eg, every few hours) c159

Other bladder management techniques r7

  • Pelvic muscle (Kegel) exercises c160
    • Instruction and supervision should be provided by a practitioner trained to teach the method
  • Bladder training r10c161
    • 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 c162

Vacuum devices for erectile dysfunction r55

  • Consist of a closed-end cylinder, vacuum pump, and constriction ring c163
  • 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 the risks for hyperthermia and heat stroke r46c164c165

Procedures
Gastric electrical stimulation c166
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
Indication
  • Nausea and vomiting associated with diabetic gastroparesis that is refractory to other measures
Intravesical injection of botulinum toxin r24c167
General explanation
  • Botulinum toxin (usually onabotulinumtoxinA) is injected at various points in the bladder, most commonly the detrusor muscle
Indication
  • Persistent incontinence due to overactive bladder despite behavioral and pharmacologic treatment
Complications
  • Urinary retention requiring intermittent straight catheterization
  • Systemic effects of the toxin (ie, dysphagia, eyelid weakness, visual impairment, limb and/or trunk weakness)
Electrical stimulation of posterior tibial nerve c168
General explanation
  • Application of low level electrical current applied to posterior tibial nerve via needle electrode r10
  • Treatment consists of 30 minutes weekly for 12 weeks or more; some protocols involve periodic follow-up maintenance treatments r24
Indication
  • Persistent incontinence due to overactive bladder despite behavioral and pharmacologic treatment
Implantation of penile prosthesis c169
General explanation
  • Surgical implantation of a semirigid or hydraulic (inflatable) device
Indication
  • Organic erectile dysfunction refractory to medical therapy
Contraindications
  • Cardiac function inadequate for safe sexual activity

Special populations

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

Monitoring

  • 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

Complications and Prognosis

Complications

  • 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 r56
      • Labile blood pressure c170
        • Normal diurnal variation in blood pressure may be disrupted in cardiac autonomic neuropathy, resulting in absence of 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 r22
        • Lack of normal hemodynamic response increases risk of profound and refractory hypotension during anesthesia r22
      • Cardiomyopathy c171
        • Systolic and diastolic dysfunction have been associated with cardiac autonomic neuropathy even in the absence of atherosclerotic coronary disease r2
      • Silent myocardial infarction r3c172
        • Absence of pain with myocardial ischemia may be multifactorial but is associated with presence of cardiac autonomic neuropathy
        • May delay recognition and treatment, contributing to worse prognosis of myocardial infarction in patients with diabetes
      • Increased mortality after myocardial infarction c173
        • Decreased heart rate variability is a marker for mortality risk r2
      • Sudden death r2c174
        • Cardiac autonomic neuropathy is associated with prolonged QTc interval and malignant arrhythmias
      • Stroke c175
        • Presence of cardiac autonomic neuropathy has been correlated with an increased risk of ischemic stroke r4r22
    • Gastrointestinal complications r16
      • Bezoars may form as a result of poor gastrointestinal motility c176
      • Gastritis and/or gastric ulcers may result from gastroparesis c177c178
      • 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 r4c179c180c181c182
      • Frequent infection 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 r46c183

Prognosis

  • 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 3 times higher than in people with diabetes who do not have autonomic dysfunction

Screening and Prevention

Screening

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: r22
    • 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 r43

Screening tests r6r28

Prevention

  • To prevent autonomic neuropathy, 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 in patients with type 2 diabetes r1
    • Intensive glucose control resulted in a 45% reduction in the development of cardiac autonomic neuropathy in type 1 diabetes in the Diabetes Control and Complications Trial r32
    • 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: r34c196
      • Low fat diet (less than 30% daily calorie intake from fat; less than 10% of daily calorie intake from fatty acids) c197
      • Light to moderate exercise (30 minutes 3 to 5 times per week) c198c199
      • ACE inhibitor or angiotensin receptor blocker (regardless of blood pressure) c200c201
      • Daily aspirin (150 mg) c202
      • Treatment of dyslipidemia c203
      • Smoking cessation if applicable c204
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