Autonomic Neuropathy

Background

• Autonomic neuropathy is due to damage to autonomic small diameter myelinated or unmyelinated nerve fibers, resulting in impairment of cardiovascular, thermoregulatory, gastrointestinal, urogenital, sudomotor, and/or pupillomotor function.
• Many underlying causes of autonomic neuropathy exist, including diabetes mellitus (most common cause), uremia, alcohol use disorder, primary systemic amyloidosis, certain autoimmune disorders, infections, drugs and toxins, and hereditary conditions.
• The estimated prevalence of autonomic neuropathy is about 30%-70% in patients with diabetes mellitus. However, the overall incidence/prevalence of autonomic neuropathy is generally not known for most etiologies, and the evidence for risk based on the underlying etiology is limited.
• Clinical presentations of autonomic neuropathies can be acute, subacute, or chronic, and variable in signs and symptoms depending on the underlying etiology and the organ systems that are affected.

Evaluation

• Suspect autonomic neuropathy in patients presenting with symptoms such as:
  • dizziness, light-headedness, weakness, and/or visual and hearing disturbances upon standing (orthostatic hypotension)
  • exercise intolerance
  • fainting (syncope)
  • heart palpitations
  • gastrointestinal disturbances such as bloating, loss of appetite, nausea, constipation, diarrhea, or fecal incontinence
  • urinary incontinence or difficultly urinating
  • sexual dysfunction such as erectile dysfunction or ejaculatory failure in men and reduced vaginal lubrication in women
  • reduced or increased sweating
  • hypersalivation, dry mouth, or dry eyes
  • sensation of pain in head, neck, and trapezius region (coat-hanger ache) related to orthostatic hypotension
• Patients may present with concomitant sensory, motor, or other symptoms depending on the underlying etiology and which nerve fiber types are impaired. The pattern of clinical presentation may help to narrow the cause of autonomic neuropathy.
• Tests can be performed based on clinical suspicion to help identify the presence and underlying cause of autonomic neuropathy, including:
  • Blood tests including glucose testing, antibody and antigen tests for suspected immune-mediated autonomic neuropathy, and genetic testing for suspected hereditary causes.
  • Urine studies (such as for suspected porphyria, amyloidosis, or heavy metal exposure).
  • Biopsy of skin, fat aspirate, bone marrow aspirate, or biopsy of lip, intestine, lesion, or nerve depending on suspected etiology.
  • Echocardiography (for suspected amyloidosis) and other diagnostic testing for specific conditions.
• Consider autonomic function testing for suspected autonomic neuropathy to confirm and quantify autonomic dysfunction. It is especially important to test for cardiac autonomic neuropathy which is associated with increased mortality.

Management

• Symptomatic management
  • For orthostatic hypotension:
    • Education on warning symptoms and avoiding triggers, adequate hydration, and exercises to strengthen and maintain postural tone.
    • Medication in rare patients with severe orthostatic hypertension who fail conservative nonpharmacological therapy, such as:
      • midodrine 2.5 mg orally 3 times daily, titrated by 2.5 mg/day weekly up to 10 mg orally 3 times daily
      • droxidopa 100 mg orally 3 times daily, titrated every 24-48 hours as needed up to maximum dose of 1,800 mg/day orally in 3 divided doses
    • See Orthostatic Hypotension and Orthostatic Syncope for additional information.
  • For constipation:
    • Dietary modification (high-fiber diet and fluid supplementation) as initial management for primary functional constipation.
    • If medication is needed, laxative therapy (such as polyethylene glycol [PEG] daily) or drug therapy (such as lubiprostone 24 mcg orally twice daily) if laxatives are ineffective.
    • See Constipation in Adults for additional information.
  • For fecal incontinence:
    • Conservative management includes avoiding foods and supplements that may exacerbate fecal incontinence symptoms, biofeedback therapy, and pelvic floor exercises.
    • Medications include systemic medications such as amitriptyline or loperamide and topical medications such as zinc aluminum or estrogen.
    • See Fecal Incontinence in Adults for additional information.
  • For urinary incontinence/overactive bladder:
    • Conservative management includes bladder training, prompted voiding, pelvic floor muscle training, absorbent pads, altering fluid intake pattern, reducing caffeine and alcohol intake, and reducing weight (if overweight).
    • Anticholinergics (including oxybutynin and tolterodine) are first-line medication treatment.
    • See Urinary Incontinence in Men, Urinary Incontinence in Women, and Neurogenic Bladder for additional information.
  • For urinary retention/underactive bladder:
    • Self-catheterization for immediate drainage and relief.
    • Alpha-blockers or cholinergic drugs may improve bladder emptying.
    • See Acute Urinary Retention in Men, Urinary Retention in Women, and Neurogenic Bladder for additional information.
  • For sexual dysfunction:
    • For erectile dysfunction - oral phosphodiesterase-5 (PDE-5) inhibitor is a first-line medication for most men.
    • For reduced vaginal lubrication - nonhormonal vaginal lubricants and moisturizers may help maintain moisture.
    • See Erectile Dysfunction, Female Sexual Dysfunction, and Atrophic Vaginitis for additional information.
  • For salivary and lacrimal dysfunction
    • For dry mouth:
      • Nonpharmacologic strategies such as oral hygiene, reduce alcohol and caffeine intake, dietary changes, and adequate hydration.
      • Salivary stimulants such as pilocarpine and cevimeline or salivary substitutes.
    • For dry eyes:
      • Avoiding air drafts, low-humidity environments, and antihistamine or diuretic use if possible
      • Increased blink frequency.
      • Tear substitutes (including artificial tears), tear conservation, and tear stimulation.
    • See Xerostomia and Treatment of Dry Eye Disease for additional information.
• Disease-specific management options for autonomic neuropathies include:
  • For diabetes mellitus or impaired glucose tolerance:
    • Glycemic control typically consisting of diet, physical activity, and glucose-lowering medications if necessary may reduce risk and severity of autonomic neuropathy.
    • See Management of Type 2 Diabetes in Adults, Diabetic Peripheral Neuropathy, and Diabetes Mellitus Type 1 for additional information.
  • For alcohol use disorder:
    • Perform brief psychological or behavioral interventions to reduce alcohol use in patients with positive screening or diagnosis of alcohol use disorder.
    • Consider pharmacologic therapy (as adjunct to psychologic treatment) with 1 of disulfiram, naltrexone, acamprosate, and topiramate.
    • Follow-up to mitigate relapse, consisting of nonjudgmental monitoring of progress toward goals, medication adherence, and strategies to address common relapse triggers.
    • See Alcohol Use Disorder for additional information.
  • For autoimmune autonomic ganglionopathy: IV immunoglobulin (IVIG), plasma exchange, immunosuppressant agents such as mofetil and rituximab, or a combination of these treatments has been reported in case reports/case series to be effective in some patients
  • For Guillain-Barre syndrome:
    • Hospital admission is required while symptoms progress (usually 2-4 weeks).
    • Carefully monitor for potentially life-threatening manifestations such as respiratory failure, cardiac arrhythmias, dysphagia, hemodynamic instability, and ileus.
    • Start IVIG or plasmapheresis (not both) as soon as possible after diagnosis.
    • Also monitor for gastrointestinal and bladder dysfunction, and pulmonary and urinary tract infections; manage pain and consider physical therapy, occupational therapy, and psychosocial support.
    • See Guillain-Barre Syndrome for additional information.
  • For amyloid light chain amyloidosis:
    • Autologous stem cell transplant (ASCT) with chemotherapy in low-risk patients, those who did not respond to initial chemotherapy, or those experiencing a relapse
    • Other options such as melphalan plus high-dose dexamethasone for intermediate- or high-risk patients ineligible for ASCT, or thalidomide plus dexamethasone for relapsing or refractory patients.
    • See Immunoglobulin Light Chain (AL) Amyloidosis for additional information.
  • For hereditary transthyretin (hATTR) amyloidosis:
    • Liver transplant is reported to increase survival, reduce symptoms, and improve neurophysiological measures.
    • Disease modifying medications such as patisiran, inotersen, diflunisal, and tafamidis may reduce progression.
  • For Lambert-Eaton myasthenic syndrome:
    • Treatment of the underlying tumor if there is a neoplastic etiology as malignancy (most often small cell lung cancer) occurs in 50%-60% of patients.
    • 3,4-diaminopyridine (3,4-DAP, amifampridine) for symptomatic treatment.
    • See Lambert-Eaton Myasthenic Syndrome for additional information.