Kristen Thornton, MD, Autonomic dysfunction: CWSP, FAAFP, AGSF; Marlon O. Mitchell, MD Highland Hospital Family Medi- A guide for FPs cine Residency, University of Rochester School of Medicine & Dentistry, NY (Dr. Thornton); Impotence, bladder dysfunction, GI symptoms, MedStar Washington Hospital Center, Washington, DC and can signal autonomic (Dr. Mitchell) dysfunction. Here’s what you’ll see and how to respond. Kristen_Thornton@URMC. Rochester.edu

The authors reported no potential conflict of interest relevant to this article.

igns and symptoms of autonomic dysfunction com- PRACTICE monly present in the primary care setting. Potential RECOMMENDATIONS causes of dysfunction include certain medications and ❯ Begin a trial of an S age-related changes in physiology, as well as conditions such antimuscarinic if initial as mellitus, , and Parkinson’s dis- nonpharmacologic treatment of 1 urge incontinence or overactive ease (TABLE ). This evidence-based review details common bladder is ineffective. B manifestations of autonomic dysfunction, provides a stream- lined approach to patients presenting with symptoms, and re- ❯ Start step-wise treatment views appropriate step-wise management. beginning with metoclo- pramide A , followed by domperidone, and, finally, oral erythromycin B in patients When a delicate balance is disrupted with who have The autonomic provides brisk physiologic failed conservative measures. adjustments necessary to maintain homeostasis. Physiologic ❯ Employ step-wise pharmaco- functions impacted by the central nervous system include: logic treatment, starting with heart rate, blood pressure (BP), tone of the bladder sphinc- fludrocortisone, for patients ter and detrusor muscle, bowel motility, bronchodilation and with disabling symptoms of constriction, pupillary dilation and constriction, sweating, cat- orthostatic hypotension who echolamine release, erection, ejaculation and orgasm, tearing, fail to respond to nonpharma- and salivation.1 cologic measures. B Disorders of the autonomic system may result from pa-

Strength of recommendation (SOR) thologies of the central or peripheral nervous system or from A Good-quality patient-oriented medications including some antihypertensives, selective evidence serotonin-reuptake inhibitors (SSRIs), and opioids.1 Such B Inconsistent or limited-quality disorders tend to be grouped into one of 3 categories: those patient-oriented evidence involving the brain, those involving the , and auto-  C Consensus, usual practice, opinion, disease-oriented nomic neuropathies.1 evidence, case series The source of can often be determined by clinical context, coexisting neurologic abnormalities, targeted testing of the , and neuroimaging.1

Worrisome symptoms prompt a visit A thorough history is critical to zeroing in on a patient’s com- plaints and ultimately providing treatment that will help man- age symptoms. CONTINUED

JFPONLINE.COM VOL 66, NO 9 | SEPTEMBER 2017 | THE JOURNAL OF FAMILY PRACTICE 539 When patient complaints are suggestive TABLE of autonomic dysfunction, a review of sys- Conditions associated tems should include inquiry about lighthead- 1 edness, abnormal salivation, temperature with autonomic dysfunction changes of the extremities, gastrointestinal • Alcoholism/alcoholic neuropathy issues (, , or ), • and symptoms of presyncope/syncope or • urinary or sexual dysfunction.1 The physical • Cerebral infarcts exam should include recordings of BP and heart rate in the supine and standing posi- • Diabetes mellitus tions and a complete neurologic examina- • Guillain-Barré syndrome tion.1 Findings will typically point to one or • Huntington’s disease more common complications. • Multiple sclerosis • Multiple systems atrophy • Parkinson’s disease Common complications of autonomic dysfunction • Porphyria Complications of autonomic dysfunction • Postural orthostatic syndrome include impotence, bladder dysfunction, • Primary hyperhidrosis If diabetic gastrointestinal (GI) dysfunction, and ortho- • Pure autonomic failure autonomic static hypotension and vasomotor abnormal- • Reflex sympathetic dystrophy neuropathy ities. A less common condition—autonomic • Spinal cord lesions dysreflexia, which is a distinct type of auto- is the suspected • Toxic neuropathies etiology nomic dysfunction, and a true medical emer- • Tumors, paraneoplastic neuropathies of impotence, gency—is also important to keep in mind. consider prescribing a Impotence Bladder dysfunction phosphodiester- Autonomic neuropathy is a common cause of Sympathetic activity increases bladder ase inhibitor. impotence and retrograde ejaculation. Loss sphincter tone and inhibits detrusor activity, of early morning erections and complete loss while the parasympathetic nervous system of nocturnal erections often have an etiology increases detrusor activity and decreases related to vascular disease and/or autonomic sphincter tone to aid in voiding.1 Disrupted neuropathy. In addition, poor glycemic con- autonomic activity can lead to urinary fre- trol and vascular risk factors appear to be quency, retention, and hesitancy; overactive associated with the development of diabetic bladder; and incontinence.1 Brain and spinal autonomic neuropathy.2 cord disease above the level of the lumbar Development of an erection requires an spine results in urinary frequency and small increase in parasympathetic activity and a de- bladder volumes, whereas diseases involving crease in sympathetic output. Nocturnal penile autonomic nerve fibers to and from the blad- tumescence testing has been used to infer para- der result in large bladder volumes and over- sympathetic damage to the penis in men with flow incontinence.9 diabetes who do not have vascular disease.3 Patients presenting with lower urinary ❚ First- and second-line agents. Phos- tract symptoms require a comprehensive phodiesterase-5 inhibitors (eg, sildenafil, evaluation to rule out other pathologies, as tadalafil, vardenafil) have demonstrated -ef the differential for such symptoms is broad ficacy in improving the ability to achieve and and includes infection, malignancies, inter- maintain erections in patients with auto- stitial cystitis, and bladder stones. The initial nomic dysfunction, including diabetic auto- evaluation of lower urinary tract symptoms nomic neuropathy.4-6 Second-line therapies should include a history and physical exam with proven efficacy include intraurethral including that of the abdomen, pelvis, and application and intracavernosal injections of neurologic system. Lab work should assess alprostadil.7,8 renal function and blood glucose, and should

540 THE JOURNAL OF FAMILY PRACTICE | SEPTEMBER 2017 | VOL 66, NO 9 AUTONOMIC DYSFUNCTION

include urinalysis and culture to rule out in- mittent straight catheterization or chronic fection and/or hematuria. A prostate-specific indwelling foley or suprapubic catheters antigen (PSA) test may be appropriate in to void. men with a life expectancy >10 years, after counseling regarding the risks and benefits of Gastrointestinal dysfunction screening. In patients with diabetes, GI autonomic ❚ drugs with antimus- neuropathy can result in altered esophageal carinic effects, such as oxybutynin, may be motility leading to gastroesophageal reflux used to treat symptoms of urge incontinence disease (GERD) or , gastroparesis, and overactive bladder. They work to sup- or diabetic enteropathy.14 Gastroparesis often press involuntary contractions of the blad- presents as , vomiting, and bloating.1 der’s smooth muscle by blocking the release It may be diagnosed via gastric emptying of acetylcholine. These medications relax the studies (scintigraphy), and often requires a bladder’s outer layer of muscle—the detru- multidimensional approach to treatment. sor. Such medications often have a number ❚ Management. Food may be chopped of anticholinergic adverse effects, such as dry or pureed to aid in digestion. Metoclopramide mouth and constipation, sometimes lead- is the most commonly used prokinetic agent, ing to discontinuation. A post-void residual but avoid its use in patients with parkinson- (PVR) test may be helpful in guiding manage- ism. In more severe cases, consider adding ment. For example, caution should be used in domperidone and erythromycin as proki- patients with elevated PVRs, as anticholiner- netic agents. Recommend antiemetics, such type A, injected gics can worsen . as diphenhydramine, ondansetron, and pro- directly into ❚ Beta-3 agonists (eg, mirabegron) are chlorperazine for management of nausea and the detrusor a novel class of medications used to treat vomiting. Severe cases of gastroparesis may muscle, can be overactive bladder. These medications act merit a venting gastrostomy tube for decom- as effective as to increase sympathetic tone in the bladder. pression and/or feeding via a jejunostomy medication in Because they have the potential to raise BP, tube.15 Impaired intestinal mobility may lead patients with monitor BP in patients taking these agents. In to stasis syndrome, causing diarrhea. urinary urge addition, monitor patients taking antimusca- ❚ Hypermobility caused by decreased incontinence. rinics or beta-3 agonists for the development sympathetic inhibition can also contribute of urinary retention. to diarrhea. Altered anal sphincter function ❚ Other tests, treatments. Urodynamic tone may contribute to . testing is recommended for patients who Management should focus on balancing elec- fail to respond to treatment. Combining be- trolytes, maintaining adequate fluid intake, havioral therapy with medication has been and relieving symptoms. Consider antidiar- shown to be effective in patients with urge rheals such as loperamide, but use them with incontinence.10 Botulinum toxin type A, in- caution to avoid toxic megacolon.16 jected directly into the detrusor muscle, can ❚ Constipation. Another common mani- be as effective as medication in patients with festation of autonomic dysfunction in the urinary urge incontinence.11 GI tract is severe constipation.1 This may be ❚ Detrusor underactivity is defined as managed conservatively with hydration, in- contraction of reduced strength and/or dura- creased activity, and increased fiber intake. tion, resulting in prolonged bladder emptying If such measures prove inadequate, consider and/or a failure to achieve complete bladder stool softeners and laxatives. emptying within a normal timespan.12 This Patients with constipation due to spi- diagnosis is typically made using urodynamic nal cord lesions may benefit from a routine testing.13 PVRs ≥150 mL are considered evi- bowel regimen. To provide predictable def- dence of urinary retention. Overflow inconti- ecation, advise patients to begin by inserting nence can result from detrusor underactivity. a stimulant rectal suppository. Follow with Consider a trial of a cholinergic agonist, gentle digital stimulation of the distal rectum such as bethanechol, in patients with urinary for one minute or less. They’ll need to repeat retention. Some patients will require inter- the process every 5 to 10 minutes until stool

JFPONLINE.COM VOL 66, NO 9 | SEPTEMBER 2017 | THE JOURNAL OF FAMILY PRACTICE 541 evacuation is complete. A forward-leaning alpha adrenergic blockers, vasodilators, an- position may assist with evacuation. It is tipsychotics, antidepressants (SSRIs, trazo- helpful to perform this routine at the same done, monoamine oxidase inhibitors, and time each day.17 tricyclic antidepressants), phosphodiester- ase inhibitors, narcotics, and antiparkinso- Orthostatic (postural) hypotension nian medications.22 The autonomic nervous system plays an im- Lifestyle interventions, such as having portant role in maintaining BP during po- the patient arise slowly and maintain good sitional changes. The sympathetic nervous hydration, can be helpful. Eating smaller, system adjusts the tone in arteries, veins, and more frequent meals may also help if the the heart. Baroreceptors located primarily orthostatic hypotension is triggered post- in the carotid arteries and aorta, are highly prandially. Compressive stockings can help sensitive to changes in BP. When the baro- limit venous pooling in the lower extremi- receptors sense the slightest drop in pres- ties and improve venous return. Tensing the sure, a coordinated increase in sympathetic legs by crossing them while standing on both outflow occurs. Arteries constrict to increase feet has been shown to increase cardiac out- peripheral resistance and BP, and heart rate put and BP.23 An aerobic exercise regimen of and contractility increase, all in an attempt to walking or stair climbing 30 to 45 minutes/- maintain BP and perfusion.18 day 3 days/week for 6 months was shown The most ❚ The most common causes of ortho- to eliminate symptoms of orthostasis on tilt common causes static hypotension are not neurologic in table testing in elderly patients with cardiac of orthostatic origin,9 but rather involve medications, hypo- deconditioning, as opposed to chronic auto- hypotension are volemia, and impaired autonomic reflexes. nomic failure.24 not neurologic The condition is common in the elderly, with The reduction in central blood volume in origin, but one study demonstrating a prevalence of associated with autonomic insufficiency (due rather involve 18.2% in those ≥65 years.19 to increased urinary sodium and water excre- medications, Orthostatic hypotension may present tion) can be lessened by increasing sodium hypovolemia, with dimming or loss of vision, lightheaded- and water intake.25-27 and impaired ness, diaphoresis, diminished hearing, pallor, ❚ Pharmacotherapy. Fludrocortisone ac- autonomic and weakness. As a result, it is a risk factor etate, a synthetic mineralocorticoid, is the reflexes. for falls. Syncope results when the drop in BP medication of first choice for most patients impairs cerebral perfusion. Signs of impaired with orthostatic hypotension whose symp- baroreflexes are supine hypertension, a heart toms are not adequately controlled using rate that is fixed regardless of posture (the nonpharmacologic measures,28 but keep in heart rate should increase upon standing), mind that treating orthostatic hypotension postprandial hypotension, and an excessively with fludrocortisones is an off-label use of the high nocturnal BP.1 medication. ❚ Orthostatic hypotension is diagnosed Monitor patients taking fludrocorti- when, within 3 minutes of quiet standing af- sone for worsened supine hypertension and ter a 5-minute period of supine rest, one or edema. Also, check their serum potassium both of the following is present: at least a levels one to 2 weeks after initiation of ther- 20 mm Hg-fall in systolic pressure or at least apy and after dose increases. Frequent home a 10 mm Hg-fall in diastolic pressure.20 Soysal monitoring of BP in sitting, standing, and su- et al demonstrated that such a drop in BP, pine positions may be helpful in assessing re- measured one minute after standing, is ade- sponse to therapy. quate and effective for diagnosing orthostatic If the patient remains symptomatic de- hypotension in the elderly.21 spite therapy with fludrocortisone, consider ❚ Nonpharmacologic management. Rec- adding an alpha-1 adrenergic agonist, such ognition and removal of medications that can as midodrine. Avoid prescribing midodrine, exacerbate orthostatic hypotension is the however, for patients with advanced cardio- first step in managing the condition. Such vascular disease, urinary retention, or uncon- medications include diuretics, beta-blockers, trolled hypertension.29

542 THE JOURNAL OF FAMILY PRACTICE | SEPTEMBER 2017 | VOL 66, NO 9 AUTONOMIC DYSFUNCTION

Autonomic dysreflexia: Medicated Urethral System for Erection (MUSE) Study Group. N Engl J Med. 1997;336:1-7. A medical emergency 8. Linet OI, Ogrinc FG. Efficacy and safety of intracavernosal al- , a medical emergency prostadil in men with . The Alprostadil Study Group. N Engl J Med. 1996;334:873-877. that must be recognized immediately, is a 9. Engstrom JW, Maring JB. Disorders of the autonomic nervous system. In: Braunwald E, Fauci AS, Kasper DL, et al, eds. Harri- distinct type of autonomic dysfunction seen son’s Principles of Internal Medicine. 15th ed. New York, NY: Mc- in patients with spinal cord injury at or above Graw Hill; 2001. 30 10. Burgio KL, Locher JL, Goode PS. Combined behavioral and drug the T6 level. It is a condition of uncontrolled therapy for urge incontinence in older women. J Am Geriatr Soc. sympathetic response secondary to an un- 2000;48:370-374. 11. Visco AG, Brubaker L, Richter HE, et al. Anticholinergic therapy derlying condition such as infection, urinary vs. onabotulinumtoxinA for urgency . N retention, or rectal distention.30 Engl J Med. 2012;367:1803-1813. 12. Haylen BT, de Ridder D, Freeman RM, et al. An International Uro- Common symptoms include headache, gynecological Association (IUGA)/International Continence So- significant hypertension, flushing of the ciety (ICS) joint report on the terminology for female pelvic floor dysfunction. Neurourol Urodyn. 2010;29:4-20. skin, and diaphoresis above the level of in- 13. Osman NI, Chapple CR, Abrams P, et al. Detrusor underactivity jury.2 In addition, a review of systems should and the underactive bladder: a new clinical entity? A review of current terminology, definitions, epidemiology, aetiology, and screen for fever, visual changes, abnormali- diagnosis. Eur Urol. 2014;65:389-398. ties of the cardiovascular system, syncope, 14. Kempler P, Amarenco G, Freeman R, et al. Management strategies for gastrointestinal, erectile, bladder, and sudomotor dysfunction bowel and bladder symptoms, and sexual in patients with diabetes. Diabetes Metab Res Rev. 2011;27:665- dysfunction. 677. 15. Camilleri M. Clinical practice. Diabetic gastroparesis. N Engl J Patients demonstrating autonomic dys- Med. 2007;356:820-829. reflexia should be placed in the upright po- 16. Shakil A, Church RJ, Rao SS. Gastrointestinal complications of When non- diabetes. Am Fam Physician. 2008;77:1697-1702. sition to produce an orthostatic decrease in 17. Krassioukov A, Eng JJ, Claxton G, et al. Neurogenic bowel man- pharmacologic BP. 30 Patients should be evaluated to identify agement after spinal cord injury: a systematic review of the evi- measures don’t dence. Spinal Cord. 2010;48:718-733. any reversible precipitants, such as urinary 18. Bradley JG, Davis K. Orthostatic hypotension. Am Fam Physician. control retention or fecal impaction. Severe attacks 2003;68:2393-2399. orthostatic 19. Rutan GH, Hermanson B, Bild DE, et al. Orthostatic hypotension involving hypertensive crisis require prompt in older adults. The Cardiovascular Health Study. CHS Collabora- hypotension, transfer to the emergency department. tive Research Group. Hypertension. 1992;19(6 Pt 1):508-519. consider the 20. Freeman R, Wieling W, Axelrod FB, et al. Consensus statement Sublingual nifedipine or an intravenous on the definition of orthostatic hypotension, neurally mediated off-label use of agent, such as hydralazine, may be used to syncope and the postural tachycardia syndrome. Clin Auton Res. fludrocortisone. 2011;21:69-72. 31 lower BP. JFP 21. Soysal P, Aydin AE, Koc Okudur S, et al. When should orthostatic BP changes be evaluated in elderly: 1st, 3rd or 5th minute? Arch CORRESPONDENCE Gerontol Geriatr. 2016;65:199-203. Kristen Thornton, MD, 777 South Clinton Ave., Rochester, NY 22. Perlmuter LC, Sarda G, Casavant V, et al. A review of the etiology, 14620; [email protected] associated comorbidities, and treatment of orthostatic hypoten- sion. Am J Ther. 2013;20:279-291. 23. Ten Harkel ADJ, van Lieshout JJ, Wieling W. Effects of leg muscle pumping and tensing on orthostatic arterial pressure: a study in normal subjects and patients with autonomic failure. Clin Sci. References 1994;87:553-558. 1. Low PA, Engstrom JW. Disorders of the autonomic nervous sys- 24. Carroll JF, Wood CE, Pollock ML, et al. Hormonal responses in tem. In: Kasper D, Fauci A, Hauser S, et al, eds. Harrison’s Prin- elders experiencing pre-syncopal symptoms during head-up tilt ciples of Internal Medicine. 19th ed. New York, NY: McGraw-Hill; before and after exercise training. J Gerontol A Biol Sci Med Sci. 2015. Available at: http://accessmedicine.mhmedical.com/con- 1995;50:M324-M329. tent.aspx?bookid=1130&Sectionid=79755967. Accessed May 15, 25. Shannon JR, Diedrich A, Biaggioni I, et al. Water drinking as a 2016. treatment for orthostatic syndromes. Am J Med. 2002;112:355- 2. Ko SH, Park SA, Cho JH, et al. Progression of cardiovascular dys- 360. function in patients with type 2 diabetes: a 7 year follow-up study. 26. Young T, Mathias C. The effects of water ingestion on orthostatic Diabetes Care. 2008;31:1832-1836. hypotension in two groups of chronic autonomic failure: multiple 3. Brown JS, Wessells H, Chancellor MB, et al. Urologic complica- system atrophy and pure autonomic failure. J Neurol Neurosurg tions of diabetes. Diabetes Care. 2005;28:177-185. Psychiatry. 2004;75:1737-1741. 4. Rendell MS, Rajfer J, Wicker PA, et al. Sildenafil for treat- 27. Humm AM, Mason LM, Mathias CJ. Effects of water drinking on ment of erectile dysfunction in men with diabetes: a random- cardiovascular responses to supine exercise and on orthostatic ized controlled trial. Sildenafil Diabetes Study Group. JAMA. hypotension after exercise in pure autonomic failure. J Neurol 1999;281:421-426. Neurosurg Psychiatry. 2008;79:1160-1164. 5. Goldstein I, Young JM, Fischer J, et al. Vardenafil, a new phos- 28. Campbell IW, Ewing DJ, Clarke BF. 9-Alpha-fluorohydrocortisone phodiesterase type 5 inhibitor, in the treatment of erectile in the treatment of postural hypotension in diabetic autonomic dysfunction in men with diabetes: a multicenter double- neuropathy. Diabetes. 1975;24:381-384. blind placebo-controlled fixed-dose study. Diabetes Care. 29. Raj SR, Coffin ST. Medical therapy and physical maneuvers in the 2003;26:777-783. treatment of the vasovagal syncope and orthostatic hypotension. 6. Sáenz de Tejada I, Anglin G, Knight JR, et al. Effects of tadalafil Prog Cardiovasc Dis. 2013;55:425-433. on erectile dysfunction in men with diabetes. Diabetes Care. 30. Karlsson AK. Autonomic dysreflexia. Spinal Cord. 1999;37:383- 2002;25:2159-2164. 391. 7. Padma-Nathan H, Hellstrom WJ, Kaiser FE, et al. Treatment of 31. Bycroft J, Shergill IS, Choong EAL, et al. Autonomic dysreflexia: a men with erectile dysfunction with transurethral alprostadil. medical emergency. Postgrad Med J. 2005;81:232-235.

JFPONLINE.COM VOL 66, NO 9 | SEPTEMBER 2017 | THE JOURNAL OF FAMILY PRACTICE 543