J Am Board Fam Pract: first published as 10.3122/jabfm.8.4.325 on 1 July 1995. Downloaded from Shy-Drager Syndrome: Recognition And Management

Abdulrazak Abyad, MD, MPH, AGSF

Shy-Drager syndrome is an uncommon disorder been using a straight urinary catheter six times in which the patient experiences progressive auto­ daily since that hospitalization. nomic failure. It is a multisystem degenerative In the interview she said that during the last disease that involves the central autonomic, cer­ 2 years she had progressive difficulty in walking, ebellar, basal ganglia, pyramidal, or spinal motor with a tendency to fall to the left side. This neurons. The mean age of onset is 55 years. A unsteadinesss of gait had led to three falls, none male predominance is noted, with a 2 or 3:1 ratio. with loss of consciousness. She described the epi­ About 11 percent of patients with orthostatic sode of falling as loss of balance while standing hypotension have Shy-Drager syndrome. The but denied any actual vertigo, weakness, , disease is progressive, and patients die 7 to 20 years , tinnitus, or headache. It was because of after the onset of neurologic symptoms. The syn­ her falls and frequent incontinence that she in­ drome was first noted in 1925, when Bradbury sisited on retiring from a nursing career of 20 and Eggleston 1 published a paper on 3 patients years. She also had been feeling light-headed on with postural hypotension and unchanging pulse standing and used a cane intermittently. Her rate. Shy and Drager2 provided the first compre­ daughter noted deterioration in her mother's hensive clinical and pathologic details of central handwriting and that buttoning was becoming involvement in this disorder. more a difficult task. The patient denied dys­ We report 1 patient with cholinergic dysfunction phagia, bowel problems, or sleep disturbances. and . The diagnosis of this She had a weight loss of 60 pounds during the rare neurological disease in our patient was made previous 3 years, thought to be secondary to a through a work-up in a geriatric assessment unit. stressful situation at home. She had had a tonsillectomy in 1940. Thrombo­ Case Report .' . cytopenia and anemia were diagnosed in 1976 as a A 65-year-old woman was seen m our gerIatrIC consequence of hypothyroidism, and she had been assessment clinic on 31 October 1989. She was a prescribed levothyroxine since 1976. She had a http://www.jabfm.org/ registered nurse who retired because of pro­ history of a positive tuberculin test (PPD) for gressive gait and incontinence problems of about which she was prescribed isoniazid and pyridox­ 2 years' duration. ine for 1 year in 1980. Her family history included The patient had been admitted to a local hos- a benign thyroid tumor and kidney stones in the pital on 2 Apri11989 wit~ acute urina~ reten­ daughter, heart disease in both her father and tion, urinary tract infection, and ataXIa. It was mother, and colon cancer in an aunt. There was noted then that the patient had both stress and no history of neurological disorders. Her current on 24 September 2021 by guest. Protected copyright. urge incontinence with the like.l~ diagnosis of medications were amitriptyline 25 mg daily at neurogenic bladder.. Her condltl?n h~d been bedtime and levothyroxine 0.15 mg daily. treated previously WIth urethral dtlatatlOn, be­ Three weeks before her initial clinic visit, the thanechol, and nitrofurantoin, with no apparent patient was brought to Arizona from Iowa by her improvement, so the patient discontinued the daughter, who was living in Tucson. The patient's treatment on 31 March 1989. The patient had youngest daughter and her grandchildren had moved in with her in Iowa, and according to her local daughter, there was considerable familial upset and strife during these past several years that contributed to the patient's not doing well. Submitted revised, 15 March 1995 From the Arizona Center on Aging, University of Arizona Before her youngest daughter and grandchildren Medical School Tucson, AZ. Address reprint r~quests .t~ A. moved in, the patient had lived alone since her MPH AGSF Department of FamJly MedICIne, Ab ya,d MD , , , Th' d A husband's suicide in 1965. The patient's own American University of Beirut, C/O AUB Office, 850 Ir v- enue, 18th Floor, New York, NY 10022. mother was in a nursing home in Sioux City,

Shy-Drager Syndrome 325 J Am Board Fam Pract: first published as 10.3122/jabfm.8.4.325 on 1 July 1995. Downloaded from Iowa, and the patient was seeing her Illother fre­ ings from the rest of her general examination qlll:ntly and was helping in her Gm.:. were normal. The patient W~lS alert and oriented but had llIinor difliclllties ITIllelllbering the particulars of Difl'erential Diagnosis specific events. She W,lS somewhat slow in re­ Possibile diagnoses initially entertained were sponding to questions, hut her answers were in­ midline cerebellar tumor vesus hydrocephalus vari;lhly accurate, ,1S verified by her daughter. I Ier (ohstructive versus normal pressure), chronic sub­ blood pressure was 150/<)0 lIlmHg supine but dural hematoma, and Shy-Drager syndrome. dropped to ()O systolic after I minute and flO sys­ Laboratory evaluation included a complete blood tolic after 5 minutes in the standing position. The count, urinalysis, automated sequential analysis patient became markedly dizzy and felt as though (SMA-20), erythrocyte sedimentation rate, sero­ she was going to t~lint. No increase in pulse rate logic test for syphilis, serum BI2 and folate meas­ was noted. r Ter pulse rate was 70 heats per minute urements, fasting blood glucose test, and choles­ ,md regular with no beat-to-heat variability, and terol profile, in addition to nerve conduction no murmur W,lS heard. studies and thyroxine, thyroid-stimulating hor­ Iler neurological examination showed that mone levels. The only positive findings were a tri­ crani~d nerves II through XII were int'lct. A glyceride value of 110 mg/dL and a cholesterol motor exami nation of both upper and lower ex­ value of 158 mg/dL. A computed tomogram of tn.:mities failed to elicit ,my evidence of focal the brain (with and without contrast media) Illotor deficit to active or resistance testing. Deep showed a larger left ventricle without signs of ob­ tendon reflexes were diminished on the left struction and a probable small colloid cyst in the ankle. There was no Babinski reflex, no tremor, area of the third ventricle. An intravenous pyelo­ IlO masked facies, and no ll1onotonus voice or gram showed probable cystitis and mild blunting cogwheel rigidity; her skin and oral mucosa were of the calyces, possibly secondary to reflux. Find­ slightly dry. Pinprick sensation appeared to be in­ ings on a routine chest radiograph were consis­ tact. Vibratioll was diminished in the lower ex­ tent with chronic obstructive pulmonary disease. tremities and upper extremities. The laboratory data were otherwise normal. ()n gait testing, the patient's gait was unsteady A diagnosis of Shy-Drager syndrome was when she was not using a cane, and she tended to made, and the patient was educated about the dis­

veer and t:ll1 toward her left, which was accentuated ease. She was instructed to avoid activities that http://www.jabfm.org/ on turning. There was a positive Romberg sign promote venous pooling and encouraged to do toward the left. The patient was able with con­ mild exercise, especially swimming. She was in­ centration to perform rapid alternating move­ structed to drink more coffee, especially after a ment and heel-shin-toe maneuvers successfully, meal, and was advised to sit on the side of the bed although somewhat less accurately and slower for several minutes before getting up in the than normal. She also had a mild dysmetria dur­ morning. It was also suggested that she sleep with ing a finger-tn-nose maneuver (worse with the the head of her bed elevated 8 to 12 inches. She on 24 September 2021 by guest. Protected copyright. left hand). The patient fell backward when she was prescribed fludrocortisone, 0.05 mg twice closed her eyes, hut there was no drift. Her gait daily, which improved the symptoms of ortho­ was slow and careful, and she had di fflculty static hypotension. Further improvement was turning but did not shuffle. She felt lightheaded achieved when the dose was increased to 0.1 mg when asked to look up while standing and when twice daily. A higher dose was attempted, but the asked to look over her head while supine. Pres­ patient developed numerous marked side effects sure Oil each carotid ,lrtery sep;lrately did not re­ ,It th,lt level, so the dose was reduced to the previ­ produce the symptom of lightheadedness. The ous level. fundi were normal, and extraocular muscles were intact with no nystagmus. Visu,ll field testing was Discussion normal to confrontation. The Folstein Mini­ The manifestation and the neurologic findings in ivlent,ll State examinatioll score was 30/30, consis­ Shy-Drager syndrome are summarized in Tables tent with normal cognition,; and the results of the 1 and 2. The major manifestation is autonomic Ceriatric Depression Scale-+ were normal. Find- insufficiency with wide swings in blood pressure

32(' JABFP July-August I <)95 Vol. 1\ No. -+ J Am Board Fam Pract: first published as 10.3122/jabfm.8.4.325 on 1 July 1995. Downloaded from Table 1. Neurologic Findings in the Shy-Drager the central nervous system. I ,5 Cholinergic insuffi­ Syndrome. ciency also occurs, which causes abnormalities in vagal,6,7 ocular,S bladder,2 and sweat gland 9 func­ Manifestations System tions. In the patient described here, urinary tract Autonomic symptoms were prominent and preceded other Visual Visual dimness, Horners syndrome, symptoms. She refused to use medication for uri­ iris atrophy, anisocoria, decreased nary tract symptoms after failing to benefit from lacrimation, corneal insensitivity, impaired eye movement, nystagmus low doses of bethanechol. Many patients with Shy-Drager syndrome have a transurethral resec­ Genital Impotence, loss of libido tion without benefit. 10 More useful medications , Urinary Noctural diuresis, incontinence, retention such as bethanechol chloride, selectively stimu­ late muscarinic receptors. 11,12 Subcutaneous ad­ Cardiovascular , syncope, orthostatic hypo­ tension ministration of bethan echoI chloride has not only Temperature Heat intolerance, sweat disturbances relieved urinary and bowel dysfunction but regulation also activated secretions by all glands, suggesting Gastrointestinal , , incontinence hypersensitive responses of the end organs. 13 Somatic Attempts to treat the cerebellar ataxia have so Corticospinal and Dysarthria, hyperreflexia, Babinski sign far proved fruitless. There has been some success corticobulbar with some drugs, including 5-hydroxytryptophan, Cerebellum Ataxia of gait, intention tremor isoniazid, baclofen, and propranolol. Apparent Basal ganglia Resting tremors, rigidity, masked facies temporary exacerbations of ataxia have resulted Anterior horn cells Muscle atrophy and fasciculation from cigarette smoking. 13 A severe reduction in and neuromuscu- the level of noradrenaline in the central nervous lar junction system also occurs in both Parkinson disease and , but thus far trials using but no changes in pulse rate. Patients complain of drugs known to enhance or antagonize noradrena­ dizziness, syncope, or lightheadedness on stand­ line seem to be without substantial effect in either 14 ing; postexertional weakness; an.d ~steadi~ess of disorder. gait. Central neuron degeneratIon IS marufested Treatment of postural hypotension is fraught by parkinsonian features, intention tremor, ataxia, with difficulties. Principles of management in­ http://www.jabfm.org/ dysarthria, and in some cases, corti co bulbar and clude the following: First, it is important to be corticospinal tract signs. Intellec~al and. emo­ concerned about a low standing biood pressure if tional functions are preserved untIl late m the the patient has symptoms. Studies of patients with course of the disease. Laboratory studies are usu­ autonomic failure and multiple system atrophy ally normal, although some nonspecific electro­ have found that autoregulation was preserved at a encephalogram abnormalities have been reported. systolic blood pressure approaching 60 mmHg, An electromyogram might show involvement of which is well below the 80 mmHg at which auto- on 24 September 2021 by guest. Protected copyright. anterior horn cells. There are a number of simple tests that can be Table 2. Manifestations of the Shy-Drager Syndrome in used to screen for autonomic dysfunction. One Approximate Descending Order of Frequency. is the response of blood pressure and heart ~ate to assuming the upright posture. Another slm~le Orthostatic hypotension test is the diastolic pressure overshoot followmg Impotence (male) the Valsalva maneuver. A simple test is the hand­ Pyramidal signs grip test with measurement of heart rate an~ blood Sweating abnormalities pressure. An inspection of the electroca~dlOgram Extrapyramidal signs Bladder dysfunction for respiratory arrhythmia can also prOVIde useful Cerebellar signs dues. Dysarthria Autonomic dysfunction in the Shy-Drager syn- Gastrointestinal dysfunction drome is an example of multiple system atrophy Others and is attributed to efferent adrenergic failure in

Shy-Drager Syndrome 327 J Am Board Fam Pract: first published as 10.3122/jabfm.8.4.325 on 1 July 1995. Downloaded from regulation fails in normal persons. i5 ,il) Second, Table 3. Treatment Modalities for Orthostatic patients have a tendency to develop recumbent Hypotension. hypertension. Third, the long-terfll adjustment to .Vlodalitit:s f)elaillkscriptions postural hypotension is through control of blood volume, determined by antidiuretic hormone and !iJ',ldicate conditions that Etvor pooling the renin-angiotensin-aldosteronc mechanism. o'-hlood and illlpt:de venous returns (:orrect eiccrrolytt: disturbance and Sever,)l factors can lower blood pressure and volullle depiction thus enhance postural hypotension. Straining, f()r Flilllin,lIe h)'P0tensio11-inducing drugs example, might result in a Valsalva maneuver with 'I i'cat 'ldrcnal insufliciency, hypothy­ substantial reduction in blood pressure. The su­ roidislll, anelllia, '1I1d other lre,ltahk pine blood pressure in patients with autonomic diseases failure is lowest in the Illorning and rises gradu­ ( )thel' (vlcclw 11 ica I TJe'HI-up positioJl of hed ally during the day. Patients exposed to high tem­ Fbslicizl'd hody g'trIlle111 to peratures tend h,lve more symptoms. Substan­ ,Vlild exercise if tolerated tial postprandial hypotension occurs soon after Plasllla and extra­ Iligh-S

32X JABFP July-August 1995 Vol. X No.4 J Am Board Fam Pract: first published as 10.3122/jabfm.8.4.325 on 1 July 1995. Downloaded from hypertension. In higher doses it can expand the 5. Young RR, Asbury AK, Corbett JL, Adams RD. blood volume, improve cardiac output, and there­ Pure pan- with recovery. Description fore reduce postural hypotension. In the elderly, and discussion of diagnostic criteria. Brain 1975; 98:613-36. however, it can lead to heart failure or cause re­ 6. Evans DJ, Lewis PD, Malhotra 0, Pallis C. Idio­ bound hypertension, as occurred with our pa­ pathic orthostatic hypotension. Report of an autop­ tient. Desmopressin is a vasopressin-like agent sied case with histochemical and ultrastructural stud­ that has antidiuretic effects. Administered intra­ ies of the neuronal inclusions. J N eurol Sci 1972; muscularly, desmopressin prevents nocturnal 17:209-18. polyuria and overnight weight loss and raises the 7. Lewis HD Jr, Dunn M .. Orthostatic hypotension syn_ supine blood pressure in the morning.28 Studies drome: a case report. Am HeartJ 1967; 74:396-401. 8. RosenJ, Brown SI. New ocular signs in Shy-Drager with intranasal desmopressin indicate that it is syndrome. AmJ Ophthalmol1974; 78: 1032-3. equally effective; its major limiting side effect is 9. Caronna JJ, Plum F. Cerebrovascular regulation in hyponatremia. preganglionic and postganglionic autonomic insuffi­ Supportive measures include telling patients ciency. Stroke 1973; 4:12-9. to sleep with a head-up tilt at night in an attempt 10. Chokroverty S, Barron KD, Katz FH, Del Greco F, 29 Sharp JT. The syndrome of primary orthostatic to increase the patient's blood volume by reduc­ hypotension. Brain 1969; 92:743-68. ing renal arterial pressure and promoting renin 11. Koelle GB. Parasympathomimetic agents. In: Good­ release and thus increasing blood volume.27 A man LS, Gilman A, editors. The pharmacolOgical basis temporary measure after a patient has been re­ of therapeutics. New York: Macmillan, 1975: 467-76. cumbent for a few days is the use of a custom­ 12. Burleigh DE. Selectivity of bethanechol on mus­ 3D carinic receptors. J Pharm Pharmacol 1978; 30: fitted elastic counterpressure garment. These 398-9. measures were attempted in the patient described 13. Johnsen JA, Miller VT. Tobacco intolerance in here with partial improvement of her symptoms. multiple system atrophy. 1986; 36: 986-8. The use of a cardiac pacemaker can be useful to 14. N~r~bayashi H, Kondo T, Yokochi F, Nagatsu T. elevate heart rate during postural change. 31 Ben­ ~hmcal.effecn: of L-threo-3,4-dihydroxyphenylserine efit has occurred in patients who apparently have 111 parkinsomsm and pure akinesia. Adv Neurol 1987;45:593-602. had an incomplete autonomic lesion. A pacemaker 15. Hoeldtke RD, O'Dorisio TM, Boden G. Treatment can also prevent excessive bradycardia in response of autonomic neuropathy with a somatostatin ana­ to elevation of blood pressure by drugs. In the fu­ logue SMS-201-995. Lancet 1986; 2:602-5. ture there is hope for the development of a device 16. T~omas DJ, Bannister R. Preservation of autoregu­ http://www.jabfm.org/ that is closely linked to blood pressure control latIOn of cerebral blood flow in autonomic failure. J Neurol Sci 1980; 44:205-12. and that can administer short-acting drugs, such 17. Sc.hirg~r A, Sheps SG, Thomas JE, Fealey RD. as noradrenaline, when neededY Mldodrme: a new agent in the management of idio­ pathic orthostatic hypotension and Shy-Drager syn_ Conclusion drome. Mayo Clin 1981; 56:429-33. Despite the rarity of this condition, it is important 18. Diamond MA, Murray RH, Schmid PG. Idiopathic

to consider this diagnosis in the differential diag­ postural hypotension: physiologic observations and on 24 September 2021 by guest. Protected copyright. nosis of idiopathic orthostatic hypotension. report of a new mode of therapy. J Clin Invest 1970; 49:1341-8. 19. Mathias CJ, Fosbraey P, da Costa DF, Thorley A, Bannister R. Desmopressin reduces nocturnal poly­ References uria, reverses overnight weight loss and improves 1. Bradbury S, Eggleston C. Postural hypotension: a morning postural hypotension in autonomic failure. report of three cases. Am HeartJ 1925; 1:73-86. Br MedJ 1986; 293:353-4. 2. Shy GM, Drager G",:, A neurolo~ical s~d~ome asso­ 20. Nordenfelt I, Mellander S. Central haemody­ ciated with orthostanc hypotenSIOn: a climcal-patho­ namic effects of dihydroergotamine in patients with logic study. Arch Neuro11960; 2:511-27. orthostatic hypotension. Acta Med Scand 1972; 3. Folstein MF, Folestein SE, Mc Hugh PRo 'Mini 191:115-20. Mental State': a practical method for grading the 21. C~obanian AV, Volker L, Liang CS, Kershaw G, cognitive state of patients for the clinician. J Psychi­ Tifft C. Use of propranolol in the treatment of idio­ atr Res 1975; 12:189-98. pathic orthostatic hypotension. Trans Assoc Am 4. YesavageJA, Brink T~, Lum~. Development.an.d Physicians 1977; 90:324-34. validation of a geriatriC depreSSIOn scale. A prelImi­ 22. OnrotJ, Goldberg MR, Biaggioni I, Hollister AS I nary report.J Psychiatr Res 1983; 17:37-49. Kincaid D, Robertson D. Haemodynamic and hu~ l Shy-Drager Syndrome 329 J Am Board Fam Pract: first published as 10.3122/jabfm.8.4.325 on 1 July 1995. Downloaded from moral dfecls of cafkine in ,lutonomic Elilure. Thera­ sion in patients with orthostatic hypotension. New peutic implic'ltions fi)r post prandial hypotension. Engl J iVied 197<); 30 I :6X-7.l. New EnglJ ;\!Jed IlJX5; 313:54<)-54. 2K. Bannister R, Sever P, Cross M. Cardiovascular re­ .2.l. Camnn;l ././, Plulll F Cerehrov:I~Cld:lr regul:Jrion in flexes 'Inti hiochemical responses in progressive preganglionic ,lIld postganglionic autonomic insuffi­ autonomic failure. Brain t

330 JABFP July-August J995 Vol. 8 No.4