Incomplete emptying and urinary retention in multiple-system atrophy: When does it occur and how do we manage it?

Incomplete Emptying and Urinary Retention in Multiple-SystemAtrophy: When Does It Occur and How Do We Manage It?

Takashi Ito, MD,1 Ryuji Sakakibara, MD, PhD,1* Kosaku Yasuda, MD, PhD,2 Tatsuya Yamamoto, MD,1

Tomoyuki Uchiyama, MD, PhD,1 Zhi Liu, MD,1 Tomonori Yamanishi, MD, PhD,3

Yusuke Awa, MD, PhD,4 Kaori Yamamoto, MD,4 and Takamichi Hattori, MD, PhD1

1Department of Neurology, Chiba University, Chiba, Japan2Department of Urology, Koshigaya Hospital, Dokkyo Medical College, Tochigi, Japan

3Department of Urology, Dokkyo Medical College, Tochigi, Japan4Department of Urology, Chiba University, Chiba, Japan

Abstract: Neurogenic urinary retention can be a major causeof morbidity in multiple-system atrophy (MSA). However, thetiming of its appearance has not been entirely clear, and neitherhave the medical and surgical modalities for managing patients.We present the data obtained from our uroneurological assess-ment and therapeutic interventions at various stages of MSA.We recruited 245 patients with probable MSA. We measuredpostvoid residuals (PVR) and performed EMG cystometry inall patients. The grand average volume of PVR was 140 mL(range, 0–760) in our patients. The average PVR volume was71 mL in the first year, increasing to 129 mL in the second yearand 170 mL by the fifth year. The percentages of patients withcomplete urinary retention, acontractile detrusor, and detrusor–sphincter dyssynergia (DSD) also increased. The increase inPVR resulted in a decrease in functional bladder capacity,together with an increase in detrusor overactivity and neuro-

genic sphincter EMG. Clean intermittent self-catheterization(CISC) was introduced in most patients. Bladder-oriented ther-apy (cholinergic agents) had a limited value, whereas urethra-oriented therapy benefited patients with DSD (surgery) for upto 2 years, but syncope occurred in a subset of patients (�-blockers). MSA patients present with large PVR by the secondyear of illness, and that large PVR secondarily causes urinaryfrequency. CISC is the recommended treatment for most pa-tients. Urethra-oriented medication and surgery benefit patientswho would have difficulty performing CISC, although carefulconsideration of the short-term efficacy and potential adverseeffects of these alternatives is mandatory. © 2006 MovementDisorder Society

Key words: multiple-system atrophy; urinary retention;clean intermittent self-catheterization; �-adrenergic antago-nists; transurethral sphincterotomy

Neurogenic lower urinary tract (LUT) dysfunctionand/or autonomic failure are the diagnostic prerequisitesfor multiple-system atrophy (MSA).1 Compared to auto-nomic failure, LUT dysfunction is more common andtends to appear earlier in MSA.2 Early evolution of LUTdysfunction differentiates MSA from other degenerativeParkinsonism.3 Meanwhile, urinary urgency/inconti-nence (storage disorder) and incomplete emptying/uri-nary retention (voiding disorder) can occur simulta-

neously.4–6 While urinary urgency/incontinence severelyaffects patient quality of life, incomplete emptying/uri-nary retention may lead to intractable LUT infection andkidney dysfunction, both of which are major causes ofmorbidity in this disorder. In contrast to urinary incon-tinence, postvoid residual (PVR) does not make itselfobvious to patients.7 Therefore, the timing of the appear-ance of urinary retention in MSA patients has not beenentirely clear.

Clean intermittent self-catheterization (CISC) is rec-ommended as the first-line treatment for urinary reten-tion in MSA.7,8 In some patients, however, frequentCISC is a bother, particularly at night. Moreover, forpatients with hand ataxia and tremor due to MSA-C(MSA cerebellar form), which is common in Japan,9

frequent CISC is difficult to perform. Such patients re-

*Correspondence to: Dr. Ryuji Sakakibara, Neurology Department,Chiba University, 1-8-1 Inohana Chuo-ku, Chiba 260-8670, Japan.E-mail: [email protected]

Received 8 June 2005; Revised 11 August and 12 September 2005;Accepted 13 September 2005

Published online 1 March 2006 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/mds.20815

Movement DisordersVol. 21, No. 6, 2006, pp. 816–823© 2006 Movement Disorder Society

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quire various therapeutic interventions, including medi-cal4,10,11 or surgical12–14 treatment. In patients withoutmarked postural hypotension, uroselective �-adrenergicantagonists have been used.11 In patients with detrusor–sphincter dyssynergia (DSD), transurethral sphincterot-omy has been performed.13 In contrast, when LUT dys-function is the sole initial manifestation of MSA in itsearly stages in men, LUT dysfunction is often attributedto prostatic hyperplasia, and consequently urological sur-gery is performed before the correct diagnosis has beenmade. Therefore, some researchers15 cautioned urolo-gists not to perform prostatic surgery routinely in pa-tients with red flags that suggest MSA. However, it hasnot been entirely clear whether these therapeutic inter-ventions are beneficial or detrimental to patients withMSA. We present here our results of uroneurologicalassessment at various stages of MSA to clarify the pro-gression of incomplete emptying/urinary retention. Wealso present the results of therapeutic interventions thatwe have performed.

PATIENTS AND METHODS

Patients

We recruited 245 patients with probable MSA accord-ing to the published criteria1 [141 men, 104 women;mean age, 59 years (range, 40–78); mean disease dura-tion, 3.4 years (range, 1–8; 29 patients, or 12%, �1year); 145 MSA-C; 100 MSA-P (MSA-parkinsonianform)]. We added an imaging study to confirm the diag-nosis of the early cases: all patients had at least oneabnormality in brain magnetic resonance imaging (MRI)and/or computed tomography (CT) scans, including pon-tocerebellar atrophy, abnormal signal intensity in thecerebellar peduncle, cross sign in the pons, and abnormalsignal intensity in the posterolateral putamen, all ofwhich were consistent with MSA and helped to excludeParkinson’s disease.16 Gene analysis was performed tothe extent possible in order to exclude hereditary spino-cerebellar ataxia. None of the patients had abnormalitiesin blood chemistry (including blood sugar) or urinalysis.None had abnormal findings of digital examinations orultrasound echography of the pelvic organs.

PVR Measurement and Urodynamic Study

After free flowmetry, we measured PVR in all patientsby transurethral catheterization. Follow-up PVR mea-surement was performed either by portable ultrasoundechography (BVI 3000 Bladder Manager; DiagnosticUltrasound, Redmond, WA) or by transurethral catheter-ization in the patients who received CISC. We performedstandard electromyography (EMG) cystometry in all pa-

tients using a urodynamic computer (Urovision; Life-tech, Houston, TX) and an EMG computer (NeuropackSigma; Nihon Kohden, Tokyo, Japan) according to themethods proposed by the International Continence Soci-ety.17 The filling-phase parameters were bladder capacityand detrusor overactivity (indicating phasic detrusorpressure increase � 10 cmH2O). Functional bladder ca-pacity was assigned as the difference between bladdercapacity and PVR. The voiding-phase parameters wereDSD (indicating an inability to relax the sphincter whilevoiding) and acontractile detrusor (indicating an inabilityto contract the detrusor without a urinary flow in patientswith large PVR). In patients who were able to void, weperformed pressure–flow analysis by the same urody-namic computer. Using Schafer’s nomogram,18 we clas-sified detrusor contractility: strong, normal, weak, orvery weak. A detrusor that was very weak and acontrac-tile was designated an underactive detrusor in the presentstudy. After inserting a concentric needle electrode in theexternal anal sphincter, we analyzed the motor unit po-tential (MUP) using the same EMG computer. Neuro-genic change was diagnosed when at least one of thefollowing abnormalities was seen: more than 20% MUPwith a duration � 10 milliseconds, or average duration ofMUP � 10 milliseconds, particularly including the latecomponents.19,20 Repeated urodynamic studies were car-ried out in the patients in whom bladder medicationswere washed out for several days. All patients gaveinformed consent before participating in the study. Sta-tistics were analyzed by the Student’s t test and the �2

test.

Therapeutic Intervention

We performed various therapeutic interventions in thepatients with large PVR. A generally accepted figure forPVR sufficient to start therapy is 100 mL.6,7 Therefore,we first introduced CISC in patients whose PVR ex-ceeded 100 mL, in a manner such that each 100 mLvolume of PVR corresponded to the number of catheter-izations per day (e.g., if a patient had 300 mL of PVR, heor she performed CISC three times a day), as taught byexpert nurses or by us. In addition to CISC, we intro-duced the Night Balloon (Intermittent Balloon Catheter;Tsukada Medical Research, Tokyo, Japan). It has somedifferences from a Foley urethral catheter, e.g., in orderto be used repeatedly and safely by the patients and theircaregivers, the Night Balloon has a closed water-pipesystem that connects a balloon at the tip of the catheterand a water reservoir near the orifice of the catheter.After inserting the Night Balloon into their urethra, pa-tients can easily squeeze the water reservoir to inflate theballoon and lock it. After unlocking, water in the balloon

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returns to the reservoir smoothly. If the patients preferredto maximize voluntary voiding or if it would have beendifficult to perform CISC for them, we performed thetherapies described below with the patients’ informedconsent.

We administered bladder-oriented medication, i.e.,cholinergic agonists: distigmine bromide (10–15 mg/day) and bethanechol chloride (30–45 mg/day), as wellas urethra-oriented medication, i.e., �-adrenergic antag-onists: prazosin hydrochloride (1–3 mg/day) and urapidil(30 mg/day; nonselective antagonists); moxisylyte hy-drochloride (30 mg/day) and tamsulosin hydrochloride(0.1–0.2 mg/day; �-1A/D receptor–selective antago-nists). We performed urethra-oriented surgery, i.e., trans-urethral sphincterotomy, mostly in the male patients. Wecollected as much data as possible on urological surgerythat had been performed at other hospitals, includingtransurethral resection of the prostate (TUR-P) andsphincteric wall stent (extendable automatically after in-sertion into the proximal urethra). We measured post-treatment PVR volume during a follow-up period of atleast 2 months. Therapeutic interventions were consid-ered effective if posttreatment PVR volume fell to lessthan 70% of the pretreatment value or to less than 100mL. We also performed balloon catheterization: (whole-day) transurethral and suprapubic balloon catheters. Thephysiological tests and the therapeutic intervention de-scribed in the text have been performed in accordancewith the ethical standards laid down in the 1964 Decla-ration of Helsinki and in the local committee of theuniversity hospital.

RESULTS

PVR Measurement and Urodynamic Study

The grand average PVR volume was 140 mL (range,0–760; normal, �30) in our patients. The average PVR

volume increased during the course of illness, from 71mL in the first year after disease onset, to 129 mL (P �0.01) in the second year, to 170 mL (P � 0.01) by thefifth year (Fig. 1). The percentages of patients withcomplete urinary retention (voluntary voided volume �10 mL), underactive detrusor, and DSD also increasedduring a 5-year period: from 0% to 14% (P � 0.05), from20% to 61% (P � NS), and from 12% to 39% (P �0.05), respectively. The average bladder capacity was389 mL in the first year after disease onset and haddecreased to 290 mL by the fifth year, although thedifference did not reach statistical significance (Fig. 2).The percentage of patients with detrusor overactivity orneurogenic sphincter EMG increased during a 5-yearperiod: from 61% to 75% (P � 0.05) and from 52% to83% (P � 0.05), respectively; the latter we reportedpreviously.20 The increase in PVR and the decrease inbladder capacity resulted in a marked decrease in thefunctional bladder capacity (from 319 to 120 mL; Fig. 3).

FIG. 1. Postvoid residual, underactive detrusor, detrusor–sphincterdyssynergia, complete retention, and duration of illness. Statisticalsignificance of a parameter in the second or fifth year was comparedwith that in the first year after onset of illness. NS, not significant.

FIG. 2. Bladder capacity, detrusor overactivity, neurogenic sphincterEMG, and duration of illness. Statistical significance of a parameter inthe fifth year was compared with that in the first year after onset ofillness. NS, not significant; EMG, electromyography. Sphincter EMGdata are cited from Yamamoto and colleagues.20

FIG. 3. Functional bladder capacity, urinary incontinence, and dura-tion of illness. Statistical significance of a parameter in the fifth yearwas compared with that in the first year after onset of illness. Func-tional bladder capacity � naive bladder capacity � postvoid residual.

818 T. ITO ET AL.


The percentage of patients with urinary incontinenceincreased during a 5-year period (from 44% to 64%; P �0.05).

Therapeutic Intervention

We introduced CISC in 94 of our patients. CISC wasgenerally well performed by the patients, with the aid oftheir spouses, families, and regularly visiting nurses. Inmost patients, CISC during the day reduced urinaryfrequency and urgency, while CISC before going to bedresulted in fewer nocturnal awakenings for urination. Inpatients who had micturition syncope, CISC also reducedthe number of syncope episodes. We also introduced theNight Balloon in three patients who had nighttime uri-nary frequency and urgency due to detrusor overactivityor nocturnal polyuria. All three patients managed welltheir CISC in the daytime and their in-dwelling NightBalloon at night, without infection. The Night Balloonbenefited the patients and caregivers by allowing them tosleep better. Anticholinergic medication (propiverine hy-drochloride) together with CISC also benefited the pa-tients and caregivers for ameliorating urgency/frequency.However, 2 to 3 years after the patients started to use awheelchair, they began to have much difficulty usingtheir hands (due to ataxia/tremor) and sitting (due totruncal ataxia/rigidity and postural hypotension), forcingthem to discontinue CISC.

We were able to introduce cholinergic agents in only10 patients (bethanechol, 4; distigmine, 6), because amajority of our patients had urinary urgency and fre-quency due to detrusor overactivity. The effectiveness ofthe cholinergic agents was 20% among those patients(2/10); it was 0% (0/4) in the patients receiving bethane-chol and 33% (2/6) in those receiving distigmine. In onepatient, the drug was withdrawn soon after it was admin-istered because of fecal incontinence (distigmine). In thepatients for whom the drugs were effective, the effec-tiveness lasted for 0.5 to 1 year during the observationperiod.

We introduced �-adrenergic antagonists in 40 patients(prazosin, 12; urapidil, 1; moxysylyte, 18; tamsulosin, 9).The effectiveness of these �-blockers was 53% (21/40)among those patients overall; 42% (5/12) among thepatients receiving prazosin; it was not effective in the 1patient receiving urapidil; 56% (10/18) in those receivingmoxysylyte; and 67% (6/9) in those receiving tamsulo-sin. In eight patients, the drugs were withdrawn shortlyafter they were administered because of syncope in threepatients (one receiving prazosin, one moxysylyte, andone tamsulosin), diarrhea in one, and exacerbation ofurinary frequency and incontinence in four. In the pa-tients for whom the drugs were effective, the effective-

ness lasted for 0.5 to 2 years during the observationperiod. There was no difference in the effectiveness ofthe �-blockers between patients with DSD (44%; 8/18)and those without it (59%; 13/22). The effectiveness wasmore prevalent in women (63%; 10/16) than in men(46%; 11/24), and it was more prevalent in patients witha disease duration � 4 years (65%; 15/23) than in thosewith a duration � 4 years (35%; 6/17), although thesedifferences did not reach statistical significance.

Urological surgery was performed in a total of 35patients (sphincterotomy, 23; TUR-P, 10, including 1with sphincterotomy as well; sphincteric wall stent, 3).Of these, 11 patients underwent surgery at our hospital,while the remaining patients did so at other hospitals,mostly before the correct diagnosis was made. The ef-fectiveness of the urological surgery was 74% among thepatients overall (26/35); it was 78% (18/23) in the pa-tients who underwent sphincterotomy and 80% (8/10) inthose who underwent TUR-P; but 33% (1/3) in thosewho underwent sphincteric wall stent. Three patientsdeveloped intractable urinary incontinence. In the pa-tients for whom the surgery was effective, the effective-ness lasted for 0.2 to 2 years in nine patients; it lasted �2 years in four patients, but two of them became totallyincontinent. The effectiveness was more prevalent inpatients with DSD (81%; 13/15) than in those without it(65%; 13/20), although the difference did not reach sta-tistical significance. There was no difference in effec-tiveness between patients with a disease duration � 2years (63%; 10/16) and those with a duration � 2 years(84%; 16/19).

We introduced the whole-day balloon catheter (13)and the suprapubic catheter (1) in patients at advancedstages of MSA. Three of them had frequent pyelonephri-tis requiring antibiotics therapy, but none developed kid-ney dysfunction.

DISCUSSION

Progression of Incomplete Emptying and UrinaryRetention in MSA

Time Course.

Results of urodynamic studies involving a total ofmore than 400 MSA patients have already been reported,with an average PVR volume of 160 to 275 mL in manystudies.4–6,14,21 Compared with those findings, the grandaverage PVR in the present study was slightly lower (140mL). This is presumably because up to 12% of ourpatients had a disease duration of 1 year or less, which isattributable to both a recent increase in early referrals toour department and to patients’ access to the department



without a referral. Therefore, the diagnosis of MSA insuch early cases should be made with extreme caution. Inaddition to the clinical diagnostic criteria,1 we added animaging study to confirm the diagnosis in all patients,and we performed gene analysis to the extent possible.Although a simple measure of PVR � 100 mL helps todistinguish MSA from Parkinson’s disease,4,6 the preva-lence of a large PVR as well as that of urinary retentionin the early stages of MSA has not previously been wellknown. We report here for the first time that the averagevolume of PVR was 71 mL in the first year after diseaseonset, increasing to 129 mL (P � 0.01) in the secondyear and to 170 mL (P � 0.01) by the fifth year. Com-plete urinary retention also increased during a 5-yearperiod (P � 0.05). Therefore, as expected, it is apparentthat the prevalence of incomplete emptying/urinary re-tention in MSA is time-dependent. In the very earlystages of MSA, the PVR volume is not large. In thesecond year of illness, the volume often exceeds 100 mL,the threshold for therapeutic intervention.7,8 Incompleteemptying felt by the patients can be a red flag for PVR.However, since patients with large PVR sometimes lacksuch complaints,7 the PVR volume should be checked atregular intervals in MSA patients in the second year ofillness or longer.

Underlying Mechanism.

The major abnormalities of the voiding-phase cystom-etry in neurogenic LUT dysfunction are underactive de-trusor for the bladder and DSD for the urethra.22 In thepresent study, the percentage of patients with underactivedetrusor and DSD increased during a 5-year period from20% to 61% and from 12% to 39% (P � 0.05), respec-tively. Therefore, as suggested previously,5,6,21 detrusorfailure seems to contribute more than DSD does to uri-nary retention in MSA. Since we defined an underactivedetrusor in this study as a urodynamically apparent, veryweak, and acontractile one, the incidence of detrusorfailure in MSA seems to be higher than it would be ifother definitions were used. The acontractile detrusor hasbeen considered a postganglionic dysfunction of the pel-vic nerves that innervate the bladder.22 In our previousstudy,2 repeated urodynamic tests in MSA patientsshowed that detrusor overactivity (reflecting central-typedysfunction) tended to change to low-compliance detru-sor (reflecting preganglionic dysfunction), which furtherchanged to acontractile detrusor together with the devel-opment of cholinergic supersensitivity; this latter changewas also noted by Khurana.23 Therefore, in these pa-tients, the responsible site of the lesion for detrusordysfunction seems to change from the center to theperiphery during the course of illness.2 These urody-

namic findings are relevant to the sites of pathologicallesions reported in MSA24: the pontine micturition center(the locus ceruleus or its adjacent area)25,26; the striatumand the substantia nigra27,28; the cerebellar vermis29; thesacral intermediolateral nucleus and Onuf’s nucleus19,20,30;and, contributing even less to the urodynamic abnormal-ities, the postganglionic cholinergic fibers24. Since MSAis primarily a preganglionic disorder, transsynaptic de-generation may account for the development of a post-ganglionic type of cholinergic dysfunction.

Like the percentage of underactive detrusor on void-ing, the percentage of detrusor overactivity during stor-age increased during a 5-year period (P � 0.05). There-fore, it is not uncommon for patients with urinaryretention to have urinary urgency also during storage.Because of the urgency sensation, some patients neededto perform CISC very frequently, even at night. Thiscondition is described as detrusor hyperactivity withimpaired contracting function (DHIC).31 Although we donot know the exact mechanism underlying DHIC, inMSA patients this condition presumably reflects multiplelesions in the brain that facilitate and inhibit the micturi-tion reflex25 (i.e., lesions in the pontine micturition center(facilitatory) and the basal ganglia [mainly inhibitory])or a single partial lesion in the spinal autonomic path-ways, where the micturition reflex arc is disrupted, andbelow the lesion, a C-fiber–mediated novel sacral reflexarc can emerge.25 Detrusor overactivity and, to a lesserextent, sphincter weakness due to a lesion on Onuf’snucleus20 contribute to the decrease in bladder capacityduring a 5-year period. In combination with the de-creased bladder capacity, increased PVR significantlydecreased the functional bladder capacity, which second-arily caused urinary frequency and incontinence, whichalso increased during a 5-year period (P � 0.05).

Therapeutic Intervention for Incomplete Emptyingand Urinary Retention in MSA

Catheterization: CISC, Night Balloon,and In-Dwelling Balloon Catheter.

Up to now, CISC has been considered the gold stan-dard for managing neurogenic urinary retention, since itis the surest method (mechanical evacuation) and thesafest (intermittent use to prevent infection; no generaladverse event).7,8 CISC has fewer burdens than the in-dwelling balloon catheter, which causes sociopsycho-logical stress, although the in-dwelling balloon catheteris chosen in most advanced cases. In keeping with thestandard method,7,8 we introduced CISC to our MSApatients with urinary retention, to the benefit of mostpatients. In our patients, CISC ameliorated urinary fre-

820 T. ITO ET AL.


quency and urgency since it increased functional bladdercapacity. In our MSA patients with micturition syncope,CISC also reduced the number of syncope episodes,presumably by reducing abdominal strain.32 However, inthe MSA patients with DHIC or nocturnal polyuria,33

frequent CISC is a bother, particularly at night. Threesuch patients were taught to use the Night Balloon, and allof them successfully managed it without infection. There-fore, the Night Balloon will become a good option beforethe introduction of an in-dwelling balloon catheter. Anti-cholinergic medication together with CISC is another op-tion for ameliorating nighttime urgency/frequency.10

Bladder-Oriented Medication and CholinergicAgonists.

The bladder has an abundance of M2 and M3 types ofmuscarinic receptors, and the latter accounts for smoothmuscle contraction in humans.34 The stimulation of thesereceptors by cholinergic agonists seems to improve thetreatment of detrusor failure through the augmentation ofsmooth muscle contraction. Previously, Khurana andcolleagues35 reported improved bladder function in twoMSA patients after subcutaneous injection of bethane-chol. However, in our patients, the effectiveness of cho-linergic drugs was low (only 20%) and lasted for lessthan 1 year. In addition, due to DHIC, in which cholin-ergic stimulation might worsen detrusor overactivity, wewere able to introduce cholinergic drugs in only 10patients. Therefore, there seems to be a limited scenariofor the use of cholinergic drugs in the treatment ofurinary retention in MSA.

Urethra-Oriented Medication: �-AdrenergicAntagonists.

The proximal urethra has an abundance of �-1A/Dsubtypes of adrenergic receptors,36,37 whereas the vascu-lar wall, particularly in the elderly, has an abundance ofthe �-1B subtype of adrenergic receptors.38 �-1 adren-ergic antagonists that block these receptors have beenused widely to treat prostatic hyperplasia and hyperten-sion.36 They also are used to treat DSD in patients withspinal cord injuries, resulting in a decrease in EMGactivities and urethral pressure.39–41 In our previousstudy, a 4-week trial of �-blockers showed decreases inPVR by up to 38% in MSA patients.11 In the presentstudy, the effectiveness of �-blockers was modest (53%of patients) and lasted for less than 2 years; this effec-tiveness was not clearly related with DSD. Patients witha disease duration less than 4 years and female sexbenefited more from the treatment than the other patients.Of the various �-blockers, uroselective �-1A/D receptorantagonists, i.e., moxisylyte and tamsulosin, benefited up

to 67% of the patients. These drugs showed a relativelylow frequency of adverse events, such as postural hypo-tension, that were in accordance with the findings of ourprevious study,11 although higher doses of tamsulosinthat are used in many countries might cause greaterpostural hypotension. Although the treatment windowwas narrow (urinary incontinence in some patients) andthe effectiveness was transient, uroselective drugs mayhave a place in the treatment of PVR, particularly inpatients at an early stage of MSA, female patients, andpatients without postural hypotension.

In the present study, we did not analyze the effects ofsympathetic stimulants on urinary retention. However, inour previous study,42 we noted increased PVR in patientsreceiving sympathetic stimulants, which are widely usedto treat postural hypotension in MSA.43 These drugsstimulate both �-1B receptors abundant in the vascularwall and �-1A/D receptors in the proximal urethra.Therefore, nonselective sympathetic stimulants may in-crease the risk of urinary retention in MSA patients.

Urethra-Oriented Surgery: Sphincterotomy, TUR-P,and Sphincteric Wall Stent.

Surgery for neurogenic urinary retention has beenstudied most extensively in spinal cord injuries.44–47

This is because patients with cervical cord lesions oftenhave difficulty performing CISC.48 Transurethral sphinc-terotomy lessened PVR volume and the frequency ofincontinence episodes in 63% to 76% of patients.44,45

Sphincteric wall stent is reported to benefit all patientswho underwent the surgery.47 Two of the present authors(K.Y. and T.Y.) have performed transurethral sphincter-otomy and TUR-P in 26 patients with neurogenic urinaryretention of various etiologies and noted improvement in92% of them.49 Based on these experiences, we haveperformed sphincterotomy in patients with MSA. SinceMSA is a progressive neurodegenerative disorder, someresearchers believe that MSA patients should not haveurological surgery.4,15 Nearly half of the patients re-ported by Beck and colleague4 already had undergoneurological or gynecological surgery before they werediagnosed with MSA, and only 3 of 20 men and none of7 women benefited from the surgery. Six months post-operatively, eight men had developed urinary retention.In our 35 patients, 24 had undergone surgery in otherhospitals, mostly without a diagnosis of MSA, and theremaining 11 patients underwent surgery at our hospital.In contrast to the poor surgical outcome reported byBeck and colleagues,4 the short-term outcome in ourpatients was better; the effectiveness was 78% in sphinc-terotomy and 80% in TUR-P, but only 33% in sphinc-teric wall stent; and the effectiveness was higher in those



who had DSD. However, in most patients, the effective-ness lasted only for 0.2 to 2 years. This is in accordancewith the fact that the increase in underactive detrusor wasmore rapid than that of DSD during a 5-year period in thepatients with MSA. Therefore, urethra-oriented surgeryshould be undertaken only for patients who require it,especially men with DSD, although in such cases, carefulconsideration of its short-term efficacy is mandatory.Particularly, the patients need to decide themselveswhether they want to accept the risks of surgery for thesake of maximally 2 years of improved micturition.

In conclusion, the results of the present study suggestthat MSA patients present with large PVR (�100 mL)from the second year of illness, and that large PVRsecondarily causes urinary frequency. CISC is the rec-ommended treatment for most patients. Urethra-orientedmedication and surgery benefit patients who prefer tomaximize voluntary voiding or who have difficulty per-forming CISC, although careful consideration of theirshort-term efficacy and potential adverse effects ismandatory.

Acknowledgments: This study was supported in part by agrant from the U.S. National Organization of Rare Disorders.The patients were cared for by staff members of the 11th EastNeurology Ward of the Chiba University Hospital. We thankDr. Mika Kinou and Ms. Chiharu Yamaguchi for theirassistance.

REFERENCES

1. Gilman S, Low PA, Quinn N, et al. Consensus statement on thediagnosis of multiple system atrophy. J Auton Nerv Syst 1998;74:189–192.

2. Sakakibara R, Hattori T, Uchiyama T, Kita K, Asahina M, SuzukiA, Yamanishi T. Urinary dysfunction and orthostatic hypotensionin multiple system atrophy: which is the more common and earliermanifestation? J Neurol Neurosurg Psychiatry 1999;67:1–5.

3. Wenning GK, Scherfler C, Granata R, et al. Time course ofsymptomatic orthostatic hypotension and urinary incontinence inpatients with postmortem confirmed parkinsonian syndromes: aclinicopathological study. J Neurol Neurosurg Psychiatry 1999;67:620–623.

4. Beck RO, Betts CD, Fowler CJ. Genitourinary dysfunction inmultiple system atrophy: clinical features and treatment in 62cases. J Urol 1994;151:1336–1341.

5. Stocchi F, Carbone A, Inghilleri M, Monge A, Ruggieri S, Be-rardelli A, Manfredi M. Urodynamic and neurophysiological eval-uation in Parkinson’s disease and multiple system atrophy. J Neu-rol Neurosurg Psychiatry 1997;62:507–511.

6. Sakakibara R, Hattori T, Uchiyama T, Yamanishi T. Videourody-namic and sphincter motor unit potential analyses in Parkinson’sdisease and multiple system atrophy. J Neurol Neurosurg Psychi-atry 2001;71:600–606.

7. Fowler CJ, O’Malley KJ. Investigation and management of neu-rogenic bladder dysfunction. J Neurol Neurosurg Psychiatry 2003;74(Suppl. 4):27–31.

8. Fowler CJ. Neurological disorders of micturition and their treat-ment. Brain 1999;122:1213–1231.

9. Watanabe H, Saito Y, Terao S, et al. Progression and prognosis inmultiple system atrophy: an analysis of 230 Japanese patients.Brain 2002;125:1070–1083.

10. Politi P, Sandri SD, Marino V, Fanciullacci F, Catanzaro F,Zanollo A. Treatment of micturitional disorders in the Shy–Dragersyndrome with oxybutynin chloride and self-intermittent catheter-ization. Neurourol Urodynam 1986;5:391–395.

11. Sakakibara R, Hattori T, Uchiyama T, et al. Are alpha-blockersinvolved in lower urinary tract dysfunction in multiple systematrophy? a comparison of prazosin and moxisylyte. J Auton NervSyst 2000;79:191–195.

12. Yasuda K, Hattori T, Hama T, Yamashiro Y, Murayama N,Hirayama K, Shimazaki J. Management of micturitional distur-bance in the patients with Shy–Drager syndrome: part 1, relation-ship to the activity of daily living. Nihon Hinyokika Gakkai Zasshi1983;74:1837–1843.

13. Yasuda K, Hattori T, Hama T, Yamashiro Y, Murayama N,Hirayama K, Shimazaki J. Management of micturitional distur-bance in the patients with Shy–Drager syndrome: part 2, results ofself-catheterization, uro-pharmacotherapy and transurethral resec-tion of bladder neck. Nihon Hinyokika Gakkai Zasshi 1983;74:1844–1850.

14. Wheeler JS, Canning JR. Voiding dysfunction in Shy–Dragersyndrome. J Urol 1985;134:362–363.

15. Chandiramani VA, Palace J, Fowler CJ. How to recognize patientswith parkinsonism who should not have urological surgery. Br JUrol 1997;80:100–104.

16. Wenning GK, Colosimo C, Geser F, Poewe W. Multiple systematrophy. Lancet Neurol 2004;3:93–103.

17. Abrams P, Cardozo L, Fall M, et al. The standardization ofterminology of lower urinary tract function: report from the stan-dardization sub-committee of the International Continence Society.Neurourol Urodynam 2002;21:167–178.

18. Schafer W. Principles and clinical application of advanced urody-namic analysis of voiding dysfunction. Urol Clin North Am 1990;17:553–566.

19. Palace J, Chandiramani VA, Fowler CJ. Value of sphincter elec-tromyography in the diagnosis of multiple system atrophy. MuscleNerve 1997;20:1396–1403.

20. Yamamoto T, Sakakibara R, Uchiyama T, et al. When is Onuf’snucleus involved in multiple system atrophy? a sphincter electro-myography study. J Neurol Neurosurg Psychiatry (in press).

21. Kirby R, Fowler C, Gosling J, Bannister R. Urethro-vesical dys-function in progressive autonomic failure with multiple systematrophy. J Neurol Neurosurg Psychiatry 1986;49:554–562.

22. Blaivas JG. The neurophysiology of micturition: a clinical study of550 patients. J Urol 1982;127:958–963.

23. Khurana RK. Cholinergic dysfunction in Shy–Drager syndrome:effect of the parasympathomimetic agent, bethanechol. Clin AutonRes 1994;4:5–13.

24. Daniel SE. The neuropathology and neurochemistry of multiplesystem atrophy. In: Bannister R, Mathias CJ, editors. Autonomicfailure, 3rd ed. Oxford: Oxford Medical Publications; 1992. p564–585.

25. de Groat WC, Booth AM, Yoshimura N. Neurophysiology ofmicturition and its modification in animal models of human dis-ease. In: Maggi CA, editor. Nervous control of the urogenitalsystem. London: Harwood Academic Publishers; 1993. p 227–290.

26. Benarroch EE, Schmeichel AM. Depletion of corticotrophin-re-leasing factor neurons in the pontine micturition area in multiplesystem atrophy. Ann Neurol 2001;50:640–645.

27. Sakakibara R, Nakazawa K, Uchiyama T, Yoshiyama M, Yaman-ishi T, Hattori T. Micturition-related electrophysiological proper-ties in the substantia nigra pars compacta and the ventral tegmentalarea in cats. Auton Neurosci Basic Clin 2002;102:30–38.

28. Yoshimura N, Kuno S, Chancellor MB, De Groat WC, Seki S.Dopaminergic mechanisms underlying bladder hyperactivity inrats with a unilateral 6-hydroxydopamine (6-OHDA) lesion of thenigrostriatal pathway. Br J Pharmacol 2003;139:1425–1432.

29. Sakakibara R, Uchida Y, Uchiyama T, Yoshiyama M, YamanishiT, Hattori T. Reduced cerebellar vermis activation in response to

822 T. ITO ET AL.


micturition in multiple system atrophy: 99mTc-labeled ECDSPECT study. Eur J Neurol 2004;11:705–708.

30. Vodusek DB. Sphincter EMG and differential diagnosis of multi-ple system atrophy. Mov Disord 2001;16:600–607.

31. Resnick NM, Yalla SV. Detrusor hyperactivity with impairedcontractile function. JAMA 1987;257:3076–3081.

32. Uchiyama T, Sakakibara R, Asahina M, Yamanishi T, Hattori T.Post-micturitional hypotension in patients with multiple systematrophy. J Neurol Neurosurg Psychiatry 2005;76:186–190.

33. Sakakibara R, Matsuda S, Uchiyama T, Yoshiyama M, YamanishiT, Hattori T. The effect of intranasal desmopressin on nocturnalwaking in urination in multiple system atrophy patients with noc-turnal polyuria. Clin Auton Res 2003;13:106–108.

34. Yamanishi T, Yasuda K, Kamai T, Tsuji T, Sakakibara R, Uch-iyama T, Yoshida K. Combination of a cholinergic drug and analpha-blocker is more effective than monotherapy for the treatmentof voiding difficulty in patients with underactive detrusor. IntJ Urol 2004;11:88–96.

35. Khurana RK, Nelson E, Azzarelli B, Garcia JH. Shy–Drager syn-drome: diagnosis and treatment of cholinergic dysfunction. Neu-rology 1980;30:805–809.

36. Chapple CR. Alpha-adrenergic blocking drugs in bladder outflowobstruction: what potential has alpha-adrenoceptor selectivity?Br J Urol 1995;76(Suppl. 1):47–55.

37. Malloy BJ, Price DT, Price RR, et al. Alpha 1-adrenergic receptorsubtypes in human detrusor. J Urol 1998;160:937–943.

38. Hieble JP, Bylund DB, Clarke DE, et al. International Union ofPharmacology X: recommendation for nomenclature of alpha 1-ad-renoceptors, consensus update. Pharmacol Rev 1995;47:267–270.

39. Nanninga JB, Kaplan P, Lal S. Effect of phentolamine on perinealmuscle EMG activity in paraplegia. Br J Urol 1977;49:537–539.

40. Petersen T, Husted SE. Prazosin treatment of neurological patientswith lower urinary tract dysfunction. Int Urogynecol J 1993;4:106–110.

41. Perrigot M, Delauche-Cavallier MC, Amarenco G, Geffriaud C,Stalla-Bourdillon A, Costa P, DORALI study group. Effect ofintravenous alfzosin on urethral pressure in patients with neuro-genic bladder dysfunction. Neurourol Urodynam 1996;15:119–131.

42. Sakakibara R, Uchiyama T, Asahina M, Yamanishi T, Hattori T.Amezinium metilsulfate, a sympathomimetic agent, may increasethe risk of urinary retention in multiple system atrophy. Clin AutonRes 2003;13:51–53.

43. Mathias CJ, Senard JM, Braune S, Watson L, Aragishi A, KeelingJEA, Taylor MD. L-threo-dihydroxyphenylserine (L-threo-DOPS;droxydopa) in the management of neurogenic orthostatic hypoten-sion: a multi-national, multi-center, dose-ranging study in multiplesystem atrophy and pure autonomic failure. Clin Auton Res 2001;11:235–242.

44. Jonas U, Petri E, Hohenfellner R. Indication and value of bladderneck incision. Urol Int 1979;34:260–265.

45. Lockhart JL, Vorstman B, Weinstein D, Politano VA. Sphincter-otomy failure in neurogenic bladder disease. J Urol 1986;135:86–89.

46. Vepnek JM, Couillard DR, Stone A. Is sphincterotomy the bestmanagement of the spinal cord injured bladder? J Urol 1994;15:961–964.

47. Sauerwein D, Gross AJ, Kurtzenberger J, Ringert RH. Wallstentsin patients with detrusor–sphincter dyssynergia. J Urol 1995;154:495–497.

48. Dahlberg A, Perttila I, Wuokko E, Ala-Opas M. Bladder manage-ment in persons with spinal cord lesion. Spinal Cord 2004;42:694–698.

49. Yamanishi T, Yasuda K, Tojo M, Murayama N, Wada T,Shimazaki J. Transurethral surgery for the treatment of neurogenicbladder dysfunction. Nishi Nihon Hinyokika 1991;53:933–937.



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Incomplete emptying and urinary retention in multiple-system atrophy: When does it occur and how do we manage it?