Autonomic Disorders of the Urogenital System

8/11/2019 Autonomic Disorders of the Urogenital System

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AUTONOMIC

DISORDERS OF THEUROGENITAL SYSTEMClare J. Fowler

ABSTRACT

The highly distributed nature of the neural control of the bladder and genitaliameans that disorders of these functions are very likely to occur with many differentneurologic diseases, although the range of symptoms is limited. In this chapter theclinical presentations and recommended management of urogenital symptoms inthree conditions are described: multiple sclerosis, the commonest cause ofneurogenic urogenital dysfunction; multiple system atrophy, a much less commoncondition, but one in which urogenital dysfunction occurs early; and a disorder ofvoiding, which affects neurologically healthy women, now referred to as Fowlerssyndrome.

Continuum Lifelong Learning Neurol 2007;13(6):165181.

INTRODUCTION

The lower urinary tract is peripherallyinnervated by nerves of the autonomicnervous system, but a hierarchy ofhigher centers is involved in the per-ception of bladder fullness and thedecision about the appropriateness of

when to void. In fact, continencedepends on the integrity of the centraland peripheral nervous systems at manydifferent levelspossibly more so thanany other bodily function. Thus, dis-turbances of bladder function can resultfrom disease or disorders of the neo-

cortex, basal ganglia, pons and brainstem, spinal cord, and the peripheralinnervation. But because the repertoireof bladder behavior is limited, the rangeof dysfunction is also restricted. Therecan be abnormalities of the storagephase, ie, incontinence, or abnormali-ties of the voiding phase, ie, retention,or a combination of both problems,

while the neurologic causes are diverse.The neurology of sexual function is

less well defined, but it again depends

on innervation of the genitalia byautonomic system nerves while highercenters modulate that innervation.

In this chapter three disorders thatcause bladder and or sexual dysfunc-tion will be reviewed, with a briefdescription for each condition of theneurologic basis for the urogenitaldysfunction, the clinical presentation,and the recommended management.

MULTIPLE SCLEROSIS

Neurologic Basis ofUrogenital Symptoms

Urogenital symptoms in multiple scle-rosis (MS) are common and resultmainly from spinal cord involvement,so that some correlation betweenlower limb and bladder dysfunction isoften clinically apparent (Betts et al,1993). In health, a complex of brainnetworks is involved in the two pro-cesses of bladder storage and voiding,but the final output of these processesis either activation or inhibition of acenter in the dorsal tegmentum of the

165

KEY POINTS:

A The highly

distributed

nature of the

neural control ofthe bladder and

genitalia means

that disorders of

these functions

are very likely to

occur with many

different

neurologic

diseases,

although the

range of

symptoms

is limited.

A The lower urinary

tract is

peripherally

innervated by

nerves of the

autonomic

nervous system,

but a hierarchy of

higher centers is

involved in the

perception of

bladder fullness

and the decision

about the

appropriateness

of when to void.

A Urogenital

symptoms in MS

are common and

result mainly

from spinal cord

involvement, so

that some

correlationbetween lower

limb and bladder

dysfunction is

often clinically

apparent.

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.


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pons, the pontine micturition center(PMC) (Figure 7-1).

From the PMC, direct pathways

project to the sacral segments of thespinal cord (S2-S4) and control para-sympathetic outflow to the detrusorand reciprocal activation of the striatedurethral sphincter. During storage, pa-rasympathetic motor innervation of thedetrusor is inhibited so that the de-trusor pressure does not rise as thebladder fills and tonic firing of themotor units of the striated urethralsphincter and pelvic floor maintain thepressure of the urethra higher than

that within the bladder. At the initia-tion of micturition, a relaxation of thestriated urethral sphincter and pelvicfloor occurs, followed by a coordinatedcontraction of the detrusor muscle.This synergistic activity between thesphincter and the detrusor depends on

connections with the PMC. If theseconnections are damaged or interrup-ted, sphincter contraction may occur as

the detrusor contracts, causing thedisorder known as detrusor sphincterdyssynergia. The most marked abnor-mality, however, which develops fol-lowing disconnection from the PMC, isa newly formed segmental reflex thatcauses reflex detrusor contractions inresponse to bladder distension. Unmy-elinated C fibers, hitherto quiescent(and therefore known as silent Cfibers), become mechanosensitive andrespond to bladder stretch (de Groat

et al, 1990). This afferent activity,through synaptic activity in sacral seg-ments of the cord, causes detrusorcontractions and is responsible for theemergence of the condition of neuro-genic detrusor overactivity (DO) andcomplaints of urinary frequency, ur-gency, and urgency incontinence.

Evidence also points to spinal cordinvolvement as the major cause oferectile dysfunction (ED) in MS (Bettset al, 1994). Cord involvement in MSmay initially result in a partial deficit, sothat ED is variable but with preservedpenile erections nocturnally and onmorning waking (Kirkeby et al, 1988).In the last 20 years the error of thedictum if a man can get an erectionat anytime, impotence is likely to bepsychogenic has been recognized. EDhas been estimated to affect between50% and 75% of men with MS (Zorzonet al, 1999), depending on the severity

of disability of the group studied.Women with MS report sexual dysfunc-tion less frequently than men (Zorzonet al, 1999), but nevertheless, it is aproblem that is thought to affect morethan 50% of women, and incidence in-creases with increasing disability.

Clinical Presentation

Bladder dysfunction. Urinary fre-quency, urgency, and urgency incon-tinence, reflecting the underlying DO

166

FIGURE 7-1 Location of pontine micturitioncenter (PMC). This illustrationhighlights the need for spinal

cord integrity for bladder control since it isparasympathetic and somatic innervation arisesfrom the sacral segments 2-4.

KEY POINT:

A In the last

20 years the

error of the

dictum if aman can get

an erection at

anytime,

impotence is

likely to be

psychogenic

has been

recognized.

"DISORDERS OF THE UROGENITAL SYSTEM



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and easily demonstrable on cystome-try, are the most common bladdercomplaints in MS. Frequency is due to

the reduced bladder capacity. Urgencyand, if the patient cannot hold on,urgency incontinence, are due to in-

voluntary detrusor contractions. Symp-toms of incomplete bladder emptyingmay be much less prominent, thepatient only admitting to these ifdirectly asked, Do you feel emptyafter voiding? or Can you void againsoon after just doing so? It was foundthat patients who thought they werenot emptying their bladder were often

correct, but half of those who thoughtthey were emptying their bladder werelikely to be wrong; hence, the im-portance of measuring the postmictu-rition residual volume with ultrasound(Figure 7-2).

With worsening neurologic diseaseand increasing spinal cord lesions suchthat mobility deteriorates, bladder con-trol is likely to become more difficult totreat. This is a result of worsening ofDO, inefficient emptying of the blad-der, possibly recurrent urinary tractinfections, spasticity, reduction in gen-eral mobility, and sometimes, cognitiveimpairment. Fortunately, however, incontrast to urinary tract dysfunctionfollowing traumatic spinal cord injury,MS rarely causes upper urinary tractinvolvement (Sirls et al, 1994). This istrue even when long-standing MS hasresulted in severe disability and spas-ticity. The reason is not known, but the

implication is that the focus of man-agement should be on symptomaticrelief.

Sexual dysfunction. A study thatanalyzed the type of sexual dysfunc-tion that affected men with MS who

were still ambulant found that ED wasthe most common complaint (63%),followed by ejaculatory dysfunctionand/or orgasmic dysfunction (50%)and reduced libido (40%) (Zorzonet al, 1999). Other nonspecific effects

of MS may also have adverse effects onsexual function, including fatigue, de-pression, spasticity, and anxiety about

incontinence.Although a recent questionnairesurvey of 133 women with mild dis-ability in the United States, of whomhalf reported voiding symptoms, foundthat 70% still enjoyed sexual inter-course, felt aroused, and could expe-rience orgasm (Borello-France et al,

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FIGURE 7-2 Algorithm for management ofneurogenic incontinence.

PVR = postvoid residual; CISC = cleanintermittent self-catheterization.



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2004), in women with advancedMS, 62% experienced sensory dysfunc-tion in the genital area (Hulter and

Lundberg, 1995). Loss of orgasmiccapacity is the complaint for whichwomen seek treatment (Dasgupta et al,2004).

Management

Bladder dysfunction. The symptomsof urgency, frequency, and urgency in-continence are due to detrusor over-activity and can, therefore, logically betreated with antimuscarinic agents. Anumber of different preparations are

now available (Table 7-1), and long-acting formulations (extended life[XL]) have the advantage of once-dailyadministration. Patients who have cog-nitive impairment are best treated bythe medications less likely to cross theblood-brain barrier, such as trospiumchloride.

Although it might appear appropri-ate to immediately prescribe an anti-muscarinic for patients complaining ofurinary urgency, a measurement needs

to be made first. If there is any reasonto suspect that the patient is not em-ptying completely, the postmicturition

residual volume should be measured(Fowler, 1996). This can be conve-niently done using a small portableultrasound device, which many special-ist nurse continence advisors haveavailable. It is important to recognizeincomplete emptying because any resi-dual volume in the bladder can trigger

volume-determined reflex detrusorcontractions and thus exacerbate DO.Figure 7-2 shows a simple algorithmfor managing the common symptoms

of bladder dysfunction in MS. Theplace of cystometry and video cysto-metry in the routine investigation ofthese patients is questionable. It hasbeen argued that it is only throughthese investigations that detrusorsphincter dyssynergia can be recog-nized, but since no specific treatment isavailable for that disorder other thanmanaging the consequence, ie, incom-plete emptying and raised detrusorpressure, a pragmatic approach such

168

TABLE 7-1 Oral Antimuscarinic Agents for Treating Symptoms ofDetrusor Overactivity

GenericName

Trade Name inthe United States

Dose(mg) Frequency

EliminationHalf-life ofDrug (Hours)

Propantheline Pro-Banthine 7.515.0 Tid 30 minac and qhs


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as shown in Figure 7-2 has much torecommend it.

If a raised postmicturition residual

volume is demonstrated, some meansof reducing this will be necessary toimprove symptoms. This can be doneby having either the patient or some-times the caregiver perform cleanintermittent catheterization (CIC). CIChas been advocated if the postmictu-rition residual volume is greater than100 mL, a somewhat arbitrary figure,but one about which there seems to begeneral agreement. Teaching the tech-nique is more likely to be successful if

patients are well motivated and havegood cognitive skills and adequatemanual dexterity. Because patients alsoneed to have sufficient mobility to beable to get into a comfortable positionto catheterize efficiently, ideally overthe toilet, severe immobility can pres-ent a problem (Case 7-1).

Unfortunately, little else improvesbladder emptying; although there

were claims that alpha-blockers could

reduce the postmicturition residualvolume, subsequent studies have notconfirmed this. On theoretical grounds

this is not surprising since it is thoughtthe defect of bladder emptying in MSis due to poorly sustained and incoor-dinated relaxation of the striatedsphincter, a muscle on which alpha-blockers are thought to be ineffective.

If patients are performing self-catheterization, urine specimens sentto the laboratory are likely to growmicroorganisms, although other crite-ria that indicate a urinary tract infectionare not present. However, if genuine

recurrent urinary tract infections dooccur with the expected clinical symp-toms of dysuria and change in colorand odor of the urine, investigationsshould be carried out to discover ifthere is a nidus for infection in theurinary tract, and a urologic referral ismandatory. Hematuria is another indi-cation for prompt urologic referral.

An additional therapy that maysometimes be of value is the synthetic

169

Case 7-1A 42-year-old woman, diagnosed with MS 6 years ago when she presentedwith sensory symptoms followed by optic neuritis, has suffered adeterioration of mobility over the last year, such that she now needs a canefor walking. She reports poor bladder control, which has been present forthe past 2 to 3 years but has noticeably worsened in the last year. Herproblems are of urinary frequency, such that she has been restricting fluidintake, but her most troublesome symptom is urinary urgency. With herreduced mobility she finds it difficult to reach a toilet in time and noticesurgency is particularly likely to come on as she rises from a sitting position.On questioning as to whether she empties her bladder, she answers notall the time, saying that she can often void again having just emptied herbladder 30 minutes before.

Using abdominal ultrasound, she is shown to have a postmicturitionresidual volume of 160 mL. She is therefore started on clean intermittentself-catheterization (CISC) and given oral long-acting tolterodine 4 mg oncea day. Taking this medication and using CISC twice a day, she stops havingepisodes of urgency incontinence and feels it safe to drink more liquids.

Comment. This womans case history illustrates the importance ofmeasuring the postmicturition residual volume if effective treatment is tobe achieved.

KEY POINT:

A If genuine

recurrent urinary

tract infections

do occur with theexpected clinical

symptoms of

dysuria and

change in color

and odor of

the urine,

investigations

should be carried

out to discover

if there is a nidus

for infection in

the urinary tract,

and a urologic

referral is

mandatory.

Hematuria is

another

indication

for prompt

urologic referral.



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antidiuretic hormone desmopressin.Its use in children to treat nocturnalenuresis is well established, and stud-

ies have also demonstrated its efficacyin women with MS and nighttimefrequency. It was shown to be effectiveif taken during the day in providingthe patients with a period up to 6hours during which they were nottroubled by urinary frequency and

were without any rebound nighttimefrequency (Hoverd and Fowler, 1998).However, patients must be cautionedto use desmopressin only once in 24hours despite the convenience of its

effect, and it should not be given tothose with dependent leg edemacaused by immobility who have night-time frequency. Nor should desmo-pressin be prescribed for patients overthe age of 65 years as there is a risk ofits inducing cardiac failure.

There is, however, a point in theprogression of MS where first-linetreatment may be insufficient to con-tain urinary symptoms and yet thepatient does not want to have a long-term indwelling catheter. This point indecline is often reached as the neuro-logic disability, particularly mobility, isdeteriorating and the patient there-fore is not in a robust state of health toundergo bladder augmentation sur-gery, such as a clam cystoplasty. A

very promising treatment that canthen be used at this stage is detrusorinjection of botulinum A toxin. Thediscovery that injection of botulinum

toxin A directly into the smoothmuscle of the detrusor resulted in asignificant alleviation of neurogenicbladder dysfunction (Schurch et al,2000) is having far-reaching conse-quences. Originally proposed on thebasis that botulinum toxin A wouldblock the presynaptic release of para-sympathetic acetylcholine-mediatingdetrusor contraction, the benefits ofthis treatment appear to exceed thoseexpected from an agent that merely

paralyzes the detrusor muscle. Itseems likely that botulinum toxin A isalso affecting the vesicular release

of neurotransmitters involved in theafferent arm of abnormal reflex blad-der contractions (Apostolidis et al,2006).

Many hundreds of patients world-wide have now been successfully treatedby injections of 200-mU to 300-mUbotulinum toxin A (Botox) injected in20 to 30 equally spaced points in thebladder wall. In our department we haveused a minimally invasive technique,performed in 20 minutes as a clinic

procedure under local anesthetic, totreat 43 patients with MS. All benefited,

with their voiding diaries showingremarkable improvements in the re-duction of urinary urgency, frequency,and incontinence. However, they thenall needed to perform CISC, eventhe 30% who had not been doingso prior to treatment. Fortunately, thisdid not appear to affect their qualityof life, which showed highly signifi-cant improvements, with the benefitlasting for a mean of 9.7 months. Cen-ters with the longest experience ofthis treatment have been able toshow that subsequent reinjections areas effective as the initial one andof comparable duration (Grosse et al,2005).

With further neurologic progression,there may become a stage when a long-term indwelling catheter becomes nec-essary. A suprapubic catheter is the

preferred management option. Thisshould be sited by a urologic surgeonwho may want the patient to have ageneral anesthetic so that the bladdercan be distended, facilitating the supra-pubic puncture into the otherwiseshrunken organ.

Sexual dysfunction.Prior to the ad-vent of the oral erectogenic medications,men with MS were successfully treated

with intracavernosal injection therapy(Kirkeby et al, 1988). Subsequently, a

170

KEY POINT:

A The discovery

that injection of

botulinum toxin

A directly intothe smooth

muscle of the

detrusor resulted

in a significant

alleviation of

neurogenic

bladder

dysfunction

is having

far-reaching

consequences.




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multicenterplacebo-controlledtrialdem-onstrated an excellent response to sil-denafil citrate in men with MS (Fowler

et al, 2005). Although in that studyorgasmic capacity was also increased, afact that was attributed to the menbeing able to sustain an erection longer,it is known that a significant proportionof men continue to have difficulty withejaculation, for which, as yet, no effec-tive medication is available, although

yohimbine may be tried. Probably thebest recourse is to use a vibrating sexaid.

Following the success of sildenafil

citrate in the treatment of sexualfunction with men, a small placebo-controlled trial in women with sexualdysfunction and MS was carried out. Aquestionnaire was used to measuresexual response, and although there

was a significant improvement in lu-brication and some improvement insensation, there was no overall changein orgasmic response in the active-treatment group compared with thosein the placebo-treated group (Dasguptaet al, 2004). Although disappointing,this was not perhaps surprising.

The pharmaceutical industry con-tinues research to discover agents thatmight be effective in the treatment offemale sexual dysfunction, but despitethe current lack of specific treatment,

women with MS found the oppor-tunity to discuss their problem witha health care professional beneficial(Hulter and Lundberg, 1995).

MULTIPLE SYSTEM ATROPHY

Neurologic Basis ofUrogenital Symptoms

The explanation for the multiple typesof bladder dysfunction that can oc-cur in multiple system atrophy (MSA)probably reflects the neuronal atro-phy in the CNS that occurs at manydifferent sites involved in bladdercontrol (Kirby et al, 1986). It has been

proposed that cells situated in thedorsal tegmentum of the pons, possi-bly those of the PMC, are involved in

the atrophying process. It may be thattheir decline results in loss of in-hibition and thus DO. Involvement ofthe intermediolateral cell columns ofthe spinal cord, which convey thedescending sympathetic and parasym-pathetic innervation of the sacral re-gion, may account for the observedopen bladder neck and impairmentof bladder emptying. Neuronal atrophyof cells in the Onuf nucleus leads tochronic denervation of the striated

sphincters (Sakuta et al, 1978), bothanal and urethral. It is the combi-nation of DO, incomplete emptying,and sphincter weakness that accountsfor the early and severe incontinencethat so often characterizes the onsetof MSA.

Much less is known about theneuropathologic substrate of sexualdysfunction in MSA, but whereas ED

was formerly thought to be secondaryto hypotension, the dissociation ofthese disorders (Kirchhof et al, 2003)and the observation that erectile re-sponses can be restored in men withMSA and hypotension by treatment

with sildenafil citrate argue for adifferent pathophysiology. Erection isknown to result from stimulation ofdopamine receptors in the medialpreoptic area of the hypothalamus,and it has been hypothesized that EDcould result either from impairment

of sacral autonomic innervation orimpairment of dopaminergic-mediatedpathways in the CNS (Kirchhof et al,2003).

Clinical History

The earliest studies of MSA drew at-tention to the premonitory nature ofurogenital symptoms in the condition.The explanation for this remains tobe discovered, but after initial stud-ies that highlighted the fact that

171

KEY POINTS:

A The

pharmaceutical

industry

continuesresearch to

discover agents

that might be

effective in the

treatment of

female sexual

dysfunction,

but despite the

current lack of

specific

treatment,

women with

MS found that

the opportunity

to discuss their

problem with a

health care

professional

was beneficial.

A The explanation

for the multiple

types of bladder

dysfunction that

can occur in

multiple system

atrophy (MSA)

probably reflects

the neuronal

atrophy in the

CNS that occurs

at many different

sites involved in

bladder control.



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urogenital symptoms were early andalmost invariable in the disease (Becket al, 1994), recent studies have exam-

ined the chronology of evolution ofpostural hypotension compared withdisorders of bladder and sexual func-tion. It was clearly shown that, at onset,the incidence of urinary symptoms wasmore than twice that of orthostaticsymptoms (96% compared with 43%)and that no patients had orthostaticsymptoms only, but 53% had urinarysymptoms alone (Sakakibara et al,2000). There were 43% with both uri-nary and orthostatic symptoms, and

in 21% urinary symptoms appearedfirst (Figure 7-3).

A study that looked retrospectivelyat a group of 71 men with a diagnosisof probable MSA who had bladdercomplaints noted that ED was acomplaint in all men who were que-ried. The onset of ED had precededthe onset of bladder symptoms in 58%and the onset of orthostatic hypoten-sion symptoms in 91%. Bladder symp-toms also preceded symptoms oforthostatic hypotension in 76% ofpatients (Kirchhof et al, 2003).

Female sexual dysfunction in MSAhas been little studied, but a single pa-per reported that, when women with

MSA-parkinsonian type or Parkinsonsdisease and healthy controls werequestioned, 47% of the patients withMSA-parkinsonian type, but only 4% ofthe patients with Parkinsons diseaseand 4% of the control group, admittedto reduced genital sensitivity. Further-more, the appearance of this complaintin female patients with MSA showed aclose temporal relation to the onset ofthe disease (Oertel et al, 2003).

Erectile dysfunction is common in

the general population, and its inci-dence is known to increase with age.Likewise, bladder symptoms are alsocommon and often due to under-lying urologic disorders. However,the evidence points to the fact thaturogenital complaints are an early andalmost inevitable component of MSA,be it MSA-parkinsonian type or MSA-cerebellar type, and an absence ofthese symptoms makes the diagno-sis unlikely. Furthermore, urogenitalsymptoms may be valuable in distin-guishing cases of MSA from otherforms of parkinsonism and idiopathicParkinsons disease because in thoseconditions urogenital symptoms occurlate, often in the context of markedneurologic disability.


Urinary incontinence or a fear of im-minent incontinence is the most com-

mon presenting bladder complaint,although other urinary symptoms mayprecede this (Kirby et al,1986; Sakakibaraet al, 2000). Although urinary symp-toms in either men or women are com-mon, the onset of incontinence in thepreceding 4 to 5 years, together withan appropriate neurologic profile, isan ominous portent for a diagnosis ofMSA. Detailed studies of patients us-ing videourodynamics, cystometry, andsphincter EMG (Kirby et al, 1986) have

172

FIGURE 7-3 Timing of urinary and orthostatic symptomsin patients with multiple system atrophy.

Sakakibara R, Hattori T, Uchiyama T, et al. Urinarydysfunction and orthostatic hypotension in multiplesystem atrophy: which is the more common and earliermanifestation? J Neurol Neurosurg Psychiatry2000;68(1):6569. Reprinted with permission fromBMJ Publishing Group Ltd.

KEY POINT:

A A recent study

has clearly shown

that, at onset,

the incidence ofurinary symptoms

was more than

twice that of

orthostatic

symptoms (96%

compared to 43%)

and that no

patients had

orthostatic

symptoms only,

but 53% had

urinary symptoms

alone.




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shown that often a combination ofDO and sphincter weakness is pres-ent. The finding of an open bladder

neck, generally an unusual feature ina man, is quite specific in men withMSA. Occasionally a patient may pres-ent with complete urinary retention,but difficulty voiding is much morecommon and the likelihood of raisedpostmicturition residual volume seemsto increase as the disease progresses(Ito et al, 2006). A raised postmictu-rition residual volume is much morecommon in MSA than Parkinsons dis-ease and may even be of diagnostic

value in the differential diagnosis of thetwo conditions (Hahn and Ebersbach,2005).

Management

Some while ago men with MSA andincontinence were often consideredfor prostatectomy, but in recent yearsthis seems to be occurring less often,presumably due to urologists increas-ing awareness of MSA and the more

widespread use of pressure-flow stud-ies to demonstrate obstructed outflow

before surgery. Men with MSA whohave had transurethral prostatectomyseldom report that surgery improves

their bladder symptoms.Preferably, urologic surgery shouldbe avoided, using instead medicalmeans to manage incontinence orincomplete bladder emptying. Themanagement algorithm outlined inFigure 7-2 has also proved highlyeffective in patients with MSA, andmany who had been incontinent at anearly stage of the disease manage tomaintain continence until they becomeseverely disabled (Beck et al, 1994),

when a suprapubic indwelling catheteris the preferred option. Synthetic anti-diuretic hormone (desmopressin) canbe highly effective in reducing night-time frequency and may also have abeneficial effect on postural hypoten-sion (Case 7-2).

In some patients detrusor overactiv-ity predominates and does not re-spond adequately to anticholinergics.It will be interesting to see if the re-cently introduced intervention of de-trusor injections of botulinum toxin(Schurch et al, 2000) proves to have

173

Case 7-2A 57-year-old man was first seen by a urologist 3 years ago, and althoughno urologic abnormality could be found, he was demonstrated on anumber of occasions not to be emptying his bladder fully. He was startedon long-acting tolterodine 4 mg daily and shown how to do CISC. Hehad been taking sildenafil for ED for 5 years.

Two years ago a neurologist made a diagnosis of parkinsonism, and1 year ago a diagnosis of MSA was made on clinical grounds based on hisneurologic deterioration. He was complaining then that his incontinence,particularly at night, was very distressing, so he was advised to do CISCbefore going to bed and to use desmopressin spray at night. When nextseen, he was no longer experiencing nocturnal enuresis and with CISCat eight hourly intervals, his bladder control during the day had greatlyimproved. However, at his most recent examination he was noted to havedeveloped hypophonic slurring dysarthria, akinesia, and rigidity.

Comment.The bladder symptoms of MSA can be significantly alleviatedby appropriate treatment despite continuing deterioration of theunderlying neurologic condition.

A Although urinary

symptoms in

either men or

women are

common, the

onset of

incontinence in

the preceding 4

to 5 years,

together with an

appropriate

neurologic

profile, is an

ominous portent

for a diagnosis

of MSA.

A Men with MSA

who have had

transurethral

prostatectomy

seldom report

that surgery

improves

their bladder

symptoms.

KEY POINTS:

A The evidence

points to the fact

that urogenital

complaints are anearly and almost

inevitable

component of

MSA, be it MSA-

parkinsonian type

or MSA-

cerebellar type,

and an absence

of these

symptoms makes

the diagnosis

unlikely.



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a role in the management of thesepatients.

The majority of men in the general

population with ED are successfullytreated by oral phosphodiesterase in-hibitors, but a small study of six men

with MSA showed that, in those withpreexisting postural hypotension, sil-denafil citrate exacerbated the bloodpressure fall to a potentially dangerousdegree, whereas those without pos-tural hypotension did not showchanges (Hussain et al, 2001). Fromthis, the recommendation has beenmade that lying and standing blood

pressure should be checked in menwith parkinsonism before prescrib-ing oral phosphodiesterase inhibitors.Furthermore, it would seem prefer-able to use the shorter-acting phospho-diesterase inhibitors such as silden-afil or vardenafil rather than thepopular tadalafil, with its half-life of18 hours.

URINARY RETENTION IN

YOUNG WOMEN(FOWLERS SYNDROME)

Neurologic Basis

Until the latter part of the 20th cen-tury, urinary retention in women wascommonly considered to be psycho-genic. Urologic or gynecologic causesof retention are rare and can be ex-cluded by cystoscopy, leaving a signifi-cant number of women in whomretention is said to have a functional

basis. Past teaching was that urinaryretention was either the presentingsymptom of MS or that it was due tohysteria. However, in 1985 thisauthor recorded an unusual type ofEMG activity from the striated urethralsphincter using a concentric needleelectrode in a series of young women

with urinary retention. The EMG activ-ity consisted of complex repetitivedischarges and a myotonic-like sound-ing component, decelerating bursts,

which was proposed to indicate im-paired urethral relaxation. Detailed anal-

ysis of the EMG activity using single-

fiber electrode techniques showed thatthe jitter of the constituent complexeswas so low that the activity was theresult of ephaptic transmission of im-pulses between muscle fibers. A pro-portion of these young women alsohad a history or clinical features ofpolycystic ovaries (Fowler et al, 1988).It was hypothesized that the hor-monally sensitive striated sphincterhad developed a local muscle mem-brane instability, allowing direct spread

of excitatory impulses and, thus, theinappropriate and involuntary sustainedcontraction of the sphincter (Fowlerand Dasgupta, 2002). In the last 20 years,this condition has been increasinglyreferred to asFowlers syndrome.

In a group of somewhat olderwomen with urinary retention whootherwise have the characteristic fea-tures of Fowlers syndrome, altera-tions of cardiovascular autonomicfunction were discovered. It was thenproposed that the condition is due toan occult dysautonomia (Amarencoet al, 2006). In the authors experi-ence, however, if all possible urologicor neurologic disorders are eliminatedand an abnormally high urethral pres-sure is demonstrated (see below), thecondition does not evolve but remainsan isolated disorder of voiding, benignthough highly inconvenient.

A retrospective study of 247 women

with urinary retention referred to uro-neurology at Queen Square over a4-year period showed that Fowlerssyndrome was the most commondiagnosis, accounting for 58%. Nodiagnosis to explain the urinary reten-tion could be made in 32% of the

women, but in only two of that largeseries of women was urinary retentionthe presenting symptom of a neuro-logic disease (Kavia et al, 2006). Ifurinary retention is due to either

174

KEY POINTS:

A The

recommendation

has been made

that lying andstanding blood

pressure should

be checked in

men with

parkinsonism

before

prescribing oral

phosphodiesterase

inhibitors.

A Urologic or

gynecologic

causes ofretention are

rare and can

be excluded by

cystoscopy,

leaving a

significant

number of

women in

whom retention

is said to have

a functional

basis.

A It was

hypothesized

that the

hormonally

sensitive striated

sphincter had

developed a local

muscle

membrane

instability,

allowing direct

spread of

excitatory

impulses and,

thus, the

inappropriate

and involuntary

sustained

contraction of

the sphincter.




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central or peripheral nervous systemdisease, neurologic features with ab-normalities on imaging and CSF exam-

ination are almost invariably presentand often prominent (Sakakibara et al,2006). This is not the case in Fowlerssyndrome.


A retrospective questionnaire surveyof 91 women with Fowlers syndromeshowed that the common clinicalfeatures are painless urinary retention,

with a demonstrated bladder capacityat some stage of the history in excess

of 1 L and difficulty in removingcatheters used for self-catheterization(Swinn et al, 2002). Abdominal strain-ing does not help voiding. A strikingaspect of these womens history is anabsence of the sense of bladderfullness that would be expected withsuch large bladder capacities andgeneral decrease in bladder sensation.

Animal studies indicate that contrac-tion of the striated sphincter has aninhibitory effect on detrusor contrac-tion and on bladder afferent activity(de Groat et al, 2001), and theactivation of comparable neural path-

ways in these women could accountfor the observed clinical features.

In many of the patients a clinicalincident, such as a surgical procedureunder general anesthesia, a urinarytract infection, or childbirth, may havetriggered the onset of retention. In

younger women in particular, the

onset is often apparently spontaneous(Swinn et al, 2002). Sometimes afteracute catheterization voiding abilitymay recover, but retention then recurssome months or even years later. A

young woman with retention mayadmit on direct questioning to havinghad an interrupted urinary stream formany years, although this was unrec-ognized as being abnormal, or recur-rent urinary tract infections, probablyresulting from incomplete emptying.

Intermittent self-catheterization is un-doubtedly more difficult for these

young women than for women with

MS, and it is not uncommon for themto describe difficulty with removingthe catheter, as if something is grip-ping it as it is withdrawn. This isthought to be due to contraction ofthe normally innervated but patholog-ically overactive striated sphincteraround the catheter.

Although the syndrome was origi-nally described on the basis of needleEMG of the striated urethral sphincter(the abnormality is not found in the

anal sphincter), urethral sphincterEMG is not an easy test to perform,and despite the use of local anes-thetic, it is uncomfortable for thepatient. Furthermore, although EMGsampling gives some indication as to

whether or not the abnormality ispresent, the result gives no quanti-tative estimate of dysfunction, unlikethe urethral pressure profile. Usinga pull-through catheter, urethralpressure can be measured at rest withthe expected value derived from thefollowing equation: expected value(cm H2O) = 92 age (in years).

Women with Fowlers syndromecommonly have values in excess of100 cm H2O (Kavia et al, 2006). The

volume of the sphincter muscle esti-mated by a vaginal ultrasound probemay show enlargement, so if there is atypical history and both the urethralpressure profile and the sphincter

volume are abnormally raised, EMGis now less commonly required toconfirm the diagnosis (Kavia et al,2006).

Management

The mainstay of management is CISC,but many women find this uncomfort-able; it is not unusual for a suprapubiccatheter to be required. Psychologi-cally, the prospect of indefinite self-catheterization for a young woman

175

KEY POINTS:

A A retrospective

study of 247

women with

urinary retentionreferred to

uro-neurology at

Queen Square

over a 4-year

period showed

that Fowlers

syndrome was

the most

common

diagnosis,

accounting

for 58%.

A The common

clinical features

of Fowlers

syndrome are

painless urinary

retention with a

demonstrated

bladder capacity

at some stage

of the history

in excess of 1 L

and difficulty

in removing

catheters used

for self-

catheterization.

A Intermittent self-

catheterization

is undoubtedly

more difficult

for young

women with

Fowlers

syndrome than

for women with

MS, and it is not

uncommon for

them to describe

difficulty with

removing the

catheter, as if

something is

gripping it as

it is withdrawn.



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is understandably distressing. The onlyintervention that has been found torestore voiding is sacral nerve stimu-

lation (SNS), also called sacral neuro-modulation (Swinn et al, 2002). Thisinvolves inserting a unilateral stimu-lating lead into the presacral plexusthrough the third sacral foramenand connecting it to an external bat-tery with its settings adjusted so thatthe patient senses pelvic sensations.The stimulation is then set to sub-threshold intensity so that the sub-

ject rapidly adapts to the continuousstimuli.

Exactly the same intervention is

used to treat intractable urinary fre-quency and urgency, and the paradoxof the same treatment being used totreat clinically opposite conditions isprobably best understood by consider-ing the underlying pathophysiologyof each disorder: in overactive blad-der conditions it seems likely the sti-mulation of afferents is having aninhibitory effect, whereas in Fowlers

176

Case 7-3A 37-year-old nurse was first seen at age 22 after she had undergonean ear, nose, and throat procedure under general anesthetic. Followingthis she was unable to urinate. She had some feeling of pressure whenher bladder was full but had lost normal sensation. In addition, shewas complaining of vague sensory symptoms in her left leg. Clinicalexamination was essentially normal except for some inconsistent sensorydisturbance on the left. However, neurologic investigations, includinga myelogram, MRI of the brain, and visual evoked potentials, were normal.A neurologist suggested her urinary retention might have been ofpsychogenic origin.

A year later, urethral sphincter EMG was highly abnormal. Profusecomplex repetitive discharges and decelerating bursts were recorded,consistent with the diagnosis of Fowlers syndrome.

She remained in complete urinary retention and for 7 years managedto empty her bladder by intermittent self-catheterization. This did notprevent her from working full time, and she spent 1 year backpackingin the Far East. Then 8 years ago an SNS was implanted, and although shepassed urine postoperatively, within 24 hours she developed symptomsand signs of an infection at the stimulator site. The stimulator had tobe removed, and the infective microorganism was the nosocomialmultiresistantStaphylococcus aureus. She was required to avoid contactwith patients and was off work for many months. She remained reluctantto consider a repeat attempt at SNS and continued with intermittentself-catheterization for another 6 years until she accepted the offer ofa stimulator implant using the new 2-stage technique. Fortunately,this was successful, and she was able to urinate spontaneously for the firsttime in 15 years. She no longer needs to self-catheterize.

Comment.The young woman was initially the victim of then prevailingmedical prejudice some 20 years ago, which asserted urinary retentionin women was commonly psychogenic. It is particularly importantthat neurologists are aware of this condition because urologists often referthese patients when their investigations fail to reveal an abnormality.If the diagnosis is recognized, sacral neuromodulation can restorevoiding ability.

KEY POINT:

A The only

intervention

which has been

found to restorevoiding is

sacral nerve

stimulation,

also called sacral

neuromodulation.




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" Betts CD, DMellow MT, Fowler CJ. Urinary symptoms and the neurologicalfeatures of bladder dysfunction in multiple sclerosis. J Neurol NeurosurgPsychiatry 1993;56(3):245250.

Clinical study that showed a clear association between the extent of spinal cord

dysfunction and urinary symptoms in multiple sclerosis (MS).

" Betts CD, Jones SJ, Fowler CG, Fowler CJ. Erectile dysfunction in multiplesclerosis. Associated neurological and neurophysiological deficits, andtreatment of the condition. Brain 1994;117(pt 6):13031310.

The neurologic context of erectile dysfunction in MS.

" Borello-France D, Leng W, OLeary M, et al. Bladder and sexual functionamong women with multiple sclerosis. Mult Scler 2004;10(4):455461.

Women mildly affected by MS are still mostly able to enjoy sexual intercourse.

" Dasgupta R, Critchley HD, Dolan RJ. Fowler CJ. Changes in brain activityfollowing sacral neuromodulation for urinary retention. J Urol2005;174(6):22682272.

A PET study of women examining the central mechanisms of response to sacral

neuromodulation.

" DasGupta R, Fowler CJ. Urodynamic study of women in urinary retentiontreated with sacral neuromodulation. J Urol 2004;171(3):11611164.

Sacral neuromodulation in urinary retention does not work by reversing the sphincter

abnormality.

" Dasgupta R, Wiseman OJ, Kanabar G, et al. Efficacy of sildenafil in thetreatment of female sexual dysfunction due to multiple sclerosis. J Urol2004;171(3):11891193.

Sildenafil citrate had little effect on sexual function in women with MSaplacebo-controlled trial.

" Datta SN, Kavia RB, Gonzales G, Fowler CJ. Results of double-blindplacebo-controlled crossover study of sildenafil citrate (Viagra) in womensuffering from obstructed voiding or retention associated with theprimary disorder of sphincter relaxation (Fowlers Syndrome). Eur Urol2007;51(2):489497.

Sphincter relaxation, which is under nitric oxide control, did not improve with

sildenafil citrate in women with voiding dysfunction.

" de Groat W, Kawatani T, Hisamitsu T, et al. Mechanisms underlying therecovery of urinary bladder function following spinal cord injury. J Auton

Nerv Syst 1990;30(suppl):7177.An important basic science paper that showed the emergence of an unmyelinated

fiber reflex causes detrusor overactivity following spinal injury.

" de Groat WC, Fraser MO, Yoshiyama M, et al. Neural control of the urethra.Scand J Urol Nephrol Suppl 2001;35(207):3543.

Review of the experimental evidence showing the effect of sphincter contraction on

detrusor activity.

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" De Ridder D, Ost D, Bruyninckx F. The presence of Fowlers syndromepredicts successful long-term outcome of sacral nerve stimulationin women with urinary retention. Eur Urol 2007;51(1):229233.

A study that shows that among all women with retention treated with sacral

neuromodulation, those with Fowlers syndrome do better in the long term.

" Fowler CJ. Investigation of the neurogenic bladder. J Neurol NeurosurgPsychiatry 1996;60(1):613.

A review stressing the importance of measurement of the postvoid residual volume in

the management of neurogenic incontinence.

" Fowler CJ, Christmas TJ, Chapple CR, et al. Abnormal electromyographicactivity of the urethral sphincter, voiding dysfunction, and polycysticovaries: a new syndrome? BMJ 1988;297(6661):14361438.

The original proposal of Fowlers syndrome.

" Fowler CJ, Dasgupta R. Electromyography in urinary retention andobstructed voiding in women. Scand J Urol Nephrol Suppl 2002;(210):5558.

A review explaining more recent thinking about the pathophysiology of urinary

retention in women with Fowlers syndrome.

" Fowler CJ, Miller JR, Sharief MK, et al. A double blind, randomised studyof sildenafil citrate for erectile dysfunction in men with multiple sclerosis.J Neurol Neurosurg Psychiatry 2005;76(5):700705.

Sildenafil citrate was highly effective in treating erectile dysfunction in men with

MSplacebo-controlled trial.

" Grosse J, Kramer G, Stohrer M. Success of repeat detrusor injections of

botulinum a toxin in patients with severe neurogenic detrusoroveractivity and incontinence. Eur Urol 2005;47(5):653659.

The first paper to review the long-term benefits of repeated injections of botulinum

toxin.

" Hahn K, Ebersbach G. Sonographic assessment of urinary retention inmultiple system atrophy and idiopathic Parkinsons disease. Mov Disord2005;20(11):14991502.

Raised postmicturition residual volume may have diagnostic value for the diagnosis of

MSA.

" Hoverd PA, Fowler CJ. Desmopressin in the treatment of daytime urinaryfrequency in patients with multiple sclerosis. J Neurol Neurosurg

Psychiatry 1998;65(5):778780.Desmopressin in patients with MS taken during the day did not result in rebound

nighttime frequency.

" Hulter BM, Lundberg PO. Sexual function in women with advancedmultiple sclerosis. J Neurol Neurosurg Psychiatry 1995;59(1):8386.

An important early study of sexual dysfunction in women with MS.

179



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" Hussain IF, Brady CM, Swinn MJ, et al. Treatment of erectile dysfunctionwith sildenafil citrate (Viagra) in parkinsonism due to Parkinsons diseaseor multiple system atrophy with observations on orthostatic hypotension.J Neurol Neurosurg Psychiatry 2001;71(3):371374.

Small placebo-controlled study that stressed the importance of measuring blood

pressure in patients with parkinsonism before prescribing sildenafil citrate.

" Ito T, Sakakibara R, Yasuda K, et al. Incomplete emptying and urinaryretention in multiple-system atrophy: when does it occur and how do wemanage it? Mov Disord 2006;21(6):816823.

Repeated measures of postvoid residual volume show that this increased with the

progression of MSA.

" Kavia RB, Datta SN, Dasgupta R, et al. Urinary retention in women: itscauses and management. BJU Int 2006;97(2):281287.

Outcome of investigation of management of a large number of women with urinary

retention referred to a UK tertiary center.

" Kirby R, Fowler C, Gosling J, Bannister R. Urethro-vesical dysfunction inprogressive autonomic failure with multiple system atrophy. J NeurolNeurosurg Psychiatry 1986;49(5):554562.

Early study highlighting the many different types of bladder dysfunction that can occur

in MSA.

" Kirchhof K, Apostolidis AN, Mathias CJ, Fowler CJ. Erectile and urinarydysfunction may be the presenting features in patients with multiplesystem atrophy: a retrospective study. Int J Impot Res 2003;15(4):293298.

A retrospective study.

" Kirkeby HJ, Poulsen EU, Petersen T, Drup J. Erectile dysfunction inmultiple sclerosis. Neurology 1988;38(9):13661371.

Before the advent of sildenafil citrate men with erectile dysfunction and MS were

successfully treated with intracavernosal injections.

" Oertel WH, Wachter T, Quinn NP, et al. Reduced genital sensitivity in femalepatients with multiple system atrophy of parkinsonian type. Mov Disord2003;18(4):430432.

The only report of female sexual dysfunction in MSA.

" Sakakibara R, Hattori T, Uchiyama T, et al. Urinary dysfunction andorthostatic hypotension in multiple system atrophy: which is the morecommon and earlier manifestation? J Neurol Neurosurg Psychiatry

2000;68(1):6569.An important study that shows urinary dysfunction occurs earlier than orthostatic

hypotension in MSA.

" Sakakibara R, Yamanishi T, Uchiyama T, Hattori T. Acute urinary retentiondue to benign inflammatory nervous diseases. J Neurol 2006;253(8):11031110.

A helpful review of the central and peripheral neurologic causes of urinary retention and

the associated neurologic features.

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" Sakuta M, Nakanishi T, Toyokura Y. Anal muscle electromyograms differin amyotrophic lateral sclerosis and Shy-Drager syndrome. Neurology1978;28(12):12891293.

Remarkably early study giving the basis for sphincter EMG in the diagnosis of MSA.

" Schurch B, Stohrer M, Kramer G, et al. Botulinum-A toxin for treatingdetrusor hyperreflexia in spinal cord injured patients: a new alternativeto anticholinergic drugs? Preliminary results. J Urol 2000;164(3 pt 1):692697.

Much-cited paper, the first report of the benefits of botulinum toxin A treatment for

intractable detrusor overactivity.

" Sirls LT, Zimmern PE, Leach GE. Role of limited evaluation and aggressivemedical management in multiple sclerosis: a review of 113 patients. J Urol1994;151(4):946950.

Postvoid residual volume measurement only, the recommended management in

patients with MS.

" Swinn MJ, Wiseman OJ, Lowe E, Fowler CJ. The cause and natural historyof isolated urinary retention in young women. J Urol 2002;167(1):151156.

A retrospective review of women with Fowlers syndrome, which defined the

clinical history.

" Zorzon M, Zivadinov R, Bosco A, et al. Sexual dysfunction in multiplesclerosis: a case-control study. I. Frequency and comparison of groups.Mult Scler 1999;5(6):418427.

Clinical features of patients with sexual dysfunction due to MS.

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Autonomic Disorders of the Urogenital System

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