Botulinum toxin and the overactive bladder

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					Botulinum toxin and the overactive bladder
Overactive bladder (OAB) is associated with a significant economic burden to
hospital trust and patient alike and is associated with significant morbidity. In this
article, Drs Sahai, Khan, and Dasgupta detail the successful use of botulinum
toxin, a new novel treatment for this condition, in patients for whom traditional
anti-cholinergic drug treatment has failed and for whom traditional surgical
intervention is either unsuitable or unacceptable.

In recent years the pathophysiology of overactive bladder (OAB) and the
pharmacological options available for the treatment of this condition have
stimulated much debate and research. Traditionally patients were treated with
anti-cholinergic drugs, however, recent developments in this field have instigated
new treatment options including other oral pharmacological agents, new
intravesical therapies, and botulinum toxin. This paper will review the definitions
and impact of OAB on the patient’s quality of life and will mainly focus upon the
use of botulinum toxin, a new and promising modality, for the treatment of this
condition.

Defining OAB

The International Continence Society has defined OAB as urgency, with or
without urge incontinence, usually with frequency and nocturia, in the absence of
local pathological or hormonal factors 1 . This has major implications for the
general practitioner (GP) and urologist alike. Previously a diagnosis of detrusor
overactivity needed confirmation with urodynamic studies. Now, however, ini tial
treatment for OAB can be started in the community, based on symptoms alone.
The preferred terminology for OAB is neurogenic where there is a neural cause,
obstructive for obstructed cases or idiopathic detrusor overactivity when there is
no proven cause established.

Epidemiology

It is estimated that the overall prevalence of OAB in Western Europe is 16per
cent2 and 17per cent in the USA 3. Its incidence increases with age 4. In the USA,
the cost of managing this condition has been estimated at a staggering 26billion
dollars a year, if all possible costs are considered 5. Only recently has the
magnitude of the problems that OAB causes urologists and GPs been realized.

Quality of life

OAB has significant impact on the patient’s quality of life. Studies have shown
that patients with OAB have significantly lower quality of life scores using the 8 -
domain Short Form (SF) 36 questionnaire compared with matched controls 6 .
Patients also suffer with depression and poorer quality of sleep when compared
with controls. Several other studies have confirmed the above findings in the US
and Europe2,7,8.
In the UK, using the King’s Health Questionnaire (recommended by the
International Consultation on Incontinence), women with urge incontinence
scored poorly when compared to women with stress incontinence or those who
had normal cystometry9. It is postulated that approximately 30per cent of patients
with OAB suffer with incontinence 6, and those who do clearly suffer significant
morbidity from it, even when compared with other types of incontinence.

Falls, fractures, skin irritation and urinary tract infections are some of the other
co-morbidities OAB patients may suffer10.

Treating overactive bladder

Anticholinergic medication has been the primary treatment for patients with OAB
in recent years. This class of drugs act on muscarinic receptors as competitive
inhibitors of acetylcholine and thus inhibit involuntary bladder contractions.
Unfortunately they are also associated with troublesome side-effects including:
     Dry mouth
     Constipation
     Blurred vision
     Drowsiness
     Tachycardia.

Newer, slow release or long-acting preparations of tolterodine and oxybutynin,
the two commonest drugs prescribed in OAB, have less side effects 11,12.
Unfortunately, some patients cannot tolerate these side effects or may build up
tolerance to the medication. These patients suffer a poor quality of life but only
severe cases are considered for surgical intervention. This of course is
dependent on medical fitness and until recently, there has been little else to offer
them.

Newer pharmacological agents have been researched and include:
5-HT3 reuptake inhibitors
    Noradrenaline reuptake inhibitors
    Desmopressin
    Potassium channel openers
    Neurokinin receptor antagonists
    Intravesical oxybutynin
    Intravesical capsaicin5 .

None of these treatment modalities have reached wide acceptance. This article
will now focus on another treatment option, the use of botulinum toxin.


Botulinum toxin
Botulinum toxin is a neurotoxin produced by the gram-positive, anaerobic, spore-
producing organism Clostridium botulinum. It is the most poisonous naturally
occurring toxin known to mankind 13. Botulinum toxin has been incorporated into
national biological weapons programmes because of this fact. It causes an acute
and symmetrical paralysis. Severity can range from mild weakness to respiratory
failure, coma and death. The toxin works by inhibiting acetycholine release at the
neuromuscular junction. As a result of blocking synaptic transmission the muscle
becomes clinically weak and atrophies. The fact that local injection of the toxin
into striated muscle can induce paralysis has spurred researchers to investigate
its effects in muscle overactivity.

Autonomic effects are also observed, as it blocks acetylcholine release in all
parasympathetic neurones and at post-ganglionic sympathetic nerves. This has
fuelled interest into overactive smooth muscle conditions and conditions where
there is abnormal activity due to excessive post-ganglionic sympathetic activity
such as occurs in hyperhidrosis.

Botulinum toxin is currently licensed for use in torticollis, strabismus,
blepharospasm, hemifacial spasm and paediatric cerebral palsy spasticity. In the
US, in addition to the above it is also licensed for axillary hyperhidrosis and
achalasia14–19. It has received media attention recently for its cosmetic potential
in reducing facial wrinkles. Only in recent years have the urology community
looked into the potential benefit of this toxin in the urinary tract.

Botulinum toxin injections into the external urethral sphincter to treat detrusor
sphincter dyssynergia or pelvic floor spasticity and injections into the prostate
gland to treat benign prostatic hypertrophy or prostatitis have all had beneficial
outcomes20–27 . Other studies showed botulinum toxin injections into the urethral
sphincter in patients with chronic retention to be of benefit in patients with voiding
dysfunction due to detrusor underactivity28 . Intradetrusal injections of botulinum
toxin in patients with OAB have shown very promising results in both neurogenic
and idiopathic cases.

Botulinum toxin and OAB: the literature

Work in OAB has focused primarily on those cases of neurogenic origin. Schurch
et al published data in 2000 using botulinum toxin A 29. Patients with
urodynamically proven OAB and spinal cord injury who emptied their bladder with
clean intermittent self-catheterization were recruited. Two hundred or three
hundred units of botulinum toxin were injected into the bladder (sparing the
trigone) at 20–30 different sites using a cystoscope technique.

The authors hypothesized that local injection of the toxin would block the
transmission of acetylcholine in the bladder, thus paralyzing the muscle and
preventing the contractions associated with neurogenic incontine nce. The trigone
was spared to avoid impairing non-cholinergic nerves and the possibility of
vesico-ureteric reflux. Another reason to spare the trigone would be due to its
greater density of sensory nerves, which would theoretically be more painful to
the patient if this were injected.

At six week follow-up, 17 of the 19 patients were completely continent. The two
patients who remained incontinent but still had a moderate improvement in
symptoms had the lower dose of toxin at 200 units. Some patients were able to
reduce the amount of anticholinergic medication required and others no longer
felt the need to take them at all.

Urodynamic studies confirmed significant increases in bladder capacity and a
decrease in maximum detrusor voiding pressure. At 16 a nd 36weeks post-
injection, 11 patients were followed up and showed ongoing improvement in
bladder function. Complete continence persisted in seven cases and in four
cases only mild incontinence was observed which was attributed to bladder
infection.

No side effects were observed and they concluded that the toxin suppressed
bladder overactivity and increased bladder filling. They also noted in the study
that the injections lasted for at least 9months longer than when other groups had
injected the toxin into the external urethral sphincter. This has been attributed to
the way the toxin works on different types of muscle present in the bladder and
external sphincter.

Another study recruited 17 children with OAB due to myelomeningocoele 30 .
Botulinum toxin was given at 12 units/Kg upto a maximum of 300units.
Researchers found that reflex volume and maximal bladder capacity increased,
maximal detrusor pressure decreased, and detrusor compliance improved
significantly. Significant increases in maximum bladder capacity as well as a
decrease in mean voiding pressure have also been reported in a retrospective
multicentre European study consisting of 200 patients with neurogenic OAB 31, at
six and 36 weeks post-injection of 300units.

These patients were also able to reduce or discontinue their anticholinergic
medication31. More recently, work has been carried out in patients with idiopathic
OAB. Radziszewski reported that intradetrusal injections with botulinum toxin in
patients with idiopathic OAB or functional outle t obstruction improved voiding
efficiency and caused resolution of incontinence 32. Zermann et al looked into
intradetrusal injections of toxin into the trigone of seven patients with urgency-
frequency-syndrome refractory to anticholinergics. Four out of se ven patients
responded to the toxin with decreases in frequency and increased bladder
capacity33.

Administrating botulinum toxin
For patients with OAB, a new minimally invasive technique which allows patients
to go home on the same day as the procedure, is now employed for the
administration of intradetrusal botulinum toxin34. Patients undergo flexible
cystoscopy in an outpatient setting under local anaesthetic. Botulinum toxin is
administered through a sheathed flexible injection needle that is passed t hrough
the flexible cystoscope. The bladder is injected in 20–30 separate sites
depending on the dose of the toxin to be administered and the trigone area is
avoided.

The procedure is usually complete within 30 minutes. It takes approximately one
week before the effects of the toxin begin to give patients symptomatic relief.
Harper et al showed in their study using this technique for patients with
intractable detrusor overactivity that patients tolerated the procedure well, with
average pain scores of 3/10, using a visual analogue scale. All patients were
reported to be happy to undergo further injections if their symptoms were to
recur. The 39 patients in this study reported on so far showed improvement in
their urinary tract symptoms and urodynamic variables with an increase in
maximum bladder capacity34 .

Side effects
Side effects of botulinum toxin are rare when used in the context of urology.
Localized injection into the detrusor muscle may be associated with an allergic
reaction to the toxin or transient flu-like symptoms. Doses used in the
intradetrusal injection of botulinum toxin are well below (one thousandth) the
presumed fatal dose in a 70Kg man19,35 and as the injection is localized, minute
quantities only reach the systemic circulation.
However, two case reports from Belgium have reported generalized muscle
weakness and weakness in the arm muscles following botulinum toxin injection
into the detrusor muscle36. These two cases are the only ever significant reports
of side effects associated with injection of botulinum toxin into the bladder in the
literature.

Although in one case the cumulative dose may have been too high, the second
case was injected with 300 units of botulinum toxin. It has been postulated that
the injection may have taken place in a thin-walled bladder where perivesical
diffusion of the toxin took place, although this could not be proven.

Current research in the Urology Department at Guy’s Hospital is focusing on
using botulinum toxin in patients with idiopathic OAB. Patients who cannot
tolerate side effects associated with anti-cholinergic therapy or who build up
tolerance to the medication are being recruited for a double-blinded, randomized,
intradetrusal injection of 200 units of botulinum toxin versus placebo trial.


Conclusion
The initial results of work carried out with botulinum toxin and lower urinary tract
pathology is promising, however, further work in this field is necessary to further
elucidate the toxin’s mechanism of action in the urinary tract. Randomized,
placebo-controlled trials must be carried out to further elucidate this treatment
with studies to ascertain the correct dosage for best possible symptomatic
results.

Mr A Sahai is Research Fellow, Mr MS Khan is Consultant Urologist and
Transplant Surgeon, and Mr P Dasgupta is Consultant and Senior
Lecturer in Urology, Department of Urology, Guy’s Hospital, London Bridge,
London

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