1. No category

Special Article
Arch. Esp. Urol. 2010; 63 (10): 829-840
USE OF BOTULINUM TOXIN IN THE TREATMENT OF LOWER URINARY TRACT
DISORDERS. CURRENT STATUS
Altaf Mangera1 and Christopher R. Chapple2.
Department of Urology Research. Sheffield Teaching Hospitals NHS. Royal Hallamshire Hospital. Sheffield.UK.
Sheffield Hallam University and Consultant Urological Surgeon at the Royal Hallamshire Hospital. Sheffield. UK.
1
2
Summary.- The role of botulinum toxin in the treatment
of lower urinary tract disorders has vastly expanded in
the last few years. The indications list growing to include
conditions ranging from detrusor sphincter dyssynergia,
neurogenic and idiopathic detrusor overactivity, painful
bladder syndrome and lower urinary tract symptoms
consequent upon bladder outflow obstruction. This treatment is minimally invasive, shows a remarkable efficacy
and has effects lasting up to one year. We review the latest evidence both basic science and clinical to address
some of the key questions regarding this treatment mo-
dality. There is an abundance of evidence supporting
the efficacy, safety and tolerability of this treatment.
However, It is clear that much work is still required to
understand the mechanism(s) of action of the toxin and
more robust placebo controlled randomised trials need
to be undertaken to answer the many remaining questions concerning this novel treatment. Nevertheless this
treatment modality has remarkable efficacy and minimal
side effects and thus will be a key future treatment option
for a wide range of indications.
Keywords: Botulinum toxin. Detrusor overactivity.
Urgency. Neurogenic bladder dysfunction. Idiopathic bladder dysfunction. Prostate.
@
CORRESPONDENCE
Altaf Mangera
Department of Urology
Sheffield Teaching Hospitals NHS
Royal Hallamshire Hospital
Sheffield UK.
[email protected]
Accepted for publication: December, 27th, 2009
Resumen.- El papel de la toxina botulínica en el tratamiento de los síntomas del tracto urinario inferior (STUI),
ha aumentado enormemente en los últimos años. La lista
de indicaciones crece hasta incluir condiciones que
van desde la obstrucción por disinergia vesico-esfinteriana, hiperactividad neurogénica e idiopática del detrusor, síndrome de vejiga dolorosa y los STUI consiguientes a la obstrucción del flujo urinario. Este tratamiento es
mínimamente invasivo, presenta una notable eficacia y
sus efectos tienen una duración de hasta un año. Revisamos la evidencia más reciente tanto en ciencia básica como clínica para tratar algunas de las cuestiones
fundamentales que atañen a esta modalidad de tratamiento. Existen abundantes pruebas que respaldan la
eficacia, seguridad y tolerabilidad de este tratamiento.
Sin embargo, está claro que todavía hace falta mucho
trabajo para comprender el/los mecanismo (s) de la
acción de la toxina y deben llevarse a cabo ensayos
aleatorizados y controlados con placebo mas sólidos
para responder a las muchas preguntas aún pendientes
830
C. R. Chapple and A. Mangera.
sobre este novedoso tratamiento. No obstante, esta modalidad terapeútica tiene una eficacia notable y efectos
secundarios mínimos y por lo tanto será una futura opción de tratamiento clave para un amplio espectro de
indicaciones.
Palabras clave: Toxina botulínica. Hiperactividad del detrusor. Urgencia. Disfunción neurogénica
vesical. Disfunción vesical idiopática. Próstata.
INTRODUCTION
Produced by the bacterium Clostridium botulinum, botulinum toxins are amongst the most potent
toxins known to man. The neurotoxin has for some
years been known to decrease the release of Acetyl choline (ACh) from pre-synaptic membranes thereby blocking the transmission of impulses wherever
ACh is the neurotransmitter. Kerner first conceived a
possible therapeutic role for botulinum toxin. It was
first used to treat conditions of hypertonicity in striated muscle. The first use in humans, in 1980, was
for the treatment of strabismus and subsequently the
food and drug administration agency approved its
use for conditions such as strabismus, blepharospasm
and hemifacial spasm in patients over 12 years old.
Its indications have since expanded and it has been
used successfully in many conditions characterised by
muscle spasticity.
In 1996 Schurch first published the use of
botulinum toxin-A (BTX-A), injected into the external
urinary sphincter, to treat detrusor sphincter dyssynergia (DSD) in patients with spinal cord injury (1).
This was followed by using local injections of BTX-A
to treat neurogenic detrusor overactivity (NDO) (2).
Efficacy approaching 100% has been described with
over 600 patients treated for NDO and a further 200
with idiopathic detrusor overactivity (IDO) reported
in the literature. Most groups reporting improvements
in quality of life and symptoms of urgency, frequency and incontinence with concomitant improvements
in urodynamic parameters. This review will discuss
the postulated mechanism of action and the reported
data regarding efficacy in the various disorders of the
lower urinary tract.
Rationale for botulinum toxin based on past experiences
The introduction of BTX in the treatment of
detrusor overactivity was based on the supposition
that it would block the efferent neural pathway, the-
reby decreasing the involuntary detrusor smooth muscle contractions characteristic of detrusor overactvity.
However this is unlikely to represent the whole picture.
The precise mechanism of action in bladder storage
disorders is unknown. It is unlikely to be acting primarily via the efferent pathway. The toxin is injected
into both the suburothelial layer and detrusor muscle.
The supposition of causing localised islands of detrusor muscle paralysis could potentially abolish the
overactivity associated with OAB but how could this
mechanism explain the efficacy achieved in treating
painful bladder syndrome/ interstitial cystitis (PBS/IC)
where the pathophysiology is unlikely to involve detrusor overactivity? Furthermore, it does not explain
the relief of the symptom of urgency, unless urgency is
postulated to result as a consequence of detrusor overactivity propelling urine into the proximal urethra thereby stimulating urethral afferents. Below we discuss
the mechanisms of action including current theories to
explain its effects.
Mechanism of action
There are 7 serotypes of the toxin; BTX-A to
BTX-G, the most commonly used being BTX-A (botulinum toxin A). However; BTX-B has also recently been
licensed due to some reports of efficacy in those resistant to BTX-A. The other known serotypes are not currently licensed for clinical use. The neurotoxin causes
a highly specific neuromuscular blockade of vesicular
Ach release at somatic and autonomic pre-synaptic
nerve terminals (3). BTX is a protein consisting of a
light chain (50kDa) and a heavy chain (100kDa)
bound together by a labile disulphide bond. The heavy chain binds to complex gangliosides located in
the presynaptic nerve terminals at the neuromuscular
junction and mediates the internalisation of the light chain, the neurotoxic component. The light chain
is then thought to work by cleaving SNARE proteins
SNAP-25, VAMP and syntaxin which causes inhibition
of vesicular SNARE dependent ACh release from the
presynaptic terminal of the motor end plates (3). This
prevents vesicular release of ACh causing a sustained
flaccid paralysis of the innervated muscle. It is highly
selective and this supplies the basis for its potency.
Clinical effects appear 24-72 hours after injection,
the reason for this delay being unknown (4).
The various toxins disrupt different parts of
the SNARE complex with BTX-A acting against SNAP25 and BTX-B against VAMP (3). The defective SNARE complexes have a prolonged life within the nerve
terminal, which may account for the sustained action. This action is not permanent as neuronal death
does not occur and the toxins are eventually inactivated and removed. Histological assessments show
USE OF BOTULINUM TOXIN IN THE TREATMENT OF LOWER URINARY TRACT DISORDERS. CURRENT STATUS
831
the intoxicated nerve terminals degenerate and it is
thought re-sprouting of axons leading to new synaptic
contacts occurs forming new functional synapses and
may presumably account for the return to muscular
function which occurs after a number of months (3).
Unnecessary sprouts are gradually eliminated.
decrease in DO (18). In conclusion, clinically it may
mean autonomic hyperactivity in detrusor overactivity
may be susceptible to blockade by BTX yet the lower
frequency normal parasympathetic detrusor is unaffected permitting normal voiding (16).
Moreover, local injection leads to local flaccidity but due to its tissue specificity very little has any
systemic effect and therefore minimal side effects are
reported. Indeed, even with the most potent of substances no fatalities have been reported. The effect of
the toxin lasts for a number of months and repeat administration has been demonstrated to have reproducible efficacy. A small number of patients after repeated doses have however been noted to develop an
immune response forming antibodies that neutralise
its effect.
Role in management of
New concepts on the action of BTX include
the release of neurotransmitters including ATP (5), Ach
and substance P from the Urothelium. Once thought
to be inert the urothelium is in fact a complex organ,
involved directly in bladder storage (6). It has been
shown that ATP is released due to stretch stimulating
the suburothelial purinergic neuronal receptors (7).
In summary the urothelium acts as an intermediary
in transduction of urothelial stretch to the reflex and
afferent nerves, possibly modulating the signal. This
transmission giving rise to bladder sensations and ultimately activating the micturition reflex (6).
Detrusor Sphincter Dyssynergia (DSD)
Dykstra et al. (19) and Schurch et al. (20)
first used BTX-A to treat DSD in patients with spinal
cord injuries. A paralytic effect was described affecting the external urethral sphincter, either by injection
transurethrally or transperineally. The latter study concluded an improvement in 21 out of 24 patients with
the effect lasting between 3 to 9 months. In the former
study the urethral pressure profile was decreased,
electromyography showed signs of sphincter denervation and PVR volumes were down by an average
of 146mls. In addition to this there was a decrease in
autonomic dysreflexia in some patients.
The importance of the afferent innervation in
overactive bladder disorders (OAB) and urinary incontinence is becoming clear (8). Elevated levels of
ATP have been demonstrated in patients with urgency
(9) and following spinal cord injury (10). Moreover,
elevated levels of ATP have been found to induce detrusor overactivity (DO) (11) and the expression of
purinergic ATP activated receptors is up-regulated in
DO (12).
This was later echoed by Petit et al. (21)
using 150u of Dysport, the therapeutic effect (of the
low dose) lasting 2 to 3 months. Later Kou et al. reported using Botox in 29 patients with DSD resulting
in improvements in 80% of patients lasting 4 months
(22). De Seze et al. compared 100u of Botox against
0.5% lidocaine injected into the urethral sphincter via
a transperineal approach and found only patients in
the former group had a significant decrease in PVR
and maximum detrusor pressure (23). More recently,
after investigating patient quality of life (QoL) scores
and urodynamic assessments, Kou reported mixed results of satisfaction in patients with DSD (24). The study reported that 60% of patients were satisfied with
the outcome, the remainder being dissatisfied due to
resulting incontinence. This calls for careful patient selection.
It is difficult to explain the remarkable efficacy of BTX by simple ACh blockage causing detrusor
paralysis alone. Surely this paralysis would cause a
higher rate of urinary retention? BTX has interestingly
been found to have analgesic properties in conditions
such as interstitial cystitis, signifying its role in altering
sensory pathology (13) (14). In hyperactive neurons
BTX-A has been found to reduce pathologically raised neurotransmitters, including ATP in the urothelium
(15). Also BTX A treatment lead to a decrease in the
number of suburothelial afferent neurons expressing
purinergic receptors (16), in particular the P2X3 and
TRPV1 receptors (10) (17). In addition to that BTX
decreases nerve growth factor which may result in
reduced afferent C-fibre hyperexcitability and thus a
Indications for BTX have been further expanded to include patients with non-relaxing urethral
sphincter and detrusor underactivity who wish to void
via by the valsalva manoeuvre (25) (26). In 6 females
with chronic idiopathic retention, Fowler et al. found
no improvement in symptoms and 3 out of 6 patients
developed stress incontinence (25). Phelan et al. reported better results in 8 patients with a non-relaxing
urethral sphincter showing improved PVR and voiding
pressures (26). Kuo et al. injected 50-100u of Botox
into the external sphincter of 30 patients with a nonrelaxing urethral sphincter. Significant improvement
was seen in 89% of patients both subjectively and on
urodynamic parameters (22). Better results were seen
in patients with detrusor underactivity (27). Overall
832
C. R. Chapple and A. Mangera.
stress incontinence rates were 7%; and 3% developed nocturnal urinary incontinence.
Neurogenic detrusor overactivity (NDO)
NDO commonly occurs in patients with spinal cord injury, multiple sclerosis and myelomeningocele principally due to a disruption of the descending
pathways providing the inhibitory input to the sacral
micturition centre. This loss of inhibition leads to involuntary contractions and, frequently, incontinence.
In addition to this, uncoordinated contraction of the
sphincter (DSD) leads to structural bladder damage,
vesicoureteric reflux and consequent renal impairment
due to elevated bladder pressures. Clean intermittent
self catheterisation (CISC) has been the mainstay of
treatment supplemented with anticholinergic preparations. These lead to autonomic side effects and preclude usage at a sufficient dose to improve the condition
significantly.
Over 600 patients are reported in the literature with neurogenic overactivity. Notable improvements have been seen in the urodynamic parameters
of maximal cystometric capacity and the reflex volume (volume at the start of the first hyperreflexive contraction) thereby increasing bladder storage. Many
patients are reported to have no involuntary contractions following treatment thus reducing symptoms of
urgency and frequency and many patients gaining
complete continence (28). In addition to this many
patients have a lower maximal detrusor pressure on
voiding, offering protection to the upper tracts. Treatment benefit lasts 3-14 months and only short lived
side effects are reported.
The first multicentre RCT of 59 patients randomised to either 200 units, 300 units or placebo found,
on average, incontinence episodes were reduced by
50% (p< 0.05). The maximal cystometric capacity,
maximal detrusor pressure and residual volume were
all improved (29). The efficacy of treatment was maintained for the 6 months of the study. Quality of life
assessment also improved (p<0.002). No dose differences were demonstrated; however the sample size
was small. Those with severe detrusor overactivity appeared to have greater benefit than those with less
severe detrusor overactivity. Approximately 25% of
patients developed a UTI (including placebo group).
Reitz et al. describe the largest collection of
patients with NDO; 231 from 10 centres. Using 300u
in a trigone sparing technique, they found significant
improvements in bladder capacity, reflex volume and
voiding pressure. Many patients even stopped taking their anticholinergic prescriptions (30). No side
effects were reported in this study. From the clinical
point of view 73% of patients achieved full continence between CISC and at 9 months the majority still
experienced significant urodynamic and clinical improvement.
Del popolo et al. reported on the use of Dysport in 93 patients with NDO refractory to anticholinergics using CISC. They found improvements in
mean bladder capacity and mean maximum detrusor
pressure. The average length of effect was 1 year.
Patients receiving 1000u, with complete cord transection were more prone to develop hyposthenia in
supralesional muscles, which occurred in 5% of patients.
The other major benefit of BTX injections in
NDO patients is the reduction in urinary infectionspyelonephritis, orchitis, and prostatitis commonly observed in NDO patients. The reason for this decrease
is most likely associated with a reduction in detrusor
pressure, PVR and vesico-ureteric reflux and consequent protection of the upper tracts (31,32). Consequently, recent analysis in the UK and Germany have
shown BTX to be cost effective, although the cost in
the UK per BTX injection and follow up was high
(£874.62) in neurogenic patients. This was less than
the standard cost of care for these patients (33). Similarly in Germany the cost of incontinence aids and
urinary infection treatments meant a drop in cost by
50% (34). With all these benefits and little by the way
of adverse events, to be licensed BTX treatment still
requires completion of robust randomised controlled
studies, some of which are already underway.
Paediatric NDO
BTX has been used to treat NDO in a number
of studies using 4-12u/Kg Botox (35) (36) (37). Results are comparable to adult studies, with significant improvements in urodynamic parameters and symptom
scores with side effects being rare. Duration of effect
was 6 months; which may be due to a bias towards
a selective population with conditions such as myelomeningocele having a less well developed autonomic
nervous system.
Idiopathic detrusor overactivity
Following the remarkable efficacy seen with
BTX in NDO, a number of authors have investigated its use in patients suffering from intractable IDO,
when all other non-surgical treatment modalities have
failed. Results show similar efficacy and tolerability in
IDO as NDO. Radziszewski and Borowski conducted
USE OF BOTULINUM TOXIN IN THE TREATMENT OF LOWER URINARY TRACT DISORDERS. CURRENT STATUS
the first clinical trial using Dysport in 18 patients with
IDO and found increase in bladder capacity and return of continence without any side effects (38). Popat
et al. compared BTX-A in non randomised neurogenic
patients (300 units, 30 sites) with idiopathic patients
(200 units, 20 sites); the lower dose given to reduce
the risk of the need for CISC. Both groups showed
improvements in symptoms and urodynamic parameters with no differences between the two groups (39).
Chancellor et al. reported similar efficacy between
the 2 groups with injections involving the trigone and
no patients affected by urinary retention or vesico ureteric reflux (40).
Sahai et al. recently published a single
centre, randomised, double blind, placebo controlled trial of patients with IDO. Participants received
200units BTX-A or placebo via a trigone sparing flexible cystoscopic approach. Significant improvements
were seen in QoL scores with benefits lasting the 6
months of the study (41). Using 100 units of BTX no
cases of urinary retention were noted and the effect
on the post void residual was short lived, however
2 of 26 women were not affected by the treatment
(42). Similarly Brubaker et al. compared 200u Botox
with placebo. Approximately 60% of women receiving BTX-A had a significant improvement in lower
urinary tract symptoms with a median duration of
373 days. However 43% of women had a transient
increase in PVR and 75% of these had urinary tract
infections (43). Schmid et al. injected 100u of Botox
in 100 patients with IDO, more than 80% of patients’
incontinence symptoms had resolved and temporary
incontinence was reported in 4% (44). In a recent
randomised dosing study comparing 100u to 150u
BTX no difference was found in urodynamic or QoL
results suggesting the lower dose may be the starting
point, increasing as the need arose (45).
In response to the increased understanding
of the urothelium in OAB, Kuo gave BTX injections
sub-urethrally (46). Although this method was found
to be more effective than detrusor injections, bladder
sensations and voiding efficiency were impaired.
30% of patients required catheterisation and 75% reported voiding difficulty. Thus suggesting that detrusor
blockade was higher through sub-urothelial sensory
fibres than neuromuscular junctions or a small amount
of diffusion occurs from the detrusor to the sub-urothelium following detrusor injection.
BTX has also been used in patients with refractory OAB symptoms, with no evidence of DO
on urodynamics, with significant improvements in
symptom scores, bladder diary and urodynamic parameters (47,48). The decrease in urgency may be
due to the effect on the afferent detrusor innervations.
833
Even with a dose of 300u of BTX no increase in post
void residuals or need for CISC was noted; possibly
because all these patients had 50-75u of BTX injected
into the external sphincter concurrently. This did not
lead to increased rates of stress incontinence.
It is increasingly likely BTX will play an increasingly important role in the management of IDO,
filling the void between unsuccessful pharmacotherapy and invasive surgical therapy. Initial studies have
been supportive, often in patients with intractable
symptoms. Unfortunately many unanswered questions remain which must be resolved before mainstream
acceptance of this treatment modality.
Paediatric IDO
Hoebke et al. describe BTX use in a paediatric population with IDO with a response rate of 80%,
with a significant proportion of patients continuing
with a response 12 months following treatment (49).
Of the 21 patients, 4 had transient side effects including retention and VUR. Peeren et al. retrospectively
analysed paediatric patients treated with BTX and
found after 18 months 33% had continued symptom
control, which is higher than other sub-groups (50).
Painful bladder syndrome/ Interstitial cystitis (PBS/
IC)
Giannantoni et al. (51) reported success with
the use of 200u BTX-A in 12 out of 14 patients with
PBS/IC at 1 and 3 months follow up, 2 patients reported incomplete bladder emptying. BTX-A lead to significant improvements in urodynamic parameters, urinary frequency and bladder pain. Continuing this on
to one year they found, at the 5 month mark, 26.6%
of patients reported beneficial effects to have lasted
and at 12 months pain had recurred in all 15 patients
(52). All the patients in the above study were given
intra-trigonal injections. Smith et al. also reported benefit in 9 out of 13 patients with PBS/IC given 100200u BTX into the trigone and floor of the bladder
(53). More recently Kuo and Chancellor reported a
randomised trial of suburothelial injections of either
200u or 300u of BTX followed by hydrodistension
or hydrodistension alone (54). They found that subjective improvements occurred in both groups, more
so in the former group. Urodynamic parameters were
significantly improved only in the BTX group. Given
the lack of evidence for the use of BTX in PBS/IC it
should still be considered an experimental treatment.
In men with chronic pelvic pain syndrome
(chronic prostatitis) BTX injection decreased pain and
834
C. R. Chapple and A. Mangera.
improved voiding symptoms (55). Three out of four
patients were satisfied with the treatment and none
complained of urinary incontinence. This adds weight to the theory of anti-nociceptive actions of BTX
(56,57).
Botox in prostatic obstruction
Another new role for botulinum toxin is in the
management of LUTS arising from benign prostatic
enlargement. This potential was first explored in animal studies (58), where the prostate was seen to undergo atrophy after injection. This was subsequently
reported in man by Maria et al (59,60). Intraprostatic injections of 200u BTX have been compared to
an injection of an equivalent volume of saline in two
randomised groups consisting of 15 men. Injections
were made through the perineal route under transrectal ultrasound guidance. No side effects were noted
from treatment. The AUA symptom index score halved
in the BTX arm but not in the placebo arm. This was
supported by a significant increase in peak flow and
decrease in PVR. Interestingly the prostate size and
PSA level also decreased by 51% (60). It is difficult
to explain this phenomenon completely without adequate histology; but it may be due to gland atrophy
due to toxin action locally or due to blockage of autonomic nerve fibres. Injecting small prostate glands
(<30 mls) has been found to cause a reduction of
13% (61), whereas injection of larger prostates (>70
mls) has been found to cause a reduction of 40% volume (62).
Chaung et al. reported similar improvements
in subjective symptoms starting at one week and lasting up to 6 months. Two of these patients underwent
prostatic biopsy and were found to have increased
apoptotic activity in both glandular and stromal components of the prostate (61). Other authors have noted improvements in voiding in patients with prostatic
obstruction who are too unfit for more invasive procedures. Improvements usually commence at 1 week
(presumably time taken for the prostate to atrophy
significantly enough for improvement to be noted).
Improvements are noted in Qmax and PVR, also prostate volume and PSA decrease and patients with long
term catheters may start spontaneously voiding (62).
At a mean follow up of 9 months, Kuo et al. found
none of their cases with previous urinary retention
had recurrence of their retention (63). Silva et al. continued their 6 month study described above (62) in
11 patients and found the prostate volume began to
recover from 6 months onwards to return to baseline
at 18 months. The PSA, Qmax, IPSS and QoL scores
did not change significantly from the 3 month scores
(64).
The use of botulinum toxin in obstructive
conditions of the prostate still needs much work both
scientifically and clinically with longer follow up periods. No consensus exists upon the favoured route;
whether it be perineal, urethral or transrectal? Also
the dose of toxin to be used needs investigating as
does the number of injections and in to which zones?
Like all new applications it will take time for the true
answers to become apparent.
Preparations and dose
BTX-A was the first licensed serotype in clinical use under the name Botox, however another
brand of BTX-A called Dysport is also available but
has not been used or studied as widely in the lower
urinary tract. Although these two products are the
same serotype, their dose, efficacy and safety profile are different enough for them not be considered
as generic equivalents (65). Furthermore, BTX-B products have been licensed for use and have a different
efficacy, diffusion, duration of effect, immunogenicity
profile and mechanism of action and again the two
must not be considered clinically alike (66). BTX-B has
been reported to have more side effects. 1u of BTX-A
is approximately equal to 50-100units of BTX-B (67)
and 3-5u of disport (4,68,59).
Dysport has been described in 12 patients
with IDO, who were all given 300u. All patients had
a return of continence and improvements in maximum
cystometric capacity and frequency without any adverse events (38). Del Popolo et al. showed a significant increase in maximum cystometric bladder capacity, decreased detrusor pressures and subjective
improvements in continence and QOL with primary
and repeat injections. Also no differences were found
between three different Dysport doses (69).
In patients with NDO Truzzi et al. compared 100 to 300 units of Botox. Although some patients became continent with just 100u, the results
were better with 300u (70). This raises the need to
identify those in whom 100u would suffice. In IDO
patients Gousse et al. randomised patients to receive 100 or 150u of BTX-A. They found that the lower
dose was equally effective in frequency, voided volume, QoL and PVR, suggesting that lower doses
could be used. However no mention was made of
duration of action (71). The issue of dose requires
further robust study.
A couple of case reports describe the continued efficacy of BTX-B in cases where resistance has
developed to BTX-A (59,72). The different target proteins for these toxins may explain why there is conti-
USE OF BOTULINUM TOXIN IN THE TREATMENT OF LOWER URINARY TRACT DISORDERS. CURRENT STATUS
nued efficacy. However one must be wary of crossreactive antibodies which may limit this use.
Using 5000u of BTX-B (neurobloc) injected
in 20 sites, Hirst et al. found good efficacy but the
duration of action was less than 10 weeks in 52%
of patients and no patients had benefit lasting to 6
months (73). However Dykstra et al. reported a dose
escalation study on 15 patients showing a significant
correlation with dose and duration of effect (p<0.001),
with the longest effect being with doses >10 000u. A
burning pain was noticed on initial injections; however
this was relieved with dilution of the toxin with lidocaine. At the highest dose of 15 000u, 2 out of 3 patients
noticed mild general malaise and dry mouth (74).
Ghei et al. performed a randomised cross
over trial using 5000u of BTX-B. The study was done
at 6 weeks and there was some evidence of carry over
effects in the placebo group at the time. Statistically significant results were demonstrated in voided volume,
frequency and incontinent episodes with the treatment
but 2 patients developed AUR and left the study and
2 other patients had some transient autonomic side
effects suggesting some systemic absorption (75).
Administration
Initially the administration of BTX was via a
rigid cystoscope but with improvements in fine bore
injection equipment, flexible cystoscopes are utilised
more frequently. This has lead to many studies using
only intra-urethral local anaesthetic gel instead of the
previously used general or spinal anaesthesia. If a
rigid cystoscope is used the anterior bladder wall is
spared from treatment (76).
Variability in the number and volume of injections may affect the diffusion characteristics and efficacy of BTX treatment as well the possibility of adverse events. No change in efficacy, safety or QoL was
found by Karsenty et al. when comparing 300u given
at 30 sites or 10 sites. This provides indirect evidence that a dose dependant diffusion of BTX-A activity
occurs (77). This may allow the for fewer injection
sites thus simplifying the procedure. In our experience
injecting 0.5ml containing 10u is effective.
Controversy exists regarding injecting the trigone. There is concern that injecting close to the ureteric orifices may lead to vesicoureteric reflux, particularly in susceptible patients with NDO. Moreover in
awake patients, injecting the trigone, which is known
to contain a rich plexus of nerves, is postulated to
cause pain at the time of injection (78). Rapp et al. injected 300u in the bladder and trigone in 35 patients
835
from which 7 complained of haematuria, pelvic pain
or dysuria, all resolving within 3 days (48). However knowing the trigone contains this rich plexus of
adrenergic, cholinergic, and nonadrenergic noncholinergic fibres may make it a chief site for injection
(79). Indeed Zermann et al. injected the trigone and
bladder base and reported no complications with a
57% improvement in frequency and bladder capacity
(80). Recently Karsenty et al. showed no induction
of vesico-ureteric reflux in patients that have trigonal
injection (81).
Failure of treatment
Patients with severe diminished bladder compliance (<1.8l) have been found to be non responders to treatment (82). Despite improving compliance
in some studies BTX treatment may not overcome very
poor bladder compliance. The minimum level of acceptable compliance is unknown.
Adverse events
The adverse events reported with BTX have
been very small with no serious events or fatalities
reported. Patients must be counseled of the need to
perform CISC, if not regularly done, if there is difficulty voiding post procedure. Patients in whom de novo
voiding difficulty has occurred, it has been short lived.
In larger series the rate of CISC post BTX treatment
lies between 0-5% (44) (80), although higher rates
of up to 36% have been reported (83) (84) . In IDO
patients, Schulte-Baukloh et al. reported injecting BTX
into the sphincter if patients were found to have more
than 15 mls PVR. This was compared to a group that
had just injection into the bladder. On comparison of
the 2 groups the PVR was distinctly higher in the detrusor only group (p<0.05), but was unchanged in the
detrusor and sphincter group, suggesting that concurrent injection will provide protection against developing a high PVR and requiring CISC following Botox
for IDO. One would postulate a higher incidence of
stress incontinence with this strategy but this was not
found during this study (29).
No reports of generalised muscle paralysis
have been reported. However there are reports of
transient mild muscular weakness in the upper limbs,
particularly in patients with high cervical lesions, given the maximum dose of 300u Botox (85) or 1000u
Dysport (86).
Due to the antigenicity of BTX a small number
of patients mount an immune response with the formation of neutralising antibodies. To minimise the small
836
C. R. Chapple and A. Mangera.
risk of BTX resistance, most investigators currently recommend waiting at least 3 months between treatments, avoiding the use of booster doses and using
the smallest dose that achieves the desired clinical
effect (59). The newer formulations of Botox used after 1998 is thought to have drastically reduced the
occurrence of resistance (87).
Reinjection
The action of BTX is naturally reversed by
neural regeneration and therefore repeat injections
become necessary. Grosse et al. found repeat injections of Botox 300u or Dysport 750u were as
effective as the first injection; with patients receiving
up to 7 injections. The interval between the treatments remained the same. No drug resistance was
encountered (68). This was found by Karsenty et al.
in 17 neurogenic patients who had a mean of 5.4
injections. The reinjections were as efficacious as the
first injection and did not have an effect on compliance or side effects (88). In both studies tolerance
which may be anticipated due to enhancement of
pathological innervation following repeat injection
did not occur. Over a period of 6 years, Del Popolo
and colleagues injected 49 patients with at least 5
injections of Dysport and found no change in the
efficacy of repeat injections both subjectively and
objectively (69). Giannantoni et al. re-iterated these
findings recently (31).
There was concern repeated injections may
cause detrusor atrophy or bladder wall fibrosis. This
has been found not to be the case and in fact in NDO
patients repeat injections have not caused a decrease
in bladder compliance (69,89). In both NDO or IDO
patients no inflammatory change, fibrosis or dysplasia has been seen (90-92).
Further research
The potential of BTX in disorders of the lower
urinary tract has only been touched upon. There is
considerable research required for this novel treatment. There is a paucity of data coming from well
designed randomised placebo controlled studies
answering questions such as the optimum dose for
each preparation to give the longest duration of efficacy with the least side effects; needing systematic
dose ranging studies. Also we need to identify the
most appropriate method of administration including
the number and volume of injections and whether we
should include the trigone. The timing of repeat injections needs clarification as does the need to inject the
sphincter in cases at risk of retention.
More work needs to be done on the different serotypes; the efficacy, safety and dose ranges to
allow us to consider use if resistance develops. There may even be a role for synergistic therapy with
the use of 2 or more serotypes. Moreover patients in
most studies are highly selective, often those with the
severest symptoms (and possibly needing the treatment the most) being excluded. BTX in patients with
reflux disease and subsequent renal impairment may
demonstrate a different efficacy and have a different
threshold of toxicity. Also sub-groups of patients such
as those with intractable DO but no DO on urodynamics should be included. Finally all these studies need
to be assessing the quality of life in those treated with
BTX as this is the measure of greatest clinical significance to most patients.
CONCLUSIONS
BTX is a minimally invasive outpatient procedure which may be given under local anaesthetic that
has shown remarkable efficacy with effects lasting up
to a year after a single treatment. Adverse events are
rare. There is no doubt botulinum toxin has a promising future in management of lower urinary tract disorders. However considerable work, both basic science
and clinical, still needs to done if we are to answer
the remaining questions with regards to this treatment
option. Many questions still remain unanswered; what
is the appropriate dose range for optimal efficacy?
What is the best method of administration? What is
the optimal number and site of injection? Should we
include the trigone or the external sphincter during
injection- if so by how much? Should we use and/or
combine different serotypes? And what is the effect of
long term treatment?
The results of ongoing placebo controlled
randomised controlled trials are awaited with much
interest. Hopefully these and other case control studies in real life clinical practice may provide us with
information on health related quality of life data and
cost effectiveness of this novel treatment modality. Currently all BTX use for urological reasons is off-label
and not licensed, therefore caution should be exercised until future large randomised licensing studies are
reported.
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