Key words
neurogenic detrusor hyperreflexia - botulimium toxin A - spinal cord injuries - urodynamics
- voiding
Introduction
Annually there are up to 40 cases per million people of spinal cord injury (SCI) resulting
from a range of traumatic and non-traumatic incidents [1]. Neurogenic detrusor hyperrefflexia (NDH) is a well-known clinical emergency which
appears in 96% of patients with spinal cord injuries [2]. Successful control of (NDH) in spinal cord-injured patients is a major challenge
for urologists. Therefore, the primary goal of bladder management is to preserve kidney
functions by attaining safe bladder pressures, in addition to achieve acceptable social
continence and low urinary tract infection. Spinal cord injuries induce neurogenic
detrusor hyperreflexia and simultaneous detrusor sphincter dyssynergia that reduces
the storage and emptying functions of the urinary bladder. Anticholinergic medications
combined with clean intermittent catheterization (CIC) is the first line “gold standard”
treatment for NDH. However, due to the high incidence of side effect related to their
systemic actions, the long-term use of anticholinergic medication and intermittent
catheterization is restricted.
Botulinum toxin (BTX), first described by van Ermengem as “sausage poison” in 1895,
is probably most potent occurring natural biological toxin that can affect humans
[3]. Botulinum toxin was first isolated by Emile Van Ermengem in 1987, from the bacterium
Clostridium botulinum [3]. Out of the 7 immunologically distinct but structurally similar types of botulinum
toxins, types A and B have been used with clinically beneficial effects in various
neuromuscular disorders and are commercially available. Botulinum toxin primarily
effects on the release of acetylcholine from nerve ending and inhibits parasympathetic
neural transmission into the detrusor muscle [4]
[5]. Initially, clinical trials of botulinum toxin A (BTX-A) started with treatment
of bladder overactivity resulting from neurological insult in 2000. This therapy is
a minimally invasive treatment option positioned between oral anticholinergic treatment
that was ineffective or not tolerated and invasive surgery [6]. The rapid expansion in the use of BTX-A to treat overactive bladder is due, in
large part, to the inadequacy of current standard pharmacologic treatment (i. e.,
antimuscarinic agents) as well as to the demonstration of the efficacy, and tolerability
of BTX in early clinical series. The safety and efficacy have been confirmed in a
randomized placebo-controlled study by Schurch et al. [7] and in the local administration of BTX-A into the bladder by Reitz et al. [8], Schurch et al. [6] and Stohrer et al. [9]. The safety profile seen in these studies suggests that this a promising treatment
for the management of neurogenic urinary incontinence.
Many studies have appraised the use of botulinum toxin type A injections into the
detrusor muscle of SCI patients in order to increase bladder capacity, reduce neurogenic
detrusor hyperreflexia, and reduce urge incontinence [6]
[7]
[10]. In the current study, we have observed differing clinical responses following use
of this drug, despite improvement in most urodynamic parameters. In this study, we
present the results of the effect of injecting botulinum toxin type A into the detrusor
muscle on various voiding parameters for spinal cord injured patients with NDH in
China.
Subjects and Methods
Selection of subjects
A total of 24 study subjects with spinal cord injuries (SCI) were admitted in the
study which extended from January 2012 to February 2014, the basic demographic data
of whose is presented in [Table 1]. Inclusion criteria included detrusor hyperreflexia (DH) and urinary incontinence
that proved difficult to treat, despite upon the use of 2 different anticholinergics
at maximal doses, patients having intolerable side effects from anticholinergic therapy
(e. g., dry mouth, constipation) and patients with poorly compliant bladders. Exclusion
criteria included patients with hydronephrosis or renal disease, coagulopathy disease,
myasthenia gravis, aminoglycoside treatment, hypersensitivity to BTX-A, previous sphincterotomy,
and patients who were unable to perform clean intermittent catheterization. The study
was approved by the ethics committee of Jinling Hospital, Southern Medical University.
Each patient was fully informed about the procedure and written consent was obtained
before the treatment.
Table 1 Basic demographic data of the patients with spinal cord injury.
|
Characteristics
|
Value
|
|
Total number of patients
|
24
|
|
Age in years, mean (SD)
|
42.6 (12.4)
|
|
Gender, men/women, n (%)
|
19 (80%)/5 (20%)
|
|
ASIA scale, n (%)
|
|
|
Grade A
|
13 (54)
|
|
Grade B
|
3 (12.5)
|
|
Grade C
|
5 (21)
|
|
Grade D
|
3 (12.5)
|
|
Injury level, n (%)
|
|
|
Cervical
|
14 (58)
|
|
Lumbar
|
6 (25)
|
|
Thoracic
|
4 (17)
|
SD: standard deviation; ASIA: American Spinal Injury Association [11]
Pre-treatment assessment
Patient evaluations included a complete medical history, physical examination, a 3-day
voiding diary, a video urodynamic studies, upper tract evaluation, plain abdominal
radiograph, an urodynamics assessment 2 week prior to the treatment and a day zero
baseline assessment (Multichannel urodynamics studies – Medtronic Duet systems, version
8.20, Minneapolis, MN, USA) before intravesical botulinum neurotoxin A injection.
The urodynamic parameters measured included maximum cystometric capacity (MCC), reflex
detrusor volume (RDV) and maximum detrusor pressure during bladder contraction (MDP).
The standard International Continence Society definitions were used at the time of
protocol writing [12]. Reflex volume is the infused volume that induces the first detrusor contraction.
Bladder compliance is calculated by the change in volume divided by the change in
detrusor pressure. The patients received BTX-A injections in conjunction with clean
intermittent catheterization (CIC) to treat detrusor hyperreflexia (DH) and urinary
incontinence. DH was diagnosed urodynamically. Incontinence was defined as any episode
of urinary voiding between 2 CICs and was quantified with an absorbent pad.
Treatment
All procedures were done on an outpatient basis in the operating room using general
anesthesia and vital sign monitoring equipment was set up. Perioperative antibiotics
were administered orally for 7 days, according to urine culture, and the botulinum
toxin A injection performed on the fifth day of drug administration. Clostridium botulinum
toxin type A (commercial grade onabotulinum toxin A, Botox®, Alergan) [13] was diluted in 0.9% preservative-free saline to a final concentration of 10 IU/ml.
Shaking of the vial was prevented because this may break the disulfide linkage between
the light and heavy chains, rendering the toxin ineffective [13]. Using flexible cystoscope, an ultrafine 4 mm needle (Dasgupta technique) which
is less invasive, a total maximal dose of 300 IU (dilution: 10 IU/mL) was injected
at 30 detrusor muscle sites in approximately equal aliquots except the trigone as
described by Schurch et al. [6]. The sparing of trigone from injection was based on a few facts, including a desire
to avoid inducing reflux to the upper tract. Moreover, the injection of the dense
trigone innervation from both sensory, adrenergic and non-cholinergic pathways might
complicate the efficacy analysis of a cholinergic blockade. No patients were administered
with repeated/augmentation doses during the period of study. Patients were instructed
to progressively taper and then discontinue their anticholinergic medications within
the first week following the procedures.
Post treatment follow-up
A clinical and urodynamic follow-up was obtained and visits occurred at 2, 6, 12,
18 and 24 weeks after treatment and compared to the baseline values. The voiding characteristics
were measured and recorded at 2, 6, 12, 18 and 24 weeks and the urodynamic parameters
were measured and recorded at 2, 6, and 24 weeks. The urodynamic parameters measured
included maximum cystometric capacity (MCC), reflex detrusor volume (RDV) and maximum
detrusor pressure during bladder contraction (MDP). Subsequently, the patients returned
to our practice if urinary losses reoccurred. All patients were asked to complete
a 22-item, domain-specific, validated Incontinence Quality of Life Questionnaire (I-QOL)
[10] before and 2 weeks after the injections that detected changes in the self-perceived
severity of incontinence. The QoL index was expressed as a score ranging from 0 (poor
self-perceived QoL due to incontinence) to 100 (incontinence does not negatively affect
QoL).
Statistical methods
Paired t-test was used to compare urodynamic parameters pre- and post-injection. Repeated
measures analysis of variance (ANOVA) were used to analyse longitudinal data. The
data was analysed using SPSS (Version 20.0) with statistical significance set at p<0.05.
Results
A total of 24 subjects were selected for the study, out of which 2 were dropped with
one showing adverse effects (transient hematuria and mild UTI), which resulted his
unwillingness to continue the treatment, and other showed lack of efficacy at 4 weeks.
18 out of the 22 left subjects were men and the other 4 women with a mean age of 42.6
(SD=12.4) ranging from 32 years to 61 years. American Spinal Injury Association (ASIA)
scale, were also measured and there were 13 (54%) Grade A, 3 (12.5%) Grade B, 5 (21%)
Grade C, and 3 (12.5%) Grade D subjects. No subjects were classified under class E
of ASIA scale. The distribution of SCI levels was: 14 (58%) cervical, 4 (17%) thoracic
and 6 (25%) lumbar. The basic demographic data are shown in [Table 1]. The results from the 3-day voiding diary after statistical analysis are as shown
in [Table 2]. At pre-injection, all patients experienced leakage despite maximal anticholinergic
therapy. The percentages of those who achieved complete continence and were completely
dry at 2, 6, 12, 18 and 24 weeks post-injection were 82%, 76%, 77%, 68%, and 59%,
respectively. The mean number of leakages was reduced from 2.8±1.55 pre-injection
to 1.22±1.41 at 2 weeks post-treatment and 1.4±1.52 at 24 weeks post treatment ([Fig. 1]). Compared to the number of leakages pretreatment, the reduction in the amount of
leakage was statistically significant. Improvements were demonstrated in the daily
frequency of incontinence episodes and urodynamic parameters. Improvements occurred
from the first post-treatment evaluation visit at week 2 and were generally maintained
for the duration of the 24-week study. No evidence of a treatment by site interaction
effect was observed. At baseline the mean daily frequency of incontinence episodes
was significantly different from the baseline at 2, 6, 12, 18 and 24 weeks (
[Fig. 2]).
Fig. 1 Plot of Urodynamic measures; cystometric capacity (MCC), reflex detrusor volume (RDV)
and maximum detrusor pressure during bladder contraction (MDP) before and 2, 6, and
24 weeks after BTX-A injection therapy (p<0.05), depicting statistically significant
decrease in MCC and MDP, and increase in RDV over a 24-week study period.
Fig. 2 Representative graph of changes in involuntary urine loss and catheterization frequency
at 2, 6, 12, 18, 24 weeks post-treatment, showing significant reduction in involuntary
urine loss and cauterization frequency during 24-week study.
Table 2 Results of characteristics from 3-day voiding diary.
|
Timeline
|
Baseline
|
2 weeks
|
6 weeks
|
12 weeks
|
18 weeks
|
24 weeks
|
|
Involuntary urine loss frequency
|
2.8 (1.55)
|
1.3 (1.41)
P=0.017(S)
|
1.2 (1.36)
P=0.015 (S)
|
1.2 (1.66)
P=0.015 (S)
|
1.2 (1.39)
P=0.016 (S)
|
1.4 (1.52)
P=0.02 (S)
|
|
Catheterization frequency
|
4.7 (1.62)
|
0.1 (0.76)
P=0.0017 (S)
|
0.1 (0.65)
P=0.0019 (S)
|
0.1 (0.71)
P=0.0017 (S)
|
0.3 (0.78)
P=0.008 (S)
|
0.2 (0.76)
P=0.006 (S)
|
|
Percentage of patients completely dry over 24 h
|
0 (0%)
|
18/22 (82%)
|
16/21 (76%)
|
17/22 (77%)
|
15/20 (68%)
|
13/22 (59%)
|
S=Statistically Significant by ANNOVA @ 5% level of significance
Following treatment there were significant decreases in incontinence episodes at all-time
points however the frequency tended to increase at 24 week time point. The decreases
represented a reduction in incontinence episodes of approximately 50% despite a lower
baseline than anticipated. In terms of urodynamic parameters, maximum detrusor pressure
decreased significantly from 91.4±35.8 cmH2O pre-treatment to 40.8±39.7 and 53.6±50.1 cmH2O at 2 and 24 weeks post-treatment, respectively. These differences were statistically
significant (P<0.05) as compared to baseline MDP. The volume at which reflex detrusor
contractions first occurred increased from 234.4±102.2 mL pre injury to 256.6±118.6 mL
at 2 weeks and 308.4±136.8 mL at 24 weeks post-treatment (P<0.05). Pre-injection,
all patients had detectable detrusor overactivity during urodynamic study. At 2 weeks
post injection, 40% of patients had no detectable detrusor activity during videourodynamic
study. This percentage, however, decreased to 9.5% at 24 weeks post-injection, indicating
the return of reflex activity. The mean cystometric bladder capacity increased from
270.6±110.5 mL to 452.2±130.6 mL and 380.6±168.1 mL at 2 and 24 weeks, respectively
(P<0.05 ([Fig. 1]). The results of videourodynamic study are summarized in [Table 3].
Table 3 Video urodynamic characteristics pre- and post-treatment.
|
Timeline
|
Baseline
|
2 weeks
|
6 weeks
|
24 weeks
|
|
Mean cystometric bladder capacity (mL)
|
270.6±110.5
|
452.2±130.6
P=0.0012(S)
|
446.2±188.4
P=0.0015(S)
|
380.6±168.1
P=0.0019(S)
|
|
Mean reflex volume (mL)
|
234.4±102.2
|
256.6±118.6
P=0.0011(S)
|
300.5±130.2
P=0.0009(S)
|
308.4±136.8
P=0.0007(S)
|
|
Maximal detrusor pressure (cmH
2
O )
|
91.4±35.8
|
40.8±39.7
P=0.034(S)
|
44.7±42.5
P=0.0.029(S)
|
53.6±50.1
P=0.036(S)
|
S=Statistically Significant by ANNOVA @ 5% level of significance
After treatment, the mean QoL index increased from 19.7±15.4 initially to 80.3±21.8
two weeks after injection (P=0.001). Most patients were either satisfied or very satisfied
with their overall experience with the treatment. Satisfaction levels correlated with
fewer leakages per day. Those with a less involuntary urine loss frequency were more
satisfied with their voiding pattern. The overall incidence of patients’ adverse effects
was 40%, who reported condition of dry mouth, UTI and injection site pain. Patients
with UTI were successfully treated with oral antibiotics. No cases of autonomic dysreflexia
or clinically relevant changes in vital signs, hematology, and ultrasound or cystography
observations were recorded during the study.
Discussion and Conclusion
Discussion and Conclusion
Spinal cord injuries accompany physiological changes that can lead to significant
bladder dysfunction, which has major influence on overall morbidity and quality of
life [14]. Botulinum toxin injections into the detrusor provide clinically significant improvement
in patients with neurogenic detrusor overactivity refractory to antimuscarinics and
are very well tolerated [7]. Management strategies for NDH syndrome should meet 3 main objectives: low episodes
of leakage per day, maximal voiding volume and adequate reflex volume. However, from
the patient’s point of view, the most important goals are continence and good tolerability
of the therapy [8]. The results of this study indicated that injection of 300 IU botulinum into the
detrusor, showed statistically significant effect. The significant effects were observed
on the episodes of leakage per day, maximal voiding volume, and urodynamic parameters
of reflex volume such as cystometric capacity and maximal detrusor pressure at 6 and
24 weeks after injection ([Fig. 2]). Also, the mean reflex volume remained high after 24 weeks post-injection and 59%
of treated patients were completely dry after 24 weeks post-injection. These results
are similar to the findings reported in Schurch et al. [6] and Reitz et al. [8]. The results of this study not only indicated significant reduction of detrusor
overactivity but also reflected significant improvement on quality of life and patient
satisfaction due to reduction in leakage and subsequent improvement of continence
([Fig. 1]), which is consistent with results of Stohrer et al. [9] and Schulte-Baukloh et al. [15]. Overall, most of the patients in the present study were satisfied with the BTX-A
treatment with an average satisfaction score of 6.9, which is comparable to the previous
studies [16]
[17].
The most probable reason for elongated effect of botulinum toxin up to 24 weeks, in
our research could be because of its effect on smooth muscle as compared to shorter
duration of action described in striated muscle. Botulinum toxin inhibits the release
of acetylcholine in the synaptic vesicles by binding to the peripheral presynaptic
nerve terminals of motor endplates, thus blocking the enzymatic process of ATP dependent
exocytosis without affecting membrane transport. It has been shown that there could
be differences in the mechanism of action of botulinum toxin in smooth muscles [18]. Khera et al., [19] in an in vitro study on spinal cord injured rats suggested that one mechanism by
which BTX-A reduces detrusor overactivity is through impairment of ATP release due
to hypo-osmotic stimulation of bladder urothelium markedly caused by administration
of BTX-A.
Although there is no consensus regarding the optimal dose of botulinum toxin, most
of the studies have suggested and used a maximal dose of 300 IU [6]
[20]. However, some studies such as Reitz et al. [8] in randomized placebo controlled study found that both doses of botulinum toxin
of 200 and 300 IU showed similar responses. Kuo [21] also reported efficacious results with 200 IU botulinum A toxin in spinal cord injured
patients, with improvement of incontinence in 91.6% of patients. These results reflect
possible use of 200 IU of botulinum toxin. However, this study was conducted in patients
with neurogenic detrusor overactivity and a dose of 300 IU showed statistically significant
effect with respect to the episodes of leakage per day, maximal voiding volume, and
urodynamic parameters. In addition, as in our study, we recommended botulinum toxin
injection in accordance with the clinical response to treatment (incontinence despite
anticholinergic in high doses) and urodynamic results. Furthermore, injection technique
is an important issue affecting efficacy [22], again there is no consensus regarding a standard injection procedure in the detrusor
muscle, most studies have used the technique described by Schurch et al. [6].
In summary, the encouraging results of this study, without any side effects, reflect
that use of botulinum toxin in the treatment of neurogenic detrusor hyperreflexia
is a safe, valuable and promising option compared to anticholinergics. From this and
other clinical studies, it can be seen that there is definite clinical efficacy, improvement
in urodynamic end-point and patient satisfaction with botulinum toxin A injection
for treatment of NDH in spinal cord-injury patients, especially those refractory to
other treatments. There is a promising role for botulinum toxin A injection into the
detrusor in spinal cord injured patients resistant to anticholinergic medications,
who do not want invasive reconstructive surgery, or are not fit for surgery.
