Abstract
Purpose
To study the value and efficacy of botulinum toxin for treatment of cases of non-neurogenic detrusor overactivity (NNDO) that are refractory to anticholinergic drugs.
Materials and methods
A systematic review of the literature, based on a keyword search of the Medline database. Selection of articles in French and English (meta-analyses, reviews, case studies and randomized, controlled clinical trials) on intradetrusor botulinum toxin injection in the management of refractory NNDO.
Results
Nineteen publications (including three randomized, controlled trials) were selected. Intradetrusor injection of botulinum toxin in patients with refractory NNDO has produced promising results, with a significant improvement in physical symptoms, urodynamic parameters and quality of life. The rare side effects consist primarily of dose-dependent urine retention.
Conclusion
On the basis of preliminary data, botulinum toxin appears to be a valuable therapeutic option and fills the gap between anticholinergics and surgery in the treatment of NNDO that is refractory to anticholinergic agents. Botulinum toxin has a promising future in urology but requires further scientific evaluation.
Résumé
Objectif
Étudier la place et l’efficacité de la toxine botulique dans la prise en charge des patients souffrant d’hyperactivité détrusorienne réfractaire non-neurogène.
Matériels et méthodes
Revue systématique de la littérature à partir de la banque de données PubMed. Sélection d’articles en français et anglais (méta-analyses, études randomisées contrôlées, essais cliniques, revues), portant sur la place de la toxine botulique dans l’hyperactivité détrusorienne réfractaire non-neurogène.
Résultats
Dix-neuf études ont été retenues dont trois essais randomisés. L’injection intradétrusorienne de toxine botulique A pour le traitement symptomatique de l’hyperactivité détrusorienne non-neurogène a donné des résultats préliminaires encourageants en termes de diminution des signes cliniques d’hyperactivité vésicale, amélioration des paramètres urodynamiques et amélioration de la qualité de vie. Les effets secondaires sont rares, dominés par le risque de rétention urinaire qui semble corrélé à la dose utilisée.
Conclusion
La longue durée d’action de la toxine botulique, son efficacité et son innocuité en font un traitement faiblement invasif intéressant en cas d’échec du traitement anticholinergique, chez des patients pouvant réaliser ou acceptant le risque de l’auto-sondage.
1
English version
1.1
Introduction
Non-neurogenic detrusor overactivity (NNDO) is defined as the occurrence of spontaneous or triggered involuntary detrusor contractions during bladder filling, in the absence of an underlying neurological impairment . The condition manifests itself as an overactive bladder syndrome. The sometimes major sociopsychological impact of this condition justifies appropriate therapeutic management.
The prevalence of bladder overactivity varies with age and gender. Its incidence increases with age and is respectively 16.6% in people aged 40 and over in Europe and 16% in people aged 18 and over in the United States .
Anticholinergic drugs represent the first-line treatment for bladder overactivity. This therapy is usually effective but often produces troublesome side effects which may prompt patients to stop taking their medication.
In the event of clinical inefficacy or bothersome side effects that require treatment withdrawal, one of the alternative therapies currently being evaluated is botulinum toxin .
1.2
Materials and methods
We performed a systematic literature review (based on the contents of the PubMed database) by focusing on studies published since 2000 on botulinum toxin’s clinical and urodynamic effects and administration procedures and the quality of life in patients with NNDO that is refractory to conventional anticholinergic treatment. The following keywords were used: botulinum toxin, detrusor overactivity, non-neurogenic, refractory, urodynamic status.
1.3
Results and discussion
In all, we selected 19 studies (including three randomized, controlled trials) investigating the value of botulinum toxin in NNDO. After a brief recap of botulinum toxin’s properties, mode of action and administration procedures, we summarize its reported clinical and urodynamic effects, side effects and impact on quality of life.
1.3.1
The characteristics of botulinum toxin
Botulinum toxin is a neurotoxin produced by the sporulating, anaerobic, Gram-negative bacterium Clostridium botulinum , which is widely distributed in the environment (soil, dust, etc.). The toxin was first described by Van Ermengem in 1894 ; it is one of the most powerful neurotoxins found in nature and results in paralysis and cardiorespiratory failure.
Seven serotypes (A, A, B, C1, E, F and G) have been isolated and two are used in clinical practice: serotype A (sold as Botox ® and Dysport ® ) and serotype B (Myobloc ® and Neurobloc ® ).
In the 1980s, Dyskra et al. were the first to describe the effects of botulinum toxin serotypes A and B in urology for the treatment of bladder-sphincter dyssynergia . Botulinum toxin was subsequently used by Schurch in 2000 in the treatment of detrusor overactivity in spine-injured patients. Since the preliminary results in these patients were encouraging, the use of botulinum toxin has been progressively extended to non-neurological patients .
1.3.2
Botulinum toxin’s mode of action
In striated muscle, botulinum toxin has endopeptidase activity in the cytoplasm of peripheral nerve endings. The internalized neurotoxin is cleaved into two protein chains which deactivate the soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) family proteins required for exocytosis of synaptic vesicles at the nerve ending. This results in inhibition of acetylcholine release at the neuromuscular junction, with blockage of neuromuscular transmission and thus transient paralysis of the muscle .
Botulinum toxin’s mechanism of action on smooth muscle is not yet fully understood.
Several animal studies have investigated botulinum toxin’s effect on vesical smooth muscle [37].
A number of authors have demonstrated that botulinum toxin also inhibits the urothelial and suburothelial release of various mediators (acetylcholine, ATP, substance P, glutamate, etc.) involved in regulation of the vesical afferent message . This suggests an effect on both the efferent part of the voiding reflex and regulation of the afferent message.
Modified expression of certain receptors has also been reported by Apostolidis et al.; these authors noted a decrease in expression of the P2X3 and TRPV1 purinergic sensory receptors in the suburothelial nerve fibres 4 and 6 weeks after the injection of botulinum toxin. This decrease was clinically correlated with a decrease in urge incontinence in both neurological and non-neurological patients .
1.3.3
Botulinum toxin injection procedures
Intradetrusor injections of botulinum toxin are performed on an outpatient basis or during day hospitalization.
The urine must be germ-free. Prophylaxis with antibiotics is not always justified. Local anaesthesia is performed via the intravesicular instillation of 40 ml of a 2% lidocaine solution, which is held in place for 20 minutes and then evacuated by catheterization. Endoscopically guided injections are performed by a urologist after filling the bladder with 100 ml of physiological saline solution. Injections are made at between 20 and 30 detrusor sites (depending on the research protocol in question and outside the trigonal region, in most cases); this corresponds to four to six sites in the posterior, upper and left and right faces, respectively. The injections are performed in the upper part of the detrusor muscle. It is not medically justified to leave an indwelling catheter in the bladder. The concomitant use of anticoagulants contraindicates the injection of botulinum toxin, given the risk of haematuria and clotting .
The procedure usually takes around 20 minutes. The pioneers of this technique have emphasized its good safety, with a pain score of 30 on a 100 mm visual analogue scale when a flexible fibre-optic endoscope is used under local anaesthesia .
Each injection corresponds to 1 ml of Botox ® or 0.25 ml of Dysport ® and a 10 U/ml dilution for Botox ® . The optimal dose for the dilution of Dysport ® has not yet been established . These various preparations are those typically reported in the literature and the difference in dilution is related to Dysport ® ’s supposedly greater diffusion coefficient .
1.3.4
Botulinum toxin injection sites
By analogy with other indications in striated muscle, intramuscular injections were performed initially. However, other authors have used suburethral and trigonal injections , with a view to decreasing the sensory afferent influx responsible for urge incontinence and bladder pain. The theoretical risk of induction of a vesico-urethral reflux mentioned by certain authors has now been ruled out .
1.3.5
Botulinum toxin’s onset and duration of action
Botulinum toxin A starts to have an effect very rapidly – within three to four days of treatment . Its effect persists for between six and nine months, depending on the study in question. In the absence of specific studies, the reinjection criteria and frequency remain to be established. On the whole, two strategies can be used: reinjection before the recurrence of symptoms or following the reappearance of urine leakage or urgency.
Table 1 summarizes the various studies on the efficacy of botulinum toxin in the symptomatic treatment of NNDO.
| Author | Study type | Population | n | Toxin | Dose | Injection site |
|---|---|---|---|---|---|---|
| Radziszewski and Borkowski | Open-label study | Adults IDO | 12 | Dysport ® | 300 | Detrusor |
| Harper et al. | Open-label study | Adults NDO IDO | 39 | Botox ® | 10 U/site 300 200 | Detrusor |
| Verleyen et al. | Open-label study | Children IDO | 11 | Botox ® | 125–250 | Detrusor |
| Flynn et al. | Open-label study | Adults IDO | 7 | Botox ® | 150 | Detrusor |
| Kuo | Open-label study | Adults NDO UDO IDO | 12 10 8 | Botox ® | 200, 40 sites | Detrusor |
| Popat et al. | Open-label study | Adults NDO IDO | 44 31 | Botox ® | 200 | Detrusor |
| Ghei et al. | Randomized, placebo-controlled study | Adults NDO IDO | 20 3 17 | B toxin | 5000 | Detrusor |
| Kessler | Open-label study | Adults IDO NDO | 11 11 | Botox ® | 300 | Detrusor |
| Kuo | Open-label study | Adults IDO | 20 | Botox ® | 200 | Suburothelium |
| Rajkumar et al. | Open-label study | Adults IDO | 15 | Botox ® | 300 | Detrusor |
| Werner | Open-label study | Adults IDO | 26 | Botox ® | 100 | |
| Kuo | Adults IDO | 75 | Botox ® | 100 150 200 | Suburothelium | |
| Schmid et al. | Open-label study | Adults IDO | 100 | Botox ® | 100 | Detrusor |
| Jeffery et al. | Open-label study | Adults IDO | 25 | Dysport ® | 500 | Detrusor |
| Ghalayini et Al-Ghazo | Comparative study | Adults IDO NDO | 16 14 | Dysport ® | 500 | Detrusor |
| Sahai et al. | Randomized, placebo-controlled study | Adults IDO | 34 16 | Botox ® | 200 | Detrusor |
| Kuo | Randomized study | Adults IDO | 45 | Botox ® | 100 | Detrusor, suburothelium, trigone |
| White et al. | Open-label study | Adults IDO | 21 | Botox | 200 | Detrusor |
| Cohen et al. | Randomized study | Adults IDO | 44 | Botox | 100 150 | Detrusor |
1.3.6
Botulinum toxin’s efficacy
In all, 19 studies have been performed. Only three of these were randomized; the remainder were open-label studies. In general, the individual study populations were small but a total of 539 patients have been treated.
The primary inclusion criterion in these studies generally corresponded to second-line treatment for refractory or intolerably troublesome bladder overactivity or contraindication of anticholinergic drugs.
The criteria used to evaluate the efficacy of botulinum toxin in this situation vary considerably from one group to another.
The most frequently used clinical endpoints are urge incontinence, leakage, pollakiuria and nycturia via monitoring of the voiding diary and pad tests . This latter method of leakage quantification must, however, be used with caution, since it has not been validated for urge incontinence.
Functional assessment and quality of life scales (such as the Urogenital Distress Inventory and the King’s Health Questionnaire) can also be used to judge the impact of the functional signs on the patient’s mood, sleep, and sexual and social life.
Urodynamic parameters are also used to evaluate the effect of the toxin on bladder function, both in terms of efficacy and safety of use (risk of retention).
Botulinum toxin’s effect on urodynamic parameters is assessed in terms of the baseline detrusor pressure, volume at first desire to void, compliance, bladder volume at first detrusor contraction, the peak voiding pressure, the maximum cystometric capacity, and so on. Other urodynamic parameters (such as the maximum urinary flow rate and bladder contractility) are monitored to detect possible complications of treatment with botulinum toxin.
1.3.6.1
Efficacy of botulinum toxin on the clinical manifestations of NNDO in adults
Some authors suggest performing the initial clinical evaluation of efficacy 10 days after the toxin injection. However, this is usually performed after one month and/or three months.
In 2006, Schmid et al. performed a non-randomized, multicentre, prospective study of a series of 100 patients with refractory NNDO. The dose injected (avoiding the trigone) was 100 U. Eighty-eight percent of the patients reported feeling better, with a significant improvement in the clinical and urodynamic parameters after four and 12 weeks. Leakage had ceased in 74 and 86% of the patients after four and 12 weeks, respectively. On average, the toxin’s effect lasted for six months . The absence of clinical and urodynamic improvement was noted in eight patients who initially had compliance disorders. This study had the advantage of being prospective and investigated a large number of patients. However, it was not comparative and the long-term follow-up was non-optimal, since only 20 patients were monitored throughout the study .
Sahai is one of the few authors to have performed a randomized, placebo-controlled study. The trial included 34 patients, of whom 16 received an injection of 200 units of Botox ® . A statistically significant decrease in leakage episodes and pollakiuria was observed after four and 12 weeks .
Radziszewski and Borkowski , Harper et al. , Verleyen et al. , Jeffery et al. and Kuo performed open-label studies on small samples of patients and reported an improvement in clinical signs (urge incontinence, pollakiuria and leakage) after the intradetrusor injection of botulinum toxin. The duration of these studies ranged from nine to 12 months.
Certain authors have performed open-label studies to compare botulinum toxin’s respective effects in neurological and non-neurological patients; Apostolidis et al. reported that intradetrusor injection of toxin gave similar results in patients suffering from either neurogenic or idiopathic detrusor overactivity (even though the injected dose of Botox ® is lower for NNDO, at 200 U), with reductions in pollakiuria (13 and eight voidings) and leakage episodes (3 and 0.6).
Likewise, Kuo studied the effect of the injection of 200 U of Botox ® in patients presenting urological, idiopathic or neurogenic detrusor overactivity and having failed to respond to a 3-month course of anticholinergic agents. The patients received 200 U at 40 injection sites. The results were judged to be excellent (i.e. 100% continence and the absence of dysuria) in only one patient with NNDO. Five patients felt better after treatment. However, the improvement in urodynamic parameters seen three and six months after treatment was not always statistically significant. In this study, the use of a rigid fibre-optic endoscope prevented injection into the anterior bladder wall (leading to heterogeneous distribution of the toxin within the detrusor) and may thus have biased the study results.
After injection of 100 units of Botox ® into the detrusor, Schmid et al. reported the highest continence rate, with 80% of patients becoming continent after three months (versus 65% in the study by Werner ).
After injection of 200 units of Botox ® into the detrusor, Popat et al. reported a 57.3% continence rate after three months, versus 45% for Kuo’s suburothelial injection study published in 2005 .
Kessler reported a 90% continence rate after the injection of 300 units of Botox ® into the detrusor; however, this improvement came at the expense of a significant increase in the post-void residual volume and recourse to intermittent self-catheterization in 40% of cases.
1.3.6.2
Effects of botulinum toxin on urodynamic parameters
The validity of urodynamic evaluation after injection of botulinum toxin can be questioned, given that clinical symptoms and functional impairment are the main parameters used to evaluate the toxin’s efficacy. In contrast, and bearing in mind the drug’s therapeutic potential and the risk of retention, eliminating at-risk patients appears to justify this evaluation procedure.
Most of studies have reported an increase in the maximum cystometric capacity, B1 volume and compliance, together with a decrease in detrusor contractions and maximum detrusor pressure ( Table 2 ), with injected doses ranging from 100 to 300 U of Botox ® .
| Author | Study type | Population | n | Toxin | Dose | Clinical efficacy | Urodynamic efficacy |
|---|---|---|---|---|---|---|---|
| Radziszewski and Borkowski | Open-label study | Adults IDO | 12 | Dysport ® | 300 | Urge incontinence: decreased Pollakiuria: decreased Leakage: decreased | Increased MCC (321–408 ml) |
| Harper et al. | Open-label study | Adults NDO IDO | 39 | Botox ® | 10 U/site 300 200 | Increased MCC (174–580 ml) | |
| Verleyen et al. | Open-label study | Children | 11 | Botox ® | 125–250 | Urge incontinence: decreased | Increased MCC, decreased detrusor contractions |
| Flynn et al. | Open-label study | Adults IDO | 7 | Botox ® | 150 | At 3 months: Incontinence: 64% Pollakiuria: 12% No need for pads: 75% Decrease in pad weight: 50% | MCC unchanged |
| Kuo | Open-label study | Adults NDO UDO IDO | 12 10 8 | Botox ® | 200 | Continence: 26.7% Improved: 46.7% | Increased MCC (222–247 ml) |
| Popat et al. | Open-label study | Adults NDO IDO | 44 31 | Botox ® | 200 | Continence: 57.3% Urge incontinence: 50.7% Pollakiuria: 36.3% | MCC increased by 111% Max. detrusor pressure: 24.5% |
| Ghei et al. | Randomized, placebo-controlled study | Adults NDO IDO | 20 3 17 | B toxin | 5000 | Significant difference between the groups for urine volume, pollakiuria, incontinence | |
| Kessler | Open-label study | Adults IDO NDO | 11 11 | Botox ® | 300 | Continence 10 out of 11 (IDO) Pollakiuria decreased from 11 to 4 Nycturia decreased from de 3 to 1 | MCC increased (220–340 ml), compliance increased (20–55) |
| Kuo | Open-label study | Adults IDO | 20 | Botox ® | 200 | Continence: 45% Improvement: 40% Failure: 15% | MCC increased 2-fold |
| Werner | Open-label study | Adults IDO | 26 | Botox ® | 100 | Continence: 53% at 4 weeks, 65% at 12 weeks, 60% at 36 weeks | MCC increased at 3 months, (216–351 ml) B1 increased (116–192 ml) |
| Rajkumar et al. | Open-label study | Adults IDO | 15 | Botox ® | 300 | Decrease in urge incontinence and pollakiuria: 14 out of 15 | B1 increase (147–259) MCC increased (345–403) No DO in 6 patients |
| Kuo | Comparative study | Adults IDO | 75 | Botox ® | 100 U vs. 150 U vs. 200 U | 34.8% vs. 36% vs. 40.8% with excellent results | 30.4% vs. 50.2% vs. 72% PVRV > 150 ml |
| Schmid et al. | Open-label, multicentre study | Adults IDO | 100 | Botox ® | 10 U/site 100 | No more urge incontinence: 82% Continence: 86% Improvement: 88% Pollakiuria: 50% Nycturia: decreased | MCC increased by 56% Compliance: increased Inhibition of detrusor contractions: 74% |
| Ghalayini et Al-Ghazo | Comparative study | Adults IDO NDO | 16 14 | Dysport ® | 500 | At 6 weeks: Continence: 75% Reduction in urge leakage, nycturia, 14 out of 16 patients satisfied or very satisfied | MCC increased (177.5–262.5), compliance increased (24–40) |
| Sahai et al. | Randomized, placebo-controlled study | Adults IDO | 34 16 | Botox ® | 200 | Urge incontinence: decreased Pollakiuria: decreased Leakage: decreased | MCC increased |
| Jeffery et al. | Open-label study | Adults IDO | 25 | Dysport ® | 500 | Continence 63% at 1 weeks, 32% at 3 and 6 months No urge incontinence: 33% at 1 week, 26% at 6 weeks, 22% at 6 months. Leaks per week fell from 5.5 to 1.8 at 6 weeks | Increase in B1 at 3 months (177–251 ml) |
| Kuo | Randomized study | Adults IDO | 45 | Botox ® | 100 | Successful outcome at 3 months: 93% detrusor, 80% suburothelium, 67% vesical base 67, 47 and 13% at 6 months 20, 20 and 6.7% at 9 months | MCC increased except in the 3 rd group |
| White et al. | Open-label study | Adults IDO | 21 | Botox ® | 200 | After 1 month, 50% decrease in leakages in 76% of patients | |
A decrease in the maximum flow rate and an increase in the post-void residual volume are frequently observed in this indication . Less satisfactory results were observed in patients with a bladder compliance disorder . The urodynamic data reported by Schmid et al. showed an improvement in bladder capacity (from 261 to 426 ml) and volume at first desire to void (from 152 to 256 ml) six weeks after the injection. The treatment remained effective for five to nine months ( Table 2 ).
According to the study by Hashim and Abrams , it seems that the correlation between the clinical signs of bladder overactivity and the presence of detrusor overactivity is greater in cases of urge incontinence. Evaluation of the treatment’s functional efficacy is thus essentially based on clinical signs. However, the performance of a urodynamic status check before and after treatment can be justified when seeking to identify patients who are not likely to respond to botulinum toxin treatment or those likely to present side effects and thus require close monitoring. In fact, some patients with detrusor overactivity can also have compliance disorders; there is a risk of incomplete bladder voiding and an increase in post-void residual volume after botulinum toxin injections .
Large-scale, long-term clinical and urodynamic follow-up could help better identify factors that are predictive of the success or failure of botulinum toxin treatment.
In fact, in the absence of a comparative study of patients with or without detrusor overactivity, it is not possible to tell whether this latter factor is predictive of success or failure.
1.3.6.3
Effects of botulinum toxin on the patient’s quality of life
Overactivity syndrome can lead to depression, sexual disorders, sleep disorders and absenteeism from work. Hence, it can have a clearly negative impact on quality of life.
Some studies have evaluated the effect of botulinum toxin on the quality of life of patients presenting NNDO . Kalsi et al. have studied the effect of botulinum toxin type A injection on the quality of life of patients presenting neurogenic and non-neurogenic DO, as well as the correlation with changes in urinary disorders.
The questionnaires used were the short form of the Urinary Distress Inventory (UDI-6) and the Incontinence Impact Questionnaire (IIQ-7). The results were compared with cystometric and voiding diary data.
An evaluation after four and 16 weeks showed a similar, significant, persistent improvement in the quality of life in both groups after 16 weeks. This improvement was correlated with a decrease in pollakiuria, urge incontinence and leakage episodes but was not correlated with urodynamic parameters .
Furthermore, in a study of 100 patients with NNDO, Schmid et al. reported a significant improvement four and 12 weeks after injection of botulinum toxin. Ninety percent of the patients reported an improvement in at least one of the categories in the King Health Questionnaire (role limitations, sleep/energy, social limitations, physical limitations and general health perception). This effect lasted for nine months and then declined.
1.3.7
Side effects of botulinum toxin
Botulinum toxin’s rare side effects are summarized in Table 3 :
- •
side effects related to the administration procedure:
- ∘
transient haematuria can be observed and occurs more frequently when a rigid endoscope with a large-gauge needle is used ,
- ∘
Post-injection urinary infection can also occur if strict asepsis is not maintained. Intramuscular injection means that local and regional diffusion is very limited (above all with Botox ® neurotoxin type A );
- •
side effects related to the drug’s action.
| Author | Population | n | Toxin | Dose | Injection site | Side effects |
|---|---|---|---|---|---|---|
| Verleyen et al. | Children IDO | 11 | Botox ® | 125–250 | Detrusor | Intermittent catheterization for 2 weeks: 1 |
| Schmid et al. | Adults IDO | 100 | Botox ® | 100 | Detrusor | Temporary catheterization: 4% Significant residual volume without use of intermittent catheterization: 15% |
| Sahai et al. | Adults IDO | 34 16 | Botox ® | 200 | 37% increase in PVRV | |
| Kuo | Adults | 45 | Botox ® | 100 | Detrusor urothelium trigone | Retention: 2/2/0 Dysuria: 5/7/2 Urinary infection: 1/2/1 Haematuria: 0/1/1 Pain: 1/1/1 |
| Kuo | Adults IDO | 20 | Botox ® | 200 | Detrusor | PVRV × 7 at 2 weeks, × 3 at 3–6 months Retention 30% Infection 35% Haematuria 5% |
| Popat et al. | Adults NDO IDO | 44 31 | Botox ® | 200 | Haematuria: 3.2% Urinary infection: 6.4% Intermittent catheterization: 19.3% (9 patients) | |
| Kuo | Adults DNO UDO IDO | 12 10 8 | Botox ® | 200 | Retention: 13% Dysuria: 20% | |
| Kuo | IDO | 75 | Botox ® | 100 150 200 | Suburothelial | 30.4% vs. 50.2% vs. 72% PVRV > 150 ml |
| Jeffery et al. | Adults IDO | 25 | Dysport ® | 500 | Detrusor | Intermittent catheterization: 35% at 6 weeks and 3 months, 22% at 6 months, 9% at 9 months |
| Ghalayini et Al-Ghazo | Adults IDO NDO | 16 14 | Dysport ® | 500 | Detrusor | Intermittent catheterization for 2 weeks: 3 patients |
| Ghei et al. | Adults NDO IDO | 20 3 17 | B toxin | 5000 | Detrusor | Intermittent catheterization: 10% Constipation: 10% Mouth dryness: 10% Illness: 5% |
| Kessler | Adults IDO NDO | 11 11 | Botox ® | 300 | Detrusor | Intermittent catheterization: 4 out of 11 |
| Werner | Adults IDO | 26 | Botox ® | 100 | Intermittent catheterization: 7% 2 out of 26 Urinary infection: 17.6% | |
Allergic reactions aggravated neurological impairments and cases of generalized muscle weakness following the injection of botulinum toxin types A and B for indications other than the NNDO have been reported in the literature . The authors have speculated that these phenomena were linked to the high doses and the potential intravascular diffusion of the botulinum toxin used .
Grosse et al. reported four cases of generalized muscle weakness after the injection of 750 and 1000 units (10 ml dilution) of Dysport ® botulinum toxin type A . No other authors have reported this complication with the doses used in non-neurological patients.
A risk of bladder hypocontractility (and thus urine retention and the need for self-catheterization) has also been reported in the literature [2,18,22,28,33,39]. The risk of urine retention appears to be greater when high doses of botulinum toxin are injected (40% for 300 U versus 4% for 100 U ), although no variable-dose studies are currently available. Sahai et al. selected a low maximum urine flow rate (< 15 ml/s) and a bladder contractility index below 120 as being predictive of the risk of incomplete bladder emptying after injection of botulinum toxin in NNDO patients ; this latter parameter may evidence detrusor hypocontractility. A number of risk factors for probable or reported retention deserve to be validated, such as detrusor hypocontractility, high pressure voiding and abnormal flow rates; this now justifies a pre- and post-treatment urodynamic evaluation .
However, all the selected studies can be criticized in some respects, such as a low sample size with insufficient statistical power and the inability to extrapolate the results to the rest of the population .
Furthermore, the patient inclusion and exclusion criteria in the various studies may also give rise to bias and prevent intertrial comparisons.
The studies also differed in terms of the injection sites and the equipment used.
Lastly, the toxin dose and dilution also varied from one study to another. It is currently recommended to inject 100 U of Botox ® – the effective lowest dose which limits the risk of requiring intermittent self-catheterization. The total dose is distributed across the 20 to 30 detrusor injection sites.
1.4
Alternatives to botulinum toxin injections
Treatment with anticholinergic agents remains the front-line treatment for NNDO. It must be attempted with a single drug or a combination, in view of the risk of intensifying the side effects. In the event of treatment failure or poor tolerance, other treatment approaches can be attempted, such as sacral root neuromodulation and peripheral tibial nerve electrostimulation . Furthermore, new treatments and novel drugs for modulating urothelial sensitivity are under development.
1.5
Conclusion
The intradetrusor injection of botulinum toxin A for the symptomatic treatment of NNDO has yielded encouraging preliminary results. Side effects are infrequent and primarily consist of the (dose-dependent) risk of urine retention.
Botulinum toxin’s long duration on action and innocuousness and the ability to perform repeat injections make it a minimally invasive treatment that is of value if therapy with anticholinergic agents fails.
At present, this therapeutic technique should only be used in clinical research protocols. In fact, many aspects remain to be elucidated, such as the minimal optimal dose and the risk factors for failure or the occurrence of adverse events. Botulinum toxin’s position in the therapeutic arsenal will no doubt be better defined in the future – probably as a second-line treatment after failure or intolerance of anticholinergic agents in patients willing and able to perform subsequent intermittent self-catheterisation if required.
2
Version française
2.1
Introduction
L’hyperactivité détrusorienne non-neurogène (HADNN) est définie par la survenue de contractions détrusoriennes involontaires spontanées ou provoquées, pendant la phase de remplissage de la vessie, sans affection neurologique sous-jacente . Elle se manifeste par un syndrome d’hyperactivité vésicale. Le retentissement sociopsychologique parfois majeur de cette pathologie justifie une prise en charge thérapeutique adaptée.
La prévalence de l’hyperactivité vésicale varie en fonction de l’âge et du sexe. Son incidence augmente avec l’âge. Elle est respectivement de 16,6 % chez les personnes âgées de 40 ans et plus en Europe et de 16 % chez les personnes âgées de 18 ans et plus aux États-Unis .
Le traitement anticholinergique est le traitement de première intention de l’hyperactivité vésicale. Son efficacité est prouvée mais il est souvent pourvoyeur d’effets secondaires gênants motivant parfois l’arrêt du traitement.
En cas d’inefficacité clinique ou de manifestations secondaires gênantes nécessitant l’arrêt du traitement, des alternatives thérapeutiques en cours d’évaluation peuvent être proposées, dont la toxine botulique .
2.2
Matériels et méthodes
Nous avons réalisé une revue systématique de la littérature à partir de la banque de données PubMed, ayant intéressé les études publiées depuis 2000 portant sur les effets cliniques, urodynamiques et sur la qualité de vie de la toxine botulique en cas d’hyperactivité détrusorienne d’origine non-neurogène et résistante au traitement anticholinergique classique, ainsi que ses modalités d’utilisation. Les mots clés utilisés ont été : toxine botulique, HADNN, réfractaire, bilan urodynamique.
2.3
Résultats et discussion
Au total, 19 études étudiant la place de la toxine botulique dans l’HADNN ont été retenues dont trois essais randomisés contrôlés. Après un bref rappel des propriétés de la toxine botulique, son mode d’action et ses modalités d’utilisation, nous rapportons respectivement les effets cliniques, urodynamiques, sur la qualité de vie et les effets secondaires de la toxine botulique.
2.3.1
Présentation de la toxine botulique
Il s’agit d’une neurotoxine produite par une bactérie Gram négatif anaérobie sporulée, le Clostridium botulinium , présente dans l’environnement (sol, poussière). La toxine botulique a été décrite par Van Ermengem en 1894 . C’est l’un des plus puissants poisons neurotoxiques naturels responsable de paralysie et de défaillance cardiorespiratoire.
Sept sérotypes (A, A, B, C1, E, F, G) de neurotoxine ont été isolés . Deux sérotypes sont utilisées en pratique clinique : le sérotype A commercialisé sous le nom de Botox ® ou Dysport ® et le sérotype B commercialisé sous le nom de Myobloc ® ou Neurobloc ® .
Dyskra et al., dans les années 1980, ont été les premiers à décrire les effets des sérotypes A et B de la toxine botulique en urologie pour le traitement de la dyssynergie vésicosphinctérienne . La toxine botulique a été par la suite utilisée par Schurch en 2000 pour le traitement de l’hyperactivité détrusorienne chez des patients blessés médullaires. Les résultats préliminaires ayant été encourageants chez ces patients, l’utilisation de la toxine botulique a été progressivement étendue aux patients non neurologiques .
2.3.2
Mode d’action de la toxine botulique
Dans le muscle strié, la toxine botulique exerce une activité d’endopeptidase dans le cytoplasme des terminaisons nerveuses périphériques. La neurotoxine internalisée subit un clivage des deux chaînes protéiques qui vont désactiver les protéines du groupe SNARE – Soluble N-ethylmaleimode-sensitive factor (NSF) attachment receptors – nécessaires à l’exocytose des vésicules synaptiques dans la terminaison nerveuse. Il en résulte une inhibition de la libération de l’acétylcholine au niveau de la jonction neuromusculaire striée, avec blocage de la transmission neuromusculaire et une paralysie transitoire du muscle .
Le mécanisme d’action de la toxine botulique sur le muscle lisse n’est pas encore parfaitement bien connu.
Plusieurs études ont étudié l’action de la toxine botulique sur le muscle lisse vésical chez les animaux [37].
Certains auteurs ont démontré que la toxine botulique inhibe également la libération par l’urothélium ou le sous-urothélium de différents médiateurs (Ach, l’ATP, substance P, glutamate, etc.) impliqués dans la régulation du message afférent vésical . Cela évoque donc un double effet à la fois sur la partie efférente du réflexe mictionnel, mais aussi sur la régulation du message afférent.
Une action sur la modification de l’expression de certains récepteurs a également été rapportée par Apostolidis et al. qui ont noté une diminution de l’expression des récepteurs sensitifs purinergiques P2X3 et TRPV1 dans les fibres nerveuses sous-urothéliales quatre et six semaines après l’injection de toxine botulique, cette diminution était corrélée cliniquement à la diminution de l’urgenturie chez les patients neurologiques et les non neurologiques .
2.3.3
Modalités d’injection de la toxine botulique
Les injections intradétrusoriennes de la toxine botulique sont réalisées en ambulatoire ou en hospitalisation de jour.
Les urines doivent être stériles. L’antibioprophylaxie n’est pas toujours justifiée. L’anesthésie locale se fait par instillation intravésicale de 40 ml de lidocaïne à 2 % maintenue pendant 20 minutes puis évacuée par sondage. Les injections sont réalisées en milieu urologique sous contrôle endoscopique et après remplissage vésical avec 100 ml de sérum physiologique. Le détrusor est injecté en 20 à 30 points selon les auteurs, épargnant souvent la région trigonale, respectivement quatre à six points dans les zones suivantes : face postérieure, supérieure, latérales. Les injections sont réalisées dans la partie superficielle du muscle détrusor. Il n’est pas justifié médicalement de laisser une sonde à demeure dans la vessie. La prise concomitante d’anticoagulants contre-indique l’injection de toxine botulique vu le risque d’hématurie et de caillotage .
La procédure dure généralement 20 minutes. Les pionniers de cette technique ont vanté sa bonne tolérance, avec une échelle visuelle analogique de la douleur à 30/100 mm au fibroscope souple avec anesthésie locale .
Le volume injecté à chaque ponction est le plus souvent 1 ml pour Botox ® , 0,25 ml pour Dysport ® et à une dilution de 10 U/ml pour le Botox ® . La dose optimale pour la dilution du Dysport ® n’est pas encore établie . Ces différentes préparations sont celles rapportées habituellement dans la littérature et la différence de dilution est liée à une probable capacité de diffusion plus importante du Dysport ® .
2.3.4
Sites d’injection de la toxine botulique
Les injections ont été décrites initialement en intramusculaire par assimilation aux autres indications dans le muscle strié. Mais d’autres auteurs ont tenté des injections sous-urétrales ou dans le trigone , dans l’optique de diminuer les influx sensitifs afférents responsables de l’urgenturie et des douleurs vésicales. Le risque théorique d’induire un reflux vésico-urétéral rapporté par certains auteurs a été récemment écarté .
2.3.5
Délai et durée d’action de la toxine botulique
L’effet de la toxine botulique A commence très rapidement entre trois et quatre jours . Son effet se maintient entre six et neuf mois selon les études. Le rythme et les critères de réinjection restent à déterminer en l’absence d’études spécifiques. Globalement, deux stratégies peuvent être utilisées : injecter avant la reprise des symptômes ou attendre la reprise des fuites ou des urgences pour reprogrammer l’injection.
Le Tableau 1 résume les différentes études réalisées sur l’efficacité de la toxine botulique dans le traitement des manifestations de l’HADNN.
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