Botulinum toxin: From life-threatening disease to novel medical therapy
2007; Elsevier BV; Volume: 196; Issue: 1 Linguagem: Inglês
10.1016/j.ajog.2006.03.108
ISSN1097-6868
AutoresSangeeta T. Mahajan, Linda Brubaker,
Tópico(s)Cardiovascular Syncope and Autonomic Disorders
ResumoBotulinum toxin A is the newest therapy for the treatment of a variety of medical disorders caused by abnormalities of muscle activity. After successful use in other medical subspecialties, the newest applications of this potent neurotoxin are within the lower urinary tract. The toxin has evolved from a cause of fatal disease into the newest neuropharmacologic medical therapy. Botulinum toxin A is the newest therapy for the treatment of a variety of medical disorders caused by abnormalities of muscle activity. After successful use in other medical subspecialties, the newest applications of this potent neurotoxin are within the lower urinary tract. The toxin has evolved from a cause of fatal disease into the newest neuropharmacologic medical therapy. Botulinum toxin is the newest therapy for the treatment of lower urinary tract dysfunction. Although popularized for cosmetic purposes, multiple novel applications exist for the treatment of various disorders of muscle, including some forms of lower urinary tract dysfunction. This article will review the evolution of this therapy. Botulinum toxin is a potent neurotoxin produced by the Gram-negative, rod-shaped anaerobic bacteria Clostridium botulinum. First described in 1895 by Emile van Ermengem, the bacteria produces a toxin that acts on peripheral cholinergic nerve endings to inhibit calcium-mediated release of acetylcholine vesicles at the presynaptic neuromuscular junction.1Ermengem E.V. Ueber einen neuen anaeroben Bacillus und seine Beziehungen zun Botulismus.Zeitschrift fur Hygiene und Infektionskrankheiten. 1897; 26: 1-56Google Scholar Botulism, the disease resulting from toxin exposure, has been well-described and clinical symptoms include limb paralysis, dysarthria, facial muscle weakness, dyspnea, constipation, urinary retention, and opthalmoplegia.2Dasgupta B. Structures of botulinum neurotoxin, its functional domains, and perspectives on the cristalline type A toxin.in: Jankovic M.H. Therapy with botulinum toxin. Marcel Dekker, Inc, New York1994Google Scholar, 3Davis L. Botulinum toxin: from poison to medicine.West J Med. 1995; 158: 25-29Google Scholar Toxin exposure commonly occurs via lower gastrointestinal tract colonization with the bacteria resulting from the ingestion of contaminated food, especially after poor canning practices. Over the last 50 years, botulinum toxin has been transformed from a cause of life-threatening disease to a medical therapy (Table 1). In the 1920s Dr Hermann Sommer2Dasgupta B. Structures of botulinum neurotoxin, its functional domains, and perspectives on the cristalline type A toxin.in: Jankovic M.H. Therapy with botulinum toxin. Marcel Dekker, Inc, New York1994Google Scholar was the first to isolate a purified form of botulinum A toxin as a stable acid precipitate. After development for several decades as a potential biologic weapon, Dr Alan Scott was the first to propose the use of the toxin's muscle paralyzing effects as a medical therapy for strabismus.4Scott A. Botulinum toxin injection of eye muscles to correct strabismus.Trans Am Opthalmol Soc. 1981; 79: 734-770PubMed Google Scholar, 5Scott A. Rosenbaum A. Collins C. Pharmacologic weakening of extraocular muscles.Opthalmol Vis Sci. 1973; 12: 924-927Google Scholar In 1989, the Food and Drug Administration (FDA) approved Botox (Allergan, Inc, Irvine, CA) for the treatment of strabismus, blepharospasm, and cervical dystonias in humans age 12 years and older. Later, Botox (Allergan, Inc) was approved for cosmetic uses (glabellar facial lines) in 2002 and for the treatment of axillary hyperhidrosis in 2004. Many non-FDA–approved applications of Botox are currently being used (Table 2).TABLE 1Historical review of botulinum A toxin as a medical therapy1895Professor Emile van Ermengem identifies the bacteria C Botulinum1897Toxin produced by C Botulinum is isolated by van Ermengem1920Dr Hermann Sommer isolates botulinum A toxin as a stable acid precipitate1946Edward J. Schantz, PhD, purifies botulinum A toxin into a crystalline form1849Dr Vernon Brooks demonstrates botulinum toxin's ability to block transmission at the neuromuscular junction; toxin induced muscle paralysis thought to be permanent1973Dr Alan Scott publishes botulinum A toxin injection for the treatment of strabismus in nonhuman primates1981Botulinum A toxin used for the treatment of strabismus in human subjects1986Randomized, controlled trials for treatment of cervical dystonias with botulinum A toxin1988Dykstra et al publish use of botulinum A toxin for the treatment of detrusor sphincter dyssynergia1989Botox (Allergan, Inc) approved by FDA for the treatment of strabismus, blepharospasm and cervical dystonias1990Holds et al demonstrate reversible nature of botulinum toxin effects mediated by axonal resprouting at nerve endplates1992First trials of botulinum B toxin in patients with resistance to A serotype2000Schurch et al publish use of botulinum A toxin intradetrusor injection for the treatment of urge incontinence in spinal cord injury patients2002FDA approves Botox for the treatment of glabellar facial lines2003FDA approves Botox for the treatment of axillary hyperhidrosis2004First randomized, controlled trial demonstrating efficacy of botulinum A toxin for the treatment of detrusor overactivity incontinence by Schurch et al30Schurch B. Stohrer M. Kramer G. Schmid D. Gaul G. Hauri D. Botulinum-A toxin for treating detrusor hyperreflexia in spinal cord injured patients: a new alternative to anticholinergic drugs? Preliminary results.J Urol. 2000; 164: 692-697Abstract Full Text Full Text PDF PubMed Google Scholar Open table in a new tab TABLE 2Current indications for botulinum toxin therapy (FDA and non-FDA approved)Focal DystoniasInnapropriate Muscle ContractionsBlepharospasmAchalasia/pyloric stenosisCervical dystoniasAnismusLaryngeal dystoniasBruxism (TMJ)Occupational cramps (ie, writer's cramp)NystagmusOther focal dystoniasTension headachesInvoluntary movementsBack spasmHemifacial spasmvaginismusTicsStrabismusVoice, head, and limb tremorsSpasticityPalatal myoclonusLower urinary tractCosmeticDetrusor overactivity incontinenceAxillary hyperhidrosisDetrusor sphincter dyssynergiaGlabellar facial linesUrinary retention after suburethral sling Open table in a new tab Currently, 7 serologic forms of botulinum toxin exist, including A, B, C, D, E, F, and G.6Schiavo G. Rossetto O. Santucci A. Dasgupta B. Montecucco C. Botulinum neurotoxins are zinc proteins.J Biol Chem. 1992; 267: 23479-23483Abstract Full Text PDF PubMed Google Scholar Although each is antigenically distinct, they have similar molecular weights of 150 kD and structures, and all consist of a heavy and light chain linked by a disulfide bond.7Simpson L. Dasgupta B. Botulinum neurotoxin in type E: studies on the mechanism of action and on structure activity relationships.Pharmacol Exp Ther. 1983; 224: 135-140PubMed Google Scholar, 8Simpson L. Kinetic studies on the interaction between botulinum toxin type A and the cholinergic neuromuscular junction.J Pharmacol Exp Ther. 1980; 212: 16-21PubMed Google Scholar The heavy chain component determines cholinergic nerve ending specificity of the toxin, whereas, the light chain consists of the intracellular toxic portion.9Simpson L. Peripheral actions of the botulinum toxins.in: Simpson L. Botulinum neurotoxin and tetanus toxin. Academic Press, New York1989Crossref Google Scholar, 10Zhou L. Paiva Ad. Liu D. Aoki R. Dolly J. Expression and purification of the light chain of botulinum neurotoxin A: a single mutation abolishes its cleavage of SNAP 25 and neurotoxicity after reconstitution with the heavy chain.Biochem. 1995; 34: 15175-15181Crossref PubMed Scopus (51) Google Scholar Botulinum toxin specifically targets the mechanism of acetylcholine release at the neuromuscular junction.11Dolly J. General properties and cellular mechanisms of neurotoxins.in: Jankovic J. Hallet M. Therapy with botulinum toxin. Marcel Dekker, New York1994Google Scholar Toxin activation is a 2-step process. After parent molecule cleavage, the heavy and light chains joined by a single zinc atom bind to the neuronal cell membrane and are internalized.12Dolly J. Black J. Williams R. Melling J. Acceptors for botulinum neurotoxin reside on motor nerve terminals and mediate its internalisation.Nature. 1984; 307: 457-460Crossref PubMed Scopus (272) Google Scholar Once completed, a disulfide reaction separates the light chain and the heavy chain. Failure to cleave the disulfide bond results in the loss of toxicity.10Zhou L. Paiva Ad. Liu D. Aoki R. Dolly J. Expression and purification of the light chain of botulinum neurotoxin A: a single mutation abolishes its cleavage of SNAP 25 and neurotoxicity after reconstitution with the heavy chain.Biochem. 1995; 34: 15175-15181Crossref PubMed Scopus (51) Google Scholar The light chains then bind to the acetylcholine vesicles, acting as a zinc-dependent endopeptidase to cleave peptide bonds and prevent acetylcholine vesicle fusion with the plasma membrane. Inhibition of acetylcholine vesicle exocytosis inhibits neurotransmission at the presynaptic junction and results in flaccid paralysis of the treated muscle.13Stecher B. Weller U. Habermann E. The light chain but not the heavy chain of botulinum type A toxin inhibits exocytosis from permeabilised adrenal chromaffin cells.FEBS Lett. 1989; 255: 318-325Abstract Full Text PDF Scopus (71) Google Scholar, 14Binder W. Brin M. Blitzer A. Pogoda J. Botulinum toxin type A (BOTOX) for treatment of migraine.Dis Mon. 2002; 48: 323-335Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar Binding of toxin to both peripheral and central nerves is highly selective and saturable.8Simpson L. Kinetic studies on the interaction between botulinum toxin type A and the cholinergic neuromuscular junction.J Pharmacol Exp Ther. 1980; 212: 16-21PubMed Google Scholar Botulinum toxin is not believed to enter the central nervous system, but no definitive evidence to prove this has been found.15Dykstra D. Sidi A. Treatment of detrusor-sphincter dyssynergia with botulinum A toxin.Arch Phys Med Rehab. 1990; 71: 24-26PubMed Google Scholar In 1990, Holds et al16Holds J. Alderson K. Fogg S. Anderson R. Motor nerve sprouting in human orbicularis muscle after botulinum A injection.Invest Opthalmol Vis Sci. 1990; 31: 964-996PubMed Google Scholar demonstrated the reversible nature of botulinum A toxin's effect on muscle. Erratic motor axon outgrowth and resprouting from the nerve endplates has been noted in toxin-treated muscles with return of symptoms compared with controls. Progressive return of muscle function after toxin treatment occurs via axonal rearborization over nerve endplates, replacing toxin-affected nerves with new ones.17Maria G. Cassetta E. Gui D. Brisinda G. Bentivoglio A. Albanese A. A comparison of botulinum toxin and saline for the treatment of chronic anal fissure.N Engl J Med. 1998; 338: 217-220Crossref PubMed Scopus (299) Google Scholar Permanent changes in muscle fibers may occur with repetitive botulinum toxin treatment. Repetitive use of botulinum A toxin appears to cause some minor alteration in muscle fiber composition of treated muscles possibly reducing muscle strength, although there is no definitive evidence of change in muscle function with repetitive toxin treatment.18Ansved T. Odergren T. Muscle fiber atrophy in leg muscles after botulinum toxin type A treatment of cervical dystonia.Neurology. 1997; 48: 1440-1442Crossref PubMed Scopus (69) Google Scholar Accordingly, patients with preexisting neurologic disorders affecting transmission at the neuromuscular junction should not undergo any form of treatment with botulinum toxin. Currently, botulinum toxin serotype A is the most commonly used form of botulinum toxin for medical applications. Within the United States, botulinum A toxin is available as Botox (Allergen, Inc); whereas, in Europe, it is available as Dysport (Ipsen, Inc, Slough, UK). Significant differences exist between the dosage strength of the different toxin formulations and suspensions, with 1 U of Botox (Allergan, Inc) equivalent to 3 to 5 U of Dysport (Ipsen, Inc). Attempts to convert dosages between the 2 drug formulations are not reliable and should be avoided.19Leippold T. Reitz A. Schurch B. Botulinum toxin as a new therapy option for voiding disorders: current state of the art.Eur Urol. 2003; 44: 165-174Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar Care must be taken in preparation of the toxin suspension, as suspension strength is determined by the amount of saline used to reconstitute the purified crystalline form of the toxin. Despite the increasing popularity of botulinum toxin as a medical therapy, its efficacy as a potent neurotoxin remains an important clinical consideration. Known side effects of botulinum toxin treatment may include: nausea, vomiting, dry mouth, and respiratory muscle weakness or paresis.19Leippold T. Reitz A. Schurch B. Botulinum toxin as a new therapy option for voiding disorders: current state of the art.Eur Urol. 2003; 44: 165-174Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar Cases of fatal cardiovascular compromise (including myocardial infarction or arrhythmia) or spontaneous death caused by major debility are cited in the drug package insert. Although the lethal dose in humans of botulinum toxin is unknown, it is estimated that 3000 U would be lethal for a 70-kg person.14Binder W. Brin M. Blitzer A. Pogoda J. Botulinum toxin type A (BOTOX) for treatment of migraine.Dis Mon. 2002; 48: 323-335Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar Most therapeutic doses of botulinum A toxin range from 25-300 U. Peak neuromuscular blockade effects of toxin exposure occur within 24-72 hours after exposure and persist for several weeks.15Dykstra D. Sidi A. Treatment of detrusor-sphincter dyssynergia with botulinum A toxin.Arch Phys Med Rehab. 1990; 71: 24-26PubMed Google Scholar An antidote to the toxin is available to treat overdoses but is only useful in an acute setting and ineffective on the long-lasting symptoms of botulism. Special precautions should be taken in patients with known neurologic disease if being considered for treatment with botulinum A toxin. Patients with impaired neurotransmission (ie, Myasthenia Gravis, Charcot-Marie-Tooth disease) are at high risk to experience detrimental effects from distal botulinum toxin effects and should be treated with caution, though successful treatment of spastic muscle conditions in these patients has been documented.20Emerson J. Botulinum toxin for spasmodic torticollis in a patient with myesthenia gravis.Mov Disord. 1994; 9: 367Crossref PubMed Scopus (33) Google Scholar A small percentage of patients undergoing repeat treatment with botulinum A toxin will demonstrate eventual resistance to the effects of the toxin. Toxin resistance appears to be antibody mediated. Greene et al21Greene P. Fahn S. Development on antibodies to botulinum toxin type A in patients with torticollis treated with injections of botulinum toxin type A.in: DasGupta B. Boutlinum and tetanus neurotoxins: neurotransmission and biomedical aspects. Plenum Press, New York1993Crossref Google Scholar, 22Greene P. Fahn S. Diamond B. Development of resistance to botulinum toxi type A in patients with torticollis.Mov Disord. 1994; 9: 213-217Crossref PubMed Scopus (360) Google Scholar noted 4% to 10% of patients to have detectable antibodies to the toxin after repeated treatment for cervical dystonias. Patients who developed antibody-mediated toxin resistance were noted to have a history of shorter dosing intervals, more booster doses, and higher overall treatment doses.22Greene P. Fahn S. Diamond B. Development of resistance to botulinum toxi type A in patients with torticollis.Mov Disord. 1994; 9: 213-217Crossref PubMed Scopus (360) Google Scholar To prevent antibody development, the FDA recommends dosing intervals of no less than 8 weeks between treatments. Other recommendations include: (1) use the minimal effective dose; (2) avoid booster injections; and (3) extend the intervals between treatments to at least 8 weeks.23Brin M. Botulinum toxin: chemistry, pharmacology, toxicity, and immunology.Muscle Nerve Suppl. 1997; 6: S146-S168Crossref PubMed Google Scholar Until recently, information regarding effective toxin doses in the lower urinary tract was limited to personal communications and unpublished data. Recent randomized controlled trials have begun to compare efficacy of different dosing regimens.19Leippold T. Reitz A. Schurch B. Botulinum toxin as a new therapy option for voiding disorders: current state of the art.Eur Urol. 2003; 44: 165-174Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar, 24Gousse A. Tunuguntla H. Bateman D. Velazquez A. Dose-finding prospective randomized study to evaluate the efficacy and safety of botulinum-A toxin for refractory non-neurogenic overactive bladder. 2005Google Scholar However, consensus opinion on the ideal effective treatment doses for the different lower urinary tract applications of botulinum toxin has yet to be obtained. Lower urinary tract dysfunction is a well-known complication of neurologic disease and a significant source of morbidity and mortality for affected patients. Spinal cord injury, cerebrovascular accident, multiple sclerosis, and other patients with upper motor neuron disease comprise the majority of affected individuals, although patients with less significant neurologic disorders can also be affected.25Simpson D. Clinical trials of botulinum toxin in the treatment of spasticity.Muscle Nerve Suppl. 1997; 6: S169-S175Crossref PubMed Google Scholar Today botulinum A toxin is being used in the treatment of several lower urinary tract disorders involving abnormal muscular activity as an alternative to more invasive and aggressive therapies. Detrusor sphincter dyssynergia (DSD) is defined as detrusor contraction concurrent with an involuntary contraction of the urethral and/or periurethral striated muscle; occasionally preventing urine flow altogether.26Abrams P. Cardozo L. Fall M. et al.The standardisation of terminology of lower urinary tract function: report from the Standardisation Sub-Committee of the International Continence Society.Neurourol Urodyn. 2002; 21: 167-178Crossref PubMed Scopus (5716) Google Scholar Commonly found in patients with spinal cord injury and other neurologic disease, DSD is a frequent cause of voiding dysfunction caused by high urethral resistance and obstructed voiding.27Wein A. Neuromuscular dysfunction of the lower urinary tract and its management.in: Walsh P. Retik A. Vaughan E. Wein A. Campbell's urology. Vol.2. WB Saunders, Philadelphia2002Google Scholar Significant outlet obstruction and high intravesical pressures pose a risk for ureteral reflux and potential upper tract injury.28Petit H. Wiart L. Gaujard E. et al.Botulinum A toxin treatment for detrusor-sphincter dyssynergia in spinal cord disease.Spinal Cord. 1998; 36: 91-94Crossref PubMed Scopus (131) Google Scholar Traditionally, treatments for DSD are limited and often ineffective. Pharmacologic treatment with alpha-blockers and antispastic agents is often ineffective. Intermittent self-catheterization may be a useful option, but its use is limited only to those with sufficient upper limb function and dexterity to self-catheterize or individuals with a willing caregiver. Patients in whom conservative managements are unsuccessful or not possible, chronic catheterization and sphincterotomy have been final treatment options.28Petit H. Wiart L. Gaujard E. et al.Botulinum A toxin treatment for detrusor-sphincter dyssynergia in spinal cord disease.Spinal Cord. 1998; 36: 91-94Crossref PubMed Scopus (131) Google Scholar In 1988 Dr Dennis D. Dykstra published the first case series of botulinum A toxin for the treatment of DSD (Table 3).29Dykstra D.D. Sidi A.A. Scott A.B. Pagel J.M. Goldish G.D. Effects of botulinum A toxin on detrusor-sphincter dyssynergia in spinal cord injury patients.J Urol. 1988; 139: 919-922Abstract Full Text PDF PubMed Scopus (400) Google Scholar In 1990 the first randomized controlled trial demonstrating the efficacy of botulinum A toxin for the treatment of DSD was published by Dykstra and Sidi.15Dykstra D. Sidi A. Treatment of detrusor-sphincter dyssynergia with botulinum A toxin.Arch Phys Med Rehab. 1990; 71: 24-26PubMed Google Scholar Subjects were treated via cystoscopic injection of botulinum A toxin or placebo into the external urethral sphincter. Posttreatment urodynamics in the botulinum A toxin–treated group revealed a mean reduction of maximum urethral closure pressure of 25-cm water and postvoid residual of 125 mL; whereas, saline-treated patients demonstrated no significant change. Botulinum A toxin effects lasted for approximately 2 months.TABLE 3Studies examining the efficacy of intrasphincteric botulinum toxin A for the treatment of DSD (mixed gender, adult patients unless otherwise specified)AuthorYearNToxin doseOutcomePatient populationStudy designDykstra et al29Dykstra D.D. Sidi A.A. Scott A.B. Pagel J.M. Goldish G.D. Effects of botulinum A toxin on detrusor-sphincter dyssynergia in spinal cord injury patients.J Urol. 1988; 139: 919-922Abstract Full Text PDF PubMed Scopus (400) Google Scholar198811140 U (3 injections in 3 wks)Decreased urethral motor unit activation and elevated PVRNeurogenic DSDCSDykstra et al15Dykstra D. Sidi A. Treatment of detrusor-sphincter dyssynergia with botulinum A toxin.Arch Phys Med Rehab. 1990; 71: 24-26PubMed Google Scholar199035620 U total (3 injections in 3 wks)Decreased urethral motor unit activation and urethral pressure profilesNeurogenic DSDRCTSchurch et al45Schurch B. Hodler J. Rodic B. Botulinum A toxin as a treatment of detrusor-sphincter dyssynergia in patients with spinal cord injury: MRI contriolled transperineal injections.J Neurol Neurosurg Psychiatry. 1997; 63: 474-476Crossref PubMed Scopus (71) Google Scholar1996243 protocols: - 100 U Botox - 25 U Botox - 250 IU Dysport21 patients with decreased MUCP, 8 with total DSD resolution; repeated injections longer lasting effectsNeurogenic DSDCSSchurch et al44Schurch B. Hauri D. Rodic B. Curt A. Meyer M. Rossier A. Botulinum-A toxin as a treatment of detrusor-sphincter dyssynergia: a prospective study in 24 spinal cord injury patients.J Urol. 1996; 155: 1023-1029Abstract Full Text Full Text PDF PubMed Scopus (300) Google Scholar19976150 UTested 3 dosing regimens; 100 U every 3 mos most effective; No difference between transurethral and transperineal routeNeurogenic DSDCSPetit et al28Petit H. Wiart L. Gaujard E. et al.Botulinum A toxin treatment for detrusor-sphincter dyssynergia in spinal cord disease.Spinal Cord. 1998; 36: 91-94Crossref PubMed Scopus (131) Google Scholar199817150 IU Dysport10 patients with elevated PVR and reduced urethral pressureNeurogenic DSDCSWheeler et al46Wheeler J. Walter J. Chintam R. Rao S. Botulinum toxin injections for voiding dysfunction following SCI.J Spinal Cord Med. 1998; 21: 227-229Crossref PubMed Scopus (33) Google Scholar19983100 USubjective improvement in voiding and catheter passageNeurogenic DSDCSCS, Case series; MUCP, maximum urethral closure pressure; PVR, post-void residue. Open table in a new tab CS, Case series; MUCP, maximum urethral closure pressure; PVR, post-void residue. Although requiring repetitive treatments, injection of the external urethral sphincter with botulinum toxin for the treatment of DSD has demonstrated significant reduction of maximum urethral closure pressures and postvoid residual volumes, offering new hope for DSD-affected patients. An alternative to more invasive traditional therapies, botulinum toxin injection is a minimally invasive, yet highly effective therapeutic option. The off-label use of intradetrusor botulinum toxin for the treatment of detrusor overactivity incontinence (DOI) has revolutionized the care of affected patients. In 2000, Schurch et al30Schurch B. Stohrer M. Kramer G. Schmid D. Gaul G. Hauri D. Botulinum-A toxin for treating detrusor hyperreflexia in spinal cord injured patients: a new alternative to anticholinergic drugs? Preliminary results.J Urol. 2000; 164: 692-697Abstract Full Text Full Text PDF PubMed Google Scholar published their landmark study of 31 intermittent self-straight catheterization-dependent spinal cord injury patients who underwent cytoscopic detrusor injection with 300 U Botox (Allergan, Inc) for the treatment of DOI. After treatment, maximum cystometric capacity and postvoid residual volumes increased; whereas, mean maximum detrusor voiding pressure decreased significantly and 17 of 19 patients were continent. These findings of were supported by Reitz and Schurch31Reitz A. Stohrer M. Kramer G. et al.European experience of 200 cases treated with bolutlinum-A toxin injections into the detrusor muscle for urinary incontinence due to neurogenic detrusor overactivity.Eur Urol. 2004; 45: 510-515Abstract Full Text Full Text PDF PubMed Scopus (377) Google Scholar in the largest case series to date, demonstrating 73% of 231 patients with neurogenic detrusor overactivity (NDO) to have complete resolution of incontinence complaints; whereas, the remaining patients were improved, although not cured. Although not a first-line treatment for DOI, intradetrusor botulinum A toxin is an important new option for the treatment of patients with inadequate response to more conservative therapies. Initial studies were focused on patients with refractory NDO, but an increasing number of recent studies have examined outcomes in idiopathic DOI (IDO) patients, the most common cause of DOI. Future research appears to be aimed at studying NDO and IDO patients as 2 separate populations. Randomized control trials (RCT) examining the efficacy of intradetrusor botulinum A toxin for the specific treatment of NDO are beginning to be performed (Table 4). In July 2005, Schurch et al32Schurch B. de Seze M. Denys P. et al.Botulinum toxin type A is a safe and effective treatment for neurogenic incontinence: results of a single treatment, randmized, placebo controlled 6-month study.J Urol. 2005; 174: 196-200Abstract Full Text Full Text PDF PubMed Scopus (488) Google Scholar published the first RCT demonstrating the use of the therapy in 59 patients with NDO. After receiving either 200 or 300 U of toxin or placebo, both dose groups demonstrated a statistically significant improvement in incontinence episode frequency and urodynamic testing parameters compared with placebo. No statistically significant difference in incontinence episode frequency was noted between the 2 toxin dose groups. Safety information demonstrated no significant adverse events with any treatment group.TABLE 4Studies examining the efficacy of intradetrusor botulinum toxin A for the treatment of NDO (mixed gender, adult patients unless otherwise specified)AuthorYearNToxin doseOutcomePatient populationStudy designSchurch et al30Schurch B. Stohrer M. Kramer G. Schmid D. Gaul G. Hauri D. Botulinum-A toxin for treating detrusor hyperreflexia in spinal cord injured patients: a new alternative to anticholinergic drugs? Preliminary results.J Urol. 2000; 164: 692-697Abstract Full Text Full Text PDF PubMed Google Scholar200021200 or 300 U89% of patients continentNeurogenic DOICSSchulte-Baukloh et al47Schulte-Baukloh H. Michael T. Schobert J. Stolze T. Knispel H. Efficacy of botulinum-A toxin in children with detrusor hyperreflexia due to myelomeningocele: preliminary results.Urology. 2002; 59: 325-327Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar20021785-300 UIncontinence decreased 39.4% with improved urodynamic findingsChildren with neurogenic DOICSLoche et al48Loche A. Loche T. Osterhage J. Alloussi S. Stockle M. Botulinum-A toxin detrsuor injections in the treatment of non-neurogenic and neurologic cases of urge incontinence.Eur Urol Suppl. 2003; 2: 172Abstract Full Text PDF Google Scholar200330200 U67% of patients reported improved continenceRefractory mixed DOICSRadziszeweski and Borkowski49Radzieszewski P. Borkowski A. Botulinum toxin type A intravesical injections for instable bladder overactivity.Eur Urol Suppl. 2002; 1: 134Abstract Full Text PDF Google Scholar200212300 U100% of patients improved DO symptomsRefractory mixed DOICSYokoyama et al50Yokoyama T. Kumon H. Smith C. Somogyi G.T. Chancellor M.B. Botulinum toxin treatment of urethral and bladder dysfunction.Acta Med Okayama. 2002; 56: 271-277PubMed Google Scholar200210300 U80% improved symptomsNeurogenic voiding dysfunctionCSAbdelmalak et al51Abdelmalak J. Rackley R. Vasavada S. Ghoniem G. El-Azab A.S. Moy L. Botluinum A toxin (Botox) injection for the treatment of refractory overactive bladder.J Pelvic Med Surg. 2004; 10: S42-S43Crossref Google Scholar200418300 U100% patients improved mean UDS findings and frequencyRefractory DOICSGrosse et al52Grosse J. Kramer G. Stohrer M. Botulinum toxin A (BTX-A) injections for detrusor overactivity in patients with congenital spinal cord defects—first three years of experience. 2004Google Scholar200435N/A53% improved urodynamic findingsCongenital spinal cord injury patients with DOCSCorcos et al53Corcos J. Taweel W.A. Robichaud C. Botulinum-A toxin as an alternative treatment to bladder augmentation in children with neurogenic bladder due to myelomeningocele. 2004Google Scholar2004205 U/Kg up to a max of 300 U65% improved urodynamic findingsChildren with neurogenic DOICSSmith et al37Smith C. O'Leary M. Erickson J. Somogyi G. Chancellor M. Botulinum toxin urethral sphincter injection resolves urinary retention after pubovaginal sling operation.Int J Urogyn. 2002; 13
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