Botulinum Toxin Injection to the Detrusor

I. Botulinum Toxin in General

1. History

  • In 1897, Van Ermengem first isolated Clostridium botulinum and its exotoxins [van Ermengem 1897].
  • In 1923, Dickson and Shevky [Dickson 1923] demonstrated that the toxin impaired transmission at the nerve endings.
  • In 1980, the first clinical application was to correct strabismus [Scott 1980].

2. Chemistry

  • Botulinum toxin exists as seven sero types, designated A, B, C, D, E, F, and G.
  • Serotypes A and B are available for clinical use.
  • It consists of a light (50 kD) and a heavy chain (100 kD) which are linked by a disulfide bond.
  • After the binding of the heavy chain of the toxin to the neuronal cell membrane, internalization occurs, and then the light chain is translocated into the cytosol.
  • With the heavy chain the toxin binds to the cell surface and helps the light chain to migrate through the cellular membrane.
  • The light chain is the effective part of the toxin.
  • Inside the cell, the light chain acts as an endopeptidase that splits several proteins needed for the fusion of neurotransmitter vesicles with the cell surface
  • Thereby the toxin interferes with nerve transmission by blocking the release of acetylcholine (Ach) from the motor end plate.

3. Pharmacology

  • A presynaptic neuromuscular blocking agent:
  • Temporarily inhibits the release of acetylcholine at the cholinergic nerve terminal.
  • Inducing flaccid muscle paralysis selectively and reversibly  
  • The clinical effect is transient: effect lasts up to several months with intramuscular injection
  • The effect is dose-related.
  • Also may affect the sensory feedback loop to the central nervous system by decreased input from the muscle tissue.
  • Providing autonomic blockade, as well as somatic neuromuscular blockade [Comella 2000]

4. Characteristics
(1) Effectiveness
(2) Specificity
(3) Reversibility

  • Initially formation of new neural sprouts at the end of the affected nerve terminal.
  • The process reconnects pre-synaptic nerve endings with their target organs.
  • Recovery is essentially complete in about 90 days (correlates with the clinical duration of effect).

(4) Local administration and local effects:

  • Without the generalized effects of muscle relaxants that are orally administered

5. Clinical applications

  • Blepharospasm, spastic dysphonia, spasmodic torticollis, facial dyskinesias, oromandibular dystonia, hyperhidrosis, palatal myoclonus, achalasia, anal fissure and sphincter spasm, and cosmetic surgery for wrinkles
  • The afore-mentioned characteristics make the botulinum toxin a powerful versatile tool in a variety of clinical diseases entities associated with muscle spasm and associated pain.
  • Clinically, the botulinum toxin has been injected in multiple sites rather than one large bolus. This helps to reduce complications.

6. Commercial availability

  • Botulinum toxin type A: are currently licensed for clinical use.
    • Botox (Allergan, Irvine, CA)  available in vials of 100 U
    • Dysport (Ipsen, Berks, UK) available in vials of 500 U
  • Botulinum toxin type B: FDA approved
    • Myobloc in the U.S. available in vials of 2500, 5000, and 10,000 U
    • Neurobloc in Europe [Elan, Dublin, Ireland]

7. Risks and adverse effects in general

(a) Local side effects

  • Constituting most instances of reported side effects
    • Mostly due to local diffusion of the toxin from injected sites.
    • Some are due to deep or misplaced injections.
  • Dysphagia and local pain: after treatment of cervical dystonias
  • Ptosis: after treatment of blepharospasm and hemifacial spasm

(b) Systemic side effects: very rare

  • Temporary general muscle weakness [Dykstra 1988] and weakness or pathological EMG changes in muscles distal to the injection site [Elston 1985; Lange 1988]
  • Severe generalized muscle weakness after injection of botulinum toxin type A (Dysport and Botox) in the detrusor muscle in 2 SCI/D patients, where the weakness resolved within 2-3 months [Wyndaele 2002]
  • Transitory exacerbation of autonomic hyperreflexia [Dykstra 1990]
  • Dry mouth: possible systemic effect with botulinum toxin type B preparation

 (c) Cautions

  • No data are available on pregnancy, not recommended during lactation.
  • Extreme caution in patients with a pre-existing neuromuscular condition such as motor neuron disease or myasthenia gravis.

8. Other Comments

  • Other toxins, for example bungarotoxin, a toxin extracted from the venom of a Formosan snake  improved voiding in SCI rats with by  reducing urethral outlet resistance [Yoshiyama 2000]. This toxin given intravenously induces striated muscle relaxation by selectively blocking nicotinic receptors without influencing transmission in autonomic ganglia. The results provide further support for the view that drugs that depress striated muscle activity can be potentially useful in the treatment of voiding dysfunction after SCI.

II. Botulinum Toxin for Urological Applications

1. Concept and History

  • The clinical treatment of neurogenic bladder overactivity with a SCI/D: first described by Schurch et al [Schurch 1990]
  • The treatment for the DSED: first reported by Dykstra et al [Dykstra 1988]

2. Purpose of Application

  • A promising alternative option to conservative medication or surgery
  • Treatment of neurogenic detrusor overactivity and DSD

3. Advantages and Disadvantages

  • Advantages
    • Reversible
    • Safe
    • Minimally invasive
  • Disadvantages
    • Temporary effect, repeat injections are required
    • Considerable expense

III. Botulinum Toxin Injection to the Detrusor

1. Concept and History

  • Multiple injection of botulinum toxin into the detrusor muscle layer to reduce bladder overactivity

2. Purpose of this procedure

  • To reduce neurogenic detrusor overactivity, increase bladder capacity, and reduce urge incontinence

3. Indication

  • Overactive bladder

4. Procedure [VIDEO]

  • Cystoscopy set:
    • Transurethral rigid cystoscopic injection with either a 23-gauge Bard needle
    • Flexible cystoscope has also been reported.
  • Dosages and number of injections:
    • 200-300 U of botulinum toxin type A in 30 mL of saline and injected 1 mL into 20-30 different sites in the detrusor muscle (10U /ml) [Schurch 2000]
    • 5000 U of botulinum toxin type B (1mL) in normal saline (2mL) and injection of 0.3mL (500U) at each 10 different sites in the bladder [Dykstra 2003]
  • Trigone is spared to prevent possible VUR.
  • The duration of clinical efficacy of botulinum toxin type A in neurogenic detrusor overactivity seems to be longer than that in DSD, possibly because of the different effects on striated and smooth muscle.

5. Clinical Outcomes

  • Most studies of detrusor overactivity have used botulinum toxin type A.

Authors

Methods

Results

Comments

Hajebrahimi S, Altaweel W, Cadoret J, Cohen E, Corcos J. [Can J Urol. 2005 ]

10 neurogenic bladder and detrusor overactivity who were using CIC (5 tetraplegic; 5 paraplegic)

Multichannel urodynamic evaluation

300-400U BTA
into 30 to 40 different sites in the detrusor muscle

Reflex volume increased by 63.08%

Maximal bladder capacity was augmented by 73.63%

Maximal detrusor pressure decreased by 15.52%

No patients with side effects.

Effective and safe

These initial results confirm European literature reports.

Reitz A, Stohrer M, Kramer G, Del Popolo G, Chartier-Kastler E, Pannek J, Burgdorfer H, Gocking K, Madersbacher H, Schumacher S, Richter R, von Tobel J, Schurch B. [Eur Urol. 2004 ]

Botulinum-A toxin (BTA)

231 SCI/D patients

10 European medical centers

Evaluation: initial (mean 12 weeks after injection) and long term (mean 36 weeks after injection)

Cystometry

Mean cystometric bladder capacity, mean reflex volume, increased
mean voiding pressure decreased

Mean bladder compliance increased by the first follow-up exam

No injection related complications or toxin related side effects

The patients considerably reduced or even stopped taking anticholinergic drugs without recurrence of reflex incontinence and were satisfied with the treatment.

Safe and valuable

 

Bagi P, Biering-Sorensen F. [Scand J Urol Nephrol. 2004.]

300 IU intravesical botulinum toxin A (BTA)
15 SCI patients

Cystometry

 

87% of patients reported full continence after treatment

Anticholinergic medication was stopped in all patients after BTA treatment.

Marked reduction in pressures after treatment in all patients,

Maximum detrusor pressure during filling decreased

Maximum volume at a detrusor pressure of <40 cmH2O being increased

Maximum bladder capacity increased,

Effective period ranged from 4 to 12 months (median 7 months)

No autonomic hyperreflexia

Highly effective treatment modality

Easy to perform

Duration of effect was acceptable.

No side-effects

Dykstra DD, Pryor J, Goldish G. [Arch Phys Med Rehabil. 2003 ]

A Case report botulinum toxin type B

MS patient

Effect lasted 4 months

No side effects

 

The first reported successful use of botulinum toxin type B

6. Advantages & Disadvantages (link to the II. Botulinum Toxin for Urological Applications/ 3. Advantages and Disadvantages)

7. Current Significance

  • Botulinum toxin type A appears to be a safe and viable alternative to the conventional therapies that have failed to produce improvements or to the patients unsuited for catheterization and medical therapy, sphincterotomy, or other procedures.
  • Larger scale investigation on the cost-effectiveness is required.

Summary

Effectiveness

Effective

Safety

Relatively safe

Ease of application

Easy

Patient Comfort

Comfort

Cost

Moderate

8. Other Comments

  • It should be used under close supervision in patients with already impaired neuromuscular transmission or during treatment with aminoglycosides.

Key Points

  • Botulinum toxin has been used successfully to moderate reflex detrusor contractility, and to suppress external sphincter contractility in patients with DSD.
  • Side effects include sporadic reports of generalized muscular weakness which lasts 2 to 3 months in muscle groups below the level of injection. As well as two reported cases where the toxin was used to treat the bladder and one after injection into the external sphincter where the weakness was generalized.
  • It is not clear what effect this would have in most patients with high spinal cord injury.

References

  • Bagi P, Biering-Sorensen F. Botulinum toxin A for treatment of neurogenic detrusor overactivity and incontinence in patients with spinal cord lesions. Scand J Urol Nephrol. 2004;38(6):495-8.
  • Comella CL, Brin M, Jankovic J. Biochemistry of botulinum toxin type B. Neurology 2000; 55 (suppl 5):22–8.
  • Dickson EC, Shevky R. Botulism: studies on the manner in which the toxin of Clostridium botulinum acts upon the body. II. The effect on the voluntary nervous system. J Exp Med 1923; 38: 327–46.
  • Dykstra DD, Pryor J, Goldish G. Use of botulinum toxin type B for the treatment of detrusor hyperreflexia in a patient with multiple sclerosis: a case report. Arch Phys Med Rehabil. 2003 Sep;84(9):1399-400.
  • Dykstra DD, Sidi AA. Treatment of detrusor-sphincter dyssynergia with botulinum A toxin: a double-blind study. Arch Phys Med Rehabil. 1990 Jan;71(1):24-6.
  • Elston JS, Russell RWR. Effect of treatment with botulinum toxin on neurogenic blepharospasm. Br Med J 1985; 290: 1857-1859.
  • Hajebrahimi S, Altaweel W, Cadoret J, Cohen E, Corcos J. Efficacy of botulinum-A toxin in adults with neurogenic overactive bladder: initial results. Can J Urol. 2005 Feb;12(1):2543-6.
  • Lange DJ, Brin MF, Warner CL, Fahn S, Lovelace RE. Distant effects of local injection of botulinum toxin. Muscle Nerve. 1987 Jul-Aug;10(6):552-5.
  • Reitz A, Stohrer M, Kramer G, Del Popolo G, Chartier-Kastler E, Pannek J, Burgdorfer H, Gocking K, Madersbacher H, Schumacher S, Richter R, von Tobel J, Schurch B. European experience of 200 cases treated with botulinum-A toxin injections into the detrusor muscle for urinary incontinence due to neurogenic detrusor overactivity. Eur Urol. 2004 Apr;45(4):510-5.  
  • Schurch B, Hauri D, Largo M, Kreienbühl B, Meyer E,Rossier AB. Effets de la toxine botulinique A sur le sphinc-ter strié des vessies neurogènes. Journal D’Urologie 1990;90:375–80.
  • Schurch B, Stohrer M, Kramer G, Schmid DM, 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 Sep;164(3 Pt 1):692-7.
  • Scott AB. Botulinum toxin injection into extraocular muscles as an alternative to strabismus surgery. J Pediatr Ophthalmol Strabismus. 1980 Jan-Feb;17(1):21-5.
  • van Ermengem E. Ueber einen neuen anaeroben Bacillus and seine Beziehungen zum Botulisms. Ztsch Hyg Infekt, 1897; 26: 1.
  • Wyndaele JJ, Van Dromme SA. Muscular weakness as side effect of botulinum toxin injection for neurogenic detrusor overactivity. Spinal Cord. 2002 Nov;40(11):599-600.
  • Yoshiyama M, deGroat WC, Fraser MO. Influences of external urethral sphincter relaxation induced by alpha-bungarotoxin, a neuromuscular junction blocking agent, on voiding dysfunction in the rat with spinal cord injury. Urology. 2000 Jun;55(6):956-60.

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