Introduction

Botulinum toxin (BoTN) is the most potent toxin known in the world. Through its neuromodulatory and paralytic mechanism, BoTN has been applied to facial cosmesis, muscle and neurologic spasticity, and migraine headaches. BoTN use for the treatment of voiding dysfunction has increased over the past several years and has had profound effects on patients with neurogenic bladder dysfunction and idiopathic detrusor overactivity (i.e., overactive bladder) when medical therapies fail. BoTN is easy to use and is generally well tolerated by the patient, with the benefits usually outweighing the adverse events. At the present time, BoTN is approved by the U.S. Food and Drug Administration (FDA) for use in the genitourinary system for neurogenic bladder, and FDA approval for idiopathic detrusor overactivity is expected in the near future.

Mechanism of Action

Depending on the serotype of the organism, Clostridium botulinum, seven distinct BoTNs can be produced by the bacterium (types A, B, C1, D, E, F, and G), all with similar mechanisms of action. At the present time, only BoTN A (Botox [Allergan, Irvine, CA] or Dysport [Medicis, Scottsdale, AZ]) and BoTN B (Myobloc or Neurobloc [Solstice Neuroscience, Louisville, KY]) are commercially available for clinical use. BoTN acts by cleaving a specific site (specific to each BoTN serotype) of a protein complex (soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor [SNARE] complex) responsible for exocytosis of neurotransmitter vesicles from the neuron. In the case of BoTN A, the most well-studied toxin subtype, the specific substrate is the synaptosomal associated protein of 25 kD (SNAP-25), a component of SNARE complex, which results in the inhibition of synaptic release of acetylcholine from the peripheral motor neuron end plate at the neuromuscular junction and ensuing muscle paralysis (Figure 12-1). More recent experience also suggests toxin effect on neurotransmitters related to sensory (afferent) function in the lower urinary tract.

Figure 12-1 Mechanism of action of BoTN. A, In normal neurotransmitter release at the neuromuscular junction, the synaptic fusion complex comprising the SNARE proteins mediates synaptic vesicle fusion to the terminal membrane and acetylcholine exocytosis. B, In the presence of BoTN, which cleaves various SNARE proteins at sites specific to BoTN serotypes, the SNARE complex cannot form, and vesicle fusion and exocytosis is inhibited.

(From Koman LA, ed. Wake Forest University School of Medicine Orthopaedic Manual. Winston-Salem, NC: Orthopaedic Press; 2001.)

At therapeutic doses of 100 to 300 units, BoTN A induces paralysis in the detrusor muscle. However, BoTN A may additionally inhibit sensory nerve activity directly and modulate bladder sensory transmission to the central nervous system. In the cases of bladder overactivity (both neurogenic and idiopathic) and in bladder compliance abnormalities, both mechanisms of action are exploited.

BoTN A specifically is a noncompetitive agonist, and as such the effects are irreversible, yet also temporary as well. After administration of BoTN A, neuromuscular function is regained primarily through a process of motor neuron end plate regeneration and sprouting of the distal motor nerve. The duration of the effect is variable, but in the bladder, the clinical response to BoTN A injections lasts approximately 6 months.

The most common adverse event is increased post-void residual volume, which can occur in 10% to 20% of patients undergoing injection. Catheterization may be required, and secondary urinary tract infection may ensue. More recent changes in BoTN A labeling, in response to systemic effects associated with toxin use in skeletal muscle, include warnings regarding systemic absorption of toxin and respiratory effects resulting from disseminated toxin effects.

Case Scenario

 (Video 12-1)

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