1. Case Studies in Neurological Rehabilitation Botulinum toxin for neuropathic bladder Alireza Ashraf, M.D. Professor of Physical Medicine & Rehabilitation Shiraz Medical school

2. A 36-year-old woman with a 12 year history of multiple sclerosis ;used tolterodine, intermittent catheterisation and intravesical oxybutinin to manage her neuropathic bladder but was still having several problems with urgency, frequency and occasional incontinence.The patient is not keen on either a urethral or a suprapubic catheter as she is sexually active.

4. Neuroanatomy and Neurophysiology of Voiding Central Pathways Corticopontine Mesencephalic Nuclei–Frontal Lobe Corticopontine Mesencephalic Nuclei–Frontal Lobe Pontine Mesencephalic Pontine Mesencephalic Pelvic and Pudendal Nuclei–Sacral Micturition Pelvic and Pudendal Nuclei–Sacral Micturition Motor Cortex to Pudendal Nucleus Motor Cortex to Pudendal Nucleus Peripheral Pathways Parasympathetic Efferents–S2–S4 Parasympathetic Efferents–S2–S4 Sympathetic Efferents–T11–L2 Sympathetic Efferents–T11–L2 Somatic Efferents–S2–S4 Somatic Efferents–S2–S4 Afferent Fiber Afferent Fiber

6. Urethral Sphincter Internal Sphincter: Innervated by T11–T12 sympathetic nerve Innervated by T11–T12 sympathetic nerve Contracts sphincter for storage Contracts sphincter for storage Smooth muscle Smooth muscle External Sphincter: Innervated by S2–S4 pudendal nerve Innervated by S2–S4 pudendal nerve Prevents leakage or emptying Prevents leakage or emptying Skeletal muscle, voluntary control Skeletal muscle, voluntary control

8. autonomic receptors  Cholinergic Muscarinic–M2: Located in the bladder wall, trigone, bladder neck, urethra  Beta 2 Adrenergic: Concentrated in the body of the bladder, neck  Alpha adrenergic: Located on the base of the bladder (neck and proximal urethra) (Note: Bladder wall does not have baroreceptors alpha)

9. Bladder and proximal urethra distribution of autonomic receptors

10. Note:  Alpha Adrenergic receptors respond to the appearance of norepinephrine with contraction  Beta adrenergic receptors respond to the appearance of norepinephrine with relaxation

11. StorageSympathetic T11–L2 sympathetic efferents Travel through the hypogastric nerve Travel through the hypogastric nerve Causes the sphincter to contract and body to relax Causes the sphincter to contract and body to relax Urine is stored Urine is stored Alpha1 Receptors Adrenergic NE causes contraction of neck of bladder and prevents leakage NE causes contraction of neck of bladder and prevents leakage Closes internal urethral sphincter and detrusor outlet, promoting storage Closes internal urethral sphincter and detrusor outlet, promoting storage B2 Receptors Adrenergic Located in body of bladder Located in body of bladder Activation causes relaxation of body of bladder to allow expansion Activation causes relaxation of body of bladder to allow expansion Inhibitory when activated Inhibitory when activated

12. Storage reflexes. During the storage of urine, distention of the bladder produces low-level bladder afferent firing. Afferent firing in turn stimulates the sympathetic outflow to the bladder outlet (base and urethra) and pudendal outflow to the external urethral sphincter. These responses occur by spinal reflex pathways and represent “guarding reflexes,” which promote continence. Sympathetic firing also inhibits detrusor muscle and transmission in bladder ganglia.

13. EmptyingParasympathetic Muscarinic (M2) cholinergic receptors are located in The bladder wall The bladder wall Trigone Trigone Bladder Neck Bladder Neck Urethra Urethra Stimulation of pelvic nerve (parasympathetic) Allows contraction of bladder Allows contraction of bladder B2 Receptors Adrenergic Relaxation of the bladder neck on the initiation of voiding Relaxation of the bladder neck on the initiation of voiding

14. Voiding reflexes. At the initiation of micturition, intense vesical afferent activity activates the brainstem micturition center, which inhibits the spinal guarding reflexes (sympathetic and pudendal outflow to the urethra). The pontine micturition center also stimulates the parasympathetic outflow to the bladder and internal sphincter smooth muscle. Maintenance of the voiding reflex is through ascending afferent input from the spinal cord, which may pass through the periaqueductal gray matter (PAG) before reaching the pontine micturition center.

16. LMN Bladder: Big Hypotonic Bladder (flaccid, areflexic bladder),Tight Competent Sphincter Big Hypotonic Bladder (flaccid, areflexic bladder),Tight Competent Sphincter Results in:Failure to Empty Results in:Failure to Empty UMN Bladder: UMN Bladder: Small Hyperreflexic, Overactive,Little Bladder Small Hyperreflexic, Overactive,Little Bladder Results in:Failure to Store (Incontinence) Results in:Failure to Store (Incontinence)

17. Therapy with Botulinum toxin  increases maximal cystometric bladder capacity  reduces maximum detrusor pressure  reduces incontinence episodes Functional bladder capacity = voided volume + residual urine volume Detressor pressure=bladder pressure-rectaum pressure

18.  Botulinum toxin injection of the detrusor muscle has proved a valuable tool in refractory conditions with hyperactive bladders.  The botulinum toxin is diluted in normal saline and injected through a cystoscope.  Most patients will have a therapeutic benefit that lasts for more than six months.

19.  Some patients with problems with pain from a catheter or by-passing owing to a hyper-reflexic bladder can benefit from intravesical botulinum toxin.  The role of botulinum toxin in the management of this problem is not certain.

20.  A recent trial had to be stopped prematurely as patients with multiple sclerosis and detrusor–sphincter dyssynergia receiving intravesical botulinum toxin showed no improvement in relation to placebo-injected controls.  Several studies have shown the effectiveness of intraperineal urethral injection of botulinum toxin in patients with spinal cord injuries.