Case Studies in Case Studies in Neurological Neurological

RehabilitationRehabilitation

Botulinum toxin for Botulinum toxin for neuropathic bladderneuropathic bladder

Alireza Ashraf, M.D.Professor of Physical Medicine & Rehabilitation

Shiraz Medical school

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

Neuroanatomy and Neurophysiology of Neuroanatomy and Neurophysiology of VoidingVoiding

Central PathwaysCentral Pathways Corticopontine Mesencephalic Nuclei–Frontal Corticopontine Mesencephalic Nuclei–Frontal

LobeLobe Pontine MesencephalicPontine Mesencephalic Pelvic and Pudendal Nuclei–Sacral MicturitionPelvic and Pudendal Nuclei–Sacral Micturition Motor Cortex to Pudendal NucleusMotor Cortex to Pudendal Nucleus

Peripheral PathwaysPeripheral Pathways Parasympathetic Efferents–S2–S4Parasympathetic Efferents–S2–S4 Sympathetic Efferents–T11–L2Sympathetic Efferents–T11–L2 Somatic Efferents–S2–S4Somatic Efferents–S2–S4 Afferent FiberAfferent Fiber

Urethral SphincterUrethral Sphincter

Internal SphincterInternal Sphincter::

Innervated by T11–T12 sympathetic Innervated by T11–T12 sympathetic nervenerve

Contracts sphincter for storageContracts sphincter for storage

Smooth muscleSmooth muscle

External Sphincter:External Sphincter:

Innervated by S2–S4 pudendal nerveInnervated by S2–S4 pudendal nerve

Prevents leakage or emptyingPrevents leakage or emptying

Skeletal muscle, voluntary controlSkeletal muscle, voluntary control

autonomic receptorsautonomic receptors Cholinergic Muscarinic–M2:Cholinergic Muscarinic–M2:

Located in the bladder wall, trigone, Located in the bladder wall, trigone, bladder neck, urethrabladder neck, urethra

Beta 2 Adrenergic:Beta 2 Adrenergic:

Concentrated in the body of the bladder, Concentrated in the body of the bladder, neckneck

Alpha adrenergic:Alpha adrenergic:

Located on the base of the bladder (neck Located on the base of the bladder (neck and proximal urethra)and proximal urethra)

(Note: Bladder wall does not have (Note: Bladder wall does not have baroreceptors alphabaroreceptors alpha))

Bladder and proximal Bladder and proximal urethraurethra

distribution of autonomic distribution of autonomic receptorsreceptors

Note:Note:Alpha Adrenergic receptors Alpha Adrenergic receptors

respond to the appearance of respond to the appearance of norepinephrine with norepinephrine with contractioncontraction

Beta adrenergic receptors Beta adrenergic receptors respond to the appearance of respond to the appearance of norepinephrine with norepinephrine with relaxationrelaxation

StorageStorageSympatheticSympathetic

T11–L2 sympathetic efferentsT11–L2 sympathetic efferents Travel through the Travel through the hypogastric nervehypogastric nerve Causes the sphincter to contract and body to relaxCauses the sphincter to contract and body to relax Urine is storedUrine is stored

Alpha1 Receptors AdrenergicAlpha1 Receptors Adrenergic NE causes contraction of neck of bladder and prevents NE causes contraction of neck of bladder and prevents

leakageleakage Closes internal urethral sphincter and detrusor outlet, Closes internal urethral sphincter and detrusor outlet,

promoting storagepromoting storage

B2 Receptors AdrenergicB2 Receptors Adrenergic Located in body of bladderLocated in body of bladder Activation causes relaxation of body of bladder to allow Activation causes relaxation of body of bladder to allow

expansionexpansion Inhibitory when activatedInhibitory when activated

Storage Storage reflexesreflexes. .

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

EmptyingEmptyingParasympatheticParasympathetic

Muscarinic (M2) cholinergic receptors are Muscarinic (M2) cholinergic receptors are located inlocated in

The bladder wallThe bladder wall TrigoneTrigone Bladder NeckBladder Neck UrethraUrethra

Stimulation of pelvic nerve Stimulation of pelvic nerve (parasympathetic)(parasympathetic)

Allows contraction of bladderAllows contraction of bladder

B2 Receptors AdrenergicB2 Receptors Adrenergic Relaxation of the bladder neck on the initiation Relaxation of the bladder neck on the initiation

of voidingof voiding

Voiding Voiding reflexes. reflexes.

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

LMN Bladder:LMN Bladder:Big Hypotonic Bladder (flaccid, Big Hypotonic Bladder (flaccid,

areflexic bladder),Tight Competent areflexic bladder),Tight Competent SphincterSphincter

Results in:Failure to EmptyResults in:Failure to Empty

UMN Bladder:UMN Bladder:Small Hyperreflexic, Overactive,Little Small Hyperreflexic, Overactive,Little

BladderBladderResults in:Failure to Store Results in:Failure to Store

(Incontinence)(Incontinence)

Therapy with Botulinum toxinTherapy with Botulinum toxin increases maximal cystometric increases maximal cystometric

bladder capacity bladder capacity reduces maximum detrusor pressurereduces maximum detrusor pressure reduces incontinence episodesreduces incontinence episodes

Functional bladder capacity = voided Functional bladder capacity = voided volume + residual urine volumevolume + residual urine volume

Detressor pressure=bladder pressure-Detressor pressure=bladder pressure-rectaum pressurerectaum pressure

Botulinum toxin injection of the Botulinum toxin injection of the detrusor muscle detrusor muscle has proved a has proved a valuable tool in valuable tool in refractory conditions refractory conditions with hyperactive bladders. with hyperactive bladders.

The botulinum toxin is The botulinum toxin is diluted in diluted in normal saline and injected through a normal saline and injected through a cystoscopecystoscope. .

Most patients will have a Most patients will have a therapeutic benefit that lasts for therapeutic benefit that lasts for more than more than six months. six months.

Some patients with problems with Some patients with problems with pain from a catheter pain from a catheter or or by-passing by-passing owing to a hyper-reflexic bladder owing to a hyper-reflexic bladder can can benefit from intravesical botulinum benefit from intravesical botulinum toxin.toxin.

The role of botulinum toxin in the The role of botulinum toxin in the management of this problem is management of this problem is not not certain.certain.

A recent trial had to be stopped A recent trial had to be stopped prematurely as patients prematurely as patients with multiple with multiple sclerosis and detrusor–sphincter sclerosis and detrusor–sphincter dyssynergia receiving intravesical dyssynergia receiving intravesical botulinum toxin showed no botulinum toxin showed no improvement in relation to placebo-improvement in relation to placebo-injected controls.injected controls.

Several studies have shown the Several studies have shown the effectiveness of intraperineal urethral effectiveness of intraperineal urethral injection of botulinum toxin in patients injection of botulinum toxin in patients with spinal cord injuries.with spinal cord injuries.