Pathogenesis Of Voiding Dysfunction In Pd

Voiding is a function of the autonomic nervous system with a core segmental representation in the spinal cord. As the bladder fills, afferent stimuli are conducted to the S2-S4 segments.

During filling, the external and internal urethral sphincters are tonically contracted, and there is an increased tone of striated musculature of the pelvic floor. At a certain level of bladder distention, a reflex efferent response is triggered by activated motor neurons, which stimulate the detrusor muscle via the pelvic nerve (para-sympathetic) and relax the internal urethral sphincter via parasympathetic inhibition of sympathetic terminals that innervate the bladder neck. At the same time, inhibition of Onuf's nucleus and pudendal motor nuclei cause relaxation of the striated urethral sphincter and the perineal floor.

This segmentally organized function is subject to facilitatory and inhibitory impulses from higher neurologic centers that allow for voluntary control of the detru-sor reflex. Specifically, impulses from the cortical micturition center in the mesial frontal lobes36 would connect to the pontine-mesencephalic reticular formation. This pathway is further influenced by the basal ganglia, the thalamic nuclei, and the anterior vermis of the cerebellum (Pavlakis et al., 1983; Andersen et al., 1985).5,24 Micturition is also influenced by the anterior cyngulate gyrus, the locus coeruleus, and the nucleus tegmento lat-eralis dorsalis.36

Based on a series of experiments and subsequent experience with basal ganglia surgery, it is currently believed that the basal ganglia exert an inhibitory effect on the ponto-mesencephalic micturition center. Lesions of basal ganglia, as in PD, would result in partial or total disconnection of the micturition reflex from voluntary control. The result would be unhibited detrusor contractions elicited at low volume threshold (detrusor hyperreflexia).5 In PD, the presence of detrusor hyperreflexia with vesi-

cosphincter synergy is therefore suggestive of a suprapon-tine lesion. In contrast, in multiple sclerosis, the finding of detrusor-sphincter-dyssynergia denotes a lesion of the connections between the pontine micturition center and the spinal cord centers of micturition.

Lewin et al. performed pivotal experimental studies in cats that are still being cited as backbone for current theory on pathophysiology.1819 Lewin et al. stimulated the thalamus and different sites of the basal ganglia and found that the stimulation was inhibitory of detrusor contractions. The inhibition ranged from prolongation of intercontraction interval of the detrusor to occasional complete suppression of detrusor contractions with the activity only resuming after stimulation was stopped.

It is interesting to note that stimulation of the red nucleus, the subthalamic nucleus, and the substantia nigra was more inhibitory than that of the thalamus. This may suggest that current deep brain stimulation procedures may be more effective in improving voiding dysfunction if STN rather than the thalamus is the target. Stereotaxic thalamotomy in parkinsonian patients, on the other hand, demonstrated an increase in detrusor activity.22,25

The understanding of the pathophysiology of urethral sphincter dysfunction owes a lot to Raz' work.27 Raz pointed out that, in the initiation of normal micturition, one of the important stages is relaxation occurring prior to maximal bladder contraction. In Parkinson's disease, there can be failure of the perineal muscle floor/shincter to relax rapidly before the detrusor contraction.24 This delay in the normal relaxation of the pelvic floor would produce hesitancy and slow stream. This phenomenon of sphincter bradykinesia seems to be a condition peculiar to the parkinsonian patient, albeit not universally present. Pavlakis et al. believe that it represents a manifestation of skeletal muscle hypertonicity involving the perineal floor.

Studies in conscious rats suggest that D1 receptors (linked to stimulation of adenylate cyclase39) tonically inhibit the micturition reflex.31 Administration of mixed Dj/D2 agonists in anesthetized MPTP-lesioned monkeys increased their pathologically reduced bladder volume threshold.40 This effect could be antagonized by pretreat-ment with a D1 antagonist. This inhibitory effect of the D1 receptors would presumably be exerted via the forebrain system,39 perhaps through a potentiation of the GABAer-gic system in the basal ganglia.40 The loss of D1 activation in Parkinson's disease may therefore underlie the bladder overactivity in Parkinson's disease.

On the other hand, similar studies in conscious rats suggest that D2 receptors are involved in facilitation of the micturition reflex.31 The pure D2 agonist bromocriptine administered to MPTP-lesioned monkeys decreases their already pathologically reduced bladder volume threshold even further.40 This excitatory effect of D2 receptors on the micturition reflex would be exerted directly on the brain stem.39

This combination of effects would result in a Dj effect during bladder filling and a D2 effect during bladder emptying. We would expect a salutary effect of Dj agonists on bladder control in Parkinson's disease. Studies comparing the effects of currently available "pure" D2 versus mixed Dj/D2 receptor agonists on the voiding dysfunction of PD patients would be of interest. We are only aware of one study (reported in abstract form) where patients with Parkinson's disease affected with urinary urgency and frequency while on bromocriptine experienced an improvement in their symptoms when switched to per-golide.16

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