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URINARY PROBLEMS. The neuro-anatomic substrate for normal voiding is widespread. The detrusor motor area in the frontal lobes connects with a similar functional region in the pontomesencephalic reticular formation. Input from the basal ganglia to this cortico-mesencephalic loop depresses detrusor contraction; hypothalamic input increases detrusor contraction. Peripherally the detrusor is innervated via sacral parasympathetic neurons, a pathway that is facilitated by noradrenergic neurons in the locus ceruleus. Seemingly more important for patients with PD, however, is the loss of dopaminergic output from the substantia nigra, which appears to increase detrusor hyperreflexia. Most patients with PD suffer from detrusor hyperactivity. Relatively few have detrusor hypoactivity or urethral sphincter dysfunction. Common symptoms in PD patients that result from detrusor hyperactivity include urgency, frequency, and nocturia. Nocturia is the most common and usually the earliest complaint, only much later followed by daytime symptoms. In fact, if daytime frequency or urgency occurs as an initial complaint, causes from mechanical outlet obstructions, such as prostatic hypertrophy, must be considered. Management (breakout 5) Many patients can reduce nighttime frequency by the simple expedient of reducing liquid intake in the evening (no liquids after supper). If this nonpharmacologic intervention is ineffective, peripherally acting anticholinergics, such as oxybutynin or propantheline, can be tried. Oxybutynin, 5 to 10 mg, can be administered at bedtime only or on a tid basis. Propantheline, 7.5 to 15 mg, may also work well at bedtime or on a tid schedule. If anticholinergics prove ineffective, hyoscyamine, a parasympatholytic agent, may work on a qid regimen or at night only (0.15 to 0.30 mg). A trial of desmopressin, administered at night in escalating doses (usually 10 to 20 micro g) as an intranasal spray, may work for otherwise refractory cases. Anticholinergic agents, used in the treatment of detrusor hyperactivity, reduce detrusor contractions, an effect that may worsen voiding problems in patients with detrusor hypoactivity or outlet obstruction. Detrusor hyporeflexia, producing incomplete bladder emptying and urinary frequency, may respond to a reduction in the dosage of an anticholinergic antiparkinsonian medication when that is the cause. It is therefore essential that PD patients with urinary dysfunction have urologic evaluations that include recording of bladder and sphincter pressure, sphincter electromyography, and fluoroscopy and that these tests be performed only by a urologist familiar with their interpretation. When cystometric studies reveal a hypoactive detrusor, benefit may be obtained from alpha adrenergic-blocking agents such as phenoxybenzamine or prazosin, which decrease tone in the bladder neck. Unfortunately, these agents can exacerbate or cause orthostatic hypotension and cardiac arrhythmias and should be used with caution in patients with PD. Drugs that relax striated muscle--such as diazepam, baclofen, or dantrolene--can ocasionally be effective when the external sphincter is hyperreflexic. Intermittent catheterization is necessary with myogenic overdystension. Any deterioration in voiding pattern (even in the absence of dysuria) should raise the concern of infection, which should be treated promptly.[78]
SEXUAL PROBLEMS. Little attention has been paid to the sexual dysfunction common in patients with PD. Most treatment is aimed at impotence in men, with virtually nothing being known about the sexual function of women with PD. In men, the most common problem is achieving or sustaining an erection. Management (breakout 6). Propranolol or other beta-adrenergic blockers, sometimes used to control postural or action tremor in patients with PD, are common offenders. Other possible problem drugs include antihypertensives (alpha-adrenergic blockers such as clonidine, methyldopa, and guanfacine). Guanethidine, although less frequently used, is a potential offender, as are thiazide diuretics, anxiolytics, digoxin, and cimetidine. Looking for depression is often rewarding; medical evaluation is mandatory but rarely helpful. Although depression is a frequent cause of sexual dysfunction, it is noteworthy that antidepressant drugs (particularly the serotonin uptake inhibitors fluoxetine, paroxetine, sertraline) can cause impotence. Tricyclics also have been implicated as a less frequent cause of impotence. Depressed patients should be treated with either tricyclic antidepressants or serotonin uptake inhibitors, despite the problems described above. Tricyclics (with anticholinergic properties) have the added advantage of alleviating some of the parkinsonian symptoms, but the best approach is to use the most efficacious drug to lift depression in a given patient. Some patients with anxiety- or stress-associated sexual dysfunction benefit from low-dose anxiolytics. Endocrine function can be ascertained with serum levels of prolactin testosterone, and luteinizing hormone and studies of thyroid function. If no medical or psychologic reasons seem to be causing impotence, one can try yohimbine, 5 mg tid for 1 month. Further treatment, under consultation with an expert urologist, can include local injection of phentolamine(an alpha-adrenergic blocker) and papaverine. This combination provides a short-term vasodilator effect by acting on smooth muscle. More invasive approaches, such as implants, are less easily accepted by patients and treating physicians. Previously untreated patients may find that starting treatment with levodopa can help sexual dysfunction, probably by alleviating bradykinesia and increasing desire. In fact, some patients on high doses of antiparkinsonian agents become hypersexual, even in the face of inability to perform.
ORTHOSTATIC HYPOTENSION. The anatomic site responsible for orthostatic hypotension (OH) patients with PD are probably heterogeneous, since no consistency in abnormalities has been reported. Sympathetic efferent dysfunction in some patients can be inferred from a failure to increase heart rate with falling blood pressure and the lack of blood pressure overshoot with Valsalva. Abnormalities of renin and inadequate increases in serum norepinephrine on standing may be contributory factors. A central autonomic defect may be involved, as suggested by an increased pressor response to norepinephuine patients with PD. The finding of Lewy bodies in the hypothalamus of these patients support such an etiology in some. More likely in most patients however, is a generalized sympathetic degeneration from Lewy body disease causing cell loss in the sympathetic ganglia.[78] Management (breakout 7). OH, although not uncommon in patients with PD, should be treated only in those who are symptomatic. Levodopa or dopamine receptor agonists exacerbate OH, the latter especially during the first weeks of treatment. Many patients who have been on antihypertensive drugs begin to experience OH with progression of PD. They often can tolerate a reduction in or cessation of their antihypertensive medications. In those patients who are not taking antihypertensives, the first step in treating OH should be the addition of salt and fluids to the diet. Higher salt intake can be achieved by deliberately adding salt to food at the table (as opposed to adding it in the cooking process) so that other family members do not get additional unnecessary salt. Salt tablets, up to 2 g per day, are another alternative. Compressive stockings and behavior modification should be used in conjunction with increased salt and fluid intake. Knee-high stockings are less effective than thigh-high ones, but the former are preferable because of increased compliance. Practitioners can teach patients behavior modification that reduces OH, such as getting up slowly and sleeping with the head tilted. For parkinsonian patients with OH, fludrocortisone (a salt-retaining steroid) can be started in doses of 0.1 rug per day and titrated upwards in 0.1 mg increments up to 0.3 mg tid. Patients taking it should be monitored for possible congestive heart failure and supine hypertension, however Indomethacin, 25 mg tid is not as effective as fludrocortisone but is more easily tolerated. It probably works by inhibiting vasodilating prostaglandins. Midodrine, 5 to 10 mg qid, is an investigational alpha-adrenergic agonist that is particularly effective in some patients. In evaluating patients with "dizziness" OH should be distinguished from complaints caused by postural instability visualmotor dysfunction, or multiple sensory deficits.[79]
THERMOREGULATION. The neurochemical and anatomic regulation of temperature is complex and poorly understood. Preoptic and hypothalamic areas appear to have thermoregulatory function. Noradrenergic, serotonergic, and cholinergic systems have an incompletely understood role in thermal homeostatais. Sweating is mediated by efferent sympathetic cholinergic fibers, which may be damaged in PD. Lewy bodies and cell loss in the hypothalamus have been implicated in PD-associated sweating abnormalities. Management (breakout 8). Abnormal sensations of heat or cold, impaired sweating responses, and hypothermia all can occur in the untreated patient. Excessive sweating of the head and neck in response to external heat has been associated with poor heat dissipation. Some of these phenomena disappear with levodopa treatment, which suggests a role for central dopaminergic systems in thermoregulation.[80] Severe drenching sweats occur as an end-of-dose "off" phenomenon in patients with motor fluctuations, further supporting a role for dopamine systems in vasomotor tone and heat regulation. Dopamine agonist therapy may be of benefit to such patients. Although peak-dose chorea can cause sweating, it is rarely if ever as severe as that seen in the "off' state For patients who experience it, however, a reduction in the dopaminergic medications may help but often at the price of more "off" time. These patients are more likely to respond to beta-adrenergic blockers than are patients with "off"-period sweating. Severe hyperpyrexia after levodopa withdrawal resembles the neureleptic malignant syndrome and needs to be treated promptly with reinstitution of dopaminergic agents. Other causes of excessive sweating must not be neglected simply because the patient has PD. Benign sweating can occur with either a visual, olfactory or gustatory stimulus. Ethanol and aspirin in high doses also can cause increased intermittent sweats. Therefore, taking a thorough history usually will clarify these situations Thyrotoxicosis and postmenopausal states need to be considered and appropriate endocrine evaluation initiated. Finally, chronic infections such as tuberculosis must not be forgotten in the differential diagnosis.
PAIN. The mechanisms responsible for pain in PD are unclear and probably not the same in all patients. It can be mediated via peripheral somatic or autonomic afferent nerves. Selective autonomic block, however, does not seem to reduce the pain in PD, and signs of autonomic disturbance are not usually present. Since many of these syndromes are associated with dystonia, one possible site for the origin of PD-associated pain is afferent nerve fibers within the dystonic muscles. A spinal cord or cerebral origin for some pains is suggested by the pseudoradicular pattern seen in some patients. Many pain syndromes occur in the "off" state only, suggesting a role for dopamine-containing cells in the diencephalon,[81] which terminate on receptors in the dorsal horn and intermediolateral column.[82,83] Sensory symptoms often appear neuritic in character, including paresthesias, burning dysesthsisa, coldness or numbness, and deep aching.[84] The legs are more often involved than the arms; face and neck are rarely involved.[85] Akathisia sometimes is present. Pain is often, but not always, worse on the side of worse parkinsonism.[86]
