DOPAMINE AGONISTS Dopamine agonists offer the theoretic advantage of exerting a direct action on striatal dopamine receptors, which does not require presynaptic uptake and synaptic release by degenerating dopaminergic nerve terminals. In addition, they do not require metabolic conversion to exert their effects, and their absorption and transport into the brain are not influenced by circulating plasma amino acids. Traditionally, dopamine agonists have been developed and used largely for the treatment of patients with declining response to levodopa, motor fluctuations, dyskinesias, or other adverse levodopa effects. The early use of dopamine agonists as a levodopa-sparing strategy - to reduce or delay long-term levodopa complications - recently has been suggested. In a widely cited, uncontrolled, retrospective study, patients treated with bromocriptine and levodopa showed equivalent therapeutic benefit with fewer motor fluctuations and dyskinesias than patients treated with levodopa alone. A prospective trial from the same center, comparing patients treated with lisuride, lisuride plus levodopa, or levodopa also showed fewer fluctuations in lisuride-treated patients than patients receiving levodopa alone. However, a double-blind, randomized, prospective study of a small number of patients - comparing early combination therapy with levodopa monotherapy - showed no significant differences in frequency of long-term levodopa fluctuations after 4 years of treatment. Results of a similar but larger prospective study comparing levodopa with combination therapy have not yet been published. Despite the lack of definitive data on the comparative advantages of levodopa and combination therapy, the early use of dopamine agonists is increasingly advocated as a levodopa-sparing strategy, to delay or reduce the incidence and severity of long-term levodopa fluctuations and dyskinesias, and possibly to reduce oxidative stress from free radicals generated by high-dose levodopa replacement therapy. Bromocriptine and pergolide are the only dopamine agonists currently available for use in the United States. Bromocriptine has both presynaptic and postsynaptic effects and stimulates D2 receptors. It is started in low doses with close monitoring for such side effects as hypotension, nausea, vomiting, hallucinations, peripheral vasoconstriction, and erythromelalgia. Bromocriptine is initiated at 1.25 mg daily and titrated slowly, according to response, to a level of 10 to 25 mg daily. Some patients, however, might require dosages as high as 50 to 75 mg daily. As bromocriptine is titrated upward, the dosage of levodopa is usually lowered to reduce dopaminergic toxicity. Pergolide does not have presynaptic effects and stimulates both D1 and D2 receptors. It is more potent than bromocriptine by a factor of 10 and has a longer duration of action. It is initiated with 0.05 mg daily and titrated slowly over several weeks to a dose of 2 to 3 mg daily. Further increases in dosage might be considered, if needed, to a maximum of 5 mg daily. Although pergolide's therapeutic efficacy is similar to that of bromocriptine, pergolide may be beneficial for some patients in whom bromocriptine therapy fails because it does not produce a clinical response or cause intolerable side effects. Patients under 60 years of age. Dopamine agonist monotherapy may be considered for mild parkinsonian symptoms in patients aged 60 years and below, but it produces suboptimal benefit in many patients. Even when it is effective, its benefit might wane after several months. We therefore recommend that in most cases, dopamine agonists be held in reserve until after initiation of levodopa, when they can be used instead of increasing levodopa dosages for management of increased parkinsonian disability. It is not yet known whether this approach will reduce or delay the incidence of long-term levodopa fluctuations, but the issue is expected to be resolved by studies currently in progress. Patients over 60 years of age. The rationale for dopamine agonists in patients over age 60 is similar to that for its use in younger patients. The aim is to reduce cumulative exposure to levodopa and thereby possibly reduce long-term side effects. Controversy remains, however, as to whether cumulative levodopa exposure over the long term has any adverse consequences. It is recommended that levodopa be initiated first and that when the levodopa requirement exceeds 600 mg daily, a dopamine agonist be added according to the regimen described previously. LEVODOPA Levodopa is the most effective drug available for the treatment of early PD, and patients who fail to respond to it are highly unlikely to respond to dopamine agonists. Despite a good initial response, however, approximately 50% of patients experience motor fluctuations, such as "wearing-off" effect, unpredictable "on-off" effects, dyskinesias, and dystonias within 6 years of levodopa's initiation. Patients under 60 years of age. The treatment of patients with young-onset PD, who show earlier and more frequent appearance of severe motor fluctuations and involuntary movements, is particularly problematic with regard to the adverse effects of long-term levodopa use. Some practitioners have expressed the concern that levodopa fluctuations and dyskinesias are related more to the duration of levodopa treatment than to the duration and severity of the disease, Therefore, proponents of this theory have recommended that levodopa treatment be withheld until the appearance of significant limitations in activities of daily living and job performance. Other clinicians, however, contend that because no evidence proves that levodopa therapy is directly responsible for these late effects, delay of treatment unnecessarily deprives patients of improved function during the early phase of the disease. Despite this unresolved controversy, most practitioners agree that treatment with levodopa should be initiated when the disease markedly impairs job performance or activities of daily living. Another possibility is that the form of levodopa delivery plays a role in the development of fluctuations and dyskinesias. In experimental animals, continuous and intermittent administration of dopamine agonists exert different and frequently opposite effects on dopamine-mediated behavior. In several recent studies, chronic, intermittent levodopa administration produced greater dopamine-mediated behavioral supersensitivity than continuous treatment, although this has not been confirmed by all studies. Some research has suggested that chronic intermittent therapy is less physiologic than continuous treatment and might result in postsynaptic changes that affect the response to levodopa treatment. These dopamine receptor changes might then cause a narrowing of the therapeutic window and steepening of the dose-response curve, resulting in a fluctuating levodopa response. Dopamine replacement treatments that provide stable stimulation of dopamine receptors might possibly avoid the appearance of motor fluctuations. For this reason, the use of sustained-release formulations of levodopa for initiation of therapy has been advocated increasingly, although their ability to produce predictably smooth plasma levodopa levels and prevent motor fluctuations has not been proven. In Europe, the sustained-release benserazide-levodopa formulation utilizes the decarboxylase inhibitor benserazide rather than carbidopa. The drug is sold under the trade name Madopar. One randomized, double-blind study comparing sustained-release benserazide-levodopa with standard benserazide-levodopa in a relatively small number of patients showed fewer fluctuations and dyskinesias in patients on the sustained-release preparation 2 years after treatment began. More definitive information on the potential advantage of the early use of sustained-release carbidopa-levodopa should emerge from an ongoing clinical trial, in which patients are randomized to either immediate, or sustained- release carbidopa-levodopa. We typically introduce levodopa therapy in the form of sustained-release carbidopa-levodopa in patients who are beginning to experience significant disability in activities of daily living or professional activities. Determination of what constitutes significant disability must be made on a case- by-case basis. Once this decision has been reached, the issue of dosage must be addressed. No available prospective, controlled studies have compared low-dose with higher-dose levodopa treatment, and uncontrolled studies have yielded conflicting results regarding the effect of dosage on incidence of fluctuations. Experimental studies of alternate-day and oral-pulse levodopa therapy in early PD have been carried out in an effort to reduce total levodopa exposure. These approaches, however, are of unproven long-term benefit arid expose the patient to the potential adverse effects of intermittent rather than continuous treatment, which might be less desirable. Sustained-release carbidopa-levodopa should be initiated at 25/100 mg or 50/200 mg twice daily given early morning and early to midafternoon. If delayed onset of effect ("kick-in" time) and lack of sufficient peak effect are problematic, then standard carbidopa-levodopa may be introduced. A relatively low dose of 200 to 400 mg of levodopa should be maintained until progressively disabling symptoms require an increase in dosage or dosing frequency. When a daily dose of 500 to 800 mg of levodopa is reached, the addition of a dopamine agonist is favored over further increases in the levodopa dosage. Patients over 60 years of age. The concern for long-term adverse effects of levodopa are not as great for patients above age 60, in whom the incidence and severity of motor fluctuations and dyskinesias appears to be diminished. Since anticholinergic drugs are discouraged in patients older than age 60 and dopamine agonist monotherapy is unlikely to be of sufficient long-term benefit, carbidopa-levodopa is likely to be required earlier in this age group. As in patients 60 years or younger, sustained-release carbidopa-levodopa is recommended, but an early trial with standard carbidopa-levodopa should be considered if the response to the sustained-release preparation is suboptimal. The incidence of CNS side effects, such as hallucinations, confusion, and psychosis, is higher among patients in this age group, and appropriate caution should be exercised in determining dosage and in combining carbidopa-levodopa with other medications that exert CNS effects. ADVANCING PARKINSON'S DISEASE DYSAUTONOMIAS CONSTIPATION Pfeiffer and his colleagues have emphasized the importance of considering two distinct processes responsible for normal stool expulsion. First, stool moves through the colon by the sequential contraction of muscles within the intestinal wall. Intrinsic enteric neurons regulate this muscular activity. Second, parasympathetic afferent and efferent fibers mediate the excitatory and inhibitory input to the colon. In patients with PD, Lewy bodies have been found within degenerating colonic neurons (myenteric plexus); the primary clinical correlate is slowed stool transit time related to impaired colonic muscle contraction. In a second syndrome, colonic transit time may or may not be normal, but the primary abnormality is in defecation. Parkinsonian patients are unable to straighten the anorectal angle on straining, accentuating its flap valve action and resulting in an obstruction to the passage of stool. It has been suggested that this paradoxical contraction of the pelvic musculature is dystonic in nature and correlates with the progression of PD. In support of this argument, apomorphine has been shown to alleviate this defecatory problem in some patients with PD. Other disorders associated with constipation in patients with PD include megacolon and sigmoid volvulus. Management. Dietary modification aimed at increasing bulk and softening the stool should be the first strategy for constipation, and ultimately the most efficacious, in patients with PD. They must be encouraged to drink at least eight glasses of water each day. Low-fiber foods, such as many breads and cakes need to be reduced, and bananas must be eliminated from the diet. At least two meals per day should include high-fiber raw vegetables. Carrots, cauliflower, and broccoli are good choices. Oat bran as a hot cereal (Quaker Oats bran) adds significant fiber to the diet, especially when one-fourth to one-third cup is used in the morning. As a morning meal, it reduces the amount of protein, adds bulk, and helps stimulate the gastrocolic reflex. Increasing physical activity is also helpful. Although vigorous exercise is not necessary, just doing a few pushups, situps, or isometric exercises is not enough. Patients must be encouraged to walk as much as several miles a day, if possible, or swim regularly. If stools remain hard despite the measures outlined above, stool softeners such as docusate, given with each meal can be useful. Lactulose, 10 to 20 g per day, may benefit some patients. Patients are warned that the results with any method of softening stool will not be immediate and that persistence with dietary and pharmacologic measures is necessary. Since anticholinergic agents decrease bowel motility, stopping such drugs can be useful for alleviating constipation, but this is often at the price of increased parkinsonism. The next step is a trial of cisapride (a cholinomimetic agent) which increases intestinal motility. Even at the usual dosage of 5 mg bid, it is important to watch for occasional worsening of Parkinson's signs and symptoms. Mild laxatives such as milk of magnesia or enemas should be a last resort and used sparingly - perhaps no more than once a week as part of an overall bowel regimen - but in some patients enemas may be necessary. Apomorphine injection may provide enough benefit to permit successful defecation. 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. 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. 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. 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. Management. 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 instabilityvisualmotor dysfunction, or multiple sensory deficits. 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. 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. 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, which terminate on receptors in the dorsal horn and intermediolateral column. Sensory symptoms often appear neuritic in character, including paresthesias, burning dysesthsisa, coldness or numbness, and deep aching. The legs are more often involved than the arms; face and neck are rarely involved. Akathisia sometimes is present. Pain is often, but not always, worse on the side of worse parkinsonism. Management. Pain related to parkinsonism often responds to adjustment of antiparkinsonian medications. Most often, it is linked to levodopa "off" states or insufficient levodopa dosage; thus, optimizing medications (as described later) can be gratifying. Other causes for radicular pain and neuropathy need to be evaluated when appropriate. Pain related to arthritis is not uncommon in elderly patients with PD. DYSPHAGIA Significant dysphagia in patients with PD is usually; But not always, related to the severity of disease and occurs in up to 40% of patients. direct involvement of oropharangeal muscles is suggested by the observance that many patients suffer severe dysphagia only when "off," a situation that improves dramatically as soon as a dose of levodopa becomes effective. Swallowing abnormalities include abnormal lingual control and inability to pass a bolus of food backward into the pharynx. Silent aspiration with repetitive reflux of food from the vallecula and pyriform sinuses into the oral cavity are a significant problem. Retention of food and pills in the vallecula are another contributory cause of erratic levodopa absorption, and therefore, a secondary cause of dysphagia. Esophageal dysmotility occurs in as many as 70% of patients but also is present in a significant number of controls. Management. Soft diets help most types of dysphagia by making It easier to move food in the mouth and esophagus. Soft food also decreases aspiration by reducing the need for separate liquid intake, since liquids often cause more aspiration than solids. Since dysphagia is usually decreased dramatically during "on" times, the best strategy is to increase "on" time with additional dopaminergic medications, if possible. Increased "off" time, however; is not a realistic goal for many patients. All patients should eat only during an "on" period. Feeding gastrostomies or jejunostomies are a last resort and are rarely necessary in patients with idiopathic PD; but when needed, these procedures provide the benefit of allowing more normal intake of food and medication. janet [log in to unmask]