Practical Guidelines for Management of Parkinson Disease

J Am Board Fam Pract: first published as 10.3122/jabfm.10.6.412 on 1 November 1997. Downloaded from

CLINICAL REVIEW Practical Guidelines for Management of Parkinson Disease

Bala V Manyam, MD

Background: This article describes a specialist's perspective on the challenge of caring for patients with Parkinson disease in a changing American health care environment that places increasing responsibility on primary care physicians. Methods: Guidelines were developed by drawing from a combination of personal experience at a large university Parkinson disease clinic, literature review, presentations at various family practice continuing medical education conferences, and involvement as investigator in various clinical trials of drugs used in Parkinson disease treatment. Results and Conclusions: From a therapeutic standpoint, Parkinson disease can be divided into three stages-early, nonfluctuating, and fluctuating. Although the same drugs, namely, carbidopa-Ievodopa preparations, dopamine agonists, and anticholinergic medications, are usually prescribed, their pattern of use, including frequency and dosing, varies depending on the nature of the dominant symptoms and stage of the disease. Management of Parkinson disease requires familiarity with both the disease related and drug-related components. Optimal functional efficiency for the patient is gained through striking a delicate balance between the drug regimen and the disease-related components. (J Am Board Fam Pract 1997;10:412-24.)

Parkinson disease remains the most treatable of be a growing number of patients with Parkinson all neurodegenerative diseases. According to a disease. With the increasing emphasis on man 1990 survey, 56 percent of all patients with agement of chronic diseases by primary care Parkinson disease are cared for by primary care physicians, it is important that they understand physicians. Because people are living longer, the therapeutic treatment of Parkinson disease. there is a concomitant increase in the number of Parkinson disease (paralysis agitans) is a disease http://www.jabfm.org/ persons at risk for developing Parkinson disease. of unknown cause characterized by rest tremor, For example, one study found the prevalence of muscular rigidity, bradykinesia, and gait distur Parkinson disease to be 0.3 percent in those aged bance; it is associated with loss of pigmented neu 55 to 64 years, 1.0 percent in those aged 65 to 74 rons in the substantia nigra and the presence of years, 3.1 percent in those aged 75 to 84 years, eosinophilic inclusion bodies in the cytoplasm and 4.3 percent in those aged 85 to 94 years.! Be called Lewy bodies. Parkinsonism is a syndrome fore levodopa was available, the death rate for characterized by the above signs and symptoms, on 30 September 2021 by guest. Protected copyright. persons with Parkinson disease was three times with or without loss of pigmented neurons in the the death rate of the general population. After the substantia nigra, and without Lewy bodies. introduction of levodopa therapy, a distinct in Parkinsonism is associated with the conditions crease in longevity has been observed in patients listed in Tables 1 through 3. Although idiopathic aftlicted with Parkinson disease.2 This increase is Parkinson disease is the most common form, even more striking in patients whose treatment about 15 percent of patients with an initial diag was started early.3 The net result will continue to nosis of idiopathic Parkinson disease are found to have one of the other forms after a few years.4 Submitted, revised, 26 March 1eN7. Classification of Parkinson disease has been From the Parkinson's Disease and lvlovement Disorders based on pathologic changes in the brain, symp Clinic, Department of Neurology, Southern Illinois University toms and clinical signs, or degree of disability. I School of Medicine, Springfield. Address reprint requests to Bala V. Many

412 JABFP Nov.-Dec. 1997 Vol.10No.6 J Am Board Fam Pract: first published as 10.3122/jabfm.10.6.412 on 1 November 1997. Downloaded from symptoms and clinical signs. Such grouping will Table 1. Differential Diagnosis of Parkinsonism. help determine therapeutic responses to various Idiopathic Parkinson disease (paralysis agitans, antiparkinsonian drugs regardless of the underly shaking palsy) ing pathological abnormality. When no specific Postencephalitic Lethargic encephalitis reference is made, treatment will focus on the (Von Economo disease) Other viral encephalitides major symptoms of the disease, namely, rigidity, Drug induced Neuroleptic medications tremor, gait disturbance, and bradykinesia. Pos (including metoclopramide) tural disturbance, which develops in later stages, Reserpine does not respond well to any known drug treat Toxin induced I-methyl-4-phenyl-l ,2,3 ,6-tetrahydropyridine (MPTP) ment. The exact cause of postural disturbance is Manganese not known, although certain theories have been Carbon monoxide postulated. Such rehabilitative measures as gait Carbon disulfide Cyanide training and using devices such as a cane or s Metabolic Hypothyroidism walker remain the only viable aids. Hypoparathyroidism with basal ganglia calcification Methods Degenerative Bilateral sttiopallidodentate calcinosis (F ahr disease) Guidelines were developed by drawing from a Diffuse Lewy body disease combination of personal experience at a large Genetic Wilson disease university Parkinson disease clinic, literature re view, presentations at various family practice con tinuing medical education conferences, and in ties, but progression of the disease and continued volvement as investigator in various clinical trials levodopa therapy eventually take their toll. Addi of drugs used in Parkinson disease treatment. tional symptoms, such as difficulty with balance, dyskinesia (involuntary choreoathetotic move Therapeutic Stages of Parkinson Disease ments), dystonia (involuntary abnormal pos From a therapeutic standpoint, Parkinson disease tures), myoclonus (quick movement caused by can be divided into three stages: early, nonfluctuat muscular contractions), nightmares, autonomic ing, and fluctuating. In early-stage Parkinson dis .symptoms (constipation, orthostatic hypoten- ease, such symptoms as tremor, changes in hand sion), depression, and dementia, begin to appear. writing, bradykinesia, and drooling begin to A patient is said to enter the fluctuating stage of appear. Sometimes these symptoms become evi Parkinson disease when motor fluctuations http://www.jabfm.org/ dent after a surgical procedure, an injury, or emo (marked inconsistencies in control of parkinsonian tional trauma. Symptoms remain mild for months signs and symptoms) occur. Motor fluctuations to years, and while they can be socially embarrass are of two types. In end-of-dose deterioration or ing to the patient, functionally little if any disability wearing-off effect, the duration of therapeutic ac is experienced. Some patients require medications tion from a given dose of levodopa preparation with mild antiparkinsonian action at this stage. lasts for decreasing periods. With time patients on 30 September 2021 by guest. Protected copyright. When the disease progresses to a point at might have to take these preparations every 90 to which mild medications can no longer control the 120 minutes. In the on-off phenomenon, patients symptoms, patients are considered to have en fluctuate suddenly from no therapeutic benefit to tered non fluctuating Parkinson disease. At this complete improvement of symptoms, often with time, adding a carbidopa-Ievodopa preparation to dyskinesia unrelated to the dosage or timing of the drug regimen almost always becomes neces levodopa preparations. The duration of the thera sary. With this medication, patients should expe peutic benefit (on) or lack thereof (oft) can last for rience an 80 percent improvement in symptom unpredictable periods and cause severe disability. control. It is important that physicians resist the Not every patient develops on-off phenomenon. temptation to improve functioning by 100 per Some have several years without any major com cent, because the therapeutic and toxic ranges of plications, or they experience only mild degrees of levodopa are very close. Patients usually continue delayed adverse effects. There are no known pre to function well for several years, are often gain disposing factors to predict who might develop fully employed, and carry out normal daily activi- complications. During this stage freezing (tempo-

Management of Parkinson Disease 413 J Am Board Fam Pract: first published as 10.3122/jabfm.10.6.412 on 1 November 1997. Downloaded from

Table 2. Diseases With Parkinsonism Characteristics. be managed by the family physician, whereas the Progressive supranuclear palsy fluctuating stage is best handled by a neurologist Multiple system atrophy who has special training in movement disorders. Striatonigral degeneration Patients who have any atypical symptoms of the Shy-Drager syndrome disease (Tables 1 to 3) and patients who do not re OlivoJlontocerebellar atrophy Parkinson-dementia-amyotropic lateral sclerosis complex of spond to standard treatment should always be re Guam ferred to a neurologist. Since the introduction of levodopa, the growing number of new drugs for rary, involuntary inability to move when ini6a6ng treatment often causes confusion among physi gait) can also occur. cians, who might be unsure which drug or combi The transformation from nonfluctuating to nation of drugs to prescribe. Unlike treatment for fluctuating is gradual. It is estimated that the inci many diseases, treatment of Parkinson disease is dence of adverse effects attributable to levodopa tailor-made for each patient. The plan should be therapy, such as motor fluctuations, dyskinesia, to redefine the therapeutic goal at various stages and dystonia, is 50 percent after 5 years of con of the disease. This plan should be discussed with tinuous therapy.6-9 Levodopa-naive Parkinson the patient to promote realistic expectations. The disease patients who were given either immediate primary goal in all stages is to attain functional release carbidopa/levodopa (Sinemet,) or con improvement in the patient's condition by using trolled-release carbidopa/levodopa (Sinemet CR) the fewest drugs as infrequently as possible. in a double-blind trial had an incidence of motor In early-stage Parkinson disease functional im fluctuations and dyskinesia after 5 years of 20.6 provement can range from 85 to almost 100 per percent for the immediate-release group and 21.8 cent. In the nonfluctuating stage, improvement percent for the controlled-release group. JO Motor can range from 75 to 85 percent; and in the fluc fluctuations, dyskinesia, dystonia, freezing, de tuating stage, a 50 to 60 percent improvement mentia, and depression, either singly or in combi might be the highest attainable. nation, can greatly impair a person's ability to per The choice of drug therapy varies with each pa form activi6es of daily living. In addition, evening tient and is dependent upon several factors. Dur confusion followed by agitation (sundown syn ing the initial evaluation of Parkinson disease, it is drome) and visual hallucinations can occur during important to determine whether the patient is al the fluctuating stage; these effects usually do not ready taking anti parkinsonian medications, and disturb the patient initially, but with time can be whether the patient should continue with the same http://www.jabfm.org/ come unpleasant. As the disease progresses, diffi drug regimen or would benefit more by a dosage culty with balance, combined with motor fluctua change or the addition or deletion of certain drugs. tions, dyskinesia, dystonia, and freezing, can cause To make these determinations, it is important to the patient to become dependent on a wheelchair know the stage of the disease and the degree of dis or a walker for at least part of the day. ability; likewise, patient and physician expectations

should be clarified. For example, a farmer whose on 30 September 2021 by guest. Protected copyright. General Pharmacologic Management initial major signs are resting tremor and some Family physicians often recognize early-stage bradykinesia might not require therapy, because Parkinson disease. Patients complain of tremor, the resting tremor might disappear when the pa "not doing as well as before in activities of daily tient's hands are on the steering wheel of a tractor living" (bradykinesia), difficulty with balance or or are otherwise engaged in a motor activity. A cor walking, or a number of vague symptoms. Physi porate executive might find the same symptoms cians can elicit some of these symptoms and signs unacceptable and will want therapeutic interven during an annual physical examination, or they tion. What might be considered disabling in one might surface after a traumatic physical, emo profession will not be in another. tional, or surgical event. When a patient with early-stage Parkinson dis Therapeutic management of the three stages of ease is examined, it is important that the phy Parkinson disease varies, with the management of sician assess whether the patient's symptoms in the fluctuating stage being the most difficult. terfere with any function and whether the Most often, early and nonfluctuating stages can predominant symptoms are tremor or bradykine-

414 }ABFP Nov.-Dec. 1997 Vol. 10 No.6 J Am Board Fam Pract: first published as 10.3122/jabfm.10.6.412 on 1 November 1997. Downloaded from sia and rigidity. Findings from this assessment can Table 3. Diseases With Associated Parkinsonian help shape therapeutic intervention strategies and Features. determine the type of initial medications. Early System or Process Disorder or Disease stage Parkinson disease usually lasts from several months to 2 to 3 years after symptoms develop. If Degenerative Alzheimer disease Corticobasalganglionic a patient is not taking any drugs and is function degeneration ing well, no intervention is necessary, at least ini Primary pallidal atrophy tially. The patient should be told about the vari Huntington disease (hypokinetic ous modes of treatment to consider as symptoms rigid form) Hallervorden-Spatz disease worsen or new symptoms develop. It is difficult to N euroacanthocytosis predict precisely when to begin various treat Dystonia-parkinsonism ments, but most patients generally require treat Normal pressure hydrocephalus ment within 2 years of disease onset. Vascular Multi-infarct During early-stage Parkinson disease, if the Binswanger disease symptoms are not severe, mild antiparkinsonian Arteriovenous malformation drugs, such as amantadine (Symmetrel), anti Structural Basal ganglia-tumor, abscess cholinergic medications (trihexyphenidyl or Infection Creutzfeldt-Jakob disease benztropine), selegiline (Eldepryl, Carbex), Trauma "Punch-drunk syndrome" diphenhydramine (Benadryl), or the dopamine Subdural hematoma agonists bromocriptine (Parlodel) and pergolide (Permax) can provide up to 90 percent improve bioavailability of controlled-release is less than ment in symptoms. If patients are taking a car that of immediate-release carbidopa/levodopa, bidopallevodopa preparation, it is important that dose frequency should be based on the patient's dosage and frequency be adequate. When tremor wake-up time to bedtime with 8 hours inter is a predominant symptom, the first drug of vening. Controlled-release carbidopa/levodopa choice might be propranolol, especially the con should be taken twice daily, generally between 7 trolled-release formulation (Inderal LA). The and 8 AM and 3 and 4 PM, for adequate control of second choice would be anticholinergic medica symptoms. If the initial 251100.mg dose of con tions. A 70 percent reduction in tremor ampli trolled-release formulation is inadequate, it is tude was reported after administration of con better to prescribe one 501200-mg tablet instead trolled-release propranolol (160 mg/d) compared of two 2 5/100-mg tablets. http://www.jabfm.org/ with a 50 percent reduction from administration Because of the slow release of controlled-re of trihexyphenidyl (an anticholinergic), and a 25 lease carbidopa/levodopa, the interval between percent reduction from amantadine. 11,12 Selegi the time the drug is administered and the onset of line also has a mild antiparkinsonian effect. therapeutic effect (kick-in) might be unacceptable for the patient. To speed up onset of action, one

Levodopa Preparations 501200-mg controlled-release tablet may be bro on 30 September 2021 by guest. Protected copyright. Patients can do well on amantadine therapy, 100 ken in half (the unscored 251100-mg tablet can mg twice daily, for several months, but con not be broken) and both halves swallowed at the trolled-release or immediate-release carbidopa/ same time. Breaking the tablet exposes the uncov levodopa should be prescribed when symptoms ered segment of the matrix, speeding tablet ero worsen and amantadine is no longer effective. sion in the gastrointestinal tract, facilitating Controlled-release carbidopa/levodopa is be absorption, and resulting in early relief of symp lieved to provide continuous stimulation to toms. Initially a night-time dose is not required. dopaminergic neurons, resulting in a possibly re Immediate-release carbidopa/levodopa (avail duced risk of motor fluctuation onset, whereas able in 10/100 mg, 25/100 mg, and 251250 mg) immediate-release carbidopallevodopa provides a has a short half-life and should be taken three to pulsatile effect or intermittent stimulation. A four times daily, preferably before meals to en controlled-release formulation (Sinemet CR) is hance absorption. In a recent 5-year study involv available in either a carbidopallevodopa combina ing 680 patients (about one half were taking im tion of 25/100 mg or 501200 mg. Because the mediate-release and the other half were taking

Management of Parkinson Disease 415 J Am Board Fam Pract: first published as 10.3122/jabfm.10.6.412 on 1 November 1997. Downloaded from controlled-release carbidopa/levodopa), scores of ease progresses, the addition oflevodopa prepara activities of daily living were significantly better tions becomes necessary. for the controlled-release group. There was no Dopamine agonists should be prescribed in significant difference in side effects between the high doses for the few patients who cannot toler two preparations except that controlled-release ate levodopa even when combined with high carbidopa/levodopa caused more dyskinesias than doses of carbidopa. For example, hromocriptine, did the immediate-release form (16.5 percent 60 to 80 mg/d in three to four divided doses, with compared with 12.2 percent).10 the dosage increased gradually, can be effective. If the patient is already taking an immediate The efficacy ratio of pergolide to bromocriptine release preparation and the physician wants to is 10:1, which means that one 0.25-mg tablet of prescribe a controlled-release form, the following pergolide equals one 2.5-mg tablet ofbromocrip formula for conversion is recommended. \3 The tine. Pergolide can have a t~lster onset and longer result gives the total number of tablets to be taken duration of action than bromocriptine. The ad in 24 hours. verse effects of pergolide and bromocriptine are almost identical, and patients should be moni Multiply the milligrams oflevodopa ill i1ll1l1ediate tored for peptic ulcer disease and livido reticularis release tablet times 1.3 divided by the 1Ililll/r,1'fImS of (a discoloration of the skin). Care should be exer levodopa in controlled-releasc tablet to get the 11 umber of tablets of controlled-release cal'bidopa/levodopa (clos cised when prescribing dopamine agonists for pa est to the next higher strmgth), ie, tients with known coronary artery disease. xx lllg IR x 1. 3/;'Cx mg CR = x tablets pCI' 24 h Early therapy combining bromocriptine with levodopa did not prevent motor fluctuations, and In an adult the minimum amount of carbidopa the overall adverse effects were the same for the required to prevent breakdown oflevodopa out group taking levodopa alone as for the group tak side the blood-brain barrier, so that the given ing a levodopa/bromocriptine combination. is dose of levodopa is utilized at the site of action in There have been several studies comparing lev the brain, is 75 mg, although a smaller dose can odopa/dopamine agonist combination therapy be effective. A few patients, most often women, with dopamine agonist monotherapy to evaluate develop dyskinesia even on low-dose levodopa whether motor fluctuations and dyskinesia can be preparations. If these patients are switched to a delayed or reduced. i6-2-i Whether early use of dopamine agonist and the dyskinesias disappear, dopamine agonists in combination with levodopa they might be sensitive to levodopa. Some physi will prevent or delay onset of motor fluctuations http://www.jabfm.org/ cians prescribe dopamine agonists, amantadine, and dyskinesia remains controversial, however. or selegiline in the belief that withholding lev The differences in the results of some studies are odopa preparations for as long as possible will de likely due to the study methods and the problems lay levodopa-related adverse effects, but there is relating to open-label trials and the use of histori no evidence to support this notion. cally matched treatment control groups.2S on 30 September 2021 by guest. Protected copyright. Dopamine Agonists Se/egiline Dopamine agonists are second to carbidopa/lev Whether to use selegiline is a question that baffles odopa preparations as the most effective drugs fiJr physicians and patients. Failure to induce parkin controlling all major symptoms associated with sonism in experimental animals exposed to MPTP parkinsonism. These drugs, however, are not as (l-methyl-4-phenyl-l ,2,3 ,6-tetrahydropyridine) effective for the non fluctuating and fluctuating after pretreatment with selegiline (a monoamine stages. In one study, adding bromocriptine or oxidase type B inhibitor) led researchers to speCll pergolide to the drug regimens of patients for late that selegiline might have a neuroprotective whom levodopa was previously prescribed re effect. 26 In several studies selegiline was evaluated sulted in substantially improved evaluation in patients with Parkinson disease, but whether the scoro~, but no difference in occurrence of dyski dmg provided any neuroprotective effect could not nesia, dystonia, or psychosis. 14 Dopamine ago be firmly concluded,27-lO The mild symptomatic nists alop.e can be adequate to control symptoms antiparkinsonian action of selegiline delays the in early-istage Parkinson disease, but as the dis- need for levodopa treatment, but this delay does

416 JABFP Nov.-Dec.1997 Vol. 10 Nfl 6 J Am Board Fam Pract: first published as 10.3122/jabfm.10.6.412 on 1 November 1997. Downloaded from not mean it has a neuroprotective effect. The should be monitored, as ~-blockers adversely degree of anti parkinsonian effect produced by se affect heart rate. The usual contraindications for legiline is not cost effective when compared with using ~-blockers, such as bronchial asthma, levodopa preparations, dopamine agonists, or bradycardia, and congestive cardiac failure, amantadine. All that could be concluded from a should be kept in mind. large study comparing selegiline (earlier generic If the patient cannot tolerate propranolol, then name was deprenyl) with placebo in patients with anticholinergic drugs would be the next choice. newly diagnosed Parkinson disease29 was that se Although dementia is much less likely when legiline might delay the need for a more powerful tremor is predominant, if the patient has demen antiparkinsonian drug, such as levodopa. Amanta tia, anticholinergic drugs should be avoided, be dine could also delay the need for treatment with cause they can precipitate confusion. Anticholin levodopa. ergic drugs can also precipitate urinary retention The decision to prescribe selegiline rather than in subclinical benign prostatic hypertrophy. Dry amantadine for early stage Parkinson disease be mouth and throat secondary to anticholinergic fore the patient requires levodopa preparations is drug therapy usually improve after a few days. based on the severity of symptoms, what the treat Anxiety can be associated with and provoke ing physician and the patient expect from selegi tremor. Diphenhydramine, which produces both line therapy, and an understanding of cost effec a sedative and anticholinergic effect, would be the tiveness. When selegiline is discontinued, a few drug of choice for those patients who experience patients might experience deterioration in mood, anxiety in addition to tremor. Diphenhydramine level of energy, or performance. Although these would also be the hypnotic of choice for patients responses are considered a placebo effect, there whose tremor causes difficulty falling asleep. A could be a pharmacologic explanation, as selegi starting dosage regimen of 25 mg 4 times daily line is metabolized to amphetamine products. 31 can be increased as necessary. Elderly patients should be monitored for confusion. In a few pa Management of Symptoms tients, diphenhydramine might not control exag Tremor gerated tremor resulting from anxiety. In such For some patients with Parkinson disease tremor cases a combination of anticholinergic drugs or is the major symptom, and rigidity and bradyki propranolol and a tranquilizer, such as diazepam nesia are minimal or absent. Tremor can be inca (Valium) or alprazolam (Xanax), can be effective. pacitating. In early-stage Parkinson disease, if Patients who are taking propranolol should be http://www.jabfm.org/ tremor is the major symptom and there is a con observed for signs of depression. If tremor is not siderable postural component, distinguishing controlled adequately with the above-mentioned Parkinson disease from essential tremor can be drugs prescribed at the maximum tolerated difficult and require the assistance of a specialist. dosages, then the patient is unlikely to benefit Treatment of tremor is often challenging. Car from pharmacologic therapy. The only choice

bidopa/levodopa preparations do not reduce available to control tremor would be a surgical on 30 September 2021 by guest. Protected copyright. tremor but must be prescribed if there is associ procedure such as thalamotomy. ated mild rigidity. Propranolol, a centrally acting adrenergic ~-blocking agent, is considered more Rigid Form ofParkinson Disease effective for controlling tremor than are anti Some patients with Parkinson disease complain cholinergic drugS. 11 ,12 Controlled-release pro of bradykinesia and rigidity as the predominant pranolol confers sustained benefit as a single daily symptoms and have minimal or no tremor. Al dose and, when taken in the morning, can provide though many of these patients will have idio uninterrupted benefit throughout the wakeful pe pathic Parkinson disease, which is diagnosed at riod. Tremor is not manifest during sleep. The autopsy, some will have one of the other forms of recommended initial dose for controlled-release parkinsonism listed in Table 1. In many patients propranolol is 60 mg in the morning; depending the initial clinical symptoms and signs suggest id on the response, the dosage may be increased to iopathic Parkinson disease, but additional symp 80, 120, or 160 mg daily. Ideally, this dose should toms and signs that appear with time often lead to be taken as a single tablet. The patient~ heart rate a more precise diagnosis. Older age at onset and

Management of Parkinson Disease 417 J Am Board Fam Pract: first published as 10.3122/jabfm.10.6.412 on 1 November 1997. Downloaded from

bradykinesia, rigidity, and postural instability can several years. A reduction in the dosage often re be associated with considerably more intellectual sults in disappearance of dyskinesia without loss and motor impairment and greater progression of of therapeutic benefit. Dyskinesia can occur dur the disease than is found in tremor-predominant, ing the on phase of on-off phenomenon. It can younger-onset patients. 12 Regarding treatment, also occur briefly at the onset of therapeutic effect carbidopa/levodopa preparations are the first and before the next dose is due (dyskinesi;l drugs of choice for controlling rigidity; dopamine improvement-dyskinesia), or at the peak effect of agonists and amantadine are second. Anticholin levodopa action, about 2 hours after dosing ergic drugs do not help alleviate rigidity. (improvement-dyskinesia-improvement). When patients complain of dyskinesia, they are Asymmetric and Hemiparkinsonism often taking a high-dose carbidopa/levodopa A few patients will manifest asymmetric parkin preparation or a combination of carbidopa/lev sonism, meaning that one side of the body shows odopa and dopamine agonists. The first step is to a more severe degree of involvement than the discontinue the dopamine agonists. If dyskinesia other. Although it is advantageous to the patient does not abate, then the dos'lge of carbidopa/lev to have fewer signs and symptoms on one side, odopa should be reduced. If dyskinesia does not treatment is a challenge. A given dose of a drug disappear or is not minimized without reducing such as carbidopa/levodopa might inadequately therapeutic benefit, and if the patient is taking a control the symptoms on one side while over sustained-release carbidopa/levodopa prepara loading the less affected side, resulting in dyski tion, which increases the incidence of dyskinesia nesia. Achieving optimal control by titrating the compared with an immediate-release prepara dose can be difficult. In hemiparkinsonism the tion, then treatment may be switched to the im symptoms persist on one side for several years, if mediate-release form. When all efforts fail, and not permanently, and tremor might be the major reducing the carbidopa/levodopa dosage results visible symptom. Otherwise, the management of in inadequate control of symptoms, a dosage asymmetric and hemiparkinsonism is identical to compromise must be worked out to maintain ade that of bilateral Parkinson disease. quate functional improvement despite some de gree of dyskinesia. Adding anticholinergic drugs Care ofPatients Intolerant to Levodopa has been advocated, but they are not always effec Some patients cannot tolerate levodopa. Severe tive. Patients often prefer to have control of http://www.jabfm.org/ nausea (and vomiting) occurs despite their taking parkinsonian symptoms with dyskinesia rather the usual combination of carbidopa and levodopa. than a dyskinesia-free state with parkinsonian Adding carbidopa, which is available as 25-mg symptoms on subtherapeutic dosages of carbi tablets, 1 hour before taking the carbidopa/lev dopa/levodopa preparations. odopa preparation can alleviate this problem. Certain other patients will develop chorea, even Motor Fluctuations with very small doses of levodopa preparation. In patients taking immediate-release carbidopal on 30 September 2021 by guest. Protected copyright. Symptom control in this group can be managed levodopa who have wearing-off effect, the imme with dopamine agonists, though a very few pa diate-release preparation may be replaced with a tients will be intolerant to both dopamine ago sustained-release preparation every 3 or 4 hours. nists and levodopa treatment. In any case, sustained-release preparations should not be taken more often than every 2 hours be Management of Treatment-related Complications cause of the extended duration of action. This Dyskinesia approach is generally effective in most patients Dyskinesia occurs with two different conditions. for a few years. With time, if this approach does For a small group of patients, especially women, not work, sustained-release carbidopa/levodopa even the smallest dose of levodopa causes dyski should be replaced with immediate-release car nesia. In this case, the dyskinesia is an enhanced bidopa/levodopa (10/100 mg), every 2 or 3 hours dopaminergic reaction, and the exact cause is not (1.5 hours for some patients) during the wakeful clear. For most patients dyskinesia develops after hours. If necessary, one or two doses can be taken taking the same dosage of carbidopa/levodopa for during sleeping hours for optimal control.

418 JABFP Nov.-Dec. 1997 Vol. 10 No.6 J Am Board Fam Pract: first published as 10.3122/jabfm.10.6.412 on 1 November 1997. Downloaded from

In patients with on-off phenomenon, manage Freezing ment is more difficult, and treatment achieving Freezing is believed to be secondary to the dis complete control is not available. The treatment ease itself, not the result of drug therapy. Gener goal is to increase "on" time (there is almost al ally, freezing is unresponsive to any known phar ways dyskinesia) and reduce "off' time. Most pa macologic agents. Patients must be trained to lift tients seem to benefit more from sustained-re one foot at a time in a marching fashion and then lease carbidopallevodopa, and some patients take propel themselves forward to overcome this dis the drug as often as every 1 to 3 hours. Adding ability. Sometimes marching to loud music is dopamine agonists, selegiline, or other drugs has beneficial. Some patients initially take a few steps not proved beneficial. backward then walk forward, but this approach is A new class of drugs is undergoing investiga unwise if they are unable to turn to see where tion as an alternative approach to manage wear they are going, before walking even a few steps ing-off phenomenon and to alleviate frequent backward. dosing. Levodopa and dopamine are catabolized by catechol O-methyltransferase (COMT), and Surgical Treatment drugs that potentially inhibit this enzyme would An autologous adrenal medullary transplant to lengthen the plasma half-life of levodopa. Two corpus striatum has been performed in more than such drugs, entacapone and tolcapone, are cur 200 patients worldwide. Although some improve rently undergoing clinical studies and might be ment in parkinsonian symptoms has been re available in the near future. 33,34 ported, no posttransplant reduction in the need There is interest in whether a protein redistri for antiparkinsonian medications occurred.35 bution diet is of any benefit for symptom man Substantial postoperative morbidity and mortal agement. A low-protein regimen during the day, ity have been reported with no definite evidence with the evening meal providing the recom of survival of graft tissue. 36 This procedure has mended daily allowance of protein, could be an been almost abandoned. important step in controlling motor fluctuations. A fetal dopamine neuron transplant, using ven Many patients past middle age find it difficult to tral mesencephalic tissue from aborted human fe change dietary habits, however, and often comply tuses stereotaxically implanted to the putamen, with such a meal plan for only a short time. De has resulted in improvement in parkinsonian spite following a protein redistribution diet plan, symptoms. In one study reduction in frequency some patients find no improved change in their and disability caused by "off" periods peaked at 4 http://www.jabfm.org/ pattern of on-off phenomenon. to 5 months, and there was evidence of survival of the grafted tissue. 37 This procedure remains ex Dystonia perimental. It is not widely available, is compli Dystonia can occur in patients who have been cated, and requires long-term immunosuppres taking levodopa preparations a long time. Al sion therapy.

though dystonia is uncommon, when it occurs, Thalamotomy can reduce contralateral tremor on 30 September 2021 by guest. Protected copyright. patients feel acutely uncomfortable because many and, to a lesser extent, rigidity, though ipsilateral of the spasms can be painful. For a few patients tremor, bradykinesia, and postural instability are the foot draws inward. Often these spasms occur not improved. The procedure is helpful in early in the morning, when the level of dopa is tremor-predominant parkinsonism if pharma lowest or absent. This condition is referred to as cotherapy is ineffective or cannot be tolerated. early morning dystonia and disappears after lev Tremor can return after a few years. Thalamic odopa is taken. A nighttime dose of controlled electrical stimulation is being investigated as an release carbidopallevodopa will usually avert the alternative approach.38 problems well. Bilateral posteroventral pallidotomy, a relatively Sometimes generalized dystonia occurs even less complicated procedure compared with fetal when the patient has an adequate amount of drug tissue transplant, involves creating a lesion be or when the drug is at peak levels. Treatment with tween the medial and lateral segments of the glo baclofen or anticholinergic medications might al bus pallidus. Improvements in rigidity, tremor, lev leviate this problem. odopa-related motor fluctuations, dyskinesia, and

Management of Parkinson Disease 419 J Am Board Fam Pract: first published as 10.3122/jabfm.10.6.412 on 1 November 1997. Downloaded from dystonia result. The complication rate is low, but til'ine), and pemoline (Cylert), h,lVe been tried the procedure is available in only a few centers, and with mixed success. A few patients have benefited a long-term benefit has not been established. from selegiline taken during the daytime. Day time sleepiness is not easy for a physician to rem Management of Secondary Effects edy. It is important to talk to a family member to of Parkinsonism ascertain the cause. Some patients require help Anxiety developing hobbies, or they can be encouraged to Many patients suffer from anxiety associated with spend the daytime in a senior center to keep oc Parlcinson disease. Bradykinesia causes patients to cupied. Activity keeps patients awake, but sleep is fall behind normal companions in such activities safer than a stimulant elmg. as walking, talking, or dining, provoking anxiety in addition to that associated with having an in Dementia curable illness. Anxiety can manifest as increased Dementia occurs with idiopathic Parlcinson dis tremor, gait disturbance, fear of falling, drooling, ease, but it occurs more often and progresses more difficulty with speech, dysphagia, and insomnia, rapidly in those who have additional neurologic as well as a host of other symptoms that might not disorders, such as extensor plantar response, or adequately respond to the usual antiparlcinsonian who have cerebellar signs such as those found in drugs unless treatment is supplemented with an olivopontocerebellar atrophy or paralysis of down antianxiety agent. When patients develop on-off gaze. Profound dementia will occur with progres phenomenon and freezing, the superimposed sive supranuclear palsy. In one study the age anxiety can make these symptoms even worse. specific prevalence of dementia for patients older Anxiety, if mild, responds to diphenhydramine, than 70 years was more than twice that of younger but moderate to severe anxiety requires treatment patients. 41 The Folstein Mini Mental State Exami with tranquilizers and counseling the patient nation42 or Blessed Short Form43 evaluation can be about the relation of parlcinsonian symptoms to administered to assess degree of dementia. Pseu anxiety. dodementia can be caused by depression, and pa tients show dramatic improvement when suitable Constipation antidepressants are prescribed. Causes of treatable Constipation is a common autonomic manifesta dementias should be evaluated and treated before tion of Parkinson disease. Studies have shown a concluding that the dementia is due to Parlcinson http://www.jabfm.org/ paradoxical anal sphincter muscle contractionl9 disease. Rarely does Parkinson disease coexist with with impaired squeeze response, secondary to in Alzheimer's disease. volvement of the pelvic floor musculature by When dementia occurs, the therapeutic goal of Parkinson disease process.40 Treatment should improving motor control should be reduced. A include mild stimulant laxatives, such as senna al few patients with dementia have sundown syn kaloid taken in dosages of 1 to 4 tablets at night drome in which they become agitated and have on a regular basis. Bulk laxatives do not help, but hallucinations with the onset of evening. If the on 30 September 2021 by guest. Protected copyright. of course patients should maintain adequate liq agitation is frequent, clozapine (Clozaril), in uid and fiber intake. doses of 2 5 to 75 mg, will control these symptoms satisfactorily, but bone marrow function should Daytime !;'leepiness be monitored for adverse effects through weekly Parkinson disease results in lack of motivation. blood tests. If the agitation is occasional, such Because most patients are disabled to some ex drugs as thioridazine (Mellaril) could be used. If tent, they tend to sit in a chair or watch television patients are unable to take oral thioridazine, in and fall asleep, especially after a meal, often to the tramuscular haloperidol (Haldol) might help. annoyance of the spouse. Contributing to this Frequent administration of haloperidol should be tendency could be disturbed sleep at night as a re avoided because of the risk of an added drug sult of depression or frequent micturition. Lev induced parkinsonism. Centrally acting anti odopa taken late in the evening can also cause cholinergic medications (including amantadine sleep disturbance. Stimulants, such as methyl and diphenhydramine) should also be avoided, as phenidate (Ritalin), dextroamphetamine (Dexe- they can precipitate confusion. Levodopa prepa-

420 }ABFP Nov.-Dec. 1997 Vol. 10 No.6 J Am Board Fam Pract: first published as 10.3122/jabfm.10.6.412 on 1 November 1997. Downloaded from

rations should be avoided between 6 PM and 3 AM. cannot prevent venous pooling in the lower ex Complications of dementia, such as agitation and tremities when the patient stands up. hallucinations, can be controlled and are dis cussed separately. Drooling Drooling is due to early impairment of the swal Depression lowing mechanism. Saliva, instead of draining Depression is common in Parkinson disease, oc posteriorly, drools anteriorly. No drug, including curring in more than 47 percent of patients.44 It the anticholinergic medications, seems to be ef appears to be part of the disease itself rather than fective in controlling this symptom. Frequently a reactive manifestation. Depression can take the wiping saliva with dry tissues can result in angular form of worrying, brooding, loss of interest, sui stomatitis. During the night it is best to place a cidal tendencies, social withdrawal, loss of libido, thick cotton Turkish hand towel over the pillow or insomnia. Psychomotor retardation can often so it can be changed every morning; occasionally be masked by underlying bradykinesia. Mild de the patient will require a bib. pression does not require any treatment except for patient education, but moderate depression Dysphagia requires pharmacotherapy. An ideal drug for Dysphagia is common in the later stages of Parkinson disease-related depression is amitripty Parkinson disease, and adequate anti parkinsonian line because of its anticholinergic effect. Taken at drug therapy must be ensured. Dysphagia re night, amitriptyline helps with sleep. Most cases quires treatment because patients generally tend of Parkinson disease-associated depression can be to give up solid food and adopt semisolid and liq managed in a primary care practice; however, uid diets. Patients with advanced disease will re some patients who develop severe depression that quire a feeding tube. does not respond to antidepressants will require electroconvulsive therapy. Electroconvulsive Hallucinations therapy, in addition to improving depression, When Parkinson disease is associated with de might require a reduction in the dosage of an mentia, visual hallucinations, which are often be tiparkinsonian drugs; hence, close monitoring is nign, are common and usually do not require any necessary. specific treatment. If the hallucinations occur during the latter part of the day, the last dose of http://www.jabfm.org/ Dizziness levodopa preparation should be given no later Patients with Parkinson disease often report a than 4 PM. Controlled-release carbidopa/lev history of vague dizziness. With questioning, odopa should not be prescribed for these patients however, this dizziness often turns out to be un because of its long half-life. Even with preventive steadiness of gait. A few patients have orthostatic measures, some patients will develop consider hypotension, which causes light-headedness able agitation associated with hallucinations. In when standing quickly from a lying or sitting po this case, the hallucinations can be effectively on 30 September 2021 by guest. Protected copyright. sition. Blood pressure measurements while treated with clozapine. supine and then erect are diagnostic. Having pa tients rise slowly and sit for a minute before Sleep DIsturbance standing up will manage the condition if the Sleep disturbance is common in Parkinson dis symptoms are mild. Some patients require salt ease. In a study of 220 patients, 215 reported dif retaining drugs, such as fludrocortisone. If, how ficulties at night or upon waking. The most com ever, the patient has concomitant congestive mon problem was an inability to turn over or get heart failure or hypertension, for example, and up to use the bathroom during the night. Two cannot take these drugs, mechanical devices to thirds of patients considered their quality of sleep promote better venous return, eg, Jobst stock to be acceptable, however.45 Causes of sleep dis ings, can help. Many patients resent these stock turbance are many and include the disease itself. ings, because they are difficult to impossible to When the patients go to bed, even searching for a put on or take off unassisted. Indomethacin and comfortable sleeping position can interfere with other milder drugs are not effective, and Ted hose falling asleep. For patients who have trouble

Management of Parkinson Disease 421 J Am Board Fam Pract: first published as 10.3122/jabfm.10.6.412 on 1 November 1997. Downloaded from : : I I EARLY STAGE I NON-FLUCTUATING STAGE I FLUCTUATING STAGE I I

I I I 1fi1il1iil1!!tirniiHJ¥I·MM•• l.lrh,ljii,n"I g.ltfiljl§iiHJ¥I·M-.I,I,@~ I Amantadine (anti PO) I I Dopamine agonists ....-.nm,i!!t@IDi"DlluIm1iE· lma!D,uIMGAILAM~. ·!lmijlll"!!ll.lrll·'DliU~lml!'ImI!D'],l!iFDI•• I I I Selegiline I I I I Propranolol (anti-tremor)

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Figure 1. Drugs for Parkinson disease at various stages of disease. PD - Parkinson disease, COMT - catechol O-methyltransferase. turning around in bed, satin sheets can be helpful will benefit from a mild hypnotic, preferably pre because they are slippery. scribed for periodic use. Severe tremor, which can prevent sleep, is best treated with diphenhydramine; its anticholinergic Speech Disturbance effect suppresses tremor and its sedative effect in Vocal loudness, articulation, rate of speech, and duces sleep. Because levodopa is a stimulant, it content are affected in Parkinson disease as the could stimulate the bladder, which would require disease progresses. Hypophonia develops as a re http://www.jabfm.org/ getting up several times during the night. Pa sult of abduction of the vocal cords. Moderate hy tients on levodopa therapy are also more suscep pophonia might require a speech amplifier, tible to myoclonus, in which case methysergide whereas severe hypophonia will require treat will be effective. Nightmares are not uncommon, ment with an injection of collagen into the vocal as levodopa and dopamine agonists are known to cards. induce vivid dreams. Depression can disturb sleep ill varIOUS ways. Conclusions on 30 September 2021 by guest. Protected copyright. Treating sleep disturbance depends on its Parkinson disease is a neurodegenerative disor cause. Adhering to a daytime exercise program der. As it progresses, additional signs and symp can be beneficial, as physical exertion induces toms occur because of the disease itself and as a sleep. If parkinsonian symptoms cause sleep dis complication oElong-term treatment. All avail turbance, a dose of controlled-release carbidopa/ able treatments are symptomatic. Several factors levodopa (diphenhydramine, if tremor is the ma influence drug selection and dosing. The main jor symptom) before going to bed might help. On goal is always to maintain activities of daily living the other hand, if levodopa causes sleep distur for as long as possible. Family physicians and bance through its stimulant effect, the last dose of neurologists caring for patients with Parkinson controlled-release carbidopa/levodopa should disease should be aware of the patients' occupa not be taken after 4 PM, and the last dose of a tions and expectations and should educate pa standard carbidopa/levodopa preparation should tients and their families on the merits and limita not be taken later than 7 PM. A very few patients tions of available drugs. Dosing of levodopa

422 ] ABFP Nov.-Dec. 1997 Vol. 10 No.6 J Am Board Fam Pract: first published as 10.3122/jabfm.10.6.412 on 1 November 1997. Downloaded from preparations and anticholinergic drugs should be 3. Diamond SG, Markham CH, Hoehn MM, Mc timed to the patients' routine of waking and Dowell FH, Muenter MD. Multi-center study of sleeping. Selegiline should not be administered Parkinson mortality with early versus later dopa later than 8 hours before bedtime because it can treatment. Ann NeuroI1987;22:8-12. 4. Rajput AA, Rozdilsky B, Rajput A. Accuracy of clini interfere with onset of sleep. All other antiparkin cal diagnosis in parkinsonism-a prospective study. sonian drugs can be administered at standard CanJ Neurol Sci 1991;18:275-8. times. The timing for various drugs that are im 5. Manyam BV. Rehabilitation of Parkinsonism, other portant at the three different stages of the disease movement disorders, and ataxia. In: Good DC, is schematically displayed in Figure 1. Couch JR, editors. Handbook of neurorehabilita tion. New York: Marcel Dekker, 1994:585-617. Although the overall management of Parkinson 6. Sweet RD, McDowell FH. Plasma dopa concentra disease can appear to be complex, the family tions and the 'on-off effect after chronic treatment physician will be involved in all stages of the dis of Parkinson's disease. Neurology 1974;24:953-6. ease, so a basic knowledge of treatment and its 7. Shoulson I, Glaubiger GA, Chase TN. On-off re limitations is important. There are times when sponse. Clinical and biochemical correlations during referral to a neurologist specializing in Parkinson oral and intravenous levodopa administration in parkinsonian patients. Neurology 1975;25: 1144-8. disease becomes necessary. If the family physician 8. Marsden CD, Parkes JD. "On-off' effects in pa or neurologist cannot successfully manage such tients with Parkinson's disease on chronic levodopa symptoms as depression, dysphagia, and hypo therapy. Lancet 1976;1:292-6. phonia that occur during the course of the dis 9. NuttJG. Levodopa-induced dyskinesia: review, ob ease, referral to other specialists will be necessary. servations, and speculations. Neurology 1990;40: 340-5. For example, depression can be so severe that a 10. Block G, Liss C, Reines S, Irr J, Nibbelink D. The patient will require referral to a psychiatrist for CR first study group: comparison of immediate-re possible electroconvulsive therapy, or a patient lease and controlled release carbidopa/levodopa in with dysphagia that occurs in the late stage of the Parkinson's disease: a multicenter 5-year study. Eur J disease might require referral to a gastroenterolo NeuroI1997;37:23-7. gist to exclude local causes or to place a feeding 11. Koller WC, Herbster G. Adjuvant therapy of park insonian tremor. Arch N eurol 1997 ;44:921. tube. Similarly, the patient might be referred to a 12. Koller We. 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