TOC | Neurology
Parkinson's disease SX | DX | RX
Parkinson's disease is characterized by
Slowness of voluntary movements is noted, particularly in the initiation of such movements as walking, rolling over in bed, and fine finger dexterity leading to micrographia. Patients have decreased facial expression, monotonous low volume speech, and decreased blinking. Posture is stooped, and gait is shuffling, with poor arm swing and reduced postural balance often associated with festination. The abnormal tone is referred to as lead-pipe and cogwheel rigidity. Most characteristic, and often present early in the course of the disease, is an asymmetric, coarse (3-7 cps) "resting" tremor characterized as pill-rolling.
The presence of oculogyric crises is associated with postencephalitic Parkinson's disease and antipsychotic drug ingestion.
The diagnosis of PD may be difficult in the early stages.
PD is characterized by the presence of resting tremor, rigidity, and bradykinesia, and a good response to levodopa.
It is now evident that many patients who were initially considered to have PD later evolved into a clinical picture more typical of multiple system atrophy (MSA) or progressive supranuclear palsy (PSP).
Other causes of parkinsonism, such as head trauma, drug ingestion, carbon monoxide, cyanide, and manganese poisoning, are usually obvious; normal-pressure hydrocephalus and Jakob-Creutzfeldt disease may not be.
Secondary parkinsonism, e.g., resulting from toxic, tumors, infarcts, hydrocephalus, post-trauma, post-encephalitic Parkinsonism, or AIDS, also should be considered in the differential diagnosis but is relatively easy to differentiate from PD on the basis of other clinical criteria.
Drug-induced parkinsonism related to neuroleptic agents should also be considered in the appropriate situation. It is particularly important to recall that metoclopramide (Reglan), which is typically used in ulcer disease, is a neuroleptic agent capable of inducing or aggravating parkinsonism.
Treatment of Parkinson's
is based on considerations of the dopaminergic-cholinergic balance.
Psychosis in Parkinson's Disease:
[Juncos JL - J Clin Psychiatry 60(Suppl 8):S42-S53, 1999 ]
In patients with advanced Parkinson's disease, there is also a high prevalence of affective comorbidity. This increase in affective symptoms and the relatively high incidence of cognitive and affective side effects of the antiparkinsonian medications contribute to the increase in psychoses observed in these older patients. The most significant risk factors for developing psychosis in Parkinson's disease are
The Use of Risperidone for Psychosis and Agitation in Demented Patients
With Parkinson's Disease
This pilot study investigated effectiveness and tolerability of risperidone for the treatment of psychosis and agitation in 9 inpatients with Parkinson's disease and dementia. Investigators found risperidone to be effective and safe, without worsening extrapyramidal symptoms or further impairing cognition. [Workman RH Jr, Orengo CA, Bakey AA, Molinari VA, Kunik ME - J Neuropsychiatry Clin Neurosci 9(4):594-7, 1997 Fall ]
Clozapine, at daily doses of 50 mg or less, is safe and significantly improves drug-induced psychosis without worsening parkinsonism. [The Parkinson Study Group - N Engl J Med 340(10):757-63, 1999 Mar 11]
The usual starting dosage is Sinemet 25-100 tid, given just after a meal to avert nausea. The dosage is increased by 1 tablet/day, every 3 or 4 days, as tolerated, over about 4 weeks. The final dosage should be kept to a minimum compatible with a useful life for the patient. This is usually less than 1 g/day of L-dopa. If more L-dopa is required, dopamine agonist drugs should be considered as additional therapy. Improvement should be obvious 2 weeks after commencing treatment. A slow-release form of Sinemet (Sinemet CR) is available but is usually not needed until symptom fluctuation becomes apparent.
Response to therapy
Approximately 80% of patients are improved significantly by L-dopa therapy, but there appears to be no way to predict which patients are responsive. Long-term studies suggest that there is a decline in benefit from L-dopa after the first 2-3 years of treatment, such that after 5 or 6 years, only 25-50% of patients have maintained their initial improvement. Long-term treatment reduces mortality, although it appears that dementia often emerges as a problem in long-term survivors. One study reported that depression existed in over 20% of patients before treatment was begun. Latent depression may become overt as a patient begins to become more mobile with L-dopa therapy, and suicidal tendencies have been reported. Tricyclic medication, but not nonspecific MAO inhibitors, may be used concurrently with L-dopa to treat depression.
Dose-related side effects
(a) Peak-dose dyskinesias.
High dosages of L-dopa preparations result in peak-dose dyskinesias, often near the end of the first year of treatment. These side effects become more severe and more generalized with time, and almost 75% of patients have them after 6 years of treatment. Peak-dose dyskinesias occur 20-90 minutes after taking medication and are clinically similar to the tardive dyskinesias seen with antipsychotic drug therapy. They are usually choreiform, although dystonic, ballistic, or myoclonic movements may occur. The abnormal movements respond to a gradual reduction in dosage over a few days, as do less troublesome side effects such as dry mouth, blurred vision, and postural hypotension. Vitamin supplementation in patients receiving L-dopa without a dopa decarboxylase inhibitor should not contain vitamin B6 because this will counteract the beneficial effect of the drug.
(b) "End-of-dose" wearing-off phenomenon
This effect may be correlated with low plasma concentrations of L-dopa. The usual approach to this problem is to administer smaller doses of L-dopa more frequently. Recent advances for "smoothing" the fluctuations in response to L-dopa have been the development of slow-release preparations.
Another approach to the problem of dose-related side effects has been the use of a low-protein 0.8 g/kg BW diet to diminish competition for absorption of phenylalamine and tyrosine, particularly at the blood-brain barrier.
(c) Biphasic dose response.
Some patients are aware of dyskinesias of brief duration that occur shortly after taking their first dose of medication in the morning, which resolves only to be followed 1-2 hours later by the onset of severe dystonic spasms, particularly in the lower extremities. These spasms can often be limited by a further dose of L-dopa. Baclofen, 5-40 mg/day, has also been used to treat this condition. These patients often progress to the "on-off" phenomenon.
(d) The most troublesome side effects are nausea and vomiting,
even when the drug is administered in minimal doses with or after meals. Mild antinauseants such as trimethobenzamide hydrochloride (Tigan), 25 mg tid; domperidone (Motilium), 10-20 mg 30 minutes before L-dopa; anticholinergics; or antihistamines may be useful in this situation.
(e) Vivid dreaming is often reduced by avoiding the last dose of L-dopa preparation at night.
(f) Anxiety, agitation, confusion, delusions, visual hallucinosis, and
usually respond quickly within a day or so to lowered dosage, although in rare cases it may take weeks to resolve completely. Euphoria, mania, and hypersexuality can also occur.
(g) Other side effects include flushing, orthostatic hypotension, and
premature ventricular contractions.
Orthostatic hypotension may be treated by elevation of the head of the bed, antigravity stockings, and 9-alpha-fludrocortisone, 0.1-0.2 mg/day. Hypertension can occur rarely. Minor transient changes can occur in liver function tests and hematologic parameters. Abrupt cessation of therapy should be avoided, as it may lead to a picture resembling neuroleptic malignant syndrome with fever, muscular rigidity, and coma.
Dose-unrelated side effects
(a) The "on-off" phenomenon
becomes a likely side effect with extended duration of therapy and is not seen in the absence of L-dopa therapy. This disability occurs in about 50% of patients treated for 5 or more years. This on-off effect consists of periods of unpredictable severe akinesia, hypotonia, and apprehension of rapid onset and termination, which last from 30 minutes to a few hours and which are unrelieved by further doses of L-dopa. The cause is unknown, although "off" episodes like "end-of-dose akinesia" have been correlated with low plasma concentration of L-dopa in some studies. However, maintaining constant L-dopa plasma levels with intravenous drug administration does not always abolish clinical fluctuations.
Administration of an L-dopa preparation q2h may help to smooth out these effects. Sinemet, for example, can be cut in quarters with a razor blade to allow smaller doses to be administered. L-Dopa methylester is an experimental drug that may prove to be of benefit in this distressing condition. A drug holiday for up to 1 week has also been advocated in the past for treatment of on-off effects but is of little or no benefit. The initial dosage regimen of L-dopa appears not to affect the incidence of the on-off phenomenon or end-of-dose wearing-off effect but may be implicated in the development of peak-dose dyskinesia.
The main treatment of the on-off phenomenon is subcutaneous apomorphine.
This medication is administered a few days after the introduction of domperidone (Motilium) to eliminate the inevitable vomiting that occurs without its use. The dose, initially commenced at 1.5 mg, is titrated for benefit up to 4.5 mg. A satisfactory result will produce a clinical improvement within 10 minutes that will last up to 50 minutes. The medication reduces the time a patient spends in the off state but does not reduce the frequency of on-off spells. Nasal and sublingual apomorphine have been of benefit in some patients.
The contraindications to L-dopa therapy are relatively few. They include narrow-angle glaucoma (most glaucoma cases are of the chronic, wide-angle type), previous melanoma, although this has recently been questioned, and concurrent use of MAO inhibitors. Caution should be used in patients who have cardiac arrhythmias or recent myocardial infarction or for whom surgery is planned.
is a dopamine-receptor agonist. There are theoretic arguments that suggest that presynaptic (L-dopa) and postsynaptic (bromocriptine) effects may best be produced by simultaneous use of the drugs.
The initial dosage of bromocriptine is 2.5 mg/day, and this is slowly
increased over several weeks. Maximum therapeutic benefit is often of
slow onset, and the dosage may be held at low levels (e.g., 12 mg/day) for
several months before full effectiveness is noted. The maximum dosage
is 30-50 mg/day usually given bid-tid. Early side effects include nausea,
which may be treated with domperidone, vomiting, and postural hypotension.
They are less troublesome than with an L-dopa preparation, but late side
effects are more troublesome, especially the acute confusional state that
occurs with visual hallucinations. This may take several weeks to clear on
cessation of the drug. Other psychogenic side effects are similar to those
found with high-dose L-dopa. Ankle edema and erythromelalgia are less of
a problem and clear rapidly when the drug is stopped. Pleuropulmonary fibrosis
There has been considerable interest in this class of drug because of its potential to avoid problems associated with levodopa. Three new dopamine agonists have recently been introduced to the market: cabergoline (Cabsar, Dostinex), pramipexole (Mirapex), and ropinirole (Requip). Cabergoline is not approved for use in the United States, but is marketed in Europe.
ergot analogues, has undergone extensive evaluation. The mean effective dosage is usually about 2-4 mg/day. The starting dosage is 0.1 mg/day.
Combined therapy of Sinemet & Bromocriptine
Many patients are now successfully manged by using an L-dopa preparation initially and then adding a dopamine agonist such as bromocriptine in low dosage. A typical regimen would be Sinemet 25-100 initially tid for 3 months and then adding bromocriptine, 2.5 mg/day, increasing over 3 months to 2.5 mg tid. Many other variations on this approach are in clinical use. The hope is that there will be fewer side effects with this strategy, particularly dyskinesias and motor fluctuations. Lowered mortality may also be possible.
are said to be useful early in the disease when tremor is the most prominent problem. They are now being used less and less as first-line therapy.
(1) Commonly used agents and the usual dosages include
(2) The maximum dose of these agents is determined by observation of the onset of side effects. The dosage is gradually increased to the tolerated maximum. For example, it may be possible to give up to 400 mg/day of ethopropazine.
Centrally acting anticholinergic drugs, such as trihexyphenidyl (Artane) and benztropine (Cogentin), have long been used in the treatment of PD and are still employed by some physicians, even in this era of levodopa and dopamine agonists. Anticholinergic drugs are typically used in younger PD patients (i.e., 70 years of age or less) in whom tremor is the dominant clinical feature and cognitive function is preserved. Anticholinergic drugs are useful for treating resting tremor but are of lesser value in the treatment of akinesia or impaired postural reflexes. In some patients, tremor may respond better to anticholinergic agents, although levodopa is the most effective drug for control of tremor. . Trihexyphenidyl (Artane) is typically initiated at 0.5 to 1.0 mg bid and is increased gradually to 2 mg tid. Benztropine (Cogentin) is given in dosages of 0.5 mg to 2.0 mg bid.
Elderly and cognitively impaired patients are particularly sensitive to
Peripheral antimuscarinic side effects include dry mouth, blurred vision, constipation, nausea, urinary retention, impaired sweating, and tachycardia. Particular caution should be exercised in the presence of prostate hypertrophy or closed-angle glaucoma. Mild peripheral effects, such as dry mouth and blurred vision, often subside with continued treatment and do not limit therapy.
hydrochloride (Symmetrel) and amphetamines
may act by increasing endogenous dopamine release at the nerve terminal in the neostriatum.
(1) Amantadine hydrochloride is used in an initial dosage of 100 mg/day and
increased to 100 mg tid. The benefit obtained is short-lived, and intermittent
use has been advocated. Prominent side effects are depression, congestive
cardiac failure, pedal edema, livedo reticularis, urinary retention, and
an acute confusional state, especially with visual hallucinations. The drug
is excreted unmetabolized in the urine. This drug may also be effective through
its anticholinergic properties.
Amantadine is an antiviral agent that is known to increase dopamine release, block dopamine reuptake, stimulate dopamine receptors and, possibly, to have peripheral anticholinergic properties. In uncontrolled studies, two-thirds of patients who received amantadine monotherapy experienced improvements in akinesia, rigidity, and tremor. Amantadine appears to be more effective than anticholinergic drugs with regard to akinesia and rigidity but is less effective with regard to tremor. Amantadine has a plasma half-life of 10 to 28.5 hours and can be administered in dosages of 100 to 300 mg one to three times daily.
(2) Amphetamine has been used in the past for treatment of oculogyric crises. Side effects generally preclude its use. Methylphenidate is said to be helpful as an analgesic for sensory symptoms, which include headache, tingling, numbness, formications, and burning pain.
(3) Subcutaneous apomorphine is used with domperidone (10-80 mg/day) as antinauseant in the treatment of on-off effects. Dyskinesia is common with this medication. Patients appear to adjust well to symptomatic self-administration.
Neuroprotection Rx: the selective
monoamine oxidase (MAO)-B inhibitor
Selegiline (Eldepryl, Deprenyl) 5-mg tab bid with meals
delays the emergence of disability and the progression of signs and symptoms in previously untreated PD patients. The drug is usually well tolerated when administered as monotherapy. When selegiline is combined with levodopa, it enhances dopaminergic effects and may lead to increased dyskinesia and neuropsychiatric side effects, particularly in the elderly. Clinical trials have evaluated selegiline in doses of 5 mg bid, but lower doses are frequently employed in practice (e.g., 5 mg qod), particularly in the elderly or in patients who experience adverse effects.
The dosage of selegiline is 100 micro-g/kg/day after a loading dose of 10
mg daily for 1 week.
At 30 mg/day, the drug inhibits both MAO A and MAO B. It is metabolized to amphetamine, which may be responsible for part of the euphoric effect. Its place in the treatment of Parkinson's disease is still controversial, but it is probably best regarded as an L-dopa sparing agent that also prolongs the effect of L-dopa in patients with end-of-dose failure. The drug should not be used in combination with meperidine, other MAO inhibitors, or fluoxetine. Common side effects include increased dyskinesia, nausea, dizziness, and confusion.
Propranolol (Inderal) may on occasion be used for action tremor, a common accompaniment of Parkinson's disease. It is also said to be useful for pain that is not associated with dystonia.
Botulinum toxin A (Botox) has been used to treat equinovarus and claw dystonia in patients who have these conditions and where other medical therapies have not helped.
The COMT inhibitors entacapone (Comtan) and tolcapone (Tasmar) have been studied as adjunctive therapy to levodopa in the treatment of PD. COMT metabolizes levodopa and dopamine to 3- O-methyldopa (3-OMD) and 3-methoxytyramine (3-MT), respectively, in both the peripheral and central nervous systems. Both tolcapone and entacapone inhibit COMT peripherally. Tolcapone also has a mild central effect. In PD, COMT inhibitors primarily exert their therapeutic effect through inhibition of peripheral levodopa catabolism to 3-OMD. Therefore, COMT inhibitors increase the bioavailability of levodopa.
(1) Ventrolateral thalamotomy has been used in patients with severe unilateral tremor, not controlled with drugs, who have the intellectual capacity for gainful employment. Bilateral thalamotomy has led to severe speech defects. Pallidotomy may be useful for bradykinesia and tremor and is coming back into favor in some centers.
(2) Transplantation of catecholamine-containing tissue from adult and neonatal sources into the basal ganglia of a few patients with Parkinson's disease resulted in major improvements and has led to the trial of this therapy in a number of coordinated centers.
(3) GPi pallidotomy, deep brain stimulation (DBS), and fetal nigral transplantation.
Manual of Neurologic Therapeutics - Martin A. Samuels
Neurology Vol.50 No. 3 March 1998 American Academy of Neurology
An Algorithm (Decision Tree) for the Management of Parkinson's Disease: Treatment Guidelines
Our findings indicate that higher coffee and caffeine intake is associated with a significantly lower incidence of PD. This effect appears to be independent of smoking. The data suggest that the mechanism is related to caffeine intake and not to other nutrients contained in coffee. JAMA. May 24, 2000;283:2674-2679 G. Webster Ross
http://www.emedicine.com/neuro/topic304.htm (Parkinson Disease)
SYMPOSIUM ON PARKINSON'S DISEASE - Postgraduate Medicine December 2001
Update on Parkinson Disease - Annal of Int. Med April 15, 2003 ( A. Siderowf and M. Stern )
see Depression in Parkinson's Disease (National Institute of Neurological Disorders and Stroke 2003)