Parkinson's Disease
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[edit] Parkinson's Disease
William Pryse-Phillips
T. Jock Murray
Parkinson's disease is a disorder of the basal ganglia and its connections of unknown etiology, characterized by tremor at rest, rigidity, akinesia or bradykinesia (slowness and poverty of movement), postural disorders, and autonomic abnormalities. Parkinson's disease is the most prevalent movement disorder after essential tremor. Its incidence is distributed unevenly throughout the world, being more common in highly industrialized countries than in agricultural societies and more frequent in Europe and North America than in the Far East. The prevalence in North America is 100 cases per 100,000 population, therefore about 500,000 people are affected in the United States, although over the age of 65 the prevalence may be as high as 1%. There is a slight (1.5:1) male predominance, and Caucasian people may be affected more than blacks. The role of hereditary factors in the idiopathic variety is uncertain, although there is a small subset of hereditary Parkinson's disease.
Parkinsonism is a pathophysiologic state caused by degeneration or dysfunction of the dopaminergic nigrostriatal system. This system includes the substantia nigra, caudate nucleus, putamen, and globus pallidus. The cell bodies are in the substantia nigra, and their axons run to the upper basal ganglion structures where dopamine normally acts as an inhibitory neurotransmitter, balancing an excitatory cholinergic system. Neuronal loss in this system leads to the depigmentation of the substantia nigra that is typical in Parkinson's disease. The disorder may be more complex than this, as other biochemical changes are also apparent and neuronal degeneration occurs not only in the substantia nigra but also more widely within the basal ganglia and sometimes diffusely in the cerebral cortex.
Features of Parkinson's disease occur in four major groups of disorders: idiopathic Parkinson's disease, secondary Parkinson's disease, Parkinson's plus syndromes, and degenerative drain disorders. The idiopathic form (once known as paralysis agitans) may be due to a viral infection, as suggested by the presence of inclusion bodies in the degenerating neurons of the substantia nigra (Lewy bodies). However, the exact replication of the pathology and clinical features in subjects poisoned with industrial chemicals, manganese, pesticides, herbicides, or MPTP (a narcotic derivative) has led to the hypothesis of a toxic cause.
[edit] CLINICAL FEATURES
The clinical features of Parkinson's disease vary with the cause (Box 169-1) but essentially the major signs occur without other clinical evidence of damage to other major structures within the central nervous system (CNS). The onset is usually after the age of 50. Early signs that help to distinguish Parkinson's disease from other parkinsonian disorders are asymmetry of signs, marked rest tremor, a clinically significant response to levodopa, and the relative absence of balance problems in the first years of the disease.
| Box 169-1 - Features of Parkinson's Disease |
Major Features
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The leading symptoms as the disease progresses are rigidity, tremor, bradykinesia, and difficulty with balance and in walking, and these are the most disabling. Other symptoms include depression, sleep disturbances, dementia, blepharospasm, hypophonia, dysphagia and drooling, constipation, difficulty voiding, dizziness, stooped posture, ankle swelling, and impotence.
The development of symptoms in the idiopathic variety is often slow, and their insidious onset may puzzle both patients and physicians, particularly if the tremor is not yet present and the patient's description of the symptoms is unclear. It is common for patients to use words such as “tiredness” for the slowing, and “pain” and “arthritis” for the difficulty with their legs.
Early nonspecific symptoms include weakness, tiredness, and fatigue; complaints of slowness of movements, impaired fine motor control, a posture characterized by flexion, and vague heaviness and stiffness or aching in the limbs, all likely related to a subclinical increase in muscle rigidity. Other early symptoms include difficulty in starting to walk or in getting into and out of a chair or car, difficulty turning over in bed, reduction in the size of the patient's handwriting (micrographia), depression, and drooling, especially at night.
Patients with moderate disease experience increased difficulty with balance and walking. Some of these complaints suggest arthritis, depression, or normal aging as the reason until rest tremor appears. As time goes by, more obvious postural disturbances appear, such as generalized flexion, a loss of associated movements (e.g., arm swing while walking), and difficulties in maintaining balance.
In the developed case, examination of the cranial nerves shows a mask-like facies with a blank stare and infrequent blinking. Voluntary and emotional facial movements are both limited and slow. If the glabella is tapped repeatedly, blinking continues, whereas normally, adaptation to the tapping will stop the blinking after three or four taps (glabellar tap sign). However, this abnormal response also occurs with other causes of diffuse cerebral dysfunction and is not specific. Speech is low, monotonous, and as the disease progresses, hard or impossible to understand. The problem is compounded by drooling of saliva.
Bradykinesia is one of the most disabling symptoms. It is characterized by a delay in starting all movements, by slowness and poverty of movements, and by the arrest of ongoing movements. It may contribute to imbalance, gait disturbance, and falls. The gait problems include difficulties in starting to walk; a decrease in the natural arm swing; short, shuffling steps; difficulty in turning; and freezing spells.
Motor examination in patients with developed disease shows that strength is normal but voluntary and spontaneous tasks are made difficult by the rigidity and slowness in initiation of movements. The patient may sit motionless, even if in an uncomfortable position, and not make those minor postural adjustments that normal people do automatically. When he or she does move, each action is performed in a series of separate steps rather than in a smooth continuum. Handwriting changes are often useful diagnostic early signs because the writing is shaky and small, tending to get even smaller as the sentence continues. Micrographia is later seen in which the writing may not be read without a magnifying glass in some instances (Fig. 169-1). Rigidity is found in most muscles, although initially it may be confined to one limb. At first, only a slight, consistent increase in tone may be felt within the muscles on movement, but eventually one can detect a ratchet-like jerking (cogwheel rigidity) that is accentuated by having the opposite arm perform rapid alternating movements, or clenching the opposite fist while tone is tested in the first limb. In the trunk, the increase in tone can be felt over the paraspinal muscles if the patient flexes and extends his or her back.
Parkinsonian tremor is characteristic when present, but it may be absent in up to 25% of patients. At first confined to one hand, it spreads eventually to all limbs. It is commonly a 4 to 6 per second alternating flexion-extension or rotatory movement, most noticeable in the thumb and index finger. This last characteristic led to the old term pill-rolling tremor, ascribed to the motion in the days when pharmacists rolled pills by hand. It rarely occurs in the head (visible head shaking usually indicates essential tremor rather than parkinsonism), but it may be seen in the closed eyelids, the tongue, or the chin. It is characteristically best seen when the limb is maintaining a posture, and it is absent when the limb is at complete rest, as during sleep. At a later stage there is sometimes an added action component, so the tremor occurs during the whole range of a voluntary movement, and the leverage effect from extending the arm may make it appear that the tremor is actually worse during movement. Any form of emotional stimulation increases tremors of all types. Tremors usually decrease when the hands are stretched out in front of the patient or when the hands are moving. In some patients, however, the tremor may increase when the hands are in this position (postural tremor).
Apart from the stooped, flexed, and shuffling gait disturbance, propulsion and retropulsion may be found. When these are present, patients who managed to start walking forward or backward find themselves unable to stop so that it is as if they were chasing their own centers of gravity (festinating gait). This inability to halt may be extremely dangerous. Patients may begin to lean backwards when standing for awhile and begin to take rapid steps backwards. Because the normal reactions to stop the movements are not taken, the patients fall and often sustain a head injury. This loss of normal postural responses, corrective actions usually made automatically, causes these patients to fall easily, often toppling like a tin soldier, when they start to go off balance. This is common when turning or when they are on an uneven terrain. To test the postural reflexes, the examiner stands behind the patient and pulls back on his or her shoulders, putting the patient off balance slightly. Normally one would put a foot back and correct the imbalance. Patients with Parkinson's disease may begin to take the small, rapid, festinating backward steps and keep going until they fall into the arms of the examiner. Loss of postural reflexes is one of the most serious symptoms of Parkinson's disease because of the danger of injuries such as subdural hematomas and fractured hips. In fact, one of the paradoxical complications of levodopa therapy when it was first introduced was an increase in the number of fractured hips as the patients suddenly became more mobile but still had poor postural reflexes and thus had an increase in falls.
In Parkinson's disease, all motor actions are performed slowly and with effort, so to get ready in the morning, patients may need an hour or two for toilet purposes, shaving, and dressing. There are no sensory changes but patients often complain of stiffness and aching in the muscles. Reflexes, including the plantar responses, are normal unless there is evidence of other generalized brain disease.
Abnormalities of the autonomic nervous system result in excessive sweating, oily skin, abnormal gastric motility, and slight bladder disturbances in some cases. Impotence is probably caused by the motor disabilities as much as by autonomic changes. Initial insomnia and frequent night-time awakenings that leave the patient exhausted in the morning are common problems. Vivid dreaming and myoclonus may be due to levodopa therapy, in which case eliminating the evening dose may suffice. However, in some patients withdrawal of levodopa makes them so rigid that they cannot turn over in bed.
In the earlier stages of the disease, intellectual abilities are unaffected despite the patient's appearance, but some degree of dementia (manifest as difficulty with memory, recognition, abstraction, and calculation) occurs eventually in at least one third of the patients. Levodopa, anticholinergics, and dopamine agonists also may cause delusions, confusion, paranoia, or hallucinations, which disappear within a few days when the drugs are stopped or the dose reduced.
Many patients are depressed, perhaps in part as a result of their encasement within a body with high inertia, but undoubtedly also because of biochemical disturbances. In about one fourth of the patients, frank hallucinatory and psychotic features occur.
Sialorrhea with drooling results from the mild to moderate dysphagia that is common in the later stages of the disease. This is especially a problem at night when the patient is recumbent and gravity is no longer available to assist swallowing. Anticholinergics decrease saliva production and may be helpful if taken in the evening.
Speech impairments consist of monotony, with the usual expressiveness of speech being impaired; impaired articulation; decreased volume, so that the patient speaks more softly and the volume fades through the utterance of sentences; and slowing of speech. Initially, these problems are most obvious on the telephone. Speech therapy and amplification devices may be helpful here.
Dysphagia is a late symptom and affects both solids and liquids. The difficulty arises either from an inability to force the food down the throat or rigidity of the voluntary muscles of the throat and leads to complaints of food getting stuck in the throat. Ingestion of only small portions of food and careful chewing, one morsel being swallowed before the next is taken, may help. The problem is important because of the risk of aspiration.
Weight loss may be related to dysphagia, depression, or the energy used up by the involuntary movements, or it may be a central, hypothalamic effect.
Constipation is a common problem, often as a result of decreased intestinal peristalsis induced by anticholinergics. Increased fluid intake, use of bulk formers such as bran or methylcellulose, glycerine suppositories, small doses of senna laxatives, or Fleet enemas may be tried. Urinary hesitancy is a common side effect of anticholinergics, but when it occurs in men, prostate gland disease should be excluded first.
Orthostatic hypotension is both a feature of the disease and a side effect of levodopa, dopamine agonists, hypotensives, and antidepressants. It is also a symptom of multiple system atrophy (see below).
Edema of the feet usually occurs at the end of the day (but disappears overnight) as a result of the inability of the rigid leg muscles to maintain venous circulation in patients with decreased mobility. Cardiac failure must be excluded. Amantadine and dopamine agonists also can cause ankle edema. If the edema is severe, elevation of the feet for 1 hour twice a day and elastic support stockings or diuretics may be tried.
A decrease in the desire for sexual activity may result from the nonspecific effects of a chronic illness, from fear of being unable to perform satisfactorily, as a symptom of depression, or because of medications. Parkinson's disease itself is not a cause of impotence. Levodopa only increases sexual function activity in relation to the patient's general improvement.
Current treatments have also led to the awareness of certain features of the disease that may have always been present but were not recognized or occur as a result of the drugs used. These include the following motor fluctuations.
Most commonly, a decline in motor performance occurs near the end of the effective period of each dose of medication. Patients change gradually from showing a good response to the medication (the “on” period) into an “off” period that occurs approximately 1 hour before the next dose is due. Involuntary dyskinetic movements (dyskinesias) may occur either when the drug levels peak after each dose is taken or when the levels are falling off.
A sudden freezing of movements is another late-stage complication in treated patients, who may be unable to walk through a doorway without a brief involuntary stop, or on sitting down may stay suspended just above the seat for a few seconds before plopping down into the chair. At its worst, freezing halts the patient while standing or walking, with the likely consequence of a fall.
[edit] SECONDARY PARKINSON'S DISEASE
The many secondary causes of parkinsonism all affect the neurons involved in basal ganglion function. The classic secondary cause was the worldwide pandemic of influenza beginning in 1917 that often resulted in von Economo's encephalitis. Many of these patients developed parkinsonism even years later, with typical degenerative changes in the basal ganglia and substantia nigra.
Parkinsonian features may be seen in acquired immunodeficiency syndrome (AIDS) and general paralysis of the insane (GPI), but they are hardly ever found in association with multiple sclerosis or cerebral tumor. Cerebral anoxia from any cause, including “successful” resuscitation after cardiac arrest, repeated hypoglycemic attacks, and repeated head injuries (as in boxers) also produce parkinsonian signs. Rigidity and akinesia, but not true Parkinson's disease, may follow multiple cerebral infarcts and have been seen in patients with normal pressure hydrocephalus and Wilson's disease.
Parkinsonism may be induced or unmasked by numerous drugs and other chemicals (see Chapter 166 ). Neuroleptic drugs are dopamine antagonists and frequently induce parkinsonism, especially the piperazines such as haloperidol and fluphenazine. Metoclopramide, the antidepressant amoxapine, some calcium channel blockers (e.g., flunarizine and cinnarizine), and amiodarone can all cause tremor or other parkinsonian features. A number of toxins can induce parkinsonism, including the illicit narcotic designer drug known as MPTP, manganese, and petroleum wastes.
In postencephalitic and phenothiazine-induced forms of secondary Parkinson's disease, severe autonomic disturbances and oculogyric crises are seen, but the latter do not occur in other types. Rigidity is severe in postencephalitic patients but is not marked in idiopathic Parkinson's disease until a late stage. Tremor is prominent in idiopathic and postanoxic forms, but may not be at all marked in postencephalitic parkinsonism nor in that caused by phenothiazine drugs, in which bradykinesia is the most striking of the four major features. Postural disturbances occur in all forms.
[edit] DIFFERENTIAL DIAGNOSIS
Diagnosis is not always easy and can require perception and acumen in the early case when signs are minimal and symptoms vague. Early signs of value include infrequent blinking, the lack of arm swinging, and cogwheel or plastic rigidity accentuated when the opposite side is stressed. The history must concentrate on those possible causes of secondary parkinsonism mentioned above, in particular recent anoxia or drug ingestion, and a family history is sometimes of value (although more commonly so in cases of essential tremor, the condition with which, in the early stages at least, it is most likely to be confused). In this disorder, however, the tremor is present with maintenance of a posture and with voluntary activities but hardly ever at rest. It is reduced by alcohol ingestion and disappears at rest. Moreover, the head and voice are often involved, and the family history suggests an autosomal dominant inheritance in half of the cases.
Juvenile Parkinson's disease is a rare familial variety of the disease.
Parkinsonism-plus is a term that includes conditions in which there are other signs of CNS dysfunction in addition to those of parkinsonism. These include hypotension, autonomic insufficiency, ocular palsies, dementia, cerebellar signs, and lower motor neuron lesions. One cluster of these conditions is multiple system atrophy. Subtypes of this condition are progressive supranuclear palsy, in which there are impairment of vertical gaze and unusual extensor rigidity of the neck; olivopontocerebellar atrophy, characterized by limb and gait ataxia and rigidity, dyssynergia, and kinetic tremor; and striatonigral degeneration, which should be suspected when features of parkinsonism such as rigidity, slowness, speech hesitancy, pyramidal signs, slow chewing and swallowing, hypomimia, slow flexed gait, and occasionally a resting tremor are accompanied by memory loss, hallucinations, insomnia, and eventually delirium. Finally idiopathic autonomic failure (Shy-Drager syndrome) produces dysautonomia that leads to crippling orthostatic hypotension, dryness of the skin, impotence, and sphincter disturbances.
Early dementia with hallucinations is a feature of diffuse cortical Lewy body disease. In hemiatrophy-hemiparkinsonism the parkinsonian features occur in young adults who show a degree of hemibody atrophy on the involved side and in whom contralateral brain hemiatrophy is seen on computed tomography (CT) scans. A positive family history of dystonia may indicate that the parkinsonian patient actually has the condition of dopa-responsive dystonia. All but the last of these parkinsonism-plus syndromes are poorly responsive to levodopa.
Parkinson's disease also has to be differentiated from severe, retarded depression and from certain rare neurodegenerative disorders. The rigid forms of Huntington's disease and Wilson's disease (see below) usually present in children and young adults in whom the family history or serum copper and ceruloplasmin levels should indicate the diagnosis. Creutzfeldt-Jakob disease is characterized by parkinsonian and pyramidal signs, myoclonus, dementia, and distal muscle atrophy. Lytico-Bodig is a disorder peculiar to Guam that is characterized by signs of parkinsonism, dementia, and amyotrophic lateral sclerosis (ALS).
[edit] PROGNOSIS
Before the advent of levodopa, the mortality rate for Parkinson's disease was substantially increased, but this has been reduced, although not normalized, by this drug. The development of dementia or the appearance of any of those physical signs indicating that the condition is actually one of the Parkinson's-plus syndromes indicates a worse prognosis for both the quality and the duration of life.
[edit] TREATMENT
[edit] General Measures
As with all conditions, the patient and his or her family should be made aware of the nature of the disorder and the possible courses it may take. The best source of printed materials is the National Parkinson Disease Association (1-800-362-3479) or other national organizations.
Physiotherapy is of value to maintain mobility and optimal activity. Massage, exercises, and posture and gait training have been found to be helpful, the latter particularly if propulsion or retropulsion is present. Falls are a particular problem in patients with parkinsonism, and physical and occupational therapy assessment is valuable and can provide gait training and appropriate ambulation aids to prevent these complications.
Many patients with Parkinson's disease benefit from deferring protein intake until the evening meal. This phenomenon is due to the fact that certain amino acids, the components of proteins, compete with levodopa for metabolism in the brain. Therefore all medications for parkinson's disease lose some effectiveness if taken with protein. Patients with fluctuations in their response to antiparkinsonian medications often benefit from a low-protein diet. Ordinarily the total protein content of breakfast and lunch is restricted to under 5 gm, and the remaining daily protein requirement (usually 50 to 100 gm) is eaten after 6 pm. There is little clinical evidence that any vitamin supplements help patients with Parkinson's disease.
Simple things, such as eating more fruits and vegetables, are best. Bran cereals are good unless the subject is taking levodopa, although patients should be careful about adding milk to their cereal because of the protein content. Commercial psyllium or methylcellulose compounds can also be helpful, but some of these compounds contain a lot of sugar. Docusate compounds are marketed as stool softeners and can be added to the above therapies. It is best to avoid laxatives such as cascara or senna because their effectiveness tends to wane with continued use and side effects can be severe.
[edit] Drug Therapy
Drug therapy is based on the observation that dopamine is depleted in the nigrostriatal tracts and the excitatory cholinergic effects are relatively increased.
Anticholinergic drugs such as trihexyphenidyl at 2 to 6 mg/day, benztropine at 0.5 to 4 mg/day, procyclidine at 2.5 to 5 mg tid, and orphenadrine at 100 to 300 mg/day are recommended. Antihistamine drugs such as diphenhydramine are used with variable results; they have more effect on the tremor than on rigidity or akinesia. If these drugs are used for any time they must not be stopped abruptly or a rebound effect with increased symptoms may occur.
Selegiline, a monoamine oxidase inhibitor (MAOI), reduces the metabolism of levodopa, the uptake of dopamine at synapses, and the production of free radicals. As an adjunctive therapy, it reduces motor fluctuations and may delay the onset of disability, but it requires a reduction in the dose of levodopa to prevent dyskinesias or hallucinations. The dose is fixed at 5 mg in the morning and again at midday. At present, this drug's place in the management of the disease is still undetermined.
Amantadine hydrochloride is less effective than levodopa in improving symptoms but is relatively free of serious side effects. It may be used alone or in conjunction with levodopa. It was originally developed and prescribed as an antiviral agent and its method of action in Parkinson's disease is unclear. Amantadine is given in oral doses of 100 mg one to two times daily. Its action on bradykinesia, rigidity, and gait disturbance is rapid but decreases over a few months. Significant side effects are not common, but depression, confusion, hypotension, and cardiac failure can occur. If patients stay on amantadine for a long time they will usually develop mottling of the skin of their lower legs (livedo reticularis) with some ankle swelling.
Propranolol (best given as the long-acting preparation at 60 to 240 mg/day) reduces the tremor and some of the psychologic effects of anxiety but is contraindicated in patients with concomitant cardiac failure or bronchospasm.
Tricyclic drugs such as amitriptyline may increase activity and lighten the frequently added depression; nocturnal antihistamines (e.g., diphenhydramine) are sedative, dry up secretions, and reduce tremor slightly.
All of the above agents can be considered before levodopa is given and may be given concurrently.
The subcutaneous injection of apomorphine (a dopamine receptor agonist) reduces parkinsonian signs, fluctuations in response, and the unpleasant features of the “off” periods. A self-injection regimen, in which the invariable nausea caused by this agent is controlled by domperidone, is occasionally used.
There are three classes of drugs more or less specific for the treatment of Parkinson's disease.
[edit] Levodopa.
A combination drug such as Sinemet, levodopa plus carbidopa, which inhibits dopa-decarboxylase and diminishes the extracerebral breakdown of levodopa, is a most effective agent. It should be started at a small dose (one 100/10 mg tablet bid) and slowly increased to a qid or 4-hourly dose when the patient starts to respond. The average dose is one 250/25 tablet tid. If the effect is variable during the day, with swings in response and a tendency for the effects of the drug to wear off before the time for the next dose, the controlled-release preparation should be used; the dosage increased; the frequency of doses increased (e.g., to every 3 or even 2 hours); or an agonist added. The long-acting preparations are often preferable to the standard formulation.
Long-term results over the years have not been encouraging because the symptoms progress despite continued therapy. It has been suggested that the prescription of levodopa should be delayed and not given on diagnosis because it appears to lose its effect after a few years. It has also been observed that many patients on long-term levodopa develop significant mental changes, although this may be due either to the therapy or to the natural history of the disease. Thus the question of when to start treatment with levodopa is vexing. In favor of early treatment is the likelihood that the patient would maintain a better quality of life, for example being able to continue to work during the latter part of his or her career, or to carry out more leisure activities and hobbies. In addition, mortality may be less in patients treated early with levodopa. On the other hand, the spectre of chronic levodopa neurotoxicity has been raised to account for that loss of efficacy and increase in side effects (especially dyskinesias) commonly seen as the disease progresses.
It has been estimated that the drug loses a third of its effect in two thirds of patients within 3 years. Because dyskinesias are most likely to develop in young-onset Parkinson's disease patients, levodopa is generally not prescribed for those age 40 years or less.
The main early complications of levodopa are nausea caused by stimulation of the vomiting center in the brain and possible direct gastric irritation; postural hypotension; anorexia; depression and confusion; abnormal movements such as retrocollis, dystonic postures, and akathisia; and cardiac arrhythmias. After long-term therapy with levodopa, an “on-off” effect, with variability in the signs and symptoms throughout the day, may be seen in which an abrupt increase of symptoms such as freezing or rigidity occurs as the serum levels of levodopa decline. In many patients dyskinesias also occur at the time when the highest drug levels are attained, usually 2 to 3 hours after ingestion. Reduction of the dose or addition of an agonist or an anticholinergic may reduce these involuntary movements. End-of-dose deterioration (wearing off), fatigue, and loss of efficacy of the drug are other problems, usually appearing after 3 to 5 years of use. The former may be helped by changing to the controlled-release preparation, by the addition of a COMT inhibitor or dopamine agonist, or by reducing the spacing between doses of levodopa. All such problems support the view that levodopa should not be used until it is really needed.
A less common complication is hip fracture caused by over-enthusiastic resumption of physical activity as the benefits of levodopa therapy appear. The formerly publicized aphrodisiac effect of the drug is probably due mainly to an increase in physical freedom rather than to stimulation of sexual appetites. In all patients given levodopa in any form, protein intake should be concentrated in the evenings because of the reduction in available dopamine when given with protein, and foods high in pyridoxine (an antagonist to levodopa) should be restricted.
[edit] Dopa-Receptor Agonists.
Direct dopamine D2 receptor agonists stimulate striatal receptors without affecting dopamine metabolism. In early or mild Parkinson's disease, these agents have been used as monotherapy, and in more advanced disease they enhance the effects of levodopa. As well as improving the overall effect of the levadopa, they can also reduce motor fluctuations. Four agents are currently available—bromocriptine, pergolide, pramipexole, and ropinirole—each with a unique profile in terms of its effects on D1, noradrenergic, and serotonergic receptor activity. One common practice is to start patients with low-dose levodopa (up to about 600 mg/day) and to add an agonist when control of symptoms is lost. Another is to start with the agonist, adding levodopa when its effect is inadequate.
Bromocriptine may reduce some of the long-term complications of levodopa, but when it is used the dosage of levodopa will need to be reduced by 10% to 50% over many weeks, or toxicity may be expected. Initial dosages should be low (2.5 mg once a day), slowly increasing by 2.5 mg weekly to a maintenance dosage of 5 mg three times a day, although side effects such as hypotension, dyskinesia, and hallucinations are to be expected in most cases at the highest dose.
Ropinirole should be given at 0.25 mg tid and increased by 0.25 mg/day each week to a maximum of 24 mg/day in divided doses. This agent is not related to ergot, so it has a good side-effect profile.
Pergolide is a longer-acting drug; it is begun at 0.05 mg per day and increased weekly to a maximum of 9 mg/day.
Pramipexole can be prescribed as monotherapy or as adjunctive treatment to carbidopa/levodopa for all stages of Parkinson's disease and may be helpful for levodopa-induced motor fluctuations. The initial dose should be 0.125 mg tid and increased weekly by 0.125 mg/day to a maximal dosage of about 4.5 mg/day. This dopamine agonist binds only to the dopamine receptors and stimulates the D2 subfamily of receptors. Again, it is not related to ergot, so it has a good side-effect profile; the occurrence of somnolence, nausea, and hallucinations is not significantly different from that resulting from placebo use.
Cabergoline is a new dopamine agonist that has a longer duration of action than the currently available drugs in this class. Cabergoline is currently used to treat certain endocrine disorders and is not yet approved for Parkinson's disease.
[edit] Drugs Delaying Levodopa Metabolism.
Two catecholamine-O-methyl transferase inhibitor agents increase the bioavailability of levodopa. Entacapone acts primarily extracerebrally and will soon be available. The dose is one 200 mg tablet with each levodopa dose. Tolcapone (100 to 200 mg tid) acts both extracerebrally and intracerebrally and inhibits the metabolism of dopamine within the brain, but it has been withdrawn from the market because of the occurrence of hepatic necrosis as a rare side effect and is now available only after administrative supplication. Both agents reduce motor fluctuations and daily levodopa requirements.
[edit] Other Agents
Some patients with Parkinson's disease who cannot tolerate levodopa because of intolerable psychiatric side effects, such as hallucinations, paranoia, or confusion, may benefit from neuroleptic medications such as clozapine or olanzapine, both of which have a slight beneficial effect on parkinsonian symptoms as well as an antipsychotic effect. Traditional neuroleptic medications are usually avoided in patients with Parkinson's disease because of their induction of unwanted motor effects.
Patients with hallucinations or psychotic features may respond well to risperidone at 0.5 to 4 mg/day or to clozapine, an antipsychotic that has significant depressant effects on the bone marrow that necessitate frequent hematologic monitoring.
[edit] Surgery
Surgical interventions in advanced Parkinson's disease include destruction or high-frequency stimulation of the thalamic nuclei, the globus pallidus, the subthalamic nucleus, or the ventrointermediate thalamic nucleus. The latter procedures require electrode implantation into the brain and are used for patients with an inadequate response to traditional antiparkinsonian therapy and in those with severe symptoms before the age of 40.
Thalamotomy is primarily beneficial for uncontrolled tremor but does not affect the bradykinesia, which is the single most disabling symptom of all. Although safe and effective in an experienced neurosurgeon's hand, ventrolateral thalamotomy is accompanied by significant morbidity, especially when done bilaterally, and it has been performed much less frequently since the advent of levodopa.
Unilateral pallidotomy can improve the duration of “off” periods, tremor, dyskinesias, and the daily levodopa requirement. Major morbidity and mortality are less than 1%, but side effects include visual field deficits, intracerebral hemorrhage, and behavioral changes.
We regard the experimental grafting of autologous adrenal tissue, fetal extracts, and other tissues into the basal ganglia as effective stimuli for further research into other methods of therapy.
[edit] WILSON'S DISEASE (HEPATOLENTICULAR DEGENERATION)
Early in this century a “pseudosclerosis” was described with changes in the lenticular (putaminal and pallidal) nuclei of the basal ganglia. In 1902 Kayser described the characteristic golden brown corneal ring, and the next year Fleischer noted the association with pseudosclerosis. In 1912 Kinnear Wilson noted the association with cirrhosis of the liver. Eventually it became clear that this disorder was due to accumulation of copper in the affected areas due to a genetic deficiency of ceruloplasmin, the enzyme that binds copper.
Wilson's disease is an autosomal recessive genetic disease with a prevalence of one in 35,000 in the population. One in a hundred people carry the abnormal gene, which has been assigned by linkage analysis to the esterase D locus on chromosome 13.
The disease usually begins in the teen years, and rarely after age 30. Tremor and slowness of movement (bradykinesia) in the tongue, lips, and larynx are early symptoms, causing dysarthria and dysphagia, and there may be a wing-beating tremor, chorea, or dystonia of the limbs. Some patients look Parkinsonian, but the involvement follows a different spread, moving from the bulbar muscles and later to the limbs, and in a very young person. As the disease progresses they become slower, rigid, and with a fixed facies, drooling, and mental deterioration. A Kayser-Fleischer ring can be seen in each cornea, best seen with a slit lamp.
Laboratory investigation shows a low serum ceruloplasmin level (below 20 mg/dl), low serum copper, increased copper excretion, high copper in the liver biopsy, and abnormal liver function tests. The CT and MRI will show widened brain sulci, slightly enlarged ventricles, and hypodensity in the posterior lenticular nuclei, with changes in the subcortical white matter, midbrain, pons, and cerebellum.
Treatment must be started early to avoid permanent damage, which is preventable. Copper intake is restricted to less than 1 mg/day by avoidance of copper-rich foods (liver, cocoa, chocolate, mushrooms, nuts, shellfish) and giving an agent to deplete copper, such as D-penicillamine (with supplementary pryidoxine to avoid anemia), zinc acetate, or triethylene tetramine (trientene). If instituted early, all changes can reverse. Some patients may show initial worsening when the drugs are instituted, perhaps because of release of a lot of copper into the system. Treatment is lifelong.
[edit] ADDITIONAL READINGS
- RD Adams, M Victor: Principles of neurology ed 5. New York: McGraw-Hill; 1993:
- AE Lang, AM Lozano: Parkinson's disease. N Engl J Med 1998; 339:1044 - 1053.1130-1143
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