Case Study

A 64-year-old architect complains of right-hand tremor at rest, which interferes with his writing and drawing. He also notes a stooped posture, a tendency to drag his left leg when walking, and slight unsteadiness on turning. He remains independent in all activities of daily living. Examination reveals hypomimia (flat facies), hypophonia, a rest tremor of the left arm and leg, mild rigidity in all limbs, and impaired rapid alternating movements in the left limbs. Neurologic and general examinations are otherwise normal. What is the likely diagnosis and prognosis, and how should his condition be managed?

Pharmacologic Management of Parkinsonism & Other Movement Disorders: Introduction

Several types of abnormal movement are recognized. Tremor consists of a rhythmic oscillatory movement around a joint and is best characterized by its relation to activity. Tremor at rest is characteristic of parkinsonism, when it is often associated with rigidity and an impairment of voluntary activity. Tremor may occur during maintenance of sustained posture (postural tremor) or during movement (intention tremor). A conspicuous postural tremor is the cardinal feature of benign essential or familial tremor. Intention tremor occurs in patients with a lesion of the brain stem or cerebellum, especially when the superior cerebellar peduncle is involved; it may also occur as a manifestation of toxicity from alcohol or certain other drugs.

Chorea  consists of irregular, unpredictable, involuntary muscle jerks that occur in different parts of the body and impair voluntary activity. In some instances, the proximal muscles of the limbs are most severely affected, and because the abnormal movements are then particularly violent, the term ballismus has been used to describe them. Chorea may be hereditary or may occur as a complication of a number of general medical disorders and of therapy with certain drugs.

Abnormal movements may be slow and writhing in character (athetosis) and in some instances are so sustained that they are more properly regarded as abnormal postures ( dystonia ). Athetosis or dystonia may occur with perinatal brain damage, with focal or generalized cerebral lesions, as an acute complication of certain drugs, as an accompaniment of diverse neurologic disorders, or as an isolated inherited phenomenon of uncertain cause known as idiopathic torsion dystonia or dystonia musculorum deformans. Various genetic loci have been reported (eg, 9q34, 8p21–q22, 18p, 1p36.32–p36.13, 14q22.1–q22.2, 14q13) depending on the age of onset, mode of inheritance, and response to dopaminergic therapy. Its physiologic basis is uncertain, and treatment is unsatisfactory.

Tics are sudden coordinated abnormal movements that tend to occur repetitively, particularly about the face and head, especially in children, and can be suppressed voluntarily for short periods of time. Common tics include repetitive sniffing or shoulder shrugging. Tics may be single or multiple and transient or chronic. Gilles de la Tourette's syndrome is characterized by chronic multiple tics; its pharmacologic management is discussed at the end of this chapter.

Many of the movement disorders have been attributed to disturbances of the basal ganglia. The basic circuitry of the basal ganglia involves three interacting neuronal loops that include the cortex and thalamus as well as the basal ganglia themselves (Figure 28–1). However, the precise function of these anatomic structures is not yet fully understood, and it is not possible to relate individual symptoms to involvement at specific sites.

Parkinsonism

Parkinsonism is characterized by a combination of rigidity, bradykinesia, tremor, and postural instability that can occur for a variety of reasons but is usually idiopathic (Parkinson's disease or paralysis agitans). Cognitive decline occurs in many patients as the disease advances. The pathophysiologic basis of the idiopathic disorder may relate to exposure to some unrecognized neurotoxin or to oxidation reactions with the generation of free radicals. Studies in twins suggest that genetic factors may also be important, especially when the disease occurs in patients under age 50. Mutations of the -synuclein gene at 4q21, the leucine-rich repeat kinase 2 (LRRK2) gene at 12cen, and the UCHL1 gene may cause autosomal dominant parkinsonism. Mutations in the parkin gene (6q25.2–q27) may cause early-onset, autosomal-recessive, familial parkinsonism, or sporadic juvenile-onset parkinsonism. Several other genes or chromosomal regions have been associated with other familial forms of the disease. Parkinson's disease is generally progressive, leading to increasing disability unless effective treatment is provided.

The normally high concentration of dopamine in the basal ganglia of the brain is reduced in parkinsonism, and pharmacologic attempts to restore dopaminergic activity with levodopa and dopamine agonists alleviate many of the motor features of the disorder. An alternative but complementary approach has been to restore the normal balance of cholinergic and dopaminergic influences on the basal ganglia with antimuscarinic drugs. The pathophysiologic basis for these therapies is that in idiopathic parkinsonism, dopaminergic neurons in the substantia nigra that normally inhibit the output of GABAergic cells in the corpus striatum are lost (Figure 28–2). Drugs that induce parkinsonian syndromes either are dopamine receptor antagonists (eg, antipsychotic agents; see Chapter 29) or lead to the destruction of the dopaminergic nigrostriatal neurons (eg, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine [MPTP]; see below). Various other neurotransmitters, such as norepinephrine, are also depleted in the brain in parkinsonism, but these deficiencies are of uncertain clinical relevance.

Levodopa

Dopamine does not cross the blood-brain barrier and if given into the peripheral circulation has no therapeutic effect in parkinsonism. However, (–)-3-(3,4-dihydroxyphenyl)-L-alanine (levodopa), the immediate metabolic precursor of dopamine, does enter the brain (via an L-amino acid transporter, LAT), where it is decarboxylated to dopamine (see Figure 6–5). Several noncatecholamine dopamine receptor agonists have also been developed and may lead to clinical benefit, as discussed in the text that follows.

Dopamine receptors are discussed in detail in Chapters 21 and 29. Dopamine receptors of the D₁ type are located in the pars compacta of the substantia nigra and presynaptically on striatal axons coming from cortical neurons and from dopaminergic cells in the substantia nigra. The D₂ receptors are located postsynaptically on striatal neurons and presynaptically on axons in the substantia nigra belonging to neurons in the basal ganglia. The benefits of dopaminergic antiparkinsonism drugs appear to depend mostly on stimulation of the D₂ receptors. However, D₁-receptor stimulation may also be required for maximal benefit and one of the newer drugs is D3 -selective. Dopamine agonist or partial agonist ergot derivatives such as lergotrile and bromocriptine that are powerful stimulators of the D₂ receptors have antiparkinsonism properties, whereas certain dopamine blockers that are selective D₂ antagonists can induce parkinsonism.

Chemistry

Dopa is the amino acid precursor of dopamine and norepinephrine (discussed in Chapter 6). Its structure is shown in Figure 28–3. Levodopa is the levorotatory stereoisomer of dopa.

Pharmacokinetics

Levodopa is rapidly absorbed from the small intestine, but its absorption depends on the rate of gastric emptying and the pH of the gastric contents. Ingestion of food delays the appearance of levodopa in the plasma. Moreover, certain amino acids from ingested food can compete with the drug for absorption from the gut and for transport from the blood to the brain. Plasma concentrations usually peak between 1 and 2 hours after an oral dose, and the plasma half-life is usually between 1 and 3 hours, although it varies considerably among individuals. About two thirds of the dose appears in the urine as metabolites within 8 hours of an oral dose, the main metabolic products being 3-methoxy-4-hydroxyphenyl acetic acid (homovanillic acid, HVA) and dihydroxyphenylacetic acid (DOPAC). Unfortunately, only about 1–3% of administered levodopa actually enters the brain unaltered; the remainder is metabolized extracerebrally, predominantly by decarboxylation to dopamine, which does not penetrate the blood-brain barrier. Accordingly, levodopa must be given in large amounts when used alone. However, when given in combination with a dopa decarboxylase inhibitor that does not penetrate the blood-brain barrier, the peripheral metabolism of levodopa is reduced, plasma levels of levodopa are higher, plasma half-life is longer, and more dopa is available for entry into the brain (Figure 28–4). Indeed, concomitant administration of a peripheral dopa decarboxylase inhibitor such as carbidopa may reduce the daily requirements of levodopa by approximately 75%.

Clinical Use

The best results of levodopa treatment are obtained in the first few years of treatment. This is sometimes because the daily dose of levodopa must be reduced over time to avoid adverse effects at doses that were well tolerated initially. Some patients become less responsive to levodopa, perhaps because of loss of dopaminergic nigrostriatal nerve terminals or some pathologic process directly involving striatal dopamine receptors. For such reasons, the benefits of levodopa treatment often begin to diminish after about 3 or 4 years of therapy, regardless of the initial therapeutic response. Although levodopa therapy does not stop the progression of parkinsonism, its early initiation lowers the mortality rate. However, long-term therapy may lead to a number of problems in management such as the on-off phenomenon discussed below. The most appropriate time to introduce levodopa therapy must therefore be determined individually.

When levodopa is used, it is generally given in combination with carbidopa (Figure 28–3), a peripheral dopa decarboxylase inhibitor, which reduces peripheral conversion to dopamine. Combination  treatment (Sinemet ) is started with a small dose, eg, Sinemet-25/100 (carbidopa 25 mg, levodopa 100 mg) three times daily, and gradually increased. It should be taken 30–60 minutes before meals. Most patients ultimately require Sinemet-25/250 (carbidopa 25 mg, levodopa 250 mg) three or four times daily. It is generally preferable to keep treatment with this agent at a low level (eg, Sinemet-25/100 three times daily) when possible, and to use a dopamine agonist instead, to reduce the risk of development of response fluctuations. A controlled-release formulation of Sinemet is available and may be helpful in patients with established response fluctuations or as a means of reducing dosing frequency. A formulation of carbidopa-levodopa (10/100, 25/100, 25/250) that disintegrates in the mouth and is swallowed with the saliva (Parcopa ) is now available commercially and is best taken about 1 hour before meals. The combination (Stalevo ) of levodopa, carbidopa, and a catechol-O-methyltransferase (COMT) inhibitor (entacapone) is discussed in a later section. Finally, monotherapy by intraduodenal infusion of levodopa-carbidopa appears to be safe and is superior to a number of oral combination therapies in patients with response fluctuations. This approach has been used to a greater extent in Europe than the USA, but interest is growing.

Levodopa can ameliorate all the clinical features of parkinsonism, but it is particularly effective in relieving bradykinesia and any disabilities resulting from it. When it is first introduced, about one third of patients respond very well and one third less well. Most of the remainder either are unable to tolerate the medication or simply do not respond at all, especially if they do not have classic Parkinson's disease.

Adverse Effects

Gastrointestinal Effects

When levodopa is given without a peripheral decarboxylase inhibitor, anorexia and nausea and vomiting occur in about 80% of patients. These adverse effects can be minimized by taking the drug in divided doses, with or immediately after meals, and by increasing the total daily dose very slowly; antacids taken 30–60 minutes before levodopa may also be beneficial. The vomiting has been attributed to stimulation of the chemoreceptor trigger zone located in the brain stem but outside the blood-brain barrier. Fortunately, tolerance to this emetic effect develops in many patients. Antiemetics such as phenothiazines should be avoided because they reduce the antiparkinsonism effects of levodopa and may exacerbate the disease.

When levodopa is given in combination with carbidopa, adverse gastrointestinal effects are much less frequent and troublesome, occurring in less than 20% of cases, so that patients can tolerate proportionately higher doses.

Cardiovascular Effects

A variety of cardiac arrhythmias have been described in patients receiving levodopa, including tachycardia, ventricular extrasystoles and, rarely, atrial fibrillation. This effect has been attributed to increased catecholamine formation peripherally. The incidence of such arrhythmias is low, even in the presence of established cardiac disease, and may be reduced still further if the levodopa is taken in combination with a peripheral decarboxylase inhibitor.

Postural hypotension is common, but often asymptomatic, and tends to diminish with continuing treatment. Hypertension may also occur, especially in the presence of nonselective monoamine oxidase inhibitors or sympathomimetics or when massive doses of levodopa are being taken.

Dyskinesias

Dyskinesias occur in up to 80% of patients receiving levodopa therapy for long periods. The form and nature of dopa dyskinesias vary widely among patients but tend to remain constant in character in individual patients. Choreoathetosis of the face and distal extremities is the most common presentation. The development of dyskinesias is dose-related, but there is considerable individual variation in the dose required to produce them.

Behavioral Effects

A wide variety of adverse mental effects have been reported, including depression, anxiety, agitation, insomnia, somnolence, confusion, delusions, hallucinations, nightmares, euphoria, and other changes in mood or personality. Such adverse effects are more common in patients taking levodopa in combination with a decarboxylase inhibitor rather than levodopa alone, presumably because higher levels are reached in the brain. They may be precipitated by intercurrent illness or operation. It may be necessary to reduce or withdraw the medication. Several atypical antipsychotic agents that have low affinity for dopamine D₂ receptors (clozapine, olanzapine, quetiapine, and risperidone; see Chapter 29) are now available and may be particularly helpful in counteracting such behavioral complications.

Fluctuations in Response

Certain fluctuations in clinical response to levodopa occur with increasing frequency as treatment continues. In some patients, these fluctuations relate to the timing of levodopa intake, and they are then referred to as wearing-off reactions or end-of-dose akinesia. In other instances, fluctuations in clinical state are unrelated to the timing of doses (on-off phenomenon). In the on-off phenomenon, off-periods of marked akinesia alternate over the course of a few hours with on-periods of improved mobility but often marked dyskinesia. The phenomenon is most likely to occur in patients who responded well to treatment initially. The exact mechanism is unknown. For patients with severe off-periods who are unresponsive to other measures, subcutaneously injected apomorphine may provide temporary benefit.

Miscellaneous Adverse Effects

Mydriasis may occur and may precipitate an attack of acute glaucoma in some patients. Other reported but rare adverse effects include various blood dyscrasias; a positive Coombs' test with evidence of hemolysis; hot flushes; aggravation or precipitation of gout; abnormalities of smell or taste; brownish discoloration of saliva, urine, or vaginal secretions; priapism; and mild—usually transient—elevations of blood urea nitrogen and of serum transaminases, alkaline phosphatase, and bilirubin.

Drug Holidays

A drug holiday (discontinuance of the drug for 3–21 days) may temporarily improve responsiveness to levodopa and alleviate some of its adverse effects but is usually of little help in the management of the on-off phenomenon. Furthermore, a drug holiday carries the risks of aspiration pneumonia, venous thrombosis, pulmonary embolism, and depression resulting from the immobility accompanying severe parkinsonism. For these reasons and because of the temporary nature of any benefit, drug holidays are not recommended.

Drug Interactions

Pharmacologic doses of pyridoxine (vitamin B6 ) enhance the extracerebral metabolism of levodopa and may therefore prevent its therapeutic effect unless a peripheral decarboxylase inhibitor is also taken. Levodopa should not be given to patients taking monoamine oxidase A inhibitors or within 2 weeks of their discontinuance because such a combination can lead to hypertensive crises.

Contraindications

Levodopa should not be given to psychotic patients because it may exacerbate the mental disturbance. It is also contraindicated in patients with angle-closure glaucoma, but those with chronic open-angle glaucoma may be given levodopa if intraocular pressure is well controlled and can be monitored. It is best given combined with carbidopa to patients with cardiac disease; even so, the risk of cardiac dysrhythmia is slight. Patients with active peptic ulcer must also be managed carefully, since gastrointestinal bleeding has occasionally occurred with levodopa. Because levodopa is a precursor of skin melanin and conceivably may activate malignant melanoma, it should be used with particular care in patients with a history of melanoma or with suspicious undiagnosed skin lesions; such patients should be monitored by a dermatologist regularly.

Dopamine Receptor Agonists

Drugs acting directly on dopamine receptors may have a beneficial effect in addition to that of levodopa (Figure 28–5). Unlike levodopa, they do not require enzymatic conversion to an active metabolite, have no potentially toxic metabolites, and do not compete with other substances for active transport into the blood and across the blood-brain barrier. Moreover, drugs selectively affecting certain (but not all) dopamine receptors may have more limited adverse effects than levodopa. A number of dopamine agonists have antiparkinsonism activity. The older dopamine agonists (bromocriptine and pergolide) are ergot (ergoline) derivatives (see Chapter 16), and their side effects are of more concern than those of the newer agents (pramipexole and ropinirole).

There is no evidence that one agonist is superior to another; individual patients, however, may respond to one but not another of these agents. Apomorphine is a potent dopamine agonist but is discussed separately in a later section in this chapter because it is used primarily as a rescue drug for patients with disabling response fluctuations to levodopa.

Dopamine agonists have an important role as first-line therapy for Parkinson's disease, and their use is associated with a lower incidence of the response fluctuations and dyskinesias that occur with long-term levodopa therapy. In consequence, dopaminergic therapy may best be initiated with a dopamine agonist. Alternatively, a low dose of carbidopa plus levodopa (eg, Sinemet-25/100 three times daily) is introduced, and a dopamine agonist is then added. In either case, the dose of the dopamine agonist is built up gradually depending on response and tolerance. Dopamine agonists may also be given to patients with parkinsonism who are taking levodopa and who have end-of-dose akinesia or on-off phenomenon or are becoming resistant to treatment with levodopa. In such circumstances, it is generally necessary to lower the dose of levodopa to prevent intolerable adverse effects. The response to a dopamine agonist is generally disappointing in patients who have never responded to levodopa.

Bromocriptine

Bromocriptine is a D₂ agonist; its structure is shown in Table 16–6. This drug has been widely used to treat Parkinson's disease in the past, but is now rarely used for this purpose, having been superseded by the newer dopamine agonists. Bromocriptine is absorbed to a variable extent from the gastrointestinal tract; peak plasma levels are reached within 1–2 hours after an oral dose. It is excreted in the bile and feces. The usual daily dose of bromocriptine for parkinsonism varies between 7.5 and 30 mg. To minimize adverse effects, the dose is built up slowly over 2 or 3 months from a starting level of 1.25 mg twice daily after meals; the daily dose is then increased by 2.5 mg every 2 weeks, depending on the response or the development of adverse reactions.

Pergolide

Pergolide, another ergot derivative, directly stimulates both D₁ and D₂ receptors. It too has been widely used for parkinsonism, and comparative studies suggest that it is more effective than bromocriptine in relieving the symptoms and signs of the disease, increasing on-time among response fluctuators, and permitting the levodopa dose to be reduced. The drug is no longer available because its use has been associated with the development of valvular heart disease.

Pramipexole

Pramipexole is not an ergot derivative, but it has preferential affinity for the D3 family of receptors. It is effective as monotherapy for mild parkinsonism and is also helpful in patients with advanced disease, permitting the dose of levodopa to be reduced and smoothing out response fluctuations. Pramipexole may ameliorate affective symptoms. A possible neuroprotective effect has been suggested by its ability to scavenge hydrogen peroxide and enhance neurotrophic activity in mesencephalic dopaminergic cell cultures.

Pramipexole is rapidly absorbed after oral administration, reaching peak plasma concentrations in approximately 2 hours, and is excreted largely unchanged in the urine. It is started at a dosage of 0.125 mg three times daily, doubled after 1 week, and again after another week. Further increments in the daily dose are by 0.75 mg at weekly intervals, depending on response and tolerance. Most patients require between 0.5 and 1.5 mg three times daily. Renal insufficiency may necessitate dosage adjustment.

Ropinirole

Another nonergoline derivative, ropinirole (now available in a generic preparation) is a relatively pure D₂ receptor agonist that is effective as monotherapy in patients with mild disease and as a means of smoothing the response to levodopa in patients with more advanced disease and response fluctuations. It is introduced at 0.25 mg three times daily, and the total daily dose is then increased by 0.75 mg at weekly intervals until the fourth week and by 1.5 mg thereafter. In most instances, a dosage between 2 and 8 mg three times daily is necessary. Ropinirole is metabolized by CYP1A2; other drugs metabolized by this isoform may significantly reduce its clearance. A prolonged-release preparation (Ropinirole XL) taken once daily is now available.

Rotigotine

The dopamine agonist rotigotine, delivered daily through a skin patch, was approved in 2007 by the FDA for treatment of early Parkinson's disease. It supposedly provides more continuous dopaminergic stimulation than oral medication in early disease; its efficacy in more advanced disease is less clear. Benefits and side effects are similar to those of other dopamine agonists but reactions may also occur at the application site and are sometimes serious. The product was recalled in 2008 because of crystal formation on the patches, affecting the availability and efficacy of the agonist.

Adverse Effects of Dopamine Agonists

Gastrointestinal Effects

Anorexia and nausea and vomiting may occur when a dopamine agonist is introduced and can be minimized by taking the medication with meals. Constipation, dyspepsia, and symptoms of reflux esophagitis may also occur. Bleeding from peptic ulceration has been reported.

Cardiovascular Effects

Postural hypotension may occur, particularly at the initiation of therapy. Painless digital vasospasm is a dose-related complication of long-term treatment with the ergot derivatives (bromocriptine or pergolide). When cardiac arrhythmias occur, they are an indication for discontinuing treatment. Peripheral edema is sometimes problematic. Cardiac valvulopathy may occur with pergolide.

Dyskinesias

Abnormal movements similar to those introduced by levodopa may occur and are reversed by reducing the total dose of dopaminergic drugs being taken.

Mental Disturbances

Confusion, hallucinations, delusions, and other psychiatric reactions are potential complications of dopaminergic treatment and are more common and severe with dopamine receptor agonists than with levodopa. Disorders of impulse control may lead to compulsive gambling, shopping, betting, sexual activity, and other behaviors. They clear on withdrawal of the offending medication.

Miscellaneous

Headache, nasal congestion, increased arousal, pulmonary infiltrates, pleural and retroperitoneal fibrosis, and erythromelalgia are other reported adverse effects of the ergot-derived dopamine agonists. Cardiac valvulopathies may occur with pergolide. Erythromelalgia consists of red, tender, painful, swollen feet and, occasionally, hands, at times associated with arthralgia; symptoms and signs clear within a few days of withdrawal of the causal drug. In rare instances, an uncontrollable tendency to fall asleep at inappropriate times has occurred, particularly in patients receiving pramipexole or ropinirole; this requires discontinuation of the medication.

Contraindications

Dopamine agonists are contraindicated in patients with a history of psychotic illness or recent myocardial infarction, or with active peptic ulceration. The ergot-derived agonists are best avoided in patients with peripheral vascular disease.

Monoamine Oxidase Inhibitors

Two types of monoamine oxidase have been distinguished in the nervous system. Monoamine oxidase A metabolizes norepinephrine, serotonin, and dopamine; monoamine oxidase B metabolizes dopamine selectively. Selegiline (deprenyl) (Figure 28–3), a selective irreversible inhibitor of monoamine oxidase B at normal doses (at higher doses it inhibits MAO-A as well), retards the breakdown of dopamine (Figure 28–5); in consequence, it enhances and prolongs the antiparkinsonism effect of levodopa (thereby allowing the dose of levodopa to be reduced) and may reduce mild on-off or wearing-off phenomena. It is therefore used as adjunctive therapy for patients with a declining or fluctuating response to levodopa. The standard dose of selegiline is 5 mg with breakfast and 5 mg with lunch. Selegiline may cause insomnia when taken later during the day.

Selegiline has only a minor therapeutic effect on parkinsonism when given alone. Studies in animals suggest that it may reduce disease progression, but trials to test the effect of selegiline on the progression of parkinsonism in humans have yielded ambiguous results. The findings in a large multicenter study were taken to suggest a beneficial effect in slowing disease progression but may simply have reflected a symptomatic response.

Rasagiline, another monoamine oxidase B inhibitor, is more potent than selegiline in preventing MPTP-induced parkinsonism and is being used for early symptomatic treatment. The standard dosage is 1 mg/d. Rasagiline is also used as adjunctive therapy at a dosage of 0.5 or 1 mg/d to prolong the effects of levodopa-carbidopa in patients with advanced disease. A large trial has recently shown that it provides neuroprotective benefit (ie, slows the disease course), but a full report has yet to be published.

Neither selegiline nor rasagiline should be taken by patients receiving meperidine. They should be used with care in patients receiving tricyclic antidepressants or serotonin reuptake inhibitors because of the theoretical risk of acute toxic interactions of the serotonin syndrome type (see Chapter 16), but this is rarely encountered in practice. The adverse effects of levodopa may be increased by these drugs.

The combined administration of levodopa and an inhibitor of both forms of monoamine oxidase (ie, a nonselective inhibitor) must be avoided, because it may lead to hypertensive crises, probably because of the peripheral accumulation of norepinephrine.

Catechol-O-Methyltransferase Inhibitors

Inhibition of dopa decarboxylase is associated with compensatory activation of other pathways of levodopa metabolism, especially catechol-O -methyltransferase (COMT), and this increases plasma levels of 3-O -methyldopa (3-OMD). Elevated levels of 3-OMD have been associated with a poor therapeutic response to levodopa, perhaps in part because 3-OMD competes with levodopa for an active carrier mechanism that governs its transport across the intestinal mucosa and the blood-brain barrier. Selective COMT inhibitors such as tolcapone and entacapone also prolong the action of levodopa by diminishing its peripheral metabolism (Figure 28–5). Levodopa clearance is decreased, and relative bioavailability of levodopa is thus increased. Neither the time to reach peak concentration nor the maximal concentration of levodopa is increased. These agents may be helpful in patients receiving levodopa who have developed response fluctuations—leading to a smoother response, more prolonged on-time, and the option of reducing total daily levodopa dose. Tolcapone and entacapone are both widely available, but entacapone is generally preferred because it has not been associated with hepatotoxicity.

The pharmacologic effects of tolcapone and entacapone are similar, and both are rapidly absorbed, bound to plasma proteins, and metabolized before excretion. However, tolcapone has both central and peripheral effects, whereas the effect of entacapone is peripheral. The half-life of both drugs is approximately 2 hours, but tolcapone is slightly more potent and has a longer duration of action. Tolcapone is taken in a standard dosage of 100 mg three times daily; some patients require a daily dose of twice that amount. By contrast, entacapone (200 mg) needs to be taken with each dose of levodopa, up to five times daily.

Adverse effects of the COMT inhibitors relate in part to increased levodopa exposure and include dyskinesias, nausea, and confusion. It is often necessary to lower the daily dose of levodopa by about 30% in the first 48 hours to avoid or reverse such complications. Other adverse effects include diarrhea, abdominal pain, orthostatic hypotension, sleep disturbances, and an orange discoloration of the urine. Tolcapone may cause an increase in liver enzyme levels and has been associated rarely with death from acute hepatic failure; accordingly, its use in the USA requires signed patient consent (as provided in the product labeling) plus monitoring of liver function tests every 2 weeks during the first year and less frequently thereafter. No such toxicity has been reported with entacapone.

A commercial preparation named Stalevo consists of a combination of levodopa with both carbidopa and entacapone. It is available in three strengths: Stalevo 50 (50 mg levodopa plus 12.5 mg carbidopa and 200 mg entacapone), Stalevo 100 (100 mg, 25 mg, and 200 mg, respectively), and Stalevo 150 (150 mg, 37.5 mg, and 200 mg). Use of this preparation simplifies the drug regimen and requires the consumption of a lesser number of tablets than otherwise. Stalevo is priced at or below the price of its individual components.

Apomorphine

Subcutaneous injection of apomorphine hydrochloride (Apokyn), a potent dopamine agonist, is effective for the temporary relief ("rescue") of off-periods of akinesia in patients on optimized dopaminergic therapy. It is rapidly taken up in the blood and then the brain, leading to clinical benefit that begins within about 10 minutes of injection and persists for up to 2 hours. The optimal dose is identified by administering increasing test doses until adequate benefit is achieved or a maximum of 10 mg is reached. Most patients require a dose of 3–6 mg, and this should be given no more than about three times daily.

Nausea is often troublesome, especially at the initiation of apomorphine treatment; accordingly, pretreatment with the antiemetic trimethobenzamide (300 mg three times daily) for 3 days is recommended before apomorphine is introduced and is then continued for at least 1 month, if not indefinitely. Other adverse effects include dyskinesias, drowsiness, chest pain, sweating, hypotension, and bruising at the injection site. Apomorphine should be prescribed only by physicians familiar with its potential complications and interactions.

Amantadine

Amantadine, an antiviral agent, was by chance found to have antiparkinsonism properties. Its mode of action in parkinsonism is unclear, but it may potentiate dopaminergic function by influencing the synthesis, release, or reuptake of dopamine. It has been reported to antagonize the effects of adenosine at adenosine A_2A receptors, which are receptors that may inhibit D₂ receptor function. Release of catecholamines from peripheral stores has also been documented.

Pharmacokinetics

Peak plasma concentrations of amantadine are reached 1–4 hours after an oral dose. The plasma half-life is between 2 and 4 hours, most of the drug being excreted unchanged in the urine.

Clinical Use

Amantadine is less efficacious than levodopa, and its benefits may be short-lived, often disappearing after only a few weeks of treatment. Nevertheless, during that time it may favorably influence the bradykinesia, rigidity, and tremor of parkinsonism. The standard dosage is 100 mg orally two or three times daily. Amantadine may also help in reducing iatrogenic dyskinesias in patients with advanced disease.

Adverse Effects

Amantadine has a number of undesirable central nervous system effects, all of which can be reversed by stopping the drug. These include restlessness, depression, irritability, insomnia, agitation, excitement, hallucinations, and confusion. Overdosage may produce an acute toxic psychosis. With doses several times higher than recommended, convulsions have occurred.

Livedo reticularis sometimes occurs in patients taking amantadine and usually clears within 1 month after the drug is withdrawn. Other dermatologic reactions have also been described. Peripheral edema, another well-recognized complication, is not accompanied by signs of cardiac, hepatic, or renal disease and responds to diuretics. Other adverse reactions to amantadine include headache, heart failure, postural hypotension, urinary retention, and gastrointestinal disturbances (eg, anorexia, nausea, constipation, and dry mouth).

Amantadine should be used with caution in patients with a history of seizures or heart failure.

Acetylcholine-Blocking Drugs

A number of centrally acting antimuscarinic preparations are available that differ in their potency and in their efficacy in different patients. Some of these drugs were discussed in Chapter 8. These agents may improve the tremor and rigidity of parkinsonism but have little effect on bradykinesia. Some of the more commonly used drugs are listed in Table 28–1.

Clinical Use

Treatment is started with a low dose of one of the drugs in this category, the dosage gradually being increased until benefit occurs or until adverse effects limit further increments. If patients do not respond to one drug, a trial with another member of the drug class is warranted and may be successful.

Adverse Effects

Antimuscarinic drugs have a number of undesirable central nervous system and peripheral effects (see Chapter 8) and are poorly tolerated by the elderly. Dyskinesias occur in rare cases. Acute suppurative parotitis sometimes occurs as a complication of dryness of the mouth.

If medication is to be withdrawn, this should be accomplished gradually rather than abruptly to prevent acute exacerbation of parkinsonism. For contraindications to the use of antimuscarinic drugs, see Chapter 8.

Surgical Procedures

In patients with advanced disease that is poorly responsive to pharmacotherapy, worthwhile benefit may follow thalamotomy (for conspicuous tremor) or posteroventral pallidotomy. Ablative surgical procedures, however, have generally been replaced by functional, reversible lesions induced by high-frequency deep brain stimulation, which has a lower morbidity.

Stimulation of the subthalamic nucleus or globus pallidus by an implanted electrode and stimulator has yielded good results for the management of the clinical fluctuations occurring in advanced parkinsonism. The anatomic substrate for such therapy is indicated in Figure 28–1. Such procedures are contraindicated in patients with secondary or atypical parkinsonism, dementia, or failure to respond to dopaminergic medication.

Transplantation of dopaminergic tissue (fetal substantia nigra tissue) has been reported to confer benefit in some parkinsonism patients, but the results are conflicting. In one controlled trial, symptomatic benefit occurred in younger (less than 60 years old) but not older patients. In another trial, benefits were inconsequential. Furthermore, uncontrollable dyskinesias occurred in some patients in both studies. This was attributed to a relative excess of dopamine from continued fiber outgrowth from the transplant. Further basic studies are required before other trials of cellular therapies are undertaken, and such approaches therefore remain investigational.

Neuroprotective Therapy

A number of compounds are under investigation as potential neuroprotective agents that may slow disease progression. These compounds include antioxidants, antiapoptotic agents, glutamate antagonists, intraparenchymally administered glial-derived neurotrophic factor, coenzyme Q10, creatine, and anti-inflammatory drugs. The role of these agents remains to be established, however, and their use for therapeutic purposes is not indicated at this time. The possibility that rasagiline has a protective effect was discussed earlier.

Gene Therapy

Three phase I (safety) trials of gene therapy for Parkinson's disease have now been completed in the USA. All trials involved infusion into the striatum of adeno-associated virus type 2 as the vector for the gene. The genes were for glutamic acid decarboxylase (the precursor of GABA, an inhibitory neurotransmitter), infused into the subthalamic nucleus to cause inhibition; for aromatic acid decarboxylase infused into the putamen to increase metabolism of levodopa to dopamine; and for neurturin (a growth factor that may enhance the survival of dopaminergic neurons), infused into the putamen. All agents were deemed safe, and the data suggested efficacy. Phase II trials are now planned or in progress.

Therapy for Nonmotor Manifestations

Persons with cognitive decline may respond to rivastigmine (1.5–6 mg twice daily), memantine (5–10 mg daily), or donepezil (5–10 mg daily) (see Chapter 60); affective disorders to antidepressants or anxiolytic agents (see Chapter 30); excessive daytime sleepiness to modafinil (100–400 mg in the morning) (see Chapter 9), and bladder and bowel disorders to appropriate symptomatic therapy (see Chapter 8).

General Comments on Drug Management of Patients with Parkinsonism

Parkinson's disease generally follows a progressive course. Moreover, the benefits of levodopa therapy often diminish with time, and serious adverse effects may complicate long-term levodopa treatment. Nevertheless, dopaminergic therapy at a relatively early stage may be most effective in alleviating symptoms of parkinsonism and may also favorably affect the mortality rate due to the disease. Therefore, several strategies have evolved for optimizing dopaminergic therapy, as summarized in Figure 28–5. Symptomatic treatment of mild parkinsonism is probably best avoided until there is some degree of disability or until symptoms begin to have a significant impact on the patient's lifestyle. When symptomatic treatment becomes necessary, a trial of rasagiline, amantadine, or an antimuscarinic drug may be worthwhile. With disease progression, dopaminergic therapy becomes necessary. This can conveniently be initiated with a dopamine agonist, either alone or in combination with low-dose Sinemet therapy. Physical therapy is helpful in improving mobility. In patients with severe parkinsonism and long-term complications of levodopa therapy such as the on-off phenomenon, a trial of treatment with a COMT inhibitor or rasagiline may be helpful. Regulation of dietary protein intake may also improve response fluctuations. Deep brain stimulation is often helpful in patients who fail to respond adequately to these measures. Treating patients who are young or have mild parkinsonism with rasagiline may delay disease progression and merits consideration.

Drug-Induced Parkinsonism

Reserpine and the related drug tetrabenazine deplete biogenic monoamines from their storage sites, whereas haloperidol, metoclopramide, and the phenothiazines block dopamine receptors. These drugs may therefore produce a parkinsonian syndrome, usually within 3 months after introduction. The disorder tends to be symmetric, with inconspicuous tremor, but this is not always the case. The syndrome is related to high dosage and clears over several weeks or months after withdrawal. If treatment is necessary, antimuscarinic agents are preferred. Levodopa is of no help if neuroleptic drugs are continued and may in fact aggravate the mental disorder for which antipsychotic drugs were prescribed originally.

In 1983, a drug-induced form of parkinsonism was discovered in individuals who attempted to synthesize and use a narcotic drug related to meperidine but actually synthesized and self-administered MPTP, as discussed in MPTP & Parkinsonism.

Other Movement Disorders

Tremor

Tremor consists of rhythmic oscillatory movements. Physiologic postural tremor, which is a normal phenomenon, is enhanced in amplitude by anxiety, fatigue, thyrotoxicosis, and intravenous epinephrine or isoproterenol. Propranolol reduces its amplitude and, if administered intra-arterially, prevents the response to isoproterenol in the perfused limb, presumably through some peripheral action. Certain drugs—especially the bronchodilators, valproate, tricyclic antidepressants, and lithium—may produce a dose-dependent exaggeration of the normal physiologic tremor that is reversed by discontinuing the drug. Although the tremor produced by sympathomimetics such as terbutaline (a bronchodilator) is blocked by propranolol, which antagonizes both ₁ and ₂ receptors, it is not blocked by metoprolol, a ₁-selective antagonist; this suggests that such tremor is mediated mainly by the ₂ receptors.

Essential tremor is a postural tremor, sometimes familial with autosomal dominant inheritance, which is clinically similar to physiologic tremor. At least three gene loci (ETM1 on 3q13, ETM2 on 2p24.1, and a locus on 6p23) have been described. Dysfunction of ₁ receptors has been implicated in some instances, since the tremor may respond dramatically to standard doses of metoprolol as well as to propranolol. The most useful approach is with propranolol, but whether the response depends on a central or peripheral action is unclear. The pharmacokinetics, pharmacologic effects, and adverse reactions of propranolol are discussed in Chapter 10. Daily doses of propranolol on the order of 120 mg (range, 60–240 mg) are usually required, prescribed as 40–120 mg orally twice daily, and reported adverse effects have been few. Propranolol should be used with caution in patients with heart failure, heart block, asthma, and hypoglycemia. Patients can be instructed to take their own pulse and call the physician if significant bradycardia develops. Metoprolol is sometimes useful in treating tremor when patients have concomitant pulmonary disease that contraindicates use of propranolol. Primidone (an antiepileptic drug; see Chapter 24), in gradually increasing doses up to 250 mg three times daily, is also effective in providing symptomatic control in some cases. Patients with tremor are very sensitive to primidone and often cannot tolerate the doses used to treat seizures; they should be started on 50 mg once daily and the daily dose increased by 50 mg every 2 weeks depending on response.

Topiramate, another antiepileptic drug, may also be helpful in a dose of 400 mg daily, built up gradually. Small quantities of alcohol may suppress essential tremor but only for a short time. Alprazolam (in doses up to 3 mg daily) or gabapentin (100–2400 mg/d) is helpful in some patients. Others are helped by intramuscular injections of botulinum toxin. Thalamic stimulation by an implanted electrode and stimulator is often worthwhile in advanced cases refractory to pharmacotherapy. Diazepam, chlordiazepoxide, mephenesin, and antiparkinsonism agents have been advocated in the past but are generally worthless. Anecdotal reports of benefit from mirtazapine were not confirmed in a double-blind study, which found no effect on the tremor in most patients.

Intention tremor is present during movement but not at rest; sometimes it occurs as a toxic manifestation of alcohol or drugs such as phenytoin. Withdrawal or reduction in dosage provides dramatic relief. There is no satisfactory pharmacologic treatment for intention tremor due to other neurologic disorders.

Rest tremor is usually due to parkinsonism.

Huntington's Disease

Huntington's disease is an autosomal dominant inherited disorder caused by an abnormality (expansion of a CAG trinucleotide repeat that codes for a polyglutamine tract) of the huntingtin gene on chromosome 4. An autosomal recessive form may also occur. Huntington disease–like (HDL) disorders are not associated with an abnormal CAG trinucleotide repeat number of the huntingtin gene. Autosomal dominant (HDL1, 20pter-p12; HDL2, 16q24.3) and recessive forms (HDL3, 4p15.3) occur.

Huntington's disease is characterized by progressive chorea and dementia that usually begin in adulthood. The development of chorea seems to be related to an imbalance of dopamine, acetylcholine, GABA, and perhaps other neurotransmitters in the basal ganglia (Figure 28–6). Pharmacologic studies indicate that chorea results from functional overactivity in dopaminergic nigrostriatal pathways, perhaps because of increased responsiveness of postsynaptic dopamine receptors or deficiency of a neurotransmitter that normally antagonizes dopamine. Drugs that impair dopaminergic neurotransmission, either by depleting central monoamines (eg, reserpine, tetrabenazine) or by blocking dopamine receptors (eg, phenothiazines, butyrophenones), often alleviate chorea, whereas dopamine-like drugs such as levodopa tend to exacerbate it.

Both GABA and the enzyme (glutamic acid decarboxylase) concerned with its synthesis are markedly reduced in the basal ganglia of patients with Huntington's disease, and GABA receptors are usually implicated in inhibitory pathways. There is also a significant decline in concentration of choline acetyltransferase, the enzyme responsible for synthesizing acetylcholine, in the basal ganglia of these patients. These findings may be of pathophysiologic significance and have led to attempts to alleviate chorea by enhancing central GABA or acetylcholine activity, but with disappointing results. As a consequence, the most commonly used drugs for controlling dyskinesia in patients with Huntington's disease are still those that interfere with dopamine activity. With all the latter drugs, however, reduction of abnormal movements may be associated with iatrogenic parkinsonism.

Reserpine depletes cerebral dopamine by preventing intraneuronal storage (see Chapter 6); it is introduced in low doses (eg, 0.25 mg daily), and the daily dose is then built up gradually (eg, by 0.25 mg every week) until benefit occurs or adverse effects become troublesome. A daily dose of 2–5 mg is often effective in suppressing abnormal movements, but adverse effects may include hypotension, depression, sedation, diarrhea, and nasal congestion. Tetrabenazine (12.5–50 mg orally three times daily) resembles reserpine in depleting cerebral dopamine and has less troublesome adverse effects; it is now available in the USA. Treatment with postsynaptic dopamine receptor blockers such as phenothiazines and butyrophenones may also be helpful. Haloperidol is started in a small dose, eg, 1 mg twice daily, and increased every 4 days depending on the response. If haloperidol is not helpful, treatment with increasing doses of perphenazine up to a total of about 20 mg daily sometimes helps. Several recent reports suggest that olanzapine may also be useful; the dose varies with the patient, but 10 mg daily is often sufficient although doses as high as 30 mg daily are sometimes required. The pharmacokinetics and clinical properties of these drugs are considered in greater detail elsewhere in this book. Selective serotonin reuptake inhibitors may reduce depression, aggression, and agitation.

Other Forms of Chorea

Benign hereditary chorea is inherited (usually autosomal dominant; possibly also autosomal recessive) or arises spontaneously. Chorea develops in early childhood and does not progress during adult life; dementia does not occur. In patients with TITF-1 gene mutations, thyroid and pulmonary abnormalities may also be present (brain-thyroid-lung syndrome). Familial chorea may also occur as part of the chorea-acanthocytosis syndrome, together with orolingual tics, vocalizations, cognitive changes, seizures, peripheral neuropathy, and muscle atrophy; serum -lipoproteins are normal. Treatment of these hereditary disorders is symptomatic.

Treatment is directed at the underlying cause when chorea occurs as a complication of general medical disorders such as thyrotoxicosis, polycythemia vera rubra, systemic lupus erythematosus, hypocalcemia, and hepatic cirrhosis. Drug-induced chorea is managed by withdrawal of the offending substance, which may be levodopa, an antimuscarinic drug, amphetamine, lithium, phenytoin, or an oral contraceptive. Neuroleptic drugs may also produce an acute or tardivedyskinesia (discussed below). Sydenham's chorea is temporary and usually so mild that pharmacologic management of the dyskinesia is unnecessary, but dopamine-blocking drugs are effective in suppressing it.

Ballismus

The biochemical basis of ballismus is unknown, but the pharmacologic approach to management is the same as for chorea. Treatment with haloperidol, perphenazine, or other dopamine-blocking drugs may be helpful.

Athetosis & Dystonia

The pharmacologic basis of these disorders is unknown, and there is no satisfactory medical treatment for them. A subset of patients respond well to levodopa medication (dopa-responsive dystonia), which is therefore worthy of trial. Occasional patients with dystonia may respond to diazepam, amantadine, antimuscarinic drugs (in high dosage), carbamazepine, baclofen, haloperidol, or phenothiazines. A trial of these pharmacologic approaches is worthwhile, though often not successful. Patients with focal dystonias such as blepharospasm or torticollis often benefit from injection of botulinum toxin into the overactive muscles. The role of deep brain stimulation for the treatment of these conditions is being explored.

Tics

The pathophysiologic basis of tics is unknown. Chronic multiple tics (Gilles de la Tourette's syndrome) may require symptomatic treatment if the disorder is severe or is having a significant impact on the patient's life. Education of patients, family, and teachers is important.

The most effective pharmacologic approach is with haloperidol, and patients are better able to tolerate this drug if treatment is started with a small dosage (eg, 0.25 or 0.5 mg daily) and then increased gradually (eg, by 0.25 mg every 4 or 5 days) over the following weeks depending on response and tolerance. Most patients ultimately require a total daily dose of 3–8 mg. Adverse effects include extrapyramidal movement disorders, sedation, dryness of the mouth, blurred vision, and gastrointestinal disturbances. Pimozide, another dopamine receptor antagonist, may be helpful in patients who are either unresponsive to or intolerant of haloperidol. Treatment is started at 1 mg/d, and the dosage is increased by 1 mg every 5 days; most patients require 7–16 mg/d.

If these measures fail, clonidine, fluphenazine, clonazepam, or carbamazepine should be tried. The pharmacologic properties of these drugs are discussed elsewhere in this book. Clonidine reduces motor or vocal tics in about 50% of children so treated. It may act by reducing activity in noradrenergic neurons in the locus coeruleus. It is introduced at a dose of 2–3 mcg/kg/d, increasing after 2 weeks to 4 mcg/kg/d and then, if required, to 5 mcg/kg/d. It may cause an initial transient fall in blood pressure. The most common adverse effect is sedation; other adverse effects include reduced or excessive salivation and diarrhea. Phenothiazines such as fluphenazine sometimes help the tics, as do dopamine agonists. The role of the newer atypical antipsychotic agents, such as risperidone, is unclear.

Injection of botulinum toxin A at the site of problematic tics is sometimes helpful. Treatment of any associated attention deficit disorder (eg, with clonidine patch, guanfacine, pemoline, methylphenidate, or dextroamphetamine) or obsessive-compulsive disorder (selective serotonin reuptake inhibitors or clomipramine) may be required. Bilateral thalamic stimulation is sometimes worthwhile in otherwise intractable cases.

Drug-Induced Dyskinesias

Levodopa or dopamine agonists produce diverse dyskinesias as a dose-related phenomenon in patients with Parkinson's disease; dose reduction reverses them. Chorea may also develop in patients receiving phenytoin, carbamazepine, amphetamines, lithium, and oral contraceptives, and it resolves with discontinuance of the offending medication. Dystonia has resulted from administration of dopaminergic agents, lithium, serotonin reuptake inhibitors, carbamazepine, and metoclopramide; and postural tremor from theophylline, caffeine, lithium, valproic acid, thyroid hormone, tricyclic antidepressants, and isoproterenol.

The pharmacologic basis of the acute dyskinesia or dystonia sometimes precipitated by the first few doses of a phenothiazine is not clear. In most instances, parenteral administration of an antimuscarinic drug such as benztropine (2 mg intravenously), diphenhydramine (50 mg intravenously), or biperiden (2–5 mg intravenously or intramuscularly) is helpful, whereas in other instances diazepam (10 mg intravenously) alleviates the abnormal movements.

Tardive dyskinesia, a disorder characterized by a variety of abnormal movements, is a common complication of long-term neuroleptic or metoclopramide drug treatment (see Chapter 29). Its precise pharmacologic basis is unclear. A reduction in dose of the offending medication, a dopamine receptor blocker, commonly worsens the dyskinesia, whereas an increase in dose may suppress it. The drugs most likely to provide immediate symptomatic benefit are those interfering with dopaminergic function, either by depletion (eg, reserpine, tetrabenazine) or receptor blockade (eg, phenothiazines, butyrophenones). Paradoxically, the receptor-blocking drugs are the very ones that also cause the dyskinesia.

Tardive dystonia is usually segmental or focal; generalized dystonia is less common and occurs in younger patients. Treatment is the same as for tardive dyskinesia, but anticholinergic drugs may also be helpful; focal dystonias may also respond to local injection of botulinum A toxin. Tardive akathisia is treated similarly to drug-induced parkinsonism. Rabbit syndrome, another neuroleptic-induced disorder, is manifested by rhythmic vertical movements about the mouth; it may respond to anticholinergic drugs.

Because the tardive syndromes that develop in adults are often irreversible and have no satisfactory treatment, care must be taken to reduce the likelihood of their occurrence. Antipsychotic medication should be prescribed only when necessary and should be withheld periodically to assess the need for continued treatment and to unmask incipient dyskinesia. Thioridazine, a phenothiazine with a piperidine side chain, is an effective antipsychotic agent that seems less likely than most to cause extrapyramidal reactions, perhaps because it has little effect on dopamine receptors in the striatal system. Finally, antimuscarinic drugs should not be prescribed routinely in patients receiving neuroleptics, because the combination may increase the likelihood of dyskinesia.

Neuroleptic malignant syndrome, a rare complication of treatment with neuroleptics, is characterized by rigidity, fever, changes in mental status, and autonomic dysfunction. Symptoms typically develop over 1–3 days (rather than minutes to hours as in malignant hyperthermia) and may occur at any time during treatment. Treatment includes withdrawal of antipsychotic drugs, lithium, and anticholinergics; reduction of body temperature; and rehydration. Dantrolene, dopamine agonists, levodopa, or amantadine may be helpful, but there is a high mortality rate (up to 20%) with neuroleptic malignant syndrome.

Restless Legs Syndrome

Restless legs syndrome is characterized by an unpleasant creeping discomfort that seems to arise deep within the legs and occasionally the arms. Symptoms occur particularly when patients are relaxed, especially when they are lying down or sitting, and they lead to an urge to move about. Such symptoms may delay the onset of sleep. A sleep disorder associated with periodic movements during sleep may also occur. The cause is unknown, but the disorder is especially common among pregnant women and also among uremic or diabetic patients with neuropathy. In most patients, no obvious predisposing cause is found, but several genetic loci have been associated with it (12q12-q21, 14q13-q31, 9p24-p22, 2q33, and 20p13).

Symptoms may resolve with correction of coexisting iron-deficiency anemia and often respond to dopamine agonists, levodopa, diazepam, clonazepam, gabapentin, or opiates. Dopaminergic therapy is the preferred treatment for restless legs syndrome and should be initiated with long-acting dopamine agonists (eg, pramipexole 0.125–0.75 mg or ropinirole 0.25–4.0 mg once daily) to avoid the augmentation that may be associated with levodopa-carbidopa (100/25 or 200/50 taken about 1 hour before bedtime). Augmentation refers to the earlier onset or enhancement of symptoms; earlier onset of symptoms at rest; and a briefer response to medication. When augmentation occurs with levodopa, the daily dose should be reduced or a dopamine agonist substituted. If it occurs in patients receiving an agonist, the daily dose should be lowered or divided, or opioids substituted. When opiates are required, those with long half-lives or low addictive potential should be used. Oxycodone is often effective; the dose is individualized. Gabapentin is an alternative to opioids and is taken once or twice daily (in the evening and before sleep); the starting dose is 300 mg daily, building up depending on response and tolerance (to approximately 1800 mg daily).

Wilson's Disease

A recessively inherited (13q14.3–q21.1) disorder of copper metabolism, Wilson's disease is characterized biochemically by reduced serum copper and ceruloplasmin concentrations, pathologically by markedly increased concentration of copper in the brain and viscera, and clinically by signs of hepatic and neurologic dysfunction. Neurologic signs include tremor, choreiform movements, rigidity, hypokinesia, and dysarthria and dysphagia. Siblings of affected patients should be screened for asymptomatic Wilson's disease.

Treatment involves the removal of excess copper, followed by maintenance of copper balance. A commonly used agent for this purpose is penicillamine (dimethylcysteine), a chelating agent that forms a ring complex with copper. It is readily absorbed from the gastrointestinal tract and rapidly excreted in the urine. A common starting dose in adults is 500 mg three or four times daily. After remission occurs, it may be possible to lower the maintenance dose, generally to not less than 1 g daily, which must thereafter be continued indefinitely. Adverse effects include nausea and vomiting, nephrotic syndrome, a lupus-like syndrome, pemphigus, myasthenia, arthropathy, optic neuropathy, and various blood dyscrasias. In some instances, worsening occurs with penicillamine. Treatment should be monitored by frequent urinalysis and complete blood counts. Dietary copper should also be kept below 2 mg daily. Potassium disulfide, 20 mg three times daily with meals, reduces the intestinal absorption of copper and should also be prescribed.

For patients who are unable to tolerate penicillamine, trientine, another chelating agent, may be used in a daily dose of 1–1.5 g. Trientine appears to have few adverse effects other than mild anemia due to iron deficiency in a few patients. Zinc acetate administered orally increases the fecal excretion of copper and is sometimes used for maintenance therapy. The dose is 50 mg three times a day. Zinc sulfate (200 mg/d orally) has also been used to decrease copper absorption. Zinc blocks copper absorption from the gastrointestinal tract by induction of intestinal cell metallothionein. Its main advantage is its low toxicity compared with that of other anticopper agents, although it may cause gastric irritation when introduced.

Summary: Drugs Used for Movement Disorders

Preparations Available

¹Not available in the USA.

References