OTHER MOVEMENT DISORDERS
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 iso-proterenol 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 bronchodi-lator) is blocked by propranolol, which antagonizes both β1 and β2receptors, it is not blocked by metoprolol, a β1-selective antag-onist; this suggests that such tremor is mediated mainly by the β2 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 β1 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, pharmaco-logic effects, and adverse reactions of propranolol are discussed. 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 signifi-cant bradycardia develops. Metoprolol is sometimes useful in treating tremor when patients have concomitant pulmonary dis-ease that contraindicates use of propranolol. Primidone (an anti-epileptic drug;), in gradually increasing doses up to 250 mg three times daily, is also effective in providing symp-tomatic control in some cases. Patients with tremor are very sensi-tive 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 ina dose of 400 mg daily, built up gradually. 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. Small quantities of alcohol may suppress essential tremor for a short time but should not be recommended as a treatment strategy because of possible behav-ioral and other complications of alcohol.
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 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, acetyl-choline, 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 post-synaptic dopamine receptors or deficiency of a neurotransmitter that normally antagonizes dopamine.
Drugs that impair dopamin-ergic 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 recep-tors 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 pathophysio-logic significance and have led to attempts to alleviate chorea by enhancing central GABA or acetylcholine activity, but with disap-pointing 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 intraneu-ronal storage ; 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) resemblesreserpine in depleting cerebral dopamine and has less troublesome adverse effects. 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 haloperi-dol 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 pharmacoki-netics 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.
Benign hereditary chorea is inherited (usually autosomal domi-nant; 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 pres-ent (brain-thyroid-lung syndrome). Familial chorea may also occur as part of the chorea-acanthocytosis syndrome, together with oro-lingual tics, vocalizations, cognitive changes, seizures, peripheral neuropathy, and muscle atrophy; serum β-lipoproteins are normal. Mutations of the gene encoding chorein at 9q21 may be causal. 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 thy-rotoxicosis, polycythemia vera rubra, systemic lupus erythemato-sus, hypocalcemia, and hepatic cirrhosis. Drug-induced chorea is managed by withdrawal of the offending substance, which may be levodopa, an antimuscarinic drug, amphetamine, lithium, pheny-toin, or an oral contraceptive. Neuroleptic drugs may also produce an acute or tardive dyskinesia (discussed below). Sydenham’s cho-rea is temporary and usually so mild that pharmacologic manage-ment of the dyskinesia is unnecessary, but dopamine-blocking drugs are effective in suppressing it.
The biochemical basis of ballismus is unknown, but the pharma-cologic approach to management is the same as for chorea. Treatment with haloperidol, perphenazine, or other dopamine-blocking drugs may be helpful.
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 dysto-nia may respond to diazepam, amantadine, antimuscarinic drugs (in high dosage), carbamazepine, baclofen, haloperidol, or phe-nothiazines. A trial of these pharmacologic approaches is worth-while, though often not successful. Patients with focal dystonias such as blepharospasm or torticollis often benefit from injection of botulinum toxin into the overactive muscles. Deep brain stimu-lation may be helpful in medically intractable cases.
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.
A common pharmacologic approach is with haloperidol. 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 ulti-mately 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 helpfulin patients as a first-line treatment or in those who are either unre-sponsive 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. It has similar side effects to haloperi-dol but may cause irregularities of cardiac rhythm.
Although not approved by the FDA for the treatment of tics or Tourette’s syndrome, certain α-adrenergic agonists may be pre-ferred as an initial treatment because they are less likely to cause extrapyramidal side effects than neuroleptics agents. 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 caeruleus. 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. Guanfacine, another α-adrenergic agonist, has also been used.
Phenothiazines such as fluphenazine sometimes help the tics, as do dopamine agonists. Atypical antipsychotics, such as risperi-done and aripiprazole, have a more favorable side-effect profile and may be especially worthwhile in patients with significant behavioral problems. Clonazepam and carbamazepine have also been used. The pharmacologic properties of these drugs are dis-cussed elsewhere in this book.
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, meth-ylphenidate, or dextroamphetamine) or obsessive-compulsive dis-order (selective serotonin reuptake inhibitors or clomipramine) may be required. Deep brain stimulation is sometimes worthwhile in otherwise intractable cases but is best regarded as an investiga-tional approach at this time.
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 administrationof 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 anti-muscarinic 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 ofabnormal movements, is a common complication of long-term neuroleptic or metoclopramide drug treatment . 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 deple-tion (eg, reserpine, tetrabenazine) or receptor blockade (eg, phe-nothiazines, butyrophenones). Paradoxically, the receptor-blocking drugs are the very ones that also cause the dyskinesia.
Tardive dystonia is usually segmental or focal; generalizeddystonia is less common and occurs in younger patients. Treatment is the same as for tardive dyskinesia, but anticholin-ergic 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 syn-drome, another neuroleptic-induced disorder, is manifested byrhythmic 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 neces-sary 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, anti-muscarinic 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 treat-ment with neuroleptics, is characterized by rigidity, fever, changes in mental status, and autonomic dysfunction (see Table 16–4). 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 tempera-ture; 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 is characterized by an unpleasant creeping discomfort that seems to arise deep within the legs and occasion-ally 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 move-ments 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). A recent study suggests that pregabalin, a related drug, is also effective at a daily total dosage of 150–300 mg, taken in divided doses.
A recessively inherited (13q14.3–q21.1) disorder of copper metabolism, Wilson’s disease is characterized biochemically by reduced serum copper and ceruloplasmin concentrations, patho-logically 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 move-ments, 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. Dietary copper should also be kept below 2 mg daily. Penicillamine (dimethylcysteine) has been used for many years as the primary agent to remove copper. It is 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, pem-phigus, myasthenia, arthropathy, optic neuropathy, and various blood dyscrasias. In about 10% of instances, neurologic worsening occurs with penicillamine. Treatment should be monitored by frequent urinalysis and complete blood counts.
Trientine hydrochloride,another chelating agent, is preferred bymany over penicillamine because of the lesser likelihood of drug reac-tions or neurologic worsening. It 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. Tetrathiomolybdate may be better than trientine for preserving neurologic function in patients with neurologic involvement and is taken both with and between meals. It is not yet commercially available.
Zinc acetate administered orally increases the fecal excretion of copper and can be used in combination with these other agents. 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 induc-tion 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.
Liver transplantation is sometimes necessary. The role of hepatocyte transplantation and gene therapy is currently under investigation.