1. Essential (Familial) Tremor
ESSENTIALS OF DIAGNOSIS
Postural tremor of hands, head, or voice.
Family history common.
May improve temporarily with alcohol.
No abnormal findings other than tremor.
The cause of essential tremor is uncertain, but it is sometimes inherited in an autosomal dominant manner. Responsible genes have been identified at 3q13, 2p22-p25, and 6p23.
Tremor may begin at any age and is enhanced by emotional stress. The tremor usually involves one or both hands, the head, or the hands and head, while the legs tend to be spared. The tremor is not present at rest, but emerges with action. Examination reveals no other abnormalities. Ingestion of a small quantity of alcohol commonly provides remarkable but short-lived relief by an unknown mechanism.
Although the tremor may become more conspicuous with time, it generally leads to little disability. Occasionally, it interferes with manual skills and leads to impairment of handwriting. Speech may also be affected if the laryngeal muscles are involved.
Treatment is often unnecessary. When it is required because of disability, propranolol (60–240 mg daily orally) may be helpful. Long-term therapy is typical; however, intermittent therapy is sometimes useful in patients whose tremor becomes exacerbated in specific predictable situations. Primidone may be helpful when propranolol is ineffective, but patients with essential tremor are often very sensitive to it. Therefore, the starting dose is 50 mg daily orally, and the daily dose is increased by 50 mg every 2 weeks depending on the patient’s response; a maintenance dose of 125 mg three times daily orally is commonly effective. Occasional patients do not respond to these measures but are helped by alprazolam (up to 3 mg daily orally in divided doses), topiramate (titrated up to a dose of 400 mg daily orally in divided doses over about 8 weeks), or gabapentin (1800 mg daily orally in divided doses). Botulinum toxin A may reduce tremor, but adverse effects include dose-dependent weakness of the injected muscles. Levetiracetam, flunarizine, and 3,4-diaminopyridine are probably ineffective, and there is insufficient evidence to support the use of pregabalin, zonisamide, and clozapine.
Disabling tremor unresponsive to medical treatment may be helped by high-frequency thalamic stimulation on one or both sides, according to the laterality of symptoms. Subdural motor cortex stimulation has also been effective in a small trial.
When refractory to first-line treatment with propranolol or primidone.
When additional neurologic signs are present (ie, parkinsonism).
Patients requiring surgical treatment (deep brain stimulator placement) should be hospitalized.
ESSENTIALS OF DIAGNOSIS
Any combination of tremor, rigidity, bradykinesia, and progressive postural instability.
Cognitive impairment is sometimes prominent.
Parkinsonism is a relatively common disorder that occurs in all ethnic groups, with an approximately equal sex distribution. The most common variety, idiopathic Parkinson disease, begins most often between 45 and 65 years of age and is a progressive disease.
Parkinsonism may rarely occur on a familial basis, and the parkinsonian phenotype may result from mutations of several different genes (alpha-synuclein, parkin, LRRK2, DJ1, and PINK1). Mutations in LRRK2 also account for some cases of apparently sporadic Parkinson disease. Postencephalitic parkinsonism is becoming increasingly rare. Exposure to certain toxins (eg, manganese dust, carbon disulfide) and severe carbon monoxide poisoning may lead to parkinsonism. Parkinsonism has occurred in individuals who have taken 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) for recreational purposes. This compound is converted in the body to a neurotoxin that selectively destroys dopaminergic neurons in the substantia nigra. Reversible parkinsonism may develop in patients receiving neuroleptic drugs (see Chapter 25), reserpine, or metoclopramide. Only rarely is hemiparkinsonism the presenting feature of a progressive space-occupying lesion.
In idiopathic Parkinson disease, dopamine depletion due to degeneration of the dopaminergic nigrostriatal system leads to an imbalance of dopamine and acetylcholine, which are neurotransmitters normally present in the corpus striatum. Treatment of the motor disturbance is directed at redressing this imbalance by blocking the effect of acetylcholine with anticholinergic drugs or by the administration of levodopa, the precursor of dopamine. Prior use of ibuprofen is associated with a decreased risk of developing Parkinson disease; age, family history, male sex, ongoing herbicide/pesticide exposure, and significant prior head trauma are risk factors.
Tremor, rigidity, bradykinesia, and postural instability are the cardinal motor features of parkinsonism and may be present in any combination. There may also be a mild decline in intellectual function. Depression, anxiety, anosmia, constipation, and sleep disturbances are common. The tremor of about four to six cycles per second is most conspicuous at rest, is enhanced by emotional stress, and is often less severe during voluntary activity. Although it may ultimately be present in all limbs, the tremor is commonly confined to one limb or to the limbs on one side for months or years before it becomes more generalized. In some patients, tremor is absent.
Rigidity (an increase in resistance to passive movement) is responsible for the characteristically flexed posture seen in many patients, but the most disabling symptoms of parkinsonism are due to bradykinesia, manifested as a slowness of voluntary movement and a reduction in automatic movements such as swinging of the arms while walking. Curiously, however, effective voluntary activity may briefly be regained during an emergency (eg, the patient is able to leap aside to avoid an oncoming motor vehicle).
Clinical diagnosis of the well-developed syndrome is usually simple. The patient has a relatively immobile face with widened palpebral fissures, infrequent blinking, and a fixity of facial expression. Seborrhea of the scalp and face is common. There is often mild blepharoclonus, and a tremor may be present about the mouth and lips. Repetitive tapping (about twice per second) over the bridge of the nose produces a sustained blink response (Myerson sign). Other findings may include saliva drooling from the mouth, perhaps due to impairment of swallowing; soft and poorly modulated voice; a variable rest tremor and rigidity in some or all of the limbs; slowness of voluntary movements; impairment of fine or rapidly alternating movements; and micrographia. There is typically no muscle weakness (provided that sufficient time is allowed for power to be developed) and no alteration in the tendon reflexes or plantar responses. It is difficult for the patient to arise from a sitting position and begin walking. The gait itself is characterized by small shuffling steps and a loss of the normal automatic arm swing; there may be unsteadiness on turning, difficulty in stopping, and a tendency to fall. The serum urate level may be a prognostic indicator in men—the rate of progression declines as the urate level increases.
Diagnostic problems may occur in mild cases, especially if tremor is minimal or absent. For example, mild hypokinesia or slight tremor is commonly attributed to old age. Depression, with its associated expressionless face, poorly modulated voice, and reduction in voluntary activity, can be difficult to distinguish from mild parkinsonism, especially since the two disorders may coexist; in some cases, a trial of antidepressant drug therapy is necessary. The family history, the character of the tremor, and lack of other neurologic signs should distinguish essential tremor from parkinsonism. Wilson disease can be distinguished by its early age at onset, the presence of other abnormal movements, Kayser-Fleischer rings, and chronic hepatitis, and by increased concentrations of copper in the tissues. Huntington disease presenting with rigidity and bradykinesia may be mistaken for parkinsonism unless the family history and accompanying dementia are recognized. In multisystem atrophy (previously called the Shy-Drager syndrome), autonomic insufficiency (leading to postural hypotension, anhidrosis, disturbances of sphincter control, erectile dysfunction, etc) may be accompanied by parkinsonism, pyramidal deficits, lower motor neuron signs, or cerebellar dysfunction. In progressive supranuclear palsy, bradykinesia and rigidity are accompanied by a supranuclear disorder of eye movements, pseudobulbar palsy, pseudo-emotional lability (pseudobulbar affect), and axial dystonia. Creutzfeldt-Jakob disease may be accompanied by features of parkinsonism, but progression is rapid, dementia is usual, myoclonic jerking is common, ataxia and pyramidal signs may be conspicuous, and the MRI and electroencephalographic findings are usually characteristic. In corticobasal degeneration, asymmetric parkinsonism is accompanied by conspicuous signs of cortical dysfunction (eg, apraxia, sensory inattention, dementia, aphasia).
Treatment is symptomatic. There is great interest in developing disease-modifying therapies, but trials of several putative neuroprotective agents have shown no benefit. Trials of various gene therapies have shown limited or no benefit.
Drug treatment is not required early in the course of Parkinson disease, but the nature of the disorder and the availability of medical treatment for use when necessary should be discussed with the patient.
Patients with mild symptoms but no disability may be helped by amantadine. This drug improves all of the clinical features of parkinsonism, but its mode of action is unclear. Side effects include restlessness, confusion, depression, skin rashes, edema, nausea, constipation, anorexia, postural hypotension, and disturbances of cardiac rhythm. However, these are relatively uncommon with the usual dose (100 mg twice daily orally). It also ameliorates dyskinesias resulting from chronic levodopa therapy.
Levodopa, which is converted in the body to dopamine, improves all of the major features of parkinsonism, including bradykinesia, but does not stop progression of the disorder. The most common early side effects of levodopa are nausea, vomiting, and hypotension, but cardiac arrhythmias may also occur. Dyskinesias, restlessness, confusion, and other behavioral changes tend to occur somewhat later and become more common with time. Levodopa-induced dyskinesias may take any conceivable form, including chorea, athetosis, dystonia, tremor, tics, and myoclonus. An even later complication is the “wearing off effect” or the “on-off phenomenon,” in which abrupt but transient fluctuations in the severity of parkinsonism occur unpredictably but frequently during the day. The “off” period of marked bradykinesia has been shown to relate in some instances to falling plasma levels of levodopa. During the “on” phase, dyskinesias are often conspicuous but mobility is increased. However, such response fluctuations may relate to advancing disease rather than to levodopa therapy itself.
Carbidopa, which inhibits the enzyme responsible for the breakdown of levodopa to dopamine, does not cross the blood-brain barrier. When levodopa is given in combination with carbidopa, the extracerebral breakdown of levodopa is diminished. This reduces the amount of levodopa required daily for beneficial effects, and it lowers the incidence of nausea, vomiting, hypotension, and cardiac irregularities. Such a combination does not prevent the development of response fluctuations and the incidence of other side effects (dyskinesias or psychiatric complications) may actually be increased.
Sinemet, a commercially available preparation that contains carbidopa and levodopa in a fixed ratio (1:10 or 1:4), is generally used. Treatment is started with a small dose—eg, one tablet of Sinemet 25/100 (containing 25 mg of carbidopa and 100 mg of levodopa) three times daily—and gradually increased depending on the response. Sinemet CR is a controlled-release formulation (containing 25 or 50 mg of carbidopa and 100 or 200 mg of levodopa). It is mainly useful when taken at bedtime to lessen motor disability upon awakening. A formulation of carbidopa/levodopa (Rytary) containing both immediate- and delayed-release beads provides a smoother response in patients with fluctuations. The commercially available combination of levodopa with both carbidopa and entacapone (Stalevo) may also be helpful in this context and is discussed in the following section on COMT inhibitors. Response fluctuations are also reduced by keeping the daily intake of protein at the recommended minimum and taking the main protein meal as the last meal of the day.
The dyskinesias and behavioral side effects of levodopa are dose-related, but reduction in dose may eliminate any therapeutic benefit. Levodopa-induced dyskinesias may also respond to amantadine or possibly levetiracetam.
Levodopa therapy is contraindicated in patients with psychotic illness or narrow-angle glaucoma. It should not be given to patients taking monoamine oxidase A inhibitors or within 2 weeks of their withdrawal, because hypertensive crises may result. Levodopa should be used with care in patients with suspected melanomas or with active peptic ulcers because of concerns that it may exacerbate these disorders.
Dopamine agonists, such as pramipexole and ropinirole, act directly on dopamine receptors, and their use in parkinsonism is associated with a lower incidence of the response fluctuations and dyskinesias that occur with long-term levodopa therapy. They are effective in both early and advanced stages of Parkinson disease. They are often given either before the introduction of levodopa or with a low dose of Sinemet 25/100 (carbidopa 25 mg and levodopa 100 mg, one tablet three times daily) when dopaminergic therapy is first introduced; the dose of Sinemet is kept constant, while the dose of the agonist is gradually increased.
Pramipexole is started at a dosage of 0.125 mg three times daily orally, and the dose is doubled after 1 week and again after another week; the daily dose is then increased 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 orally. Ropinirole is begun in a dosage of 0.25 mg three times daily orally, and the total daily dose is increased at weekly intervals by 0.75 mg until the fourth week and by 1.5 mg thereafter. Most patients require between 2 and 8 mg three times daily for benefit. Extended-release, once-daily formulations of pramipexole and ropinirole have similar efficacy and tolerability as the immediate release versions. Rotigotine is a dopamine agonist absorbed transdermally from a skin patch; it is started at 2 mg once daily and increasing weekly by 2 mg daily until achieving an optimal response, up to a maximum of 8 mg daily. Adverse effects of these various agonists include fatigue, somnolence, nausea, peripheral edema, dyskinesias, confusion, and postural hypotension. Less commonly, an irresistible urge to sleep may occur, sometimes in inappropriate and hazardous circumstances. Impulse control disorders involving gambling, shopping, or sexual activity have also been related to use of dopamine agonists. Local skin reactions may occur with the rotigotine patch.
4. Selective monoamine oxidase inhibitors
Rasagiline, a selective monoamine oxidase B inhibitor, has a clear symptomatic benefit in a daily oral dose of 1 mg, taken in the morning; it may also be used for adjunctive therapy in patients with response fluctuations to levodopa. Selegiline (5 mg orally with breakfast and lunch) is another monoamine oxidase B inhibitor that is sometimes used as adjunctive treatment for parkinsonism. By inhibiting the metabolic breakdown of dopamine, these drugs may improve fluctuations or declining response to levodopa. Although it is sometimes advised that tyramine-rich foods be avoided when either rasagiline or selegiline is taken because of the theoretical possibility of a hypertensive (“cheese”) effect, there is no clinical evidence to support the need for such dietary precautions when they are taken at the recommended dosage.
Studies have suggested (but failed to show conclusively) that rasagiline may slow the progression of Parkinson disease, and it appears to delay the need for other symptomatic therapies. For these reasons, rasagiline is often started early, particularly for patients who are young or have mild disease. However, the FDA has rejected an expansion of rasagiline’s indication to include disease modification.
Catecholamine-O-methyltransferase (COMT) inhibitors reduce the metabolism of levodopa to 3-O-methyldopa and thereby alter the plasma pharmacokinetics of levodopa, leading to more sustained plasma levels and more constant dopaminergic stimulation of the brain. Two such agents, tolcapone and entacapone, are currently available and may be used as an adjunct to levodopa-carbidopa in patients with response fluctuations or an otherwise inadequate response. Treatment results in reduced response fluctuations, with a greater period of responsiveness to administered levodopa; however, the use of these agents does not delay the eventual development of levodopa-induced dyskinesias. Tolcapone is given in a dosage of 100 mg or 200 mg three times daily orally, and entacapone is given as 200 mg with each dose of Sinemet. With either preparation, the dose of Sinemet taken concurrently may have to be reduced by up to one-third to avoid side effects such as dyskinesias, confusion, hypotension, and syncope. Diarrhea is sometimes troublesome. Because rare cases of fulminant hepatic failure have followed its use, tolcapone should be avoided in patients with preexisting liver disease. Serial liver function tests should be performed at 2-week intervals for the first year and at longer intervals thereafter in patients receiving the drug—as recommended by the manufacturer. Hepatotoxicity has not been reported with entacapone, which is therefore the preferred agent, and serial liver function tests are not required.
Stalevo is the commercial preparation of levodopa combined with both carbidopa and entacapone. It is best used in patients already stabilized on equivalent doses of carbidopa/levodopa and entacapone. It is priced at or below the price of the individual ingredients (ie, carbidopa/levodopa and entacapone) and has the added convenience of requiring fewer tablets to be taken daily. It is available in three strengths: Stalevo 50 (12.5 mg of carbidopa, 50 mg of levodopa, and 200 mg of entacapone), Stalevo 100 (25 mg of carbidopa, 100 mg of levodopa, and 200 mg of entacapone), and Stalevo 150 (37.5 mg of carbidopa, 150 mg of levodopa, and 200 mg of entacapone).
Anticholinergics are more helpful in alleviating tremor and rigidity than bradykinesia. Treatment is started with a small dose and gradually increased until benefit occurs or side effects limit further increments. If treatment is ineffective, the drug is gradually withdrawn and another preparation then tried. However, these drugs are often poorly tolerated, especially in older adults, and their usefulness has not been evaluated by adequate clinical trials.
Side effects limit the routine use of these drugs, and include dryness of the mouth, nausea, constipation, palpitations, cardiac arrhythmias, urinary retention, confusion, agitation, restlessness, drowsiness, mydriasis, increased intraocular pressure, and defective accommodation. Anticholinergic drugs are contraindicated in patients with prostatic hyperplasia, narrow-angle glaucoma, or obstructive gastrointestinal disease and are often tolerated poorly by the elderly. They are best avoided whenever cognitive impairment or a predisposition to delirium exists.
7. Atypical antipsychotics
Confusion and psychotic symptoms may occur as a side effect of dopaminergic therapy or as a part of the underlying illness. They often respond to the atypical antipsychotic agents clozapine and quetiapine, which have few extrapyramidal side effects and do not block the effects of dopaminergic medication. Clozapine may rarely cause marrow suppression, and weekly blood counts are therefore necessary for patients taking it. The patient is started on 6.25 mg at bedtime and the dosage increased to 25–100 mg/day as needed. In low doses, it may also improve iatrogenic dyskinesias. Typical antipsychotic agents and the second-generation antipsychotic agents risperidone and olanzapine may cause worsening of motor symptoms and should be avoided.
8. Serotonin(2A) agonists
Pimavanserin (34 mg once daily) reduced rates of psychosis in a randomized trial of patients with Parkinson disease and is approved in the United States for this indication.
Physical therapy or speech therapy helps many patients. Cognitive impairment and psychiatric symptoms may be helped by a cholinesterase inhibitor, such as rivastigmine (3–12 mg orally daily or 4.6 or 9.5 mg/24 hours transdermally daily). The quality of life can often be improved by the provision of simple aids to daily living, eg, rails or banisters placed strategically about the home, special table cutlery with large handles, nonslip rubber table mats, and devices to amplify the voice.
High-frequency stimulation of the subthalamic nuclei or globus pallidus internus may benefit many of the motor features of the disease but does not affect its natural history. Electrical stimulation of the brain has the advantage over ablative thalamotomy and pallidotomy procedures of being reversible and of causing minimal or no damage to the brain, and is therefore the preferred surgical approach to treatment. Deep brain stimulation is reserved for patients without cognitive impairment or psychiatric disorder who have a good response to levodopa but in whom dyskinesias or response fluctuations are problematic. It frequently takes 3–6 months after surgery to adjust stimulator programming and to achieve optimal results. Side effects include depression, apathy, impulsivity, executive dysfunction, and decreased verbal fluency in a subset of patients.
Injections of adeno-associated viruses encoding various human genes have been made into the subthalamic nucleus or putamen in various clinical trials. The procedure appears to be safe, but results have been disappointing except that transfer of the gene for glutamic acid decarboxylase (the enzyme that produces the inhibitory neurotransmitter gamma-aminobutyric acid [GABA]) into the subthalamic nucleus seems to improve motor function in patients with Parkinson disease. It is unclear whether this provides any greater benefit than subthalamic deep brain stimulation.
All patients should be referred.
Patients requiring surgical treatment should be admitted.
et al. Pharmacological treatment of Parkinson disease: a review. JAMA. 2014 Apr 23–30;311(16):1670–83.
et al. Deep brain stimulation for movement disorders: update on recent discoveries and outlook on future developments. J Neurol. 2015 Nov;262(11):2583–95.
ESSENTIALS OF DIAGNOSIS
Gradual onset and progression of chorea and dementia or behavioral change.
Family history of the disorder.
Responsible gene identified on chromosome 4.
Huntington disease is characterized by chorea and dementia. It is inherited in an autosomal dominant manner and occurs throughout the world, in all ethnic groups, with a prevalence rate of about 5 per 100,000. There is an expanded and unstable CAG trinucleotide repeat in the huntingtin gene at 4p16.3; longer repeat lengths correspond to an earlier age of onset and faster disease progression.
Clinical onset is usually between 30 and 50 years of age. The disease is progressive and usually leads to a fatal outcome within 15–20 years. The initial symptoms may consist of either abnormal movements or intellectual changes, but ultimately both occur. The earliest mental changes are often behavioral, with irritability, moodiness, antisocial behavior, or a psychiatric disturbance, but a more obvious dementia subsequently develops. The dyskinesia may initially be no more than an apparent fidgetiness or restlessness, but eventually choreiform movements and some dystonic posturing occur. A parkinsonian syndrome with progressive rigidity and akinesia (rather than chorea) sometimes occurs in association with dementia, especially in cases with childhood onset. The diagnosis is established with a widely available genetic test, although such testing should be pursued under the guidance of a licensed genetic counselor.
CT scanning or MRI usually demonstrates cerebral atrophy and atrophy of the caudate nucleus in established cases. Positron emission tomography (PET) has shown reduced striatal metabolic rate.
Chorea developing with no family history of choreoathetosis should not be attributed to Huntington disease, at least not until other causes of chorea have been excluded clinically and by appropriate laboratory studies. Nongenetic causes of chorea include stroke, systemic lupus erythematosus and antiphospholipid antibody syndrome, paraneoplastic syndromes, infection with HIV, and various medications. In younger patients, self-limiting Sydenham chorea develops after group A streptococcal infections on rare occasions. If a patient presents solely with progressive intellectual failure, it may not be possible to distinguish Huntington disease from other causes of dementia unless there is a characteristic family history or a dyskinesia develops.
Huntington disease–like (HDL) disorders resemble Huntington disease but the CAG trinucleotide repeat number of the huntingtin gene is normal. There are autosomal dominant (HDL1, a familial prion disease involving a mutation in the PRNP gene on chromosome 20; and HDL2, a triplet repeat disease involving the gene for junctophilin-3 on chromosome 16) and recessive forms (HDL3, 4p15.3).
A clinically similar autosomal dominant disorder (dentatorubral-pallidoluysian atrophy), manifested by chorea, dementia, ataxia, and myoclonic epilepsy, is uncommon except in persons of Japanese ancestry. It is due to a mutation in the ATN1 gene mapping to 12p13.31. Treatment is as for Huntington disease.
There is no cure for Huntington disease; progression cannot be halted; and treatment is purely symptomatic. The reported biochemical changes suggest a relative underactivity of neurons containing GABA and acetylcholine or a relative overactivity of dopaminergic neurons. Tetrabenazine, a drug that interferes with the vesicular storage of biogenic amines, is widely used to treat the dyskinesia. The starting dose is 12.5 mg twice or three times daily orally, increasing by 12.5 mg every 5 days depending on response and tolerance; the usual maintenance dose is 25 mg three times daily. Side effects include depression, postural hypotension, drowsiness, and parkinsonian features; tetrabenazine should not be given within 14 days of taking monoamine oxidase inhibitors and is not indicated for the treatment of levodopa-induced dyskinesias. Reserpine is similar in depleting central monoamines but has more peripheral effects and a worse side-effect profile, making its use problematic in Huntington disease; if utilized, the dose is built up gradually to between 2 mg and 5 mg orally daily, depending on the response. Treatment with drugs blocking dopamine receptors, such as phenothiazines or haloperidol, may control the dyskinesia and any behavioral disturbances. Haloperidol treatment is usually begun with a dose of 1 mg once or twice daily orally, which is then increased every 3 or 4 days depending on the response; alternatively, atypical antipsychotic agents such as quetiapine (increasing from 25 mg daily orally up to 100 mg twice daily orally as tolerated) may be tried. Amantadine in a dose of 200 mg to 400 mg daily orally is sometimes helpful for chorea. Deep brain stimulation has been used successfully to treat chorea in a small number of patients. Behavioral disturbances may respond to clozapine. Attempts to compensate for the relative GABA deficiency by enhancing central GABA activity or to compensate for the relative cholinergic underactivity by giving choline chloride have not been therapeutically helpful. A novel agent, deutetrabenazine, a selective inhibitor of the vesicular monoamine 2 transporter (VMAT2) that modulates dopamine release, is currently under investigation. Neuroprotective strategies are being explored.
Offspring should be offered genetic counseling. Genetic testing permits presymptomatic detection and definitive diagnosis of the disease.
All patients should be referred.
4. Idiopathic Torsion Dystonia
ESSENTIALS OF DIAGNOSIS
Dystonic movements and postures.
Normal birth and developmental history. No other neurologic signs.
Investigations (including CT scan or MRI) reveal no cause of dystonia.
Idiopathic torsion dystonia may occur sporadically or on a hereditary basis, with autosomal dominant, autosomal recessive, and X-linked recessive modes of transmission. One responsible gene is located at 9q34 (and has been named DYT1) and involves a unique mutation consisting of a GAG deletion in the major dominantly inherited disorder, and maps to the long arm of the X chromosome in the X-linked recessive form; the responsible gene in the autosomal recessive disorder is unknown. Symptoms may begin in childhood or later and persist throughout life.
The disorder is characterized by the onset of abnormal movements and postures in a patient with a normal birth and developmental history, no relevant past medical illness, and no other neurologic signs. Investigations (including CT scan) reveal no cause for the abnormal movements. Dystonic movements of the head and neck may take the form of torticollis, blepharospasm, facial grimacing, or forced opening or closing of the mouth. The limbs may also adopt abnormal but characteristic postures. The age at onset influences both the clinical findings and the prognosis. With onset in childhood, there is usually a family history of the disorder, symptoms commonly commence in the legs, and progression is likely until there is severe disability from generalized dystonia. In contrast, when onset is later, a positive family history is unlikely, initial symptoms are often in the arms or axial structures, and severe disability does not usually occur, although generalized dystonia may ultimately develop in some patients. If all cases are considered together, about one-third of patients eventually become so severely disabled that they are confined to chair or bed, while another one-third are affected only mildly.
Perinatal anoxia, birth trauma, and kernicterus are common causes of dystonia, but abnormal movements usually then develop before the age of 5, the early development of the patient is usually abnormal, and a history of seizures is not unusual. Moreover, examination may reveal signs of mental retardation or pyramidal deficit in addition to the movement disorder. Dystonic posturing may also occur in Wilson disease, Huntington disease, or parkinsonism; as a sequela of encephalitis lethargica or previous neuroleptic drug therapy; and in certain other disorders. In these cases, diagnosis is based on the history and accompanying clinical manifestations.
Idiopathic torsion dystonia usually responds poorly to drugs. Levodopa, diazepam, baclofen, carbamazepine, amantadine, or anticholinergic medication such as trihexyphenidyl or benztropine (in high dosage) is occasionally helpful; if not, a trial of treatment with tetrabenazine, phenothiazines, or haloperidol may be worthwhile. In each case, the dose has to be individualized, depending on response and tolerance. However, the doses of these latter drugs that are required for benefit lead usually to mild parkinsonism. Pallidal deep brain stimulation is helpful for medically refractory dystonia and has a lower morbidity than stereotactic thalamotomy, which is sometimes helpful in patients with predominantly unilateral limb dystonia. Potential adverse events of deep brain stimulation include cerebral infection or hemorrhage, broken leads, affective changes, and dysarthria.
A distinct variety of dominantly inherited dystonia, caused by a mutation in the gene for GTP cyclohydrolase I on chromosome 14q, is remarkably responsive to levodopa; therefore, a levodopa trial is warranted in all patients.
All patients should be referred.
Patients requiring surgical treatment should be admitted.
et al. Dystonia: an update on phenomenology, classification, pathogenesis and treatment. Curr Opin Neurol. 2014 Aug;27(4):468–76.
5. Focal Torsion Dystonia
A number of the dystonic manifestations that occur in idiopathic torsion dystonia may also occur as isolated phenomena. They are best regarded as focal dystonias that either occur as formes frustes of idiopathic torsion dystonia in patients with a positive family history or represent a focal manifestation of the adult-onset form of that disorder when there is no family history. Mapping of responsible genes to chromosome 8 (DYT6) and chromosome 18 (DYT7) has been reported in some instances of cervical or cranial dystonia. Medical treatment is generally unsatisfactory. A trial of the drugs used in idiopathic torsion dystonia is worthwhile, however, since a few patients do show some response. In addition, with restricted dystonias such as blepharospasm or torticollis, local injection of botulinum A toxin into the overactive muscles may produce worthwhile benefit for several weeks or months and can be repeated as needed.
Both blepharospasm and oromandibular dystonia may occur as an isolated focal dystonia. The former is characterized by spontaneous involuntary forced closure of the eyelids for a variable interval. Oromandibular dystonia is manifested by involuntary contraction of the muscles about the mouth causing, for example, involuntary opening or closing of the mouth, roving or protruding tongue movements, and retraction of the platysma. Spasmodic torticollis, usually with onset between 25 and 50 years of age, is characterized by a tendency for the neck to twist to one side. This initially occurs episodically, but eventually the neck is held to the side. Some patients have a sensory trick (“geste antagoniste”) that lessens the dystonic posture, eg, touching the side of the face. Spontaneous resolution may occur in the first year or so. The disorder is otherwise usually lifelong. Selective section of the spinal accessory nerve and the upper cervical nerve roots is sometimes helpful if medical treatment is unsuccessful. Local injection of botulinum A toxin provides benefit in most cases.
Writer’s cramp is characterized by dystonic posturing of the hand and forearm when the hand is used for writing and sometimes when it is used for other tasks, eg, playing the piano or using a screwdriver or eating utensils. Drug treatment is usually unrewarding, and patients are often best advised to learn to use the other hand for activities requiring manual dexterity. Injections of botulinum A toxin are helpful in some instances.
Occasional myoclonic jerks may occur in anyone, especially when drifting into sleep. General or multifocal myoclonus is common in patients with idiopathic epilepsy and is especially prominent in certain hereditary disorders characterized by seizures and progressive intellectual decline, such as the lipid storage diseases. It is also a feature of subacute sclerosing panencephalitis and Creutzfeldt-Jakob disease. Generalized myoclonic jerking may accompany uremic and other metabolic encephalopathies, result from therapy with levodopa or tricyclic antidepressants, occur in alcohol or drug withdrawal states, or follow anoxic brain damage. It also occurs on a hereditary or sporadic basis as an isolated phenomenon in otherwise healthy subjects.
Segmental myoclonus is a rare manifestation of a focal spinal cord lesion. It may also be the clinical expression of epilepsia partialis continua, a disorder in which a repetitive focal epileptic discharge arises in the contralateral sensorimotor cortex, sometimes from an underlying structural lesion. An electroencephalogram is often helpful in clarifying the epileptic nature of the disorder, and CT or MRI scan may reveal the causal lesion.
Myoclonus may respond to certain anticonvulsant drugs, especially valproic acid or levetiracetam, or to one of the benzodiazepines, particularly clonazepam (see Table 24–3). It may also respond to piracetam (up to 16.8 g daily; not available in the United States). Myoclonus following anoxic brain damage is often responsive to oxitriptan (5-hydroxytryptophan), the precursor of serotonin, and sometimes to clonazepam. Oxitriptan is given in gradually increasing doses up to 1–1.5 mg daily. In patients with segmental myoclonus, a localized lesion should be searched for and treated appropriately.
et al. An update and review of the treatment of myoclonus. Curr Neurol Neurosci Rep. 2015 Jan;15(1):512.
In this metabolic disorder, abnormal movement and posture may occur with or without coexisting signs of liver involvement. Psychiatric and neuropsychological manifestations are common. Wilson disease is discussed in Chapter 16.
8. Drug-Induced Abnormal Movements
Phenothiazines, butyrophenones, and metoclopramide may produce a wide variety of abnormal movements, including parkinsonism, akathisia (ie, motor restlessness), acute dystonia, chorea, and tardive dyskinesias or dystonia; several of these are also produced by aripiprazole. These complications are discussed in Chapter 25. Chorea may also develop in patients receiving levodopa, bromocriptine, anticholinergic drugs, phenytoin, carbamazepine, lithium, amphetamines, or oral contraceptives, and it resolves with withdrawal of the offending substance. Similarly, dystonia may be produced by levodopa, bromocriptine, lithium, or carbamazepine; and parkinsonism by reserpine and tetrabenazine. Postural tremor may occur with a variety of drugs, including epinephrine, isoproterenol, theophylline, caffeine, lithium, thyroid hormone, tricyclic antidepressants, and valproic acid.
9. Restless Legs Syndrome
This common disorder, affecting 1–5% of people, may occur as a primary (idiopathic) disorder or in relation to Parkinson disease, pregnancy, iron deficiency anemia, or peripheral neuropathy (especially uremic or diabetic). It may have a hereditary basis, and several genetic loci have been associated with the disorder (12q12-q21, 14q13-q21, 9p24-p22, 2q33, 20p13, 6p21, and 2p14-p13). Restlessness and curious sensory disturbances lead to an irresistible urge to move the limbs, especially during periods of relaxation; movement of the limbs provides relief. The urge occurs exclusively in the evening and at night or is worse at night than during the day. Most patients also have periodic limb movements of sleep and one-third have periodic limb movements during relaxed wakefulness; both consist of brief involuntary flexion at the ankle, knee, and hip. Disturbed nocturnal sleep and excessive daytime somnolence may result. Ferritin levels should always be measured; treatment with oral iron sulfate in patients with levels less than or equal to 75 mcg/L (13.4 mcmol/L) should be attempted prior to initiation of other pharmacotherapies. Therapy is with nonergot dopamine agonists, such as pramipexole (0.125–0.5 mg orally once daily), ropinirole (0.25–4 mg orally once daily 2 to 3 hours before bedtime), or rotigotine (1–3 mg/24h transdermal patch once daily) or with gabapentin enacarbil (300–1200 mg orally each evening). Gabapentin (starting with 300 mg orally daily, increasing to approximately 1800 mg daily depending on response and tolerance) and pregabalin (150–300 mg orally divided twice to three times daily) are related drugs that improve symptoms. Levodopa is helpful but may lead to an augmentation of symptoms, so that its use is generally reserved for those who do not respond to other measures. Extended-release oxycodone-naloxone (2.5–5 mg to 5–10 mg orally twice daily) is useful in patients with severe symptoms or those who are refractory to first-line therapies.
et al. Practice guideline summary: treatment of restless legs syndrome in adults: report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2016 Dec 13;87(24):2585–93.
10. Gilles de la Tourette Syndrome
ESSENTIALS OF DIAGNOSIS
Multiple motor and phonic tics.
Symptoms begin before age 18 years.
Tics occur frequently for at least 1 year.
Tics vary in number, frequency, and nature over time.
Simple tics occur transiently in up to 25% of children, remit within weeks to months, and do not require treatment. Tourette syndrome is a more complex disorder, with diagnostic criteria as defined above. Motor tics are the initial manifestation in 80% of cases and most commonly involve the face, whereas in the remaining 20%, the initial symptoms are phonic tics; ultimately a combination of different motor and phonic tics develop in all patients. Tics are preceded by an urge that is relieved upon performance of the movement or vocalization; they can be temporarily suppressed but eventually the urge becomes overwhelming. These are noted first in childhood, generally between the ages of 2 and 15. Motor tics occur especially about the face, head, and shoulders (eg, sniffing, blinking, frowning, shoulder shrugging, head thrusting, etc). Phonic tics commonly consist of grunts, barks, hisses, throat-clearing, coughs, etc, but sometimes also of verbal utterances including coprolalia (obscene speech). There may also be echolalia (repetition of the speech of others), echopraxia (imitation of others’ movements), and palilalia (repetition of words or phrases). Some tics may be self-mutilating in nature, such as nail-biting, hair-pulling, or biting of the lips or tongue. The disorder is chronic, but the course may be punctuated by relapses and remissions. Obsessive-compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD) are commonly associated and may be more disabling than the tics themselves. A family history is sometimes obtained. A mutation in the histidine decarboxylase gene on chromosome 15 was recently reported in one family with an autosomal dominant form of the disease. Prior reports of a linkage to chromosome 13q have been called into question.
Examination usually reveals no abnormalities other than the tics. In addition to OCD, psychiatric disturbances may occur because of the associated cosmetic and social embarrassment. The diagnosis of the disorder is often delayed for years, the tics being interpreted as psychiatric illness or some other form of abnormal movement. Patients are thus often subjected to unnecessary treatment before the disorder is recognized. The tic-like character of the abnormal movements and the absence of other neurologic signs should differentiate this disorder from other movement disorders presenting in childhood. Wilson disease, however, can simulate the condition and should be excluded.
Treatment is symptomatic and may need to be continued indefinitely. Habit reversal training or other forms of behavioral therapy can be effective alone or in combination with pharmacotherapy. Alpha-adrenergic agonists, such as clonidine (start 0.05 mg orally at bedtime, titrating to 0.3–0.4 mg orally daily, divided three to four times per day) or guanfacine (start 0.5 mg orally at bedtime, titrating to a maximum of 3–4 mg orally daily, divided twice daily) are first-line therapies because of a favorable side-effect profile compared with typical antipsychotics, which are the only FDA-approved therapies for the disorder. They also have the advantage of improving the symptoms of concomitant ADHD. Many specialists favor the use of tetrabenazine. The atypical antipsychotic risperidone (1–6 mg daily orally) is more effective than placebo in controlling tics and more effective than pimozide in improving symptoms of comorbid OCD and may be tried before the typical antipsychotic agents. When a typical antipsychotic is required in cases of severe tics, haloperidol is generally regarded as the drug of choice. It is started in a low dose (0.25 mg daily orally) that is gradually increased (by 0.25 mg every 4 or 5 days) until there is maximum benefit with a minimum of side effects or until side effects limit further increments. A total daily oral dose of between 2 mg and 8 mg is usually optimal, but higher doses are sometimes necessary. Fluphenazine (1–15 mg orally daily) or pimozide (1–10 mg orally daily) are alternatives. Typical antipsychotics can cause significant weight gain and carry a risk of tardive dyskinesias and other long-term, potentially irreversible motor side effects. Small randomized trials or observational studies have reported benefit from topiramate, nicotine, tetrahydrocannabinol, and clonazepam.
Injection of botulinum toxin type A at the site of the most distressing tics is sometimes worthwhile and has fewer side effects than systemic antipsychotic therapy. Bilateral high-frequency deep brain stimulation at various sites has been helpful in some, otherwise intractable, cases.
All patients should be referred.
Patients undergoing surgical (deep brain stimulation) treatment should be admitted.
et al; Tourette Syndrome Association International Deep Brain Stimulation (DBS) Database and Registry Study Group. Tourette syndrome deep brain stimulation: a review and updated recommendations. Mov Disord. 2015 Apr;30(4):448–71.
et al. Advances in Tourette syndrome: diagnoses and treatment. Pediatr Clin North Am. 2015 Jun;62(3):687–701.