Hyperkinetic movement disorder may reflect pathology at several levels of the nervous system including the cerebral cortex, basal ganglia, cerebellum, and even the peripheral nerve. The first step in approaching a patient with a hyperkinetic movement is to classify the movement. Observation of the patient while sitting face to face and taking their history is often sufficient. If the movement is not present, then it is usually best to ask the patient to demonstrate it, as verbal descriptions are often vague or inaccurate. When examining a patient with a hyperkinetic movement disorder, it is important not only to describe and classify the movement, but also to perform a comprehensive neurological history and examination to determine whether the abnormality is a sign of a systemic metabolic process or neurodegenerative disease.
Tremor is the rhythmic oscillation of a body part caused by alternating contraction of agonist and antagonist muscles. Patients describe tremor as shaking or trembling, or may specifically use the word tremor. Some may even diagnose themselves (usually incorrectly) with Parkinson’s disease. When examining a tremor, note its location, presence with rest or activity, frequency, amplitude, and direction.
Most tremors involve the upper extremities. Important exceptions include essential tremor involving the head and voice, oculopalatal myoclonus, resting leg tremor in Parkinson’s disease, and leg tremor upon standing in patients with orthostatic tremor. Beyond location, the most important step in diagnosing tremor is to classify it as a resting tremor, action (or postural) tremor, or intention tremor. Resting tremor is present with rest and improves or disappears with movement. Action or postural tremor develops when moving or holding a body part against gravity. Intention tremor worsens with precise, target-directed movements. In order to determine the tremor type, examine the affected body part in the following positions:
• completely still
• extended in front of the patient
• as the patient moves it rapidly back and forth between two targets
• as the patient attempts to bear weight (e.g. reaching out for a cup of water and then bringing it to their lips)
Essential or benign familial tremor is the most common type of tremor, and indeed the most common movement disorder. It typically begins in early middle age and is transmitted from generation to generation with an autosomal-dominant pattern of inheritance. The tremor is principally an intermediate-frequency, small-to-medium amplitude, symmetric action tremor of the hands. Involvement of the head (including “yes–yes” or “no–no” forms) and voice is common. The feet and legs are usually spared. Patients may report an improvement in the tremor with alcohol ingestion and an exacerbation of the tremor with stress or anxiety.
Many patients with essential tremor have mild symptoms and do not require treatment. A number of options are available for patients with disabling or socially embarrassing symptoms. Primidone and propranolol are the first-line medications, and are effective in about two-thirds of patients with essential tremor. Other treatment options are listed in Table 14.1. Deep brain stimulation of the ventral intermediate nucleus of the thalamus is an option for patients with refractory tremor. Botulinum toxin injections may be useful for patients with vocal or head tremors.
Wilson’s disease is an autosomal-recessive disorder of copper metabolism that produces a combination of neurological, psychiatric, and hepatic dysfunction.
Table 14.1 Medications used to treat essential tremor
a First-line agent.
Table 14.2 Common medications that produce tremor
Although symptoms usually develop in children and young adults, rare patients may first come to clinical attention in middle age or later. The most prominent initial neurological symptom is usually an action tremor, which may resemble essential tremor, but in many cases is of much larger amplitude (wing-beating tremor). Some patients present with rigidity and bradykinesia or ataxia rather than tremor. Kayser–Fleischer (KF) rings, brownish-green copper deposits in Descemet’s membrane of the cornea, are the tell-tale physical examination sign of Wilson’s disease. If not visible by simple visual inspection, slit-lamp examination may be used to confirm the presence of KF rings. The characteristic laboratory findings of Wilson’s disease are reduced serum ceruloplasmin (<20 mg/dl), and elevated urine 24-hour copper excretion (>40 µg/ml).1 If clinical suspicion for Wilson’s disease remains despite normal or equivocal test results, refer the patient for molecular testing or liver biopsy. Treatment with the copper-chelating agents trientine and penicillamine help both the neuropsychiatric and hepatic components of the disease.1 Wilson’s disease should be evaluated and treated in conjunction with a hepatologist.
Enhanced physiological tremor
Every person has a small-amplitude, high-frequency tremor that is usually imperceptible in day-to-day activities. Some patients, however, experience an enhanced physiological tremor, which has a very high frequency, usually involves the hands, and appears with stress such as performance anxiety. Patients with this type of tremor usually respond to a small dose of propranolol (10–40 mg prn) prior to stress exposure. Treat those who do not respond to propranolol with clonazepam (0.5–1 mg prn) or lorazepam (0.5–1 mg prn).
A variety of medications, toxins, and metabolic disturbances lead to a tremor that appears quite similar to essential tremor. Table 14.2 lists common medications that lead to tremor. Intoxication with caffeine, cocaine, and phencyclidine and withdrawal from ethanol and benzodiazepines are other important causes of secondary tremor. Hyperthyroidism, hypoglycemia, uremia, and hepatic dysfunction are the common medical precipitants. Correction of the responsible problem or withdrawal of the offending medication usually results in tremor resolution or improvement.
Up to 75% of patients with Parkinson’s disease will develop a tremor, and it is the most prominent feature in approximately 15%.2 Parkinsonian tremor is a low-frequency, small-to-medium amplitude, resting tremor that most commonly involves one hand or foot in an asymmetric fashion. It may change in appearance and distribution, even during the course of a single office visit. Classical parkinsonian tremors include:
• flexion–extension of the wrist
• pronation–supination of the wrist
• pill-rolling involving the thumbs and fingers
• foot tapping
• internal–external rotation at the hip
• up-and-down jaw movements
• “rabbit tremor” characterized by repetitive perioral and nasal muscle contractions
Anticholinergic medications such as trihexyphenidyl are the mainstays of treatment of parkinsonian tremor. Levodopa and dopamine agonists tend to be less effective in treating parkinsonian tremor than they are for bradykinesia and rigidity. Deep brain stimulation of the ventral intermediate nucleus of the thalamus or the subthalamic nucleus may help in refractory cases.3 Treatment of Parkinson’s disease is discussed in further detail in Chapter 13.
Cerebellar outflow tremor
Lesions of the dentate nucleus of the cerebellum and its connections within the cerebellum and brainstem produce very striking low-frequency, large-amplitude intention tremor. This tremor may have a postural element, but becomes much worse when attempting to reach out for a target. Ataxia and other signs of cerebellar dysfunction usually accompany the tremor. Common pathologies that produce cerebellar outflow tremor include stroke, demyelination, neoplasm, and trauma. Unfortunately, this type of tremor responds poorly to treatment.
Palatal tremor (also called palatal myoclonus) is a low-frequency tremor of the palatal and pharyngeal muscles. It is usually secondary to a lesion of the Guillain–Mollaret triangle, which connects the red nucleus, inferior olivary nucleus, and dentate nucleus. In many cases, the palatal tremor is accompanied by tremor of the extraocular muscles (oculopalatal myoclonus), diaphragm, head, and neck.
Focal or generalized dystonia is often accompanied by a mild, superimposed tremor that is usually worsened by movement. Dystonic tremor, like other aspects of dystonia, responds best to botulinum toxin injection.
Neuropathic tremor is usually a large-amplitude, low-frequency action tremor. It is most common in patients with demyelinating neuropathies, especially those caused by monoclonal gammopathies (Chapter 15).4
Psychogenic tremor should be included in the differential diagnosis of any tremor. This may be a resting or action tremor, and may have any amplitude or frequency. The tremor improves with distraction and worsens when the patient focuses on it. One feature of psychogenic tremor that may help to distinguish it from other tremors is entrainment: the patient will not be able to continue to feign a tremor in a hand (or other affected body part) when asked to tap out a complex rhythmic pattern with another body part.
Myoclonus is defined as a sudden-onset, brief-duration jerking movement of a muscle or group of muscles. It may be a manifestation of a systemic disease, associated with an epilepsy syndrome, or occur as a benign phenomenon. Essentially any part of the CNS may generate myoclonus. Unfortunately, because myoclonus often looks quite similar regardless of its cause, it may be difficult to start with the movement and work backwards toward the diagnosis. Rather, the best way to classify myoclonus at the bedside is by looking for neighborhood signs of medical or neurological disease.
Toxic and metabolic myoclonus
The metabolic disturbances that produce myoclonus include uremia, hepatic encephalopathy, and thyroid dysfunction. Commonly used medications that precipitate myoclonus include narcotics, anticonvulsants, antidepressants, calcium channel blockers, and lithium. Correction of the responsible toxic exposure or metabolic abnormality reverses the myoclonus.
Acute postanoxic myoclonus
Many patients in coma following cardiac arrest develop myoclonus, often diffuse and continuous.5 The myoclonus may be quite violent and disturbing to family members, and may persist despite all efforts short of neuromuscular junction blockade. Acute anoxic myoclonus portends a uniformly poor prognosis (Chapter 2), and should prompt serious discussions about the direction of care with family members and intensive care unit physicians.
Chronic postanoxic myoclonus (Lance–Adams myoclonus)
A patient who recovers from anoxic brain injury may develop myoclonus that is absent at rest and develops with movement. For this reason, it is often called intention myoclonus. Chronic postanoxic myoclonus is difficult to control, but may respond to clonazepam (0.5–2 mg bid) or valproate (500–1000 mg bid).
Myoclonus associated with dementia
Myoclonus is often an early feature of Creutzfeldt–Jakob disease (Chapter 4 ). It is important, however, to understand that myoclonus in a demented patient is not pathognomonic for Creutzfeldt–Jakob disease, and may develop in the later stages of any of the degenerative dementias.
Juvenile myoclonic epilepsy (Chapter 20) is the most common of the epilepsies associated with myoclonus. Rare myoclonic epilepsies include neuronal ceroid lipofuscinosis, Lafora body disease, and myoclonic epilepsy with ragged red fibers (MERRF), all of which tend to occur primarily in children.
This condition, characterized by fast, chaotic, multidirectional eye movements and myoclonus, is classically associated with neuroblastoma in children. In adults, opsoclonus–myoclonus syndrome may be a paraneoplastic process or may be associated with a variety of other inflammatory, autoimmune disorders.6 Like other forms of myoclonus, opsoclonus–myoclonus syndrome often responds to clonazepam or valproate. Adrenocorticotropic hormone infusions are effective in children, but tend not to work in adults.
Segmental myoclonus involves muscle groups supplied by one or more contiguous segments of the brainstem or spinal cord.7 It may be misdiagnosed as another abnormal movement, usually tics or hemiballismus. Common causes include multiple sclerosis, tumors, and encephalomyelitis. Clonazepam and valproic acid often provide good symptomatic control, but treating the responsible cause is the most important step in therapy.
The two most common examples of physiological myoclonus are hypnic jerks (sleep starts that occur just upon falling asleep) and hiccoughs (diaphragmatic myoclonus). With rare exception, physiological myoclonus does not require any further evaluation or treatment.
Essential myoclonus is a benign condition, often inherited in an autosomal-dominant fashion, which begins in childhood or young adulthood.8 Exhaustive evaluation discloses no underlying structural or metabolic abnormalities. Essential myoclonus improves considerably with ethanol ingestion, which obviously cannot be recommended as long-term therapy. Many patients are not bothered by their symptoms and some note an improvement over time. For patients with disabling myoclonus, clonazepam is often helpful.
Ballismus is a violent, involuntary flinging movement of a limb, which may be difficult to distinguish from myoclonus. It usually involves one side of the body, in which case it is called hemiballismus. Although hemiballismus is classically associated with strokes involving the subthalamic nucleus, this is the lesion site in only a minority of cases – other subcortical structures are often involved.9Hemiballismus is quite disruptive to the patient, and should be treated with haloperidol in divided doses up to 15 mg. Most patients need treatment for about 3 months, at which point a trial of discontinuing the haloperidol may be attempted.
Fasciculations are visible muscle twitches that are generated at the level of the motor neuron, nerve root, or peripheral nerve. They may affect the face, eyes, tongue, and limbs. Most patients with fasciculations have otherwise normal neurological examinations and a diagnosis of benign fasciculations or cramp- fasciculation syndrome, both of which reflect disorders of peripheral nerve hyperexcitability.10 The association of fasciculations with amyotrophic lateral sclerosis (ALS) (Chapter 10) is widely known, and many patients with benign fasciculations are worried that they have ALS. Reassurance that the condition is benign is often not helpful, and patients may find relief only after undergoing a negative battery of tests, including electromyography (EMG) and sometimes MRI of the brain. Symptoms improve by decreasing caffeine intake, reducing stress, and limiting heavy exercise. If these lifestyle modifications are not effective, treat benign fasciculations with carbamazepine (200–800 mg bid), gabapentin (300–1200 mg tid), or clonazepam (0.5–1 mg bid).
Twisting and cramping
Chorea and athetosis
Chorea is an irregular, purposeless, jerking movement that results from basal ganglia dysfunction. Often, a patient with chorea attempts to incorporate the movement into an intended movement in order to mask the abnormality (parakinesia). Athetosis is a slow, purposeless, writhing movement. Because these two abnormal movements frequently accompany each other, they may be discussed together under the blanket term “choreoathetosis.” Choreoathetoid movements involve the limbs, face, eyelids, lips, and tongue, and are often quite disabling. The following are common causes.
Huntington’s disease (HD) is an autosomal-dominant neurodegenerative disorder that usually presents in young adulthood or early middle age. Symptoms usually begin with mild clumsiness or fidgetiness, which evolves over time into full-blown chorea. Some patients present with dementia or with behavioral changes such as impulsivity and irritability. There may be a family history of psychiatric disease or poorly understood early institutionalization and death. As the disease progresses, chorea becomes less prominent, and rigidity and bradykinesia dominate the clinical picture. In the absence of a suggestive family history, the diagnosis of HD is made by finding CAG repeat expansion in the huntingtin gene. Striatal atrophy on MRI may
Figure 14.1 CT scan of the brain in a patient with Huntington’s disease. Note hydrocephalus ex vacuo, involving particularly the caudate nucleus (arrow).
support the diagnosis (Figure 14.1). Unfortunately, HD is a relentlessly progressive disease, and symptomatic therapy is the mainstay of treatment. Tetrabenazine, clonazepam, or neuroleptics may help to control the chorea, but, as the disease progresses, patients require around-the-clock care, often in a nursing home setting.
Benign familial chorea
Benign familial chorea is largely a pediatric disorder in which chorea is not associated with evidence of another movement disorder or neurodegenerative disease. Make this diagnosis cautiously, as most patients who initially appear to have benign familial chorea will actually prove to have a different, usually not so benign disorder.11
Chorea may develop during the first or second trimesters of pregnancy. In many cases, an underlying cause such as Sydenham’s chorea, hyperthyroidism, or the antiphospholipid antibody syndrome may be identified. In other patients, however, there is no identifiable cause, and the term chorea gravidarum is used. Although this condition usually resolves spontaneously after several weeks, neuroleptics such as haloperidol may be needed to help control disabling symptoms.
Other causes of chorea
Medications including dopamine-blocking agents, anticonvulsants, and oral contraceptives may also produce chorea. Sydenham’s chorea is an autoimmune disorder that occurs in children with rheumatic fever. In rare cases, it may occur for the first time or recur in adults. Other autoimmune disorders that may be associated with chorea include systemic lupus erythematosus and antiphospholipid antibody syndrome. Hyperthyroidism and AIDS are rare causes of chorea.
Dystonia is an abnormal movement characterized by sustained, simultaneous contraction of muscle agonists and antagonists. Dystonia produces torsion or fixation of a body part in a consistent direction, unlike choreoathetoid movements, which are in multiple directions and vary from moment to moment. Dystonic movements are often associated with local pain and spasm, and sometimes with a superimposed tremor. They are worsened by stress and resolve during sleep. Many patients have sensory tricks in which touching or stroking a body part affected by the dystonic muscle relieves the contraction briefly. Dystonias may be focal (affecting one body part), segmental (affecting several adjacent body parts), or generalized in distribution. Focal dystonias are the most common types in adults. I will not discuss generalized dystonias in great detail: although they usually persist into adulthood, they are mainly diseases of childhood and adolescence.
Most dystonic disorders are primary, meaning that there are no nervous system abnormalities beyond the dystonia and possibly a mild tremor. Secondary dystonias are those that are caused by another neurological disorder or by a structural or metabolic abnormality. Suspect a secondary dystonia in patients with accompanying neurological symptoms such as weakness, ataxia, or severe tremor. Although there are many causes of secondary dystonia, focused evaluation including a careful medical history, medication review, MRI of the brain (to look for strokes and mass lesions affecting the basal ganglia), and assessment for Wilson’s disease and HD are high-yield investigations. A comprehensive discussion of dystonia evaluation is beyond the scope of this text, and the interested reader is referred to the review by Geyer and Bressman.12
This is the most common focal dystonia in adults. The head may be twisted in any direction: turned to the side (torticollis), twisted laterally so that the ear approaches or touches the shoulder (laterocollis), bent forward (anterocollis), or bent backward (retrocollis). Simultaneous torsion of the head in more than one direction is common. The severity of cervical dystonia ranges from subtle rotation of the head that is not obvious to even friends and family members to fixation of the head in one position with unbearable pain and spasm. Although agents such as benzodiazepines and baclofen may help slightly, botulinum toxin injections are the most effective treatments. Deep brain stimulation of the bilateral globus pallidus may help patients with symptoms that are refractory to botulinum toxin.13
Task-specific (occupational) dystonias
Dystonia, as a rule, is worse with movement. Task-specific or occupational dystonias emerge exclusively when the patient attempts to perform a specific action. Writer’s cramp is the most common task-specific dystonia: patients with this condition find that their hand twists or postures when they attempt to write with a pen or pencil. Writing becomes slow, effortful, and painful, and patients resort to using larger and larger pens, writing with their other hand, or typing. The contralateral hand may be affected by milder dystonic movements. Typing, playing musical instruments, and golfing are other tasks associated with dystonia. Some patients may obtain modest symptom relief with trihexyphenidyl, but local botulinum toxin injection is the most effective treatment for task-specific dystonias.
Cramps are characterized by strong, painful, involuntary muscle contractions. Although patients perceive cramps as being muscular pains, they are actually generated by excessive discharges of the peripheral nerves. Nocturnal cramps, particularly of the calves and foot muscles, are the most common variety. Heavy exercise, dehydration, and electrolyte imbalances may also precipitate cramps. In some cases, cramps are a manifestation of a neurogenic disease such as polyneuropathy or ALS. When evaluating patients with isolated fasciculations, check thyroid function, potassium, magnesium, and calcium, and correct as needed. Stretching the affected body part usually improves symptoms. Quinine is a very effective treatment for cramps, but is unfortunately not available due to its potential to cause arrhythmias. Options for treating cramps include clonazepam (0.5–1 mg qhs), verapamil (80–120 mg qhs), diphenhydramine (25–50 mg qhs), gabapentin (300–600 mg qhs), and B-complex vitamins.
Stiff-person syndrome is an uncommon condition characterized by chronically progressive stiffness of the muscles of the trunk and limbs. The axial muscles, particularly the paraspinal muscles, are usually affected most severely, and may cause the patient to adopt an exaggerated lordotic posture, leading to opisthotonos in severe cases. Other patients first develop asymmetric symptoms in one leg or foot. Approximately 70% of patients with stiff-person syndrome will have antibodies to glutamic acid decarboxylase.14 There is a less frequent association with antibodies to amphiphysin in women with breast cancer.15 Patients with stiff-person syndrome often have other autoimmune disorders such as diabetes or pernicious anemia. The most effective treatments for stiff person syndrome include oral and intravenous diazepam titrated to effect and baclofen given orally (40 mg bid) or, in some cases, via an intrathecal pump. Periodic intravenous immunoglobulin infusions help some patients.16
Myotonia is the impaired relaxation of a muscle after voluntary contraction or percussion. A patient with myotonia may complain of disabling muscle stiffness with exercise or cold. Other patients, however, have very mild myotonia and are not bothered by it. There are several ways to elicit myotonia on examination. Observe for hand grip myotonia by asking the patient to shake your hand vigorously and then attempt to release their grip. Elicit myotonia of the orbicularis oculi by asking the patient to forcibly and rapidly open and close their eyes. Look for percussion myotonia by striking the thenar eminence, long finger extensors in the forearm, deltoid, or tongue briskly with a reflex hammer. If physical examination fails to reveal myotonia, it may be demonstrated electromyographically, especially upon muscle cooling.
Myotonic dystrophy is an autosomal-dominant, multisystem disorder characterized by myotonia and muscle weakness. Cardiac conduction block, insulin resistance, and cataracts are common systemic features that are often more important than the neurological aspects of the disease. Patients with DM1 have predominantly distal weakness (involving preferentially the finger flexors), while those with DM2 have predominantly proximal weakness. A patient with myotonic dystrophy characteristically has a long face, frontal baldness, temporal wasting, and ptosis. Myotonic dystrophy may be divided into DM1 and DM2. Genetic testing is available to confirm both DM1 and DM2. Phenytoin (100 mg tid) or mexiletine (200–400 mg tid) may be used for patients with problematic myotonia, but, in general, the myotonia of myotonic dystrophy does not require treatment. Monitoring patients for cardiac and ophthalmological problems is an essential part of caring for the patient with myotonic dystrophy.
Myotonia congenita is an inherited disorder characterized by myotonia in the first few seconds or minutes of exercise or movement that improves with continued activity. Muscle stiffness usually improves after warming up. Myotonia congenita is inherited by both autosomal-dominant (Thomsen’s disease) and -recessive (Becker’s disease) mechanisms. The recessive form may be associated with mild muscle weakness. Mexiletine (200–400 mg tid) is often helpful, but must be used cautiously as it may lead to arrhythmias. Phenytoin and carbamazepine may be useful for patients who do not respond to or do not tolerate mexiletine.
Abnormal facial movements
Myokymia is a rippling, undulating movement of the muscles, which is physiologically composed of spontaneous, rhythmic or semirhythmic motor unit discharges. Although it may manifest itself in the limb muscles (usually in association with neuropathic disorders and especially in the setting of radiation- induced brachial or lumbosacral plexopathies), it is most commonly observed in the face. Facial myokymia is usually secondary to an ipsilateral pontine tegmental lesion, particularly multiple sclerosis. Patients with disabling, persistent symptoms may benefit from botulinum toxin injections, carbamazepine, or phenytoin.17
Oromandibular dystonia is characterized by a variety of abnormal facial movements including jaw clenching, mouth opening, and facial grimacing. In severe cases, these movements impair speech and swallowing. Oromandibular dystonia frequently involves adjacent body parts including the orbicularis oculi (in which case the combination is called Meige’s syndrome) and the adjacent neck and shoulder muscles. Similar to other focal dystonias, oromandibular dystonia responds to directed botulinum toxin injections.
Tics are stereotyped movements of a muscle or group of muscles. They may be brief or sustained, and may involve the face, limbs, or voice. Because tic disorders are largely pediatric diseases that rarely begin in adulthood, I will not discuss them in further detail.18
Hemifacial spasm is the intermittent unilateral twitching of both the upper and lower halves of the face. It may be present at rest, but is more often triggered by facial movements. The cause of hemifacial spasm is believed to be microvascular compression of the facial nerve as it emerges from the brainstem. Brain MRI with thin cuts through the brainstem should be performed to exclude any responsible structural lesions. Treatment with anticonvulsants such as carbamazepine may help slightly, but most patients require botulinum toxin injections. In some refractory cases, surgical decompression of the facial nerve is necessary, although the procedure places the patient at risk for facial palsy.
Tardive dyskinesia refers to a group of abnormal movements resulting from treatment with antipsychotics or the antiemetic metoclopramide. Symptoms develop in as little as 6 months (or even less) of exposure to these dopamine-receptor blockers, often after a dose reduction or switch from a high-potency to a low-potency agent. Common dyskinesias include tics, chorea, athetosis, and dystonia. Orofacial dyskinesias such as chewing, puckering, grimacing, and repetitive eye closure are among the most easily recognizable varieties. Tardive dyskinesia may also affect the limbs, neck, trunk, and even the diaphragm. They are sometimes present continuously and may be very disabling. Tardive dyskinesia is more likely to result from treatment with older antipsychotics such as haloperidol or fluphenazine than with one of the newer agents such as risperidone or olanzapine. The risk with the newer antipsychotics, however, is not zero. Tardive dyskinesia is often difficult to treat. The first step is to taper or discontinue the responsible medication, if possible. For patients who are taking one of the older antipsychotics, it may be helpful to switch to a newer agent such as clozapine or quetiapine. In patients for whom changing or discontinuing antipsychotics does not work, clonazepam (0.5–2 mg bid) may reduce tardive dyskinesia symptoms. The dopamine-depleting agent tetrabenazine is not currently approved for tardive dyskinesia treatment in the USA, but may be useful in patients with debilitating symptoms. In some cases, resuming high-potency antipsychotics may paradoxically improve tardive dyskinesia.
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