Hyperkinetic Movement Disorders
Gonzalo J. Revuelta
William J. Weiner,
Stewart A. Factor
key points
Dystonia is a movement disorder seen in a variety of genetic, sporadic, and acquired conditions, for which multiple medical therapies and surgical interventions are available.
Essential tremor (ET) is primarily a postural and kinetic tremor that often responds to medical therapy, but if severe it can be treated effectively with deep brain stimulation (DBS).
Huntington disease (HD) is a progressive inherited neuropsychiatric disorder for which a definitive genetic diagnosis is available; however, this information is very sensitive and should be handled by multidisciplinary centers experienced with this process.
Wilson disease (WD) is a hereditary, potentially reversible condition that can be associated with myriad movement disorders, and, if not diagnosed and treated appropriately, is fatal.
Gilles de laTourette syndrome (GTS) is a tic disorder associated with a variety of behavioral disorders often necessitating a multidisciplinary treatment approach.
Tardive dyskinesia (TD) is a choreo-dystonic, persistent movement disorder that occurs as an adverse effect of neuroleptic and antiemetic therapy.
Strange, abnormal involuntary movements are the hallmarks of a number of neurologic diseases; they are collectively termed “hyperkinetic movement disorders” (also referred to as dyskinesias). In such conditions, the movements are easily visible, and observation allows the clinician, in most instances, to suggest the proper diagnosis or class of disorders. The characteristic tremor of Parkinson disease, which is present at rest but markedly diminished during volitional movements, is an example (Chapter 10). In this chapter, six hyperkinetic movement disorders are described. All are dramatic visually because bizarre and abnormal involuntary movements are their major features. The non-neurologist encounters patients with these disorders in an office practice and also identifies them in public (e.g., in parks, trains, and shopping centers).
The disorders discussed in this chapter are dystonia, essential tremor (ET), Huntington disease (HD), Wilson disease (WD), Gilles de la Tourette syndrome (GTS), and tardive dyskinesia (TD).
Definitions
Dystonia: Involuntary sustained muscle contractions producing twisting or squeezing movements and abnormal postures. Dystonia can have stereotyped, repetitive movements that vary in speed from rapid to slow and that may result in fixed postures from the sustained muscle contractions.
Tremor: Involuntary rhythmic oscillating movement that results from the alternating or synchronous contraction of reciprocally innervated antagonist muscles. Tremor may be classified according to its prominence during activity or at rest.
Chorea: Excessive, spontaneous movements that are irregularly timed, nonrepetitive, randomly distributed, and often have a flowing “dancelike” quality that involves multiple body parts.
Tics: Repetitive, brief, rapid, purposeless, stereotyped movements that involve single or multiple muscle groups. The tics can be a patterned sequence of coordinated movements that may be complex or simple, associated with a premonitory urge, and are suppressible.
Myoclonus: Rapid, shock-like, arrhythmic (usually), and often repetitive involuntary movements. Myoclonus can be classified by location (focal, multifocal, or generalized) and by etiology.
Stereotypy: Patterned, repetitive, and purposeless movements that are performed exactly the same way each time.
DYSTONIA
Dystonia is divided into primary (idiopathic) and secondary forms. Several primary dystonic conditions have been identified which are characterized by dystonia as the sole clinical feature. The prevalence of primary dystonia is estimated to be 33 per 100,000. Dystonia of primary origin has a number of unusual but characteristic features. At onset, the movements may occur in relation to specific voluntary actions (such as in writer’s cramp) or with varied movements, so-called “action-induced dystonia.” It may occur in one body part with movement of another (overflow dystonia). Later, with progression of disease, dystonia becomes present at rest. Dystonic movements typically worsen with anxiety, heightened emotions, and fatigue, whereas they decrease with relaxation and disappear during sleep. There may be diurnal fluctuations in dystonia, which manifest as little or no involuntary movements in the morning (morning honeymoon) followed by severe disabling dystonia in the afternoon and evening. Whereas morning improvement is seen with several types of dystonia, one particular form of childhood-onset dystonia is characterized by this feature (dopa-responsive dystonia [DRD] or Segawa dystonia).
Dystonia may occur in nearly any muscle group. The following terms are used to describe
dystonia in varied distributions. When the upper face and eyelids are involved and the eyes are involuntarily closed the clinical symptom is blepharospasm. When the lower face, lips, and jaw are involved and the patient presents with involuntary opening or closing of the jaw, retraction or puckering of the lips, and repetitive contractions of the platysma, the term is “oromandibular dystonia.” Pharyngeal dystonia is associated with dysphagia, dysphonia, or dysarthria and is typically action induced. Lingual dystonia may occur at rest, presenting as sustained or repetitive protrusion of the tongue or upward deflection of the tongue against the hard palate, or it may be action induced via speaking or eating. Laryngeal dystonia (involving the vocal cords) causes spasmodic dysphonia in which the speech is tight, constricted, and forced, or it may be whispery, depending on whether the adductor or abductor muscle groups are involved. The smooth flow of speech is lost, and certain sounds are held longer and overemphasized. Spasmodic dysphonia is typically action induced by speech, and it most commonly involves the adductor muscles of the larynx. Abductor dysphonia resulting in a soft whispery voice is less common.
dystonia in varied distributions. When the upper face and eyelids are involved and the eyes are involuntarily closed the clinical symptom is blepharospasm. When the lower face, lips, and jaw are involved and the patient presents with involuntary opening or closing of the jaw, retraction or puckering of the lips, and repetitive contractions of the platysma, the term is “oromandibular dystonia.” Pharyngeal dystonia is associated with dysphagia, dysphonia, or dysarthria and is typically action induced. Lingual dystonia may occur at rest, presenting as sustained or repetitive protrusion of the tongue or upward deflection of the tongue against the hard palate, or it may be action induced via speaking or eating. Laryngeal dystonia (involving the vocal cords) causes spasmodic dysphonia in which the speech is tight, constricted, and forced, or it may be whispery, depending on whether the adductor or abductor muscle groups are involved. The smooth flow of speech is lost, and certain sounds are held longer and overemphasized. Spasmodic dysphonia is typically action induced by speech, and it most commonly involves the adductor muscles of the larynx. Abductor dysphonia resulting in a soft whispery voice is less common.
Dystonic contractions of the neck muscles, referred to as spasmodic torticollis or cervical dystonia, result in torticollis, retrocollis, anterocollis, or laterocollis. In spasmodic torticollis, rapid jerking and twisting neck movements may accompany sustained posturing of the neck. Some patients have head tremor and others have a fixed abnormal neck posture without spasmodic movements or tremor. The shoulder on the side of the head tilt typically is elevated. Dystonic movements of the arms (brachial dystonia) commonly present as pronation of the arm, often behind the back. The movements are often action induced as in writing (writer’s cramp), manipulating a musical instrument (musician’s cramp), and other occupational maneuvers. Truncal or axial dystonia manifests as lordosis, scoliosis, kyphosis, tortipelvis, or opisthotonus. Dystonic movements of the legs (crural dystonia) may occur with action or at rest and present most commonly with equinovarus posturing of the foot while walking, twisting of the foot, or increased elevation of the leg when walking. The knee usually maintains a hyperextended position with crural dystonia. Some patients walk backward, run, or even dance without incident, but when they attempt to walk normally, dystonia recurs. Patients with dystonic disorders often discover ways to suppress or hide the movements using an array of “tricks.” These often consist of postural alterations or counterpressure maneuvers that are primarily sensory in nature. Examples include touching an eyebrow in blepharospasm, which leads to eye opening, or the classical geste antagonistique, where a finger placed lightly on the chin will neutralize neck-turning in cervical dystonia. There are also motor tasks that may deactivate dystonia, including singing or whistling in blepharospasm or oromandibular dystonia and dancing in cervical or truncal dystonia. Typically, these tricks lose their effectiveness with time.
The pathophysiology of dystonic movements and tricks remain a mystery. However, some clues have emerged. Briefly, it is believed that dystonia is the result of basal ganglia dysfunction. This is primarily based on work involving cases of secondary dystonia and neuroimaging studies in idiopathic cases. There appears to be decreased output from the primary output nucleus of the basal ganglia, the medial globus pallidus. Microelectrode recordings from the globus pallidus in patients undergoing surgery have demonstrated irregular, intermittent group discharges leading to irregular output from that region to the thalamus and cortex. This supports the notion that the basal ganglia are the source of the problem. There also appears to be sensory and motor cortical involvement in the physiology of dystonia. Sensory involvement is suggested by the usefulness of sensory tricks. Physiologic studies also have demonstrated that motor cortex is hyperexcitable and that there is decreased
activation of these regions. It is possible that certain patterned or learned tasks (tricks), both sensory and motor, interrupt the production of dystonia through alterations in cortical activity.
activation of these regions. It is possible that certain patterned or learned tasks (tricks), both sensory and motor, interrupt the production of dystonia through alterations in cortical activity.
Dystonia often is misdiagnosed as hysterical or psychiatric in origin. The basis for this arises from its typical features, including the varied, often bizarre, movements and postures, the fact that they are often action induced, the worsening of dystonia with stress and improvement with relaxation, the diurnal fluctuations, and the effectiveness of various tricks. Knowledge of the unusual characteristics of dystonic disorders will be helpful in avoiding a misdiagnosis.
Classification
Classification of dystonia has been based on (a) age of onset, (b) distribution of movements, and (c) etiology. Clinical and genetic studies have demonstrated that they are all connected. Use of the first two items in the patient’s initial assessment can lead to etiology. The age-of-onset classification separates patients into early onset (younger than age 26 years) and late onset (older than age 26 years). Early onset typically begins with limb involvement and carries a worse prognosis than older onset because generalization of the movement disorder is more likely. Early-onset patients more often have hereditary disease, most commonly DYT1. Late-onset patients have focal or segmental dystonia that primarily involves the craniocervical region and does not generalize.
The distribution of dystonia is focal, multifocal, hemidystonia, or generalized. Focal dystonia is dystonia in a single body part. Multifocal dystonia includes dystonic movements in more than one body part yet not fulfilling the criteria for generalized dystonia; segmental dystonia is a form of multifocal dystonia in which contiguous body parts are affected. In hemidystonia, an arm and a leg on the same side are involved. Finally, generalized dystonia refers to the presence of dystonia in at least one leg, the trunk, and an additional body part (cranial, cervical, or brachial) or in both legs and the trunk. This classification is important in formulating a proper diagnosis. For example, hemidystonia is usually the result of a basal ganglia infarction or space-occupying lesion, whereas generalized dystonia is most likely a primary early-onset disease and has a worse prognosis than focal dystonia or hemidystonia. Early-onset and generalized dystonia appear to be most responsive to deep brain stimulation (DBS) surgery.
Classification by etiology has undergone substantial change in the last decade, primarily because of the linkage (or nonlinkage) of many types of dystonia to a variety of genes (Table 13.1). The primary dystonias (also known as idiopathic torsion dystonias) are
defined as syndromes in which the sole manifestation is dystonia, with the exception that tremor may be present. It is unclear if this disorder is purely neurochemical in origin or if some degree of neurodegeneration exists. Primary dystonias are genetically and clinically heterogeneous. Dystonia genes are depicted by the symbol DYT (followed by a number) by the Human Genome Organization/Genome Database. DYT designations have been assigned to a variety of clinically defined dystonic syndromes and unmapped, genetically linked primary dystonias. Dystonia syndromes not classified as primary but with dystonia as a predominating feature are also designated (Table 13.1). Fifteen genetic causes of dystonia have been identified; four are primary dystonias, which are discussed in this chapter.
defined as syndromes in which the sole manifestation is dystonia, with the exception that tremor may be present. It is unclear if this disorder is purely neurochemical in origin or if some degree of neurodegeneration exists. Primary dystonias are genetically and clinically heterogeneous. Dystonia genes are depicted by the symbol DYT (followed by a number) by the Human Genome Organization/Genome Database. DYT designations have been assigned to a variety of clinically defined dystonic syndromes and unmapped, genetically linked primary dystonias. Dystonia syndromes not classified as primary but with dystonia as a predominating feature are also designated (Table 13.1). Fifteen genetic causes of dystonia have been identified; four are primary dystonias, which are discussed in this chapter.
TABLE 13.1 Classification of Dystonia | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
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A second etiological category comprises the dystonia-plus syndromes. These are also considered to be neurochemical in origin, but also have features other than dystonia (e.g., patients with DRD have parkinsonian features). The third category is secondary dystonia, which develops as the result of a wide variety of known etiologies (Table 13.2). The fourth category includes hereditary-degenerative syndromes that have dystonia as part of the clinical spectrum. Examples include Parkinson disease, WD, HD, and X-linked dystonia parkinsonism (Lubag).
Primary Inherited Dystonias Dystonia is the only neurologic abnormality in patients with primary dystonia (although many may have tremor), and any distribution of abnormal involuntary movements may be observed. The primary dystonias have an insidious onset and are progressive. Initially, the movements may be only action induced, but with disease progression they occur at rest and produce fixed and sustained postures. The disorder ultimately plateaus in severity. Five criteria for the diagnosis of primary dystonia are established. These include (a) the development of dystonic movements or postures, (b) a normal perinatal and developmental history, (c) no precipitating illnesses or exposure to drugs known to cause dystonia, (d) no evidence of intellectual, pyramidal, cerebellar, or sensory deficits, and (e) negative results of investigation for secondary causes of dystonia (particularly WD). Two factors are indicators of a
poor prognosis: onset in childhood and in a crural distribution. Poor prognosis in dystonia refers to increased disability. Most patients with crural dystonia have onset of disease in childhood or early adulthood. The clinical presentation is heterogeneous.
poor prognosis: onset in childhood and in a crural distribution. Poor prognosis in dystonia refers to increased disability. Most patients with crural dystonia have onset of disease in childhood or early adulthood. The clinical presentation is heterogeneous.
TABLE 13.2 Secondary Forms of Dystonia | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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The classical early-onset primary dystonia is DYT1 dystonia. It is the most severe and the most common form of hereditary early-onset dystonia. Oppenheim, who first used the term “dystonia” in 1911, called this particular disorder dystonia musculorum deformans and it has since been renamed primary torsion dystonia or Oppenheim dystonia. DYT1 dystonia is inherited in an autosomal dominant pattern, with a 30% to 40% penetrance. The gene is located at chromosome 9q34. The gene abnormality is a unique three-base pair GAG deletion. The resulting protein, torsin A, is characterized by the loss of one of a pair of glutamic acid residues. The function of this protein and its role in altering basal ganglia function to cause dystonia remain unknown. The mutant protein is distorted leading to the formation of cytoplasmic inclusions. There is a high prevalence of earlyonset dystonia in Ashkenazi Jewish families, with more than 90% resulting from a single founder mutation in the DYT1 gene. This mutation has been traced back more than 350 years to Lithuania, and the current gene frequency is approximately 1 in 2000. In 50% to 60% of non-Jewish ethnically diverse families with earlyonset dystonia, the disease results from the same DYT1 mutation that has arisen independently in varied populations. Apparently, only one variation in the encoded protein can give rise to the DYT1 phenotype.
The clinical spectrum of early-onset DYT1 dystonia is similar in all ethnic populations. Onset of symptoms occurs at an average age of 12 years, but most patients have onset before age 26. The initial presentation is with limb onset, usually leg (crural dystonia). The presence of leg or foot dystonia is the best predictor of a DYT1 mutation. The foot often is twisted and plantar flexed while ambulating, and the patient usually toe-walks. All patients ultimately have leg involvement. The disorder may start in the arm (possibly as writer’s cramp), although less frequently. In these cases, the age of onset is a little older than crural onset and the patients are less likely to end up with generalized dystonia. Early-onset dystonia progresses by spreading across or down/up over a period of approximately 5 years; 50% of patients become either bedridden or wheelchair bound. No cognitive problems or other neurologic abnormalities are seen. Spasmodic dysphonia occurs in about 5%; cervical involvement is
rare; and cranial involvement is generally not seen. Onset in the neck or vocal cords in earlyonset patients, even if they are of Ashkenazi Jewish descent, rarely is caused by the DYT1 gene. These patients rarely generalize. Lateonset (older than age 26) craniocervical dystonia indicates that the patient does not have DYT1 dystonia. The DYT1 patient often stabilizes and may even improve to some degree, but the disorder does not spontaneously remit. Genetic testing is available for DYT1 dystonia and should be considered in early-onset primary dystonias and in late-onset patients with a family history. The specificity of using age 26 as a cutoff age is 63% for Ashkenazi Jews and 43% for non-Jews.
rare; and cranial involvement is generally not seen. Onset in the neck or vocal cords in earlyonset patients, even if they are of Ashkenazi Jewish descent, rarely is caused by the DYT1 gene. These patients rarely generalize. Lateonset (older than age 26) craniocervical dystonia indicates that the patient does not have DYT1 dystonia. The DYT1 patient often stabilizes and may even improve to some degree, but the disorder does not spontaneously remit. Genetic testing is available for DYT1 dystonia and should be considered in early-onset primary dystonias and in late-onset patients with a family history. The specificity of using age 26 as a cutoff age is 63% for Ashkenazi Jews and 43% for non-Jews.
Linkage studies involving several large families with adult- or mixed-onset dystonia of a variety of distributions have excluded the DYT1 locus. However, dystonia families have been linked to other possible genes. DYT6 has been linked to chromosome 8p in two Mennonite families from the midwestern United States with an autosomal dominant form of dystonia with incomplete penetrance. The phenotype of these families includes a broader age of onset (5 to 38 years; mean, 19) and an onset distribution that includes limbs and cervical or cranial areas. There are also differences from typical adult-onset craniocervical dystonia because DYT6 dystonia commonly spreads to the limbs, but the former syndrome does not.
The DYT7 gene is linked to chromosome 18p in a family from northwest Germany. This family has an autosomal dominant form of adult-onset craniocervical dystonia with incomplete penetrance. The average age of onset was 41 years (range 28 to 70 years), and most patients had focal cervical dystonia. Some family members had cranial or laryngeal involvement, and postural hand tremor. Another family was designated DYT13 and linked to chromosome 1p36. This was an Italian family with focal and segmental dystonia usually affecting the craniocervical region. Some had early-onset disease and generalized, indicating a mixed presentation. Other inherited forms of dystonia are listed in Table 13.1.
Adult-Onset Primary Dystonia Adult-onset primary dystonia is the most common type of dystonia. It presents with brachial and craniocervical dystonia and only rarely as truncal or crural dystonia. Only 18% of these patients develop generalized dystonia, with even a smaller percentage ever becoming wheelchair bound or bedridden. The dystonia usually remains as a focal dystonia, but it may spread to a contiguous body region in some cases, becoming segmental in distribution. The course is usually benign (meaning not life threatening but it can be disabling), and remissions occur in approximately 10% of patients.
Cranial Dystonia Blepharospasm-oromandibular dystonia (Meige syndrome) was first described by the French neurologist Henry Meige in 1910. Blepharospasm and oromandibular dystonia may occur independently, but the combination is more frequent (in more than 50% of the patients). Pharyngeal, laryngeal, lingual, or cervical dystonia may occur. Blepharospasm in isolation (referred to as benign essential blepharospasm [BEB]) is more common than oromandibular dystonia. Blepharospasm is often preceded by eye irritation, photophobia, and increased blinking. It may start in one eye and spread to the other, or it may start in both. It results in involuntary blinking, repetitive contractions (blepharoclonus), squinting, or sustained closing of the eyes. Approximately 12% of these patients are functionally blind because of their inability to voluntarily open their eyes. Features that aggravate blepharospasm include sunlight (many wear wrap-around dark sunglasses, even indoors), looking upward, feeling stress, fatigue, watching television, walking, driving, talking, and even yawning. Sensory tricks used by patients to open their eyes include forced raising of the eyelids, applying pressure on the superior orbital ridges with a finger, and rubbing the eyelids. In addition, some find that forced jaw opening, neck movements, whistling, and wearing dark glasses are helpful. Some patients use eyeglasses with eyelid crutches to hold the lids open.
Oromandibular dystonia, jaw opening or closing dystonia, is frequently accompanied by lingual protrusion dystonia. It may be aggravated by talking, chewing, or swallowing. Sensory tricks include pressing on the lips or teeth with fingers, pressing on the hard palate with the tongue, or putting a finger in the mouth. About 20% of patients have their ability to eat severely compromised.
Meige syndrome affects women more commonly than men and presents in the sixth decade of life. It often begins with blepharospasm, followed by oromandibular, lingual, and pharyngeal dystonia. Other dystonic movements may occur in some patients, and hand tremor similar to ET may be an associated problem. The severity of dystonia fluctuates from day to day and disappears with sleep. Spontaneous remissions are rare.
Cervical Dystonia (Spasmodic Torticollis)Cervical dystonia is the most common adultonset focal dystonia, making up about 40% (Fig. 13.1). The age of onset is in the fourth or fifth decade (mean age, 41 years) and women are affected more frequently than men (3 to 1). The disorder is characterized by involuntary neck movements, abnormal postures of the neck and shoulders that are often painful, and hypertrophy of involved neck muscles. Pain is present in about 80% of patients, and hypertrophy is seen in all. Initially, some patients do not perceive their dystonia, and it is brought to their attention by others. This suggests that a problem with perception of head position exists. The movements may be intermittent at first and associated with specific actions. Most patients deteriorate during the initial 5 years and then stabilize. The condition may be characterized ultimately by dystonic postures that are present at rest, worsen with action, and improve in sleep. Spontaneous remissions occur in 10% to 30%, most commonly in the first year. All patients relapse eventually but few have a second remission. Rotation of the neck (torticollis) is the most common posture seen, with lateral flexion (laterocollis), flexion (anterocollis), and extension (retrocollis) occurring in various combinations. Spasmodic (dynamic) movements are not present in all patients despite the commonly used term “spasmodic torticollis.” In fact, they occur in only 10% to 15% of patients. Factors that may exacerbate cervical dystonia include emotional stress, fatigue, walking, working with the hands, and attempting to look in the opposite direction of
the dystonic contractions. When the patient tries to overcome the movements and look in the opposite direction, he or she may experience a high-amplitude, jerky tremor referred to as dystonic tremor. Some patients present with bidirectional torticollis because at varying times the head may turn in different directions and muscles of both sides of the neck may be involved.
the dystonic contractions. When the patient tries to overcome the movements and look in the opposite direction, he or she may experience a high-amplitude, jerky tremor referred to as dystonic tremor. Some patients present with bidirectional torticollis because at varying times the head may turn in different directions and muscles of both sides of the neck may be involved.
 FIGURE 13.1 Cervical dystonia resulting in rotation of the neck to the left. |
▪SPECIAL CLINICAL POINT: Many patients with cervical dystonia (spasmodic torticollis) present with head tremor (40%).The tremor varies in amplitude and, if there is little directional change, the patients frequently are misdiagnosed as having essential tremor (ET). The distinction is important because dystonia does not respond to tremor medications but does respond to botulinum toxin.
This tremor can be distinguished from essential head tremor by the presence of subtle changes in posture, a jerky nonrhythmic quality, and muscle hypertrophy along with improvement with sensory tricks. Sensory tricks usually involve the use of a light touch or pressure to the chin or cheek with fingers (geste antagonistique) (Fig. 13.2) or other objects such as a pen or eye glasses and holding the back of the head with the hand or leaning the head against a wall or a headrest. This lessens the head tilt and tremor and relaxes the muscles for variable durations of time. Tricks usually lose their effectiveness. Cervical dystonia may be associated with Meige syndrome, writer’s cramp, and ET. Complications of prolonged cervical dystonia occur in many patients including those with degenerative osteoarthritis of the cervical spine with the expected sequelae of radiculopathy and myelopathy. These complications could lead to permanent neurologic deficits.
Writer’s Cramp Writer’s cramp (Fig. 13.3) is a dystonic spasm induced by a specific task (action-induced or task-specific dystonia). When these cramps occur with a single type of action (such as writing), they are referred to as simple writer’s cramp, but when the spasms occur with a variety of activities, they are referred to as dystonic cramps. Writer’s cramp occurs in both men and women, and the age of onset ranges from 20 to 70 years. These patients present with a change in handwriting that becomes sloppy and illegible. Some patients squeeze the pen tightly and press down hard on the writing surface, which results in a jerky writing motion and tearing of the paper. In others, the fingers splay and pull away from the pen. Writing is painful in most patients. Initially, the dystonic
contraction occurs with persistence of task, but as the disorder progresses, it occurs with initiation of the task. Initially, other tasks performed with the same hand are normal, but later these too may become involved. The disorder is usually asymmetric, but those patients who learn to write with the opposite hand, the disorder may become bilateral (about 25% of patients). When some patients write with the unaffected hand, the affected hand exhibits involuntary spasms—so-called “mirror dystonia.” Writer’s cramp may be associated with ET and may be related to the syndrome of primary writing tremor, which is thought by some to be a variant of ET. Other occupational cramps that have been reported include pianist’s and violinist’s palsy, golfer’s palsy, and dart-thrower’s palsy. The common factor of these disorders is the occurrence during the performance of a welllearned motor (manual) task and perhaps the overuse of the hand with that particular task. In writer’s cramp, there appears to be co-contraction of agonist and antagonist muscles, perhaps related to loss of reciprocal inhibition. Evidence has been mounting to support abnormalities in neuroplasticity as the etiology of task-specific dystonias in genetically susceptible individuals.
contraction occurs with persistence of task, but as the disorder progresses, it occurs with initiation of the task. Initially, other tasks performed with the same hand are normal, but later these too may become involved. The disorder is usually asymmetric, but those patients who learn to write with the opposite hand, the disorder may become bilateral (about 25% of patients). When some patients write with the unaffected hand, the affected hand exhibits involuntary spasms—so-called “mirror dystonia.” Writer’s cramp may be associated with ET and may be related to the syndrome of primary writing tremor, which is thought by some to be a variant of ET. Other occupational cramps that have been reported include pianist’s and violinist’s palsy, golfer’s palsy, and dart-thrower’s palsy. The common factor of these disorders is the occurrence during the performance of a welllearned motor (manual) task and perhaps the overuse of the hand with that particular task. In writer’s cramp, there appears to be co-contraction of agonist and antagonist muscles, perhaps related to loss of reciprocal inhibition. Evidence has been mounting to support abnormalities in neuroplasticity as the etiology of task-specific dystonias in genetically susceptible individuals.
 FIGURE 13.2 Cervical dystonia improved with a trick, touching the back of the head. |
 FIGURE 13.3 Writer’s cramp is an action-induced dystonic spasm, resulting, in this patient, in wrist flexion, metacarpophalangeal joint extension, extension of the thumb, and flexion of the distal interphalangeal joints, leaving the patient with an inability to continue writing. |
Dopa-Responsive DystoniaOne “dystonia plus” syndrome that warrants discussion is DRD (DYT5). DRD is characterized by childhood (mean age, 6 years) or adolescent onset, female predominance (four times that of males), foot dystonia in childhood, parkinsonism in adults, and diurnal fluctuation. Patients function well in the morning and deteriorate as the day wears on. They improve with sleep. Purely dystonic limb presentations are most common. Some patients have mixed dystonia and parkinsonism, and the parkinsonism becomes more prominent with age. The clinical spectrum includes developmental delay and spasticity mimicking cerebral palsy. The most characteristic feature is profound and sustained response to levodopa S 300 mg/day.
▪SPECIAL CLINICAL POINT: So profound and sustained is the treatment response in dopa-responsive dystonia (DRD) that all individuals presenting with dystonia should be given a trial of levodopa.
DRD has been linked to two chromosomes. The most common is chromosome 14q1124.3—the gene codes for an enzyme in the rate-limiting step in the biosynthesis of tetrahydrobiopterin (GTP cyclohydrolase I), a cofactor in dopamine synthesis, and is dominantly inherited. The other link is to a rare defect seen on chromosome 11p15.5—the gene codes for tyrosine hydroxylase, the rate-limiting step in catecholamine metabolism—and is recessively inherited. The resulting deficiency of biopterin, a cofactor in catecholamine synthesis, leads to decreased levels of dopamine, which explains the long-term responsiveness of patients to levodopa. Dopamine transporter single-photon emission computed tomography (SPECT) scanning is normal in patients with DRD, and this helps differentiate these patients from those with early-onset Parkinson disease. Diagnosis of DRD is based on clinical profile and response to levodopa.
Secondary Dystonia To make a diagnosis of primary dystonia, known causes of dystonia (i.e., secondary or symptomatic dystonias [Table 13.2] and hereditary degenerative diseases [Table 13.1]) must be excluded. Clues to the diagnosis of a secondary dystonia can be uncovered with a thorough history and physical examination, and radiologic and laboratory testing. Usually, examination findings in addition to dystonia are suggestive of dysfunction of other parts of the central nervous system (CNS), including the cranial nerves, pyramidal system, cerebellar system, and higher cortical function. There is often an abrupt onset to dystonia, and dystonia is present at rest from the start in secondary cases.
▪SPECIAL CLINICAL POINT: The presence of hemidystonia suggests a focal lesion such as a tumor, infarction, abscess, or arteriovenous malformation in the basal ganglia.
In patients with a single nonprogressive event such as an infarction or trauma, dystonia will stabilize and not be progressive. The examiner should be cautious because secondary dystonia may mimic idiopathic dystonia. For instance, stroke in the basal ganglia may cause typicallooking cervical dystonia and neurolepticinduced (tardive) dystonia in adult patients may be symptomatically identical to adult-onset primary dystonia. Clues that tardive dystonia is more likely include retrocollis, a more phasic or dynamic form of torticollis, and the cooccurrence of choreiform movements. These patients also report less effectiveness of tricks and do not often have head tremor. A lack of muscle hypertrophy also suggests drug-induced dystonia.
An important feature of secondary dystonia is that dystonia may have a delayed onset after a cerebral insult. In adults, the most frequent cause of delayed-onset dystonia is cerebral infarction. The duration of the delay can vary from weeks to years and is often associated with an improvement of the original neurologic deficit. In children, the most frequent cause of delayed-onset dystonia is perinatal trauma or hypoxia. The reason for the delay is unclear, but it has been postulated that dystonia in these circumstances is a result of neuronal sprouting stimulated by the original injury. A history of perinatal difficulties must be ruled out if a diagnosis of primary dystonia is made.
▪SPECIAL CLINICAL POINT: The most important disorder to exclude in a new-onset young dystonia patient is Wilson disease (WD). Screening forWD and an imaging study of the brain should be performed on all young dystonia patients.The rest of the diagnostic evaluation should be tailored to the individual patient.
It had been suggested that secondary dystonia occurs in genetically susceptible individuals. However, it has been demonstrated that these patients are not genetically susceptible.
Pathology and Neurochemistry
Dystonia is related to basal ganglia dysfunction. Because there have been few neuropathologic examinations of patients with dystonia (most were without abnormality), the pathologic-anatomic basis of this movement disorder has been based
almost exclusively on cases of symptomatic dystonia. Abnormalities were seen in the putamen and, to a lesser extent, the caudate nucleus and the thalamus. These findings have been supported by imaging studies. Interestingly, in those rare cases of dystonia with pathologic abnormalities, the microscopic changes were observed in the brainstem. The neurochemical basis of dystonia is also unclear. It has been suggested that the abnormality in this disorder is in the dopamine or acetylcholine systems. Clinical evidence to suggest these hypotheses include the onset of dystonia after treatment with dopamine receptor antagonists and the response of dystonia to anticholinergic medications. In addition, the discovery that DRD is acutely responsive to small doses of levodopa and that it is caused by two genes involved in the biosynthesis of dopamine support a dopaminergic hypothesis. Finally, the expression of torsin A in the substantia nigra pars compacta also implicates the dopamine system. Norepinephrine is a neurotransmitter that, among other actions, inhibits cholinergic neurons. A deficiency of norepinephrine might explain the response of dystonia to anticholinergic medications. Other theories include alterations in y-aminobutyric acid (GABA) or cerebral somatostatin.
almost exclusively on cases of symptomatic dystonia. Abnormalities were seen in the putamen and, to a lesser extent, the caudate nucleus and the thalamus. These findings have been supported by imaging studies. Interestingly, in those rare cases of dystonia with pathologic abnormalities, the microscopic changes were observed in the brainstem. The neurochemical basis of dystonia is also unclear. It has been suggested that the abnormality in this disorder is in the dopamine or acetylcholine systems. Clinical evidence to suggest these hypotheses include the onset of dystonia after treatment with dopamine receptor antagonists and the response of dystonia to anticholinergic medications. In addition, the discovery that DRD is acutely responsive to small doses of levodopa and that it is caused by two genes involved in the biosynthesis of dopamine support a dopaminergic hypothesis. Finally, the expression of torsin A in the substantia nigra pars compacta also implicates the dopamine system. Norepinephrine is a neurotransmitter that, among other actions, inhibits cholinergic neurons. A deficiency of norepinephrine might explain the response of dystonia to anticholinergic medications. Other theories include alterations in y-aminobutyric acid (GABA) or cerebral somatostatin.
TABLE 13.3 Medical Treatment of Dystonia | |||||||||||||||||||||
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Treatment
Because the etiology and neurochemistry of dystonia is unclear, medical treatment has been less than satisfactory. A number of therapeutic modalities have been tested (for review see Table 13.3). The approach is to treat patients empirically with one agent at a time. Ultimately various combinations may be tried. Unfortunately, less than 50% of dystonic patients respond to medical therapy.
Because of the dramatic effect levodopa has on DRD, it is recommended that every patient with dystonia be tried on levodopa. Patients with DRD usually respond rapidly to low doses (<300 mg/day), but in some cases higher doses are needed. If there is no benefit, the dose is pushed to 600 mg/day over 2 to 3 weeks.
Anticholinergics are the most frequently used agents to treat primary dystonia. In an openlabel trial, improvement was seen in 61% of children and 38% of adults. The average daily dose of trihexyphenidyl in children and adults was 41 mg and 24 mg, respectively. Adverse effects include blurred vision, dry mouth, urinary difficulties, constipation, sleep pattern alteration, forgetfulness, weight loss, personality changes, and psychosis. The earlier in the course of disease patients were treated, the better they did.
Tetrabenazine, a dopamine-depleting agent, is effective in patients with Meige syndrome and other types of dystonia. Reserpine, another dopamine-depleting drug, is effective in approximately 30% of patients. The adverse effects of most concern with dopamine-depleting agents include depression (which can be severe, come on suddenly, and have a protracted course), parkinsonism, orthostatic hypotension, and gastrointestinal problems.
Dopamine antagonists should be avoided. Mixed results with baclofen, carbamazepine,
benzodiazepines (particularly clonazepam and diazepam), mexiletine, and clozapine have been observed.
benzodiazepines (particularly clonazepam and diazepam), mexiletine, and clozapine have been observed.
In patients failing medical and botulinum toxin (BoNT) therapy, surgical techniques, including both central and peripheral procedures, have been used. Central procedures are used primarily for generalized dystonia. Modern techniques include the use of DBS with electrophysiologic microelectrode cellular recording and mapping to improve localization. Two well-designed, double-blind, controlled trials (22 and 40 patients) demonstrated significant improvement (54% and 39.9% in movement, and 44% and 38% in disability scores) in patients with primary generalized dystonia after DBS using bilateral globus pallidus pars interna as targets. Both studies showed continued improvement up to a year, and a third study of 31 patients showed 79% improvement in movement scores up to 2 years following surgery. Serious complications are rare with DBS, and failures or loss of benefit have rarely been reported. The most important factors for successful treatment with DBS are patient selection, lead placement, and optimal postsurgical programming of the stimulator. Surgical candidates suffer from medically refractory, unequivocal dystonia (diagnosed by a movement disorder specialist), and significant disability.
Peripheral surgical procedures include myectomy of the orbicularis oculi for blepharospasm and selective peripheral denervation for cervical dystonia. Another technique used to treat generalized dystonia is intrathecal baclofen. Baclofen is delivered to the intrathecal space through an inserted catheter with a continuous pump. This has been highly effective in treating spasticity of spinal and cortical origin. In the few patients with dystonia treated, results have been modest. Possible adverse effects include respiratory depression from baclofen overdose, catheter malfunction, and pump infection.
Intramuscular injection of BoNT remains the treatment of choice for focal dystonias, particularly in the craniocervical distribution.
BoNT is one of the most lethal toxins known to man. Of eight subtypes produced by the anaerobic organism Clostridium botulinum, three have been linked to human botulism: types A, B, E. BoNT A (Botox) has been used therapeutically since the mid-1980s for treatment of strabismus. In 1990, BoNT A was approved by the U.S. Food and Drug Administration (FDA) for treatment of blepharospasm, strabismus, and hemifacial spasm. In 2000, it was approved for cervical dystonia as was BoNT B. The use of these toxins is more widespread than these indications because they are used to treat all types of focal dystonia, including blepharospasm, oromandibular dystonia, spasmodic dysphonia, and limb dystonias. BoNTs act presynaptically at the cholinergic neuromuscular junction. The toxin attaches to an acceptor protein that is specific for each type of BoNT, is endocytosed into the nerve terminal and blocks the release of acetylcholine. The blockade of the neuromuscular junction results in weakness and atrophy of the muscle and a decrease in muscle spasms, but the effect is transient, lasting 3 to 6 months. If a desirable clinical result is achieved, repeated injections are necessary. BoNT is administered by direct intramuscular injection and all adverse effects are local. In blepharospasm improvement is seen after 3 to 14 days. The response lasts 2 to 4 months and treatment is needed three or four times per year. Adverse effects include ptosis, diplopia, and increased tearing, all of which are transient. Cervical dystonia is the most common disorder treated with BoNT. Multiple studies with both toxins have shown significant improvement in a majority of patients. As with blepharospasm, response occurs in 3 to 14 days and lasts 3 to 6 months. Neck muscles injected are chosen based on the presence of pain and hypertrophy and spasm and in relation to the abnormal posture. Ninety percent of cervical dystonia patients respond. Side effects include transient neck weakness, dysphagia, dry mouth, and a “flu-like” syndrome.
Spasmodic dysphonia of the adductor type, previously poorly responsive to any therapy,
responds dramatically to BoNT. The thyroarytenoid muscles are approached through the neck with electromyogram (EMG) guidance. The only adverse effects are a breathy, whispery voice and dysphagia, which improves over days to weeks. Treatment of otomandibular dystonia is also frequently successful. Injections can be made into the pterygoid muscles (medial or lateral) with EMG guidance, and into the masseters, temporalis, and digastric muscles in varied combinations depending on whether the patient has jaw opening, closing, or lateral deviation as the main manifestation. Side effects include dysphagia and weakness of the soft palate that allows fluid regurgitation through the nose. Limb dystonias (writer’s cramp) respond with less consistency because the resulting weakness of the hand muscles may be more troublesome than the cramps themselves. BoNT is the treatment of choice for most focal dystonias because of greater efficacy and fewer side effects than standard medical therapies.
responds dramatically to BoNT. The thyroarytenoid muscles are approached through the neck with electromyogram (EMG) guidance. The only adverse effects are a breathy, whispery voice and dysphagia, which improves over days to weeks. Treatment of otomandibular dystonia is also frequently successful. Injections can be made into the pterygoid muscles (medial or lateral) with EMG guidance, and into the masseters, temporalis, and digastric muscles in varied combinations depending on whether the patient has jaw opening, closing, or lateral deviation as the main manifestation. Side effects include dysphagia and weakness of the soft palate that allows fluid regurgitation through the nose. Limb dystonias (writer’s cramp) respond with less consistency because the resulting weakness of the hand muscles may be more troublesome than the cramps themselves. BoNT is the treatment of choice for most focal dystonias because of greater efficacy and fewer side effects than standard medical therapies.
Physicians administering BoNT should be familiar with the disorders treated, mechanisms of action, effective doses in each disorder, and the anatomy of the area injected. The disorders treated with BoNT have expanded beyond dystonia and include spasticity, achalasia, anal and urethral sphincter disorders, hyperhydrosis, sialorrhea, and others. BoNT A also has been approved for cosmetic use for facial wrinkles.
There are no alternative medical therapies with proven effect in dystonia. Physical therapy can be a useful adjunct for maintaining mobility and preventing contractures.
When to Refer to a Neurologist
Dystonia is a complicated disorder. Neurologists, especially movement disorder specialists, are most qualified for addressing diagnosis, genetic testing, and therapy. In particular, referral should be made to neurologist well versed in the use of BoNT.
Special Challenges for Hospitalized Patients
Most hospital staff are unfamiliar with dystonia, and because of the bizarre movements, cessation with sleep, and exacerbation with anxiety they are likely to assume or suspect that the movements are psychogenic in origin. This can lead to frustration and anger on the part of the patient. Staff education is required. Patients may be unable to stay still for testing and procedures, and mild sedation may be necessary.
ESSENTIAL TREMOR
Essential tremor is a monosymptomatic (kinetic tremor) syndrome. Tremor is generally classified by its anatomic location, frequency, etiology, or in relation to rest, posture, and action. Resting tremor refers to tremor while the body part is at rest. Resting tremor is seen in Parkinson disease. Postural tremor is seen when the body part maintains posture against gravity, and is frequently seen in ET Kinetic tremor refers to tremor during goal-directed movements, as typically seen in cerebellar disease. This simple classification can be very useful in developing a differential diagnosis (Table 13.4). ET is the most common tremor disorder and is the subject of discussion in this section.
Clinical Features
ET is a nervous system disorder that occurs in a sporadic or familial form. The familial form is often autosomal dominant with high but not full penetrance. ET is the most common movement disorder, occurring in up to 6% of the population and 13% of people over age 65. It occurs equally in men and women and is characterized by a postural tremor, with or without a kinetic component, which is most evident in the upper extremities. The kinetic component is seen in finger-to-nose testing, although it is often not as dramatic as in cerebellar disorders,
and tremor at rest occurs rarely (in 5% to 10% of patients) in the most severe cases when the patient has a long-standing disease. Tremor frequency ranges from 4 to 12 Hz.
and tremor at rest occurs rarely (in 5% to 10% of patients) in the most severe cases when the patient has a long-standing disease. Tremor frequency ranges from 4 to 12 Hz.
TABLE 13.4 Differential Diagnosis of Tremor | ||||||||||||||||||||||||||||||||||||||||
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A maneuver to potentiate tremor during physical examination is to have patients hold the fingertips of their two open hands close together under the chin without touching while holding their elbows out like wings. This maneuver can also bring out a more proximal tremor distribution. Another examination technique is the cup test: the patient holds a full cup of water and pours it into another cup or takes a drink. The tremor is often worse as the hand approaches the face. The onset of ET can be at any age from early childhood to age 90, with a mean of 45 years. The patients with a family history appear to have an earlier age of onset (age 40) compared with sporadic cases (age 51). ET usually affects the fingers and hands first and then moves proximally. Tremor onset may occur bilaterally in the hands or in one hand at a time. When bilateral, it may be symmetric or asymmetric.
Tremor may spread to the head and neck. Approximately 50% to 60% of patients with ET have head involvement, and in some instances head tremor is the sole manifestation. Head tremor may present as a vertical nod (yes-yes) or as a horizontal nod (no-no). Voice tremor occurs in approximately 25% to 30% of patients with ET. The voice is characterized by rhythmic alteration in intensity at the same frequency as the hand tremor. Head and voice tremor tend to be more frequent and severe in women. Tremor of the head or voice should strongly suggest a diagnosis of ET and not Parkinson disease because both are very uncommon in the latter. Less frequently, tremor occurs in the jaw, face (lips, tongue), trunk, and legs (15%). There are also a variety of task-specific tremors (i.e., primary writing tremor), which are variants of ET. ET is a slowly progressive disorder that can remain stable in some patients for decades. It is not unusual for patients to seek medical advice after having the tremor for one or two decades. At first tremor may occur when the limb is placed in a specific posture but later it is aggravated by many different movements or postures. The tremor disappears during sleep and worsens with anxiety, fatigue, temperature changes, local pain, caffeine ingestion, aminophylline ingestion, and possibly hunger.
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