Other Movement Disorders

Clinical Manifestations

Most action tremors ( Table 379-2 ) combine postural and kinetic components. Most tremors worsen with stress, including performing an affected activity in public. Initially, a tremor may be evident only when one attempts fine, dexterous tasks such as threading a needle, soldering, or using a screwdriver. More severe tremors interfere with activities such as handwriting, fastening buttons, shaving, eating soup with a spoon, or drinking from a cup. Patients often adapt or use compensatory measures, such as switching an activity to a less affected hand (e.g., shaving with the nondominant hand), using two hands to drink, drinking only from an incompletely filled glass or cup, or completely avoiding more challenging feeding activities in public. Severe action and intention tremors can cause handwriting to become completely illegible and can result in dependence on others for care.

Head tremors, which may be side to side, up and down, or mixed, are rarely disabling but are often a source of embarrassment. Tremor of the larynx, which causes the voice to quaver, is best appreciated by asking the patient to sustain a note. Action tremor of the lower limbs is assessed by having the patient hold the foot up to a target (e.g., the examiner’s hand) and then perform a heel-knee-shin test.

Most upper limb action tremors affect many activities to a similar extent. Less commonly, tremors can affect a single task in isolation (task-specific tremors), the most common being a primary writing tremor. Orthostatic tremor is apparent in the legs and in antigravity muscles only when the patient is standing in one spot and subsides during walking or leaning against a wall; these patients commonly complain of a tremendous sense of insecurity while standing and a fear of falling. Electrophysiologic assessment demonstrates a very characteristic high-frequency tremor (14 to 18 Hz).

Definition and Epidemiology

Huntington disease is a fully penetrant autosomal dominant neurodegenerative disorder caused by an expanded trinucleotide (CAG) repeat in the gene for the protein huntingtin located on chromosome 4. The worldwide 2.71 per 100,000 prevalence ranges from 5.7 per 100,000 for individuals of European descent to 0.4 per 100,000 for Asians. The age at diagnosis is driven by the longest expanded allele and as yet unidentified genetic or environmental factors.

Pathobiology

Huntington disease is characterized neuropathologically by neuronal loss accompanied by intraneuronal inclusions and gliosis, especially in the caudate nucleus and putamen (the striatum) and the cerebral cortex. Although symptoms do not begin until later in life, early neurodevelopment is likely altered. Understanding how these changes result from the expanded polyglutamine tract in the mutated huntingtin protein is the goal of current research.

Clinical Manifestations

Symptoms typically begin between the ages of 30 and 55 years, but 5 to 10% of patients have an onset before the age of 20 years (juvenile Huntington disease) and a few patients begin to have symptoms late in life. Symptoms include a combination of a movement disorder, psychiatric disturbances, and cognitive dysfunction. Early on, the movement disorder is predominantly chorea, but parkinsonism and dystonia develop later ( Video 379-2 ). Some patients, especially those with juvenile onset, have a more rapidly progressive akinetic-rigid and dystonic form (the Westphal variant). Psychiatric manifestations, which are universal but widely variable, include personality changes, impulsiveness, aggressive behavior, depression, and paranoid psychosis. These psychiatric symptoms may precede the motor manifestations, and psychotropic drug therapy may be incorrectly blamed for the subsequent development of the movement disorder. Cognitive changes result in progressive subcortical dementia with disturbed attention, concentration, judgment, and problem solving that differs from the typical cortical dementia of Alzheimer disease. Oculomotor dysfunction, most often manifested by difficulties with refixating the gaze and a resulting tendency to use blinks and head thrusts, is another common feature.

Diagnosis

The diagnosis is confirmed by genetic testing. Normal alleles of the IT15 gene have fewer than 30 CAG repeats, whereas 40 or more repeats invariably result in clinical illness. An earlier age of onset correlates with larger numbers of CAG repeats. Patients with intermediate alleles (27 to 35) have more behavioral abnormalities, such as apathy and suicidal ideation, than unaffected individuals. Mutant huntingtin protein levels, detected by ultrasensitive single-molecule counting, are associated with the onset of symptoms and diminished cognitive and motor function.

Treatment and Prognosis

Definition and Pathobiology

In dystonia, sustained muscle contractions, often initiated or worsened by voluntary action, result in repetitive twisting and sometimes tremulous movements and abnormal postures. Dystonia can be classified as primary dystonia, dystonia-plus, secondary dystonia, and heredogenerative dystonia ( Table 379-5 ). One classification uses five descriptors to specify the clinical characteristics: age at onset, body distribution, temporal pattern, and whether dystonia occurs in isolation (or only accompanied by tremor; “pure dystonia”) or coexists with other movement disorders (typically parkinsonism and myoclonus). Etiology is defined as the presence or absence of degenerative or structural nervous system pathologic process and by whether the mode of inheritance is autosomal dominant, autosomal recessive, X-linked recessive, mitochondrial, or acquired. Probable or causal monogenic variants are found in about 20% of cases. A commonly used classification scheme for the genetic dystonias involves applying the “DYT” prefix followed by a number (e.g., 1 to 25); however, several shortcomings have encouraged an active re-evaluation of this approach. Acquired causes include drugs, toxins, infections, vascular disease, neoplasia, trauma, and psychogenic.

Clinical Manifestations

Common forms of dystonia include eyelid closure (blepharospasm), jaw opening or closing (oromandibular dystonia), pulling or turning of the neck in any one or combination of directions (cervical dystonia: rotatory torticollis, laterocollis, retrocollis, anterocollis), hyperadduction and less often excessive abduction of the vocal cords (laryngeal dystonia or spasmodic dysphonia), abnormal posturing and tightness of the hand while writing or using the hand for other tasks (writer’s cramp, manual dystonia), abnormal posturing of the trunk or pelvis (axial dystonia), or abnormal posturing of the lower limb, including plantar flexion and inversion of the foot ( Videos 379-4 , 379-5 , 379-6 , and 379-7 ). The movements are often slow and sustained, although they also may be rapid (dystonic spasms). Slower, sinuous writhing dystonic movements, particularly present in the distal limbs, are referred to as athetosis . Dystonia is often made worse by activity (action dystonia), and a unique aspect of dystonia is that only selected acts may be affected, with complete sparing of all other activities in the same limb (task-specific dystonia, including writer’s cramp and musician’s cramp) ( Video 379-8 ). Task specific dystonia (e.g., golfing, running) may occur only during specific activities. In some patients, dystonia remains isolated and action specific over many years; in others, it progresses to involve adjacent muscles (overflow dystonia) and may eventually be present at rest, in which case joint contractures may result. Another common feature of dystonia is its transient improvement with the use of a sensory trick (geste antagoniste), such as lightly touching the chin to relieve severe cervical dystonia or the lid to relieve disabling blepharospasm ( Video 379-9 ). Patients with dystonia, independent of cause, often have additional postural and action tremors, phenotypically similar to those in essential tremor. Some patients also demonstrate more irregular, coarse, lower frequency rhythmic movements called dystonic tremor .

Dystonia is often classified according to the site of involvement: focal, only one body part (e.g., blepharospasm, cervical dystonia, writer’s cramp); segmental, two or more contiguous body parts; multifocal, two or more noncontiguous body parts; generalized, trunk and at least two other sites (with or without leg involvement); and hemidystonia, unilateral (generally a causative focal brain lesion is found most often involving the putamen).

Diagnosis and Prognosis

For diagnostic and prognostic purposes, dystonia also may be distinguished by age of onset as childhood-onset, adolescent-onset, or adult-onset dystonia. The younger the age of onset, the more likely a cause can be defined. Conversely, isolated dystonia beginning in adult life is most often an idiopathic disorder; further investigations are typically unrewarding and are usually not indicated. Likewise, independent of the cause, dystonia beginning in childhood commonly progresses to segmental or generalized involvement whereas adult-onset dystonia usually remains focal or segmental.

Primary (Idiopathic) or Isolated Dystonias

Primary dystonia accounts for up to 90% of patients with a pure dystonic syndrome, in which dystonia either is the only motor feature or is accompanied only by tremor. To date, no consistent neuropathologic changes have been found in the small numbers of brains affected by primary dystonia that have been studied.

When symptoms begin in childhood, a definable genetic cause is often identified, one of the most common being DYT1, usually resulting from the autosomal dominant inheritance of a GAG deletion in the torsin A gene (Oppenheim dystonia). This disorder is more common in persons of Ashkenazi Jewish descent. The dystonia often begins in the first decade of life and can progress to severe disability, although the spectrum of disease, even within the same family, can be quite varied and penetrance is relatively low (about 40%; Video 379-10 ). Other genetic forms of dystonia include THAP1 mutations for DYT6 and TUBB4A mutations for DYT4 or “whispering dystonia.” Genetic testing is available but in the case of DYT1 is recommended only when the age of onset in the patient or another affected family member is less than 26 years. Among the many other potential genes and gene variants are the rare KMT2B missense mutation in generalized dystonia.

Adult-Onset Idiopathic Dystonia

Adult-onset idiopathic dystonia is the most common type of dystonia seen in general neurologic practice. The dystonia typically begins in the face, neck, or arm and may remain focal and nonprogressive or spread only to contiguous muscles after many years. The cause of this disorder is not known, although a positive family history may be noted if multiple family members can be examined. Genetic forms of adult-onset focal or segmental dystonia include ANO3 and GNAL mutations for craniocervical dystonia and possibly CIZ1 mutations for cervical dystonia.

Dystonia-Plus

The term dystonia-plus refers to a small number of disorders characterized by dystonia with other neurologic signs that result from a known or presumed genetic defect without an underlying progressive neurodegenerative process. In the newer classification, these conditions are included in the group of disorders with dystonia combined with other neurologic features.

Dopa-responsive dystonia, which usually results in dystonia beginning in the first decade of life, most often in the lower limbs, sometimes can be mistaken for hereditary spastic paraplegia or cerebral palsy. Most patients with dopa-responsive dystonia have a mutation in the GCH1 gene, which results in reduced production of dopamine. Approximately 75% of patients have notable worsening of dystonia as the day progresses (diurnal variation). Exercise often aggravates the dystonia. Patients commonly demonstrate some degree of bradykinesia (especially in the legs) and postural instability. Rare adult-onset disease may result in a pure parkinsonian phenotype. Dopa-responsive dystonia should be considered in all children with dystonia. Symptoms are exquisitely sensitive to low doses of levodopa (typically as little as 50 mg/day of levodopa), and this treatment allows patients to live a normal life without the usual complications seen in Parkinson disease ( Chapter 378 ).

Myoclonus dystonia, which usually begins within the first decade of life, combines dystonia with separate multifocal myoclonic jerks. Myoclonus dystonia is genetically heterogeneous; the most common definable cause is a mutation in the epsilon-sarcoglycan gene. The dystonia in these patients most often involves the neck or upper limbs, is mild, and is often overlooked. The disorder also can include psychopathology, such as obsessive-compulsive behavior. A characteristic feature of this disorder is the marked ameliorative effect of ethanol on both the myoclonus and the dystonia, a feature that sometimes results in alcohol abuse.