Clinical Overview of Movement Disorders

Physiologic Tremor

Physiologic tremor is a term applied to the 8- to 12-Hz tremor seen in any healthy person who is intentionally sustaining a posture. More proximal regions of the body oscillate at a lower frequency, more distal ones at a higher frequency. For example, physiologic tremor has a frequency of 3 to 5 Hz at the elbow, whereas metacarpophalangeal tremor usually ranges from 17 to 30 Hz. When this tremor impairs motor performance, it is referred to as enhanced physiologic tremor .

Physiologic tremor is typically symmetrical. As with other tremor types, the amplitude is reported to decrease with age, particularly after the age of 50, ^, although some authors have found otherwise. Age has not been shown to affect the frequency of physiologic tremor. ^,

It is unclear whether mild forms of the syndrome can be distinguished from ET. Both ET and physiologic tremor can be elicited by posture, both are fairly symmetrical, and both occur predominantly in the arms. Observing the progression of a tremor over time will eventually reveal whether a given patient has ET or physiologic tremor.

Essential Tremor

ET is the most common tremor disorder, with an overall prevalence of 0.4% to 0.9%. In people older than 60, it can be as high as 4.6%. It generally manifests as a low-amplitude, bilateral action and postural tremor with a frequency of 6 to 8 Hz. The tremor usually has its onset in adulthood and worsens over time, but it may begin in childhood and can coexist with other movement disorders. The overall prevalence of ET is similar between genders, although women with ET seem to be more prone to head tremor than men.

ET involves the upper limbs in more than 90% of patients. It less commonly involves the head, legs, or voice. It rarely affects the face or trunk. ET often has a postural component that may be reported as a rest tremor by patients. Although some rest tremor can be seen in advanced ET, an action tremor should clearly dominate. Patients commonly first complain of difficulty with tasks requiring fine coordination, such as threading a needle, tying knots, or writing. Later, more gross activities are also affected. In severe cases, basic activities of daily living may become impossible to perform.

Cognitive dysfunction and gait abnormalities may also be features of ET. Set shifting, verbal fluency, and other frontal cortex functions are impaired in patients with ET relative to age-matched controls. This cognitive impairment does not correlate with tremor severity.

Several features of ET point to an underlying cerebellar or brainstem pathology. Patients with ET frequently have an end point tremor and difficulty with tandem gait. Researchers have described subclinical eye movement abnormalities indicative of cerebellar dysfunction. There are case reports of ipsilateral improvement in symptoms after cerebellar infarction, and inducing lesions of the cerebellothalamic receiving area (the ventral intermediate nucleus of the thalamus) is an effective treatment of ET. Although positron emission tomography has shown increased olivary glucose utilization and cerebellar blood flow, the brains of ET patients appear to be structurally normal. Postmortem studies by Louis and colleagues suggested a cerebellar variant with Purkinje cell loss, axonal torpedoes, basket cell changes, and a Lewy body variant with increased Lewy bodies in the brainstem. The evidence for cerebellar Purkinje cell dysfunction is mixed; in a case-control study of ET, Rajput and colleagues did not find Purkinje cell loss.

A family history of tremor is common in patients in whom ET is diagnosed. A positive family history has been reported in as many as 96% of patients and as few as 17%, depending on the sample. A survey of New York City residents showed a 5- to 10-fold increase in risk for ET in first-degree relatives, as well as an increase in the likelihood of ET developing in family members with earlier onset of symptoms in the patient.

Several inherited forms of ET have been identified, including the gene loci EMT1 (on chromosome 3q13) and EMT2 (on 2p24) and an unnamed gene locus on 6p23. ^, ET has been reported in fragile X syndrome, Kennedy syndrome, XXYY syndrome, and Klinefelter syndrome. ^, Sex chromosome–related tremors often have associated ataxia and may represent a separate tremor type.

The presence of a rest tremor in a patient who otherwise meets the criteria for ET can be confusing. Current opinion among movement disorder neurologists favors the diagnosis of ET when the action and postural components of a tremor greatly outweigh the rest component and the rest component is bilateral. New-onset unilateral rest tremor should always bring PD to mind. Although isolated head tremor is often diagnosed as ET, if upper extremity tremor is absent, it is more likely to be dystonic tremor.

The question of whether ET predisposes patients to the later development of PD is also a perplexing one. There are some cases in which families appear to be prone to both PD and ET. Jankovic’s group reported that the same locus yielded pure ET and ET-PD-dystonia in different families. As of this writing, the exact association between ET and PD remains a topic of discussion.

Parkinsonian Tremor

The tremor of PD was described by James Parkinson in 1817 in his historic Essay on the Shaking Palsy and was further characterized by Charcot in the 1860s in his lectures at the Salpetriere. PD tremor is a 4- to 9-Hz low-amplitude rest tremor. The tremor often has a prominent proximal thumb component that gives it a “pill-rolling” quality. The presence of a pill-rolling tremor is not diagnostic.

Although there is some thought that PD tremor may dampen or “burn out” over time, others have observed the opposite. Parkinson himself wrote that “as the debility increases … the tremulous agitation becomes more vehement [and] the motion becomes so violent as not only to shake the bed-hangings, but even the floor and sashes of the room.”

Unlike typical ET, PD hand tremor may worsen in the ipsilateral lower limb before affecting the contralateral hand. A typical pattern of spread is for a hand to be affected first, followed by the ipsilateral foot and then the contralateral hand. Although different extremities exhibit the same frequency of tremor, they need not shake simultaneously. When tremor is bilateral in onset without involving the legs, causes other than PD should be considered. PD tremor is frequently intermittent and typically becomes more pronounced with distraction.

Reemergent tremor occurs while sustaining a prolonged position and most likely represents a rest tremor that has been reset by the relative stasis of a persistent position. Postural tremor was seen in two-thirds of patients with PD in one case series, and correlates with the degree of functional disability.

The pathogenesis of PD tremor is not well understood. In monkeys with 1 -methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)–induced parkinsonism, basal ganglia neurons begin to fire synchronously. Some authors have suggested that PD tremor originates from loss of segregation of these information channels and subsequent synchronization of adjacent circuits. Loss of dopamine in the basal ganglia may unmask pacemaker-like properties of the basal ganglia. It should be noted that the severity of PD tremor does not correlate with the severity of dopamine neuronal loss and that treatment with levodopa improves bradykinesia and rigidity more reliably than it does tremor.

The central origin of PD tremor is demonstrated by the observation that afferent denervation affects the amplitude and frequency of the tremor but does not abolish it.

Cerebellar Tremor

Cerebellar tremor can be characterized as a jerky, low-frequency (2 to 4 Hz), high-amplitude action tremor. This tremor may be accompanied by other cerebellar signs such as ataxia, dysdiadochokinesia, dysarthria, dysmetria, and telegraphic speech. The normal pattern of cerebellar ballistic control, as described by Hallett and associates, consists of sequential agonist-antagonist–second agonist activation.

Rubral Tremor (Holmes Tremor)

Patients with lesions in the region of the red nucleus may be predisposed to the development of what is referred to as a rubral tremor, first described by Holmes in 1904. Although predominantly an action tremor, rubral tremor frequently has a significant resting component. The amplitude of movement tends to be large and it can sometimes adopt a “wing-beating” appearance. Rubral tremors are among the slowest tremors, with frequencies often less than 4 Hz.

As with cerebellar and symptomatic palatal tremor (SPT), rubral tremor arises from damage to the cerebellar and brainstem motor pathways and from dysregulation of motor control during movement.

Posttraumatic Tremor

The motor coordination control centers and their connections are situated deep in the brain, and to damage them generally requires substantial injury. Consequently, posttraumatic tremor is rarely an isolated finding. The character of the tremor depends on the region of the brain that is damaged. Damage to the brainstem may produce rest tremor if it affects the substantia nigra and related pathways. Damage to the cerebellum may result in a low-frequency action tremor. Because multiple regions are usually damaged, posttraumatic tremors are generally mixed in character. In one series of severe posttraumatic tremors, all patients displayed both action and postural tremors, whereas rest tremor was seen in just 56% of cases. Posttraumatic tremor is often accompanied by myoclonus. As noted by Obeso and Narbona, this apparent myoclonus appears in some cases to be an exaggeration of a beat of the ongoing tremor rather than true myoclonus.

Drug-Induced Tremor

Drug-induced tremors are united by a common cause rather than a common appearance. Usually, drug-induced tremors have a higher frequency and involve limbs symmetrically, although lower frequency tremors are also seen. The onset of tremor should be temporally related to drug ingestion.

Drugs most commonly associated with tremor include alcohol, amiodarone, antidepressants, antiepileptic medications, beta-agonist bronchodilators, caffeine, immunosuppressive agents, lithium, neuroleptics, nicotine, steroids, and sympathomimetics. Alcohol intoxication (acute or chronic) and immunosuppressive agents may produce cerebellar tremors. Sympathomimetics, serotonin reuptake inhibitors, nicotine, and other centrally acting agents typically produce an enhanced physiologic tremor. Because the physiologic effects of an offending drug are rarely limited to tremor, the causative agent may also be recognized by associated nonneurological symptoms.

There are numerous less commonly encountered tremor types that one must consider in the differential diagnosis of tremor.

Orthostatic Tremor

Orthostatic tremor is a syndrome characterized by trembling of the legs and an intense feeling of unsteadiness that occurs on standing upright. The symptoms are relieved by walking or sitting down. ^, Orthostatic tremor was first described by Heilman in 1984. The tremor is typically of low amplitude and is present predominantly in the legs. It is less frequently observed in the face, arms, or trunk. Surface electromyography (EMG) reveals a pathognomonic pattern of a 13- to 18-Hz tremor when the patient stands upright. When other body parts are affected, the tremor occurs at the same frequency as in the legs. Orthostatic tremor in the arms may be become evident if the patient is examined while on all fours. Given the high frequency and low amplitude of the tremor, it may be difficult to appreciate and may appear as little more than a subtle quivering.

Impairment of balance and increased swaying are well-described features of the syndrome. They may result from disrupted sensory feedback or from the disruption of motor regulation at the muscular level.

Orthostatic tremor’s underlying pathology remains unknown. The tremor is not solely brought on by load bearing; even when the load on the legs is reduced by suspending patients in the upright position, the tremor pattern remains stable.

Palatal Tremor

Palatal tremor consists of a steady and constant-amplitude oscillation of either the tensor veli palatini or the levator veli palatini muscles. Palatal tremor is also referred to as palatal myoclonus ; however, most authors now classify it as a tremor syndrome.

Palatal tremor may be divided into symptomatic palatal tremor (SPT) and essential palatal tremor (EPT). EPT is characterized by a slow (2 Hz) rhythmic elevation of the soft palate because of contraction of the tensor veli palatini muscle. A typical initial complaint is a clicking noise heard in one ear; the tensor inserts at the eustachian tube, and as the muscle contracts, the tube opens and closes, which causes a clicking noise.

Patients with SPT have the same slow and rhythmic movement of the soft palate as do patients with EPT. Unlike EPT, however, in SPT the movement is thought to be due to contraction of the levator veli palatini muscle and thus is not typically associated with an ear click. In 30% of patients with SPT the tremor is accompanied by rotatory or vertical pendular nystagmus. SPT is thought to arise from damage to the area bounded by the red nucleus, the inferior olive, and the dentate nucleus (the Guillain-Mollaret triangle). This results in autonomous firing of the inferior olive. Postmortem analysis of the ipsilateral inferior olive has provided further evidence of an olivary origin for SPT: pathologic examination reveals hypertrophic degeneration and enlarged neurons with cytoplasmic vacuolization. SPT is difficult to modify and is unusual among the hyperkinesias in that it persists even in sleep.

EPT is distinguished from SPT by the presence of an ear click, relief during sleep, and an absence of structural brainstem pathology. Some authors report that EPT predominantly involves the roof of the palate’, whereas in SPT the contraction is more notable at the palatal verge.

Psychogenic Tremor

When the cause of a tremor is psychogenic, the symptoms may vary from moment to moment in their frequency, amplitude, direction, or location. Symptoms may disappear with distraction or on subsequent examinations. For this reason, it is often helpful to perform serial videotaped examinations.

Although psychogenic tremors may affect any part of the body, they most frequently involve the head, arms, and legs. The tremor tends to shift from region to region even as it alters in its other characteristics. They may disappear with distraction. Most patients display rest, postural, and action tremor to a varying degree. Symptoms may appear suddenly, with quick evolution to large amplitudes. Other clues to a psychogenic origin include entrainment and active resistance to passive range of motion. Entrainment occurs when a tremor’s frequency shifts to match that of a voluntary repetitive movement of another body part. Entrainment may be enhanced by distracting the patient. Psychogenic tremor may also respond paradoxically to loading, which increases rather than decreases the tremor in frequency and amplitude.

Psychogenic tremor can be difficult to distinguish from tremor of other causes. Deuschl and colleagues reported a case of psychogenic palatal tremor in which the patient duplicated the typical clicking movements of that disorder by repetitively clapping his soft palate against his pharynx.

A psychogenic origin of a movement disorder should be considered whenever there are obvious incongruities in a patient’s signs and symptoms. Resolution after suggestion or administration of placebo, distractibility, coexisting psychiatric disorders, or inconsistency of symptoms over time should all raise clinicians’ suspicion.

Deuschl and coworkers proposed that cocontraction of antagonist muscle groups is a necessary condition for psychogenic tremor. Patients with hand tremor of psychogenic origin tend to show EMG coactivation in the finger flexors and extensors shortly before onset of the tremor.

Task-Specific Tremor

The label task-specific tremor applies, as might be expected, to any tremor brought on by performing a particular set of actions. Onset occurs in adulthood.

Primary writing tremor (PWT) is the stereotypical task-specific tremor: a unilateral action tremor of 4 to 7 Hz that occurs during the act of writing or while adopting the posture associated with that act. The task specificity of PWT suggests a central cause, as does report of successful treatment by deep brain stimulation.

Some authors have classified task-specific tremor as a form of ET, and some as being related to task-specific dystonia, whereas others believe it to be a distinct nosologic entity. Like dystonia, task-specific tremor is asymmetrical and triggered by a task. Both sometimes respond to anticholinergic therapy. Generalized dystonia and PWT have been found to cluster within certain kindreds.

PWT and writer’s cramp may be distinguished on the basis of differential reciprocal muscle inhibition. Patients with writer’s cramp usually display forearm reciprocal muscle inhibition on EMG, whereas patients with PWT do not.

Regardless of whether PWT is truly a form of dystonia, the two occur together often enough that patients with task-specific tremor should also be examined for signs of dystonia. Actions other than writing have also been associated with task-specific tremor. For example, task-related chin tremor has been reported.

Dystonic Tremor

Dystonic tremor is a jerky postural and action tremor that is abolished by complete rest and occurs in a body part affected by dystonia. Its amplitude tends to be irregular, and it tends to have a variable frequency. Dystonic tremors usually oscillate at frequencies of 7 Hz or less. The amplitude of the movements can often be reduced if patients touch a particular part of their body (i.e., a geste antagoniste or “sensory trick”).

The mechanism of dystonic tremor differs from that of ET and PD. Dystonic tremor arises from unequally affected agonist-antagonist muscles rather than the dysfunctional CNS oscillator of ET and PD. Dystonic tremor of the neck can be distinguished from the head tremor of ET by dystonic head tremor’s irregular amplitude, relief by sensory tricks, and head greater than hand involvement. Physicians should also be careful to look for relief with sensory tricks and for dystonia in other parts of the body.

Other features of dystonia are discussed more fully in the section on dystonia.

Huntington Disease

Huntington disease (HD) is the most common form of inherited chorea. Symptoms usually begin during the third to fifth decades of life. Although chorea is the most common initial symptom, unsteadiness of gait, dystonia, myoclonus, loss of bulbar control, and cognitive changes also occur and may appear before chorea does. Bradykinesia usually develops as the disease progresses, but it may be underappreciated in the presence of more obvious symptoms.

The chorea of HD is typically symmetrical and tends to increase in amplitude over time. The first manifestation of chorea may be a slight flicking of the fingers seen while walking. Patients are frequently unaware of their movements and may continue to treat their gyrations with indifference, even when made aware of them. Early symptoms include an impairment of rapid saccades, ^, psychiatric and mood changes, and tics. Ataxia is unusual and should raise concern for another syndrome, such as neuroacanthocytosis, SCA, or Friedreich ataxia.

Impersistence of movement is a classic feature of HD. Patients typically have difficulty maintaining tongue protrusion. They also tend to have difficulty keeping their gaze fixed on an object. Paradoxically, they may have trouble switching their attention from the examiner’s face. This has been referred to as a visual grasp reflex and is not specific for HD.

HD is defined as being of juvenile onset if symptoms occur by the age of 20. It is more often associated with stiffness, eye movement difficulties, and bradykinesia than adult-onset HD is. Seizures are also more frequent in juvenile-onset HD. Adult-onset HD occasionally manifests as this phenotype.

The cognitive and behavioral features of HD are both prominent and disabling. Many features are similar to those seen after frontal lobe damage. Grasp, snout, and other primitive reflexes may be prominent. Scores on psychomotor tests such as the Trail Making Test B and Stroop interference test show declines earlier in the course of HD than do tests of memory. Worsening scores correlate with the degree of striatal atrophy present. Dementia occurs in the majority of patients, although exceptions may occur when the chorea is of late onset. Other psychiatric symptoms include apathy, depression, lability, impulsivity, outbursts of anger, mania, and paranoia. ^, Physicians should always inquire about substance abuse and suicidality.

The genetic defect responsible for HD is a CAG repeat on chromosome 4 in a region that encodes the protein huntingtin, whose function is unknown. The number of copies of this repeat determines the presence or absence of clinical HD; patients with 29 to 35 repeats are expected to be asymptomatic. ^, The number of CAG repeats may increase in transmission and result in anticipation : earlier onset and increasing severity in successive generations. Paternal inheritance of HD has been correlated with a higher number of triplet repeats in the next generation, ^, probably because of gene expansion during spermatogenesis. An increased number of triplet repeats correlates with both earlier disease onset and the degree of functional decline.

The diagnosis of HD is based on clinical features and confirmed by genetic testing for the huntingtin gene. Caudate atrophy, characterized by “boxing” of lateral ventricles best seen with coronal brain imaging, is the classic finding on imaging studies. Frontal lobe atrophy is also seen. Imaging changes predate clinical diagnosis, and correlate in degree with symptom severity. Physicians may encounter the HD phenotype in the absence of the HD genotype. In one large series, approximately 7% of patients displaying the HD phenotype proved not to have a mutation in the huntingtin gene.

Four Huntington disease–like (HDL) syndromes have been identified. All are rare. HDL1 is an inherited prion disorder. HDL2 is caused by a CAG/CTG expansion in the junctophilin-3 protein and is more common in patients of African, Mexican, Spanish, or Portuguese descent. HDL2 is the most HD-like of the HDLs in its symptomatology. It may be accompanied by erythrocyte acanthocytosis. An early childhood–onset HDL variant, HDL3, has been identified in isolated cohorts. Its genetic basis remains unknown. HDL4 is synonymous with SCA type 17 (SCA17). SCA17 has a variety of phenotypes, one of which closely mimics the symptoms of HD. HDL4 arises from a CAA-CAG repeat in chromosome 6.

Sydenham Chorea

Sydenham chorea is a delayed complication of infection with group A β-hemolytic streptococci that usually develops 4 to 8 weeks after the infection, but it may develop as long as 6 months afterward. Sydenham chorea may be the sole manifestation of rheumatic fever in as many as 20% of patients ^, and remains the most common cause of acute childhood chorea in the world.

The typical age at onset of Sydenham chorea is 8 to 9 years; it is rarely seen in children younger than 5 years. ^, The chorea usually generalizes but there are exceptions, and 20% of patients remain hemichoreic. Sydenham chorea may be accompanied by tics and psychiatric symptoms. Obsessive-compulsive disorder (OCD) and attention-deficit/hyperactivity disorder (ADHD) occur in 20% to 30% of patients and may precede or follow the onset of chorea. The disease is self-limited and spontaneously remits after 8 to 9 months in a large percentage of patients, but up to 50% may still have chorea 2 years after infection.

Antineuronal antibodies are present in a majority of patients with Sydenham chorea. Antistreptolysin (ASO) titers are typically elevated but are nonspecific for infection with group A streptococci; this test is not useful in diagnosing Sydenham chorea. However, elevated ASO titers may be of help in distinguishing a recurrence of Sydenham chorea from a chorea from some other cause. ^, MRI in patients with Sydenham chorea has been reported to show transient swelling in the striatum and globus pallidus and increased signal intensity on T2-weighted images. ^,

Tardive Chorea/Dyskinesia

Tardive dyskinesia results from treatment with dopamine receptor blocking agents. Tardive syndromes are less frequently caused by atypical (e.g., clozapine, quetiapine) than by typical (e.g., haloperidol) neuroleptics. Dopamine-depleting medications have not been definitively associated with tardive dyskinesia. Some common antiemetics (e.g., metoclopramide) and some antitussives (e.g., promethazine [Phenergan]) are dopaminergic blockers whose use may lead to the development of tardive movements.

The most common pattern of tardive dyskinesia is stereotyped and repetitive movement of the face. Tongue-thrusting and involuntary chewing movements reminiscent of those seen in choreoacanthocytosis may be seen. Tardive dyskinesia is often accompanied by a feeling of restlessness, referred to as akathisia. This may be localized and reported as a “burning” sensation, often of the genitals or mouth.

Although tardive chorea has been reported after treatment with atypical antipsychotics, it occurs infrequently in this setting. Of the neuroleptics, clozapine appears least likely to induce tardive disorders. Large clinical trials have recently suggested that although atypical antipsychotics produce tardive dyskinesia less often than first-generation antipsychotics do, the difference may not be as great as was thought. ^,

Benign Hereditary Chorea

BHC is a slowly progressive childhood-onset chorea that is not associated with worsening dementia. The lack of cognitive worsening and early chorea differentiate it from juvenile HD. Onset most commonly occurs at 1 year of age, and symptoms may improve during adolescence.

BHC is heterogeneous in its manifestations and may be associated with myoclonus, dystonia, dysarthria, and gait difficulties. This led to some doubt regarding whether it truly represented a separate disorder until the discovery that a number of families with BHC possessed mutations in the gene encoding thyroid transcription factor 1 (TITF1). Defects in TITF1 have also been tied to a disorder consisting of chorea, congenital hypothyroidism, and pulmonary dysfunction, or “brain-thyroid-lung syndrome” (BTLS). Although BTLS has been differentiated from “classic” BHC, BHC and BTLS may represent two points on the same clinical spectrum. It can also be difficult to distinguish BHC and essential myoclonus. Both syndromes have comparable ages at onset and similar appearances. Features that vary between the two include gait involvement and improvement with alcohol. Gait involvement is common in BHC but rare in essential myoclonus. Improvement with alcohol ingestion is common in essential myoclonus but rare in BHC.

Neuroacanthocytosis

Two diseases fall under the rubric of neuroacanthocytosis: choreoacanthocytosis and McLeod syndrome. Both are characterized by acanthocytes on peripheral smear, peripheral neuropathy, psychiatric symptoms, and seizures. Serum creatinine kinase may be mildly elevated in either syndrome.

Choreoacanthocytosis is an autosomal recessive disease with an age at onset of 20 to 40 years. Orofacial dystonia is one of the characteristic features of the disease, and it typically manifests as lip and tongue biting. Patients may involuntarily push food out of the mouths with the tongue when eating (“eating dystonia”). Generalized chorea, dystonia, and tics can also occur. Abnormalities of saccadic eye movement may develop, similar to those in HD. Unlike HD, peripheral neuropathy is typically present. A finding of areflexia with orolingual dystonia is highly suggestive of this syndrome. Choreoacanthocytosis is associated with mutations in the chorea acanthocytosis (CHAC) gene, which encodes a protein designated chorein.

McLeod syndrome is a rare X-linked acanthocytic disease caused by defects in a gene responsible for erythrocyte antigens. The mean age at the onset of CNS symptoms is 40 years, and they may lag behind the hematologic diagnosis by decades. Symptoms of McLeod syndrome include chorea, cognitive decline, paranoia, psychosis and limb weakness. Atrophy is neurogenic and seen predominantly in the distal ends of the lower limbs. Case series suggest that unlike autosomal recessive choreoacanthocytosis, involuntary lip and tongue biting occurs in only a minority of patients. In addition to CNS symptoms, cardiomyopathy, arrhythmias, and hemolytic anemia may develop.

Dentatorubral-Pallidoluysian Atrophy

DRPLA produces a combination of chorea and ataxia and is named for the pattern of atrophy of the dentatofugal and pallidofugal pathways often seen in this syndrome. It occurs most commonly in Japan, although variant forms have been reported in the United States. ^,

DRPLA, like HD, is an autosomal dominant triplet repeat disease. Also as in HD, successive generations of persons with DRPLA tend to have an earlier age at onset. This acceleration is more rapid with paternal transmission. There are five cardinal features of the syndrome: cerebellar ataxia, dementia or mental retardation, chorea, seizures, and myoclonus.

DRPLA may be divided primarily into juvenile- and adult-onset variants. The symptoms of juvenile-onset DRPLA often lead physicians to initially diagnose progressive myoclonic epilepsy because myoclonus and seizures are the predominant symptoms. Adult-onset DRPLA is characterized by chorea, ataxia, psychosis, and dementia. The dementia in adult-onset DRPLA is usually milder than that in juvenile-onset cases.

An adult-onset variant of DRPLA has been found in an African American family living near North Carolina’s Haw River. The Haw River variant displays a number of differences from other DRPLA variants: microcalcification of the basal ganglia, demyelination of the centrum semiovale, atrophy of the posterior column, and prominent paranoia, delusions, and hallucinations. Although generalized tonic seizures are common in this cohort, they are not myoclonic.

Pathologic findings in DRPLA include a small (but not necessarily atrophic) brainstem and cerebellum and diffuse cortical atrophy. Diffuse high-intensity signal changes may be seen in the corona radiata on T2-weighted MRI.

Other Causes of Chorea

Thyrotoxicosis can acutely result in chorea. Both generalized chorea and hemichorea have been reported. In most reports the chorea resolves once the patient is euthyroid, but cases of persistent chorea have occurred. Animal experiments suggest that the mechanism may be related to increased dopamine receptor sensitivity during thyrotoxicosis.

Neuroferritinopathy is an autosomal dominant choreic syndrome first identified in a North West England family. The mean age at onset is 39 years, and 50% of patients have chorea as their first symptom. The chorea is typically symmetrical. Eye movements are normal and there is an associated late-onset dementia of the frontal/subcortical type. The disease arises from deficits in the ferritin light polypeptide (FTL) gene. T2-weighted MRI aids greatly in distinguishing this condition from other choreas; the hallmark of this disease is hypointensity of the striatum and globus pallidus. Serum ferritin levels may be low, but this finding is insufficiently reliable for it to be diagnostic.

Polycythemia vera is a disease of red blood cell hyperproliferation that has been associated with numerous neurological symptoms, including migraine, vertigo, and chorea. Chorea may be this disease’s initial symptom. Most cases of polycythemia-associated chorea have occurred acutely in elderly women and in the setting of hematologic deterioration. Chorea is not typically seen in patients with secondary polycythemia.

Chorea gravidarum is a choreic syndrome of pregnancy, usually with onset in the first or second trimester. The severity of the chorea tends to decrease as the pregnancy progresses. The syndrome appears to be associated with autoimmune disease. Investigators in one series of patients with the syndrome reported rheumatic heart disease in five of five patients, but other series have not been as definitive. Chorea gravidarum has been associated with systemic lupus erythematosus and with elevated antiphospholipid antibody titers. Approximately a third of patients see their symptoms resolve after delivery.

Painful leg and moving toes syndrome (PLMTS) is a condition characterized by involuntary movement of the toes in the presence of chronic pain. This movement typically takes the form of low-amplitude flexion-abduction movements that may persist during sleep. The movements have been associated with lesions in the spinal cord, nerve root, or peripheral nerves. Soft tissue injury has also been associated with PLMTS. The pathophysiology of these movements remains unclear. PLMTS should always be distinguished from pseudoathetosis by checking joint position sense. PLMTS does not always manifest as chorea and may instead appear as a persistent jerking movement.

A painless variant has also been reported and has been referred to as painless legs–moving toes syndrome.

Jumpy stump refers to the involuntary twitching of an amputation stump. It is usually accompanied by severe pain. As with PLMTS, this syndrome may resemble myoclonus more than chorea.

Chorea may be an unusual manifestation of Wilson disease (15%) or Friedreich ataxia . It is also an uncommon finding in Lesch-Nyhan syndrome (23%). Paroxysmal nonkinesigenic dyskinesia (PNKD) and paroxysmal kinesigenic dyskinesia (PKD) may manifest with chorea-like movements, as may SCA2, SCA3, and SCA17. These syndromes are dealt with more extensively in subsequent sections.