Chorea, choreoathetosis and ballism

 

 

Drug-induced chorea: Tardive dyskinesia can be caused by dopamine receptor blocking agents (including antipsychotic drugs and certain antiemetics) as well as levodopa, dopamine agonists, estrogen containing oral contraceptives, anticonvulsant such as phenytoin and carbamazepine. Other drugs include lithium, cocaine, amphetamines, tricyclic antidepressants, isoniazide, methylphenidate, and pemoline.

 

Benign hereditary chorea (BHC): This is an autosomal dominant disorder causing non-progressive chorea without mental impairment which usually starts in childhood. Severity of symptoms peaks in the 2nd decade and does not progress. Differential diagnosis with HD can be difficult. The gene has been mapped to chromosome 14q. Life expectancy is normal.

    

Huntington disease (HD): The prevalence of HD is around 50/106 in the population from Western European descent. HD is characterized by the triad of autosomal dominant inheritance, choreoathetosis and subcortical dementia. On average the disease starts at the age of 40 years. Chorea (“clumsiness, fidgety”, tongue 'akathisia') is the presenting manifestation in 2/3 of patients while the remainder present with personality or cognitive changes, weight loss, dysarthria, dysphagia or gait disturbance. Changes in oculomotor control (delays in initiation, increased blinking frequency and slowing of saccadic eye movements) may also be an early sign. The disease progresses with rigidity, bradykinesia and eventually immobility. In contrast with early onset HD, in late onset (>60 years) HD, chorea is the prominent feature and runs a milder course. HD must be considered in chorea presenting in pregnancy or taking oral contraceptives. Brain MRI reveals high signal in the putamen, accompanied by symmetric caudate (increased bicaudate-cranial ratio) and putaminal atrophy in clinically affected patients. The latter is a more sensitive marker for early HD. Juvenile HD (Westphal variant) (< 20 years) resembles the rigid variant with additional features of seizures and cerebellar findings. HD is caused by an unstable (CAG)n trinucleotide repeat (n>37-40) in the IT-15 gene on chromosome 4p16.3 encoding for huntingtin. The diagnosis is based on DNA analysis of a blood sample. PET scan shows decreased glucose metabolism in the caudate nucleus early in the disease and precedes the loss of tissue. The survival is variable, but death usually occurs 15-20 years after onset of motor symptoms. Wilson disease should be specifically excluded. Late-onset cases may be misdiagnosed as AD.

 

Sydenham chorea: This self-limiting autoimmune encephalitis is now considered a curiosum in developed countries. It is a delayed complication of group a beta-hemolytic streptococcal infection. It occurs in 26% of patients with acute rheumatic fever up to six months after the acute streptococcal infection. It usually concerns adolescent girls. Plasma anti-basal ganglia antibodies can be found and often persist. EEG shows slow wave changes and brain MRI shows swelling in basal ganglia. The disease is usually severe for several weeks and than gradually resolves over 3 - 6 months. Generally the prognosis for patients with Sydenham chorea is good, and complete recovery often occurs. The duration of the disorder varies, with the average case lasting 3 to 6 weeks. Occasionally the course may be prolonged for several months. First-line therapy consists of sodium valproate (15-20 mg/kg/day), which has shown to control choreic movements in one week. Carbamazepine may have similar effect. and second-line drugs. Dopamine antagonists (haloperidol or pimozide) have been used but because of their potential side effects including the development of tardive dyskinesia, these dopamine antagonists are second choice. Pimozide is usually reserved for those patients who fail to respond to valproate or who present with severe forms (i.e., chorea paralytica). If these two options fail, the next steps may include immunomodulatory treatment, steroids, iv Ig, or plasmapheresis.

 

Chorea in systemic disease: Chorea can occur as a complication in APLS and SLE.

 

Chorea during pregnancy: HD, SLE or APLS should be considered.

 

Neuroacanthocytosis: The neuroacanthosis exists of three major groups: 1) the core neuroacanthosis syndromes with neurodegeneration of the basal ganglia, comprising autosomal recessive chorea-acanthosis due to mutation of VPS13A (chromosome 9q21) and the X-linked McLeod phenotype (indistinguishable phenotypes) due to mutation of XK gene, 2) conditions with decreased lipoproteins (abetalipoproteinemia and hypobetalipoproteinemia) consisting of peripheral neuropathy and ataxia without movement disorders, 3) associated forms such as HSD (PANK2) and HD (HDL2). The core neuroacanthosis affects men twice as common as women. Symptoms usually start in the 3rd to 5th decade (mean 32 years) and consist of limb chorea, especially affecting the legs, along with parkinsonism, oro-facial dyskinesias, self-mutilation, and dementia. 50% of cases have seizures, areflexia (chronic axonal motor polyneuropathy: small SNAPs; normal CMAPs) with distal symmetric wasting. Elevated serum CK levels and acanthocytes on a fresh wet blood film facilitate the diagnosis. The latter usually precedes the neurologic features. Needs to be differentiated from abetalipoproteinemia (abnormal serum lipoprotein profile) and McLeod syndrome (reduced expression of Kell blood group on RBC and Kx surface antigen (100%)). Brain MRI may show caudate atrophy. Acanthocytes are seen in the peripheral blood smears of some of the asymptomatic family members. Average life span is approximately 14 years from onset of illness.

 

Dentatorubropallidoluysian atrophy (DRPLA): Although described chiefly in Japan, European families are also affected by this autosomal dominant condition. It is caused by a CAG repeat expansion mutation of atrophin 1 gene mapped to chromosome 12p13 (Boston University Center, Human Genetics Laboratories).  The age of onset of symptoms ranges from adolescence to the 6th decade of life and the presentation is quite heterogeneous. Three phenotypes have been described the ataxo-choreoathetoid type, a pseudo-Huntington type, and a myoclonic epileptic type. Hence clinical features include progressive cerebellar ataxia, or dementia with chorea, or prominent chorea and dystonia or progressive myoclonic epilepsy. Variants (Haw-River syndrome) of the disease exist (subcortical demyelination; neuroaxonal dystrophy; no seizures). Brain MRI scan shows cerebellar and brainstem atrophy and multiple WMHIs on T2 sequences. DNA analysis is essential for the diagnosis. Homozygotes for DRPLA genes may have recessive predominantly spinal syndrome which has its onset in the 3rd or 4th decade and consists of spastic paraplegia, loss of vibratory in the lower limbs and truncal ataxia. In view of its resemblance DRPLA is often confused with HD.

 

Thalamic dementia: is an autosomal dominant disorder characterized by choreoathetosis, subacute dementia and myoclonus. It is often confused with CJD.

 

Panthotenate kinase-associated neurodegeneration or Hallervorden-Spatz disease (HSD): The adult onset form of this autosomal recessive disorder presents in early adulthood with atypical parkinsonism (initially affecting the legs or bulbar musculature), ataxia, myoclonus, dystonia (tongue or blepharospams), chorea or dementia. Most patients also develop pyramidal syndrome and seizures (20%). T2 weighted brain MRI shows an ”eye of the tiger” sign corresponding to pallidal hypointensity with a high signal center. Very low signal intensity is also seen in the red nucleus, and substantia nigra, consistent with increased iron deposition in these structures. Bone marrow contains sea blue histiocytes. The gene locus (PANK2) has been identified on chromosome 20. Treatment of patients with HSD is largely symptomatic. Many patients, especially in the early stages of the disease, may respond modestly to levodopa treatment. Variants have been reported such as HARP syndrome (hypoprebetalipoproteinemia [very low VLDL], acanthocytosis, retinitis pigmentosa, and pallidal degeneration). The dystonia affects cranial musculature and MRI findings are those of HSD. HSD needs to be differentiated from WD, juvenile HD, SNE, PD, DRD, Fahr disease, Lafora body disease (EPM2A gene), MS, DRPLA, Kufs disease, gangliosidoses and APBD.

 

Propionic acidemia: This autosomal recessive disorder presents in adulthood with chorea, dementia, seizures and episodes of recurrent vomiting. Plasma, urine and CSF propionic acid levels (organic acids screening) are elevated and excretion of metabolites, including methylcitrate are typical. Propionic acidemia is due to propionyl CoA carboxylase deficiency (chromosome 3q13.3-22).

 

Basal ganglia calcifications: Elderly, Fahr disease (sporadic or autosomal dominant idiopathic basal ganglia calcification), hyper- and hypoparathyroidism, pseudoparahypoparathyroidism, certain familial disorders (lipodystrophy) and idiopathic forms.

 

Lesch-Nyhan syndrome: X-linked disorder characterized by uric acid overproduction and variable neurologic impairment. Males are usually affected. Hypoxanthine-guanine phosphoribosyltransferase deficiency (HGPRT) may have two clinical forms: that of the Lesch-Nyhan syndrome (complete HGPRT deficiency) and that of Kelley-Seegmiller syndrome (partial HGPRT deficiency). Lesch-Nyhan syndrome presents with a triad of choreoathetosis with spasticity, mental retardation and the unique feature of self mutilation, while the neurologic manifestations of the patients with the Kelley-Seegmiller syndrome are very heterogeneous: psychomotor retardation with spastic movement, mentally retarded with generalized dystonia or adult onset gout with no neurologic manifestations. Plasma urate and urine urate are increased. The definitive diagnosis requires an enzymatic analysis of HRPT activity in erythrocytes or cultured skin fibroblasts. Affected males and carriers can also be identified by DNA analysis. The gene for HGPRT is mapped to chromosome Xq26. Allopurinol does not seem to affect the CNS symptoms.

 

Paraneoplastic encephalitis: Small cell lung, testicular or prostate cancer is most commonly associated with this paraneoplastic syndrome. A variety of clinical findings may be present: cerebellar degeneration, limbic encephalitis, bulbar encephalitis, ALS-like syndrome, dorsal sensory neuronopathy, autonomic neuropathy. Progression may be rapid or progressive. CSF may be inflammatory with lymphocytic pleocytosis and increased proteins. IgG levels are usually increased with oligoclonal bands. Anti-Hu antibodies are typically found in serum and CSF. Less commonly anti-Ta, anti-amphiphysin or anti-CV2 antibodies may be found.

 

Paroxysmal dyskinesia: They occur in the 3rd to 4th decades of life, consisting of different types according to the duration of the attacks. Paroxysmal dyskinesias are often classified into paroxysmal kinesigenic dyskinesia (PKD) and paroxysmal non-kinesigenic dyskinesia (PNKD), based upon precipitating factors that precede or trigger the episodes of abnormal, involuntary movement. In patients with PKD the episodes of hyperkinetic movements are provoked by sudden voluntary movement or unexpected stimuli (startle). In contrast, in those with non-kinesigenic dyskinesia, the attacks may occur spontaneously while at rest or out of a background of normal motor activity, but may be exacerbated by alcohol or caffeine consumption, stress, fatigue, or other factors. Other types of paroxysmal dyskinesias include episodes precipitated by prolonged exertion (paroxysmal exertion-induced dyskinesias, PED) or sleep (paroxysmal hypnogenic dyskinesias, PHD). The most common and best recognized paroxysmal dystonias are paroxysmal kinesigenic dyskinesia (PKD), paroxysmal hypnogenic dyskinesia (PHD) and paroxysmal dystonic non-kinesigenic dyskinesia (PNKD), also know as paroxysmal dystonia.  Age at onset can vary between childhood to 40 years. The duration of the attacks is inversely related to the number of attacks (PKD; up to 100/day, PNKD; 2/year-3 day, PHD; 2/year – 5/night). Boys are more affected than girls. Sporadic and autosomal dominant hereditary forms have been described. The attacks are often preceded by a sensory change such as tightness, numbness, pins and needles, or tingling in the affected region. The recurrent, sudden, brief and transient attacks of involuntary movements in PKD and PNKD are often a mixture of chorea, athetosis, dystonia, ballismus, or any combination of these abnormal movements involving muscle groups of the arms, legs, trunk, face, and/or neck and are triggered by various factors such as startle, exercise, anxiety, excitement, caffeine etc. Involvement of facial or oromandibular muscles often results in transient facial grimacing, difficulties speaking (dysarthria), or even muteness; however, important is that consciousness is preserved during the episodes and that the patient is normal between the attacks, which indicates that the diagnosis is based almost entirely on the history.  The attacks can even cause the person to fall. In addition to sudden movement, some episodes may also be provoked by unexpected stimuli (startle), yawning, talking, hyperventilation, the anticipation of movement, or light (photic) stimulation. Attacks may be worsened by certain factors, such as stress, cold, heat, or menstruation. PED is primarily characterized by sudden, transient, dystonic attacks, associated with involuntary, repetitive, twisting motions and distorted, often painful posturing. In some patients, attacks of dystonia may be accompanied by irregular jerky movements (chorea) and relatively slow, writhing movements that appear to flow into one another (athetosis). Such episodes are brought on by strenuous activity or prolonged exertion, such as running or walking for approximately 5 to 15 minutes. PHD, which is now generally recognized as a form of frontal lobe epilepsy, is characterized by transient attacks of involuntary movements occurring during non-REM sleep. During PHD attacks, the eyes may open and there may be abnormal, involuntary, potentially violent movements of the arms, legs, and trunk. These may include uncontrollable flinging or throwing movements of the arms and legs (ballismus); excessive rigidity, with associated, repetitive, twisting motions and distorted, potentially painful posturing (dystonia); and irregular jerky motions (chorea) and relatively slow, writhing movements that appear to merge into one another (athetosis). Although patients usually fall asleep after PHD episodes, they typically remember the attacks. Episodes may be worsened by certain factors, such as fatigue, stress, increased activity, or menstruation. PHD attacks may initially occur approximately 4 to 5 times each year. Over time, however, the frequency of episodes may increase up to 4 to 5 times nightly. The attacks are usually relatively brief, ranging from about 20 to 50 seconds or up to approximately 2 minutes.

The loci (e.g. 16p11.2) involved have been identified for some of the paroxysmal dystonias. PNKD gene is mapped to chromosome 2. Linkage data suggest that PHD is a disorder with age-dependent, variable phenotypic expression of abnormal movements as well as generalized or partial seizures. PND is associated with medial frontal lobe epilepsy. PKD responds well to phenytoin, phenobarbital, primidone, valproic acid, acetazolamide and carbamazepine. Clonazepam is often considered the medication of choice for PNKD and PHD. Patients with PED may benefit from clonazepam and the anticonvulsant agent carbamazepine. They need to be differentiated from repeated seizures or epilepsy and hyperexplexia (startle disease), tetany. Symptomatic PKD may also occur in association with MS or perinatal encephalopathy, traumatic brain injury, inflammation of the brain (encephalitis), calcium deposits in the basal ganglia, lack of oxygen supply to brain tissues (anoxia), brief interruptions of blood supply to part of the brain (transient ischemic attacks), brain tumors, and or other underlying disorders or conditions. Symptomatic PNKD may also develop in individuals with acquired immunodeficiency syndrome (AIDS), diabetes or idiopathic hypoparathyroidism.

 

Subacute sclerosing panencephalitis (SSPE): SSPE is a neurodegenerative disease due to persistent rubeola (measles) infection that affects children and young adults. Onset of the disease is insidious and often only recognized after significant neurologic deficits occur. The diagnosis of SSPE can be made if three of the following five criteria are fulfilled: 1) typical clinical presentation with progressive cognitive decline and stereotypical myoclonus (sustained myoclonus), 2) characteristic EEG changes, 3) elevated cerebrospinal fluid globulin levels without pleocytosis, 4) elevated CSF measles antibody titers, and 5) typical histopathologic findings in a brain biopsy or autopsy. Affected individuals progress through four loosely defined clinical stages at differing rates. Stage I is characterized by subtle behavioral changes, cognitive decline, emotional lability, lethargy, and nonspecific neurologic symptoms. This stage may last for weeks to months. Stage II includes continued intellectual decline, myoclonus, focal seizures with secondary generalization, choreoathetosis, apraxia, and visual changes with optic atrophy, dysarthria, and tremors. A wide variety of visual disorders have been associated with SSPE, including papilledema, retinitis, chorioretinitis, optic nerve pallor, homonymous visual field deficits, and cortical blindness. This stage may last three months or less. Neurologic decline persists in stage III (decreased level of consciousness, autonomic instability (with a variable heart rate and widely fluctuating temperatures and blood pressures), dystonia and rigidity, decorticate/decerebrate posturing), but the pace slows down, and symptoms may stabilize for one to two years. Features of stage IV include active startle reflex, flexor limb positioning, quadraparesis, akinetic mutism, wandering eye movements and coma. At this time, myoclonus, seizures, and rigidity are less frequent than in prior stages. CSF reveals markedly elevated intrathecal IgG synthesis rate and multiple oligoclonal bands in the gamma region on high-resolution electrophoresis, without a cellular reaction. Serum and CSF rubeola IgG titers are elevated with normal IgM titers. The EEG exhibits periodic complexes with generalized bilateral, usually synchronous and symmetrical sharp and slow wave complexes of high amplitude (greater than 500 uV), classically occurring every 5-10 seconds. Early in the course of the disease these periodic discharges may occur on a normal background but later the background becomes increasingly slower and disrupted. These periodic complexes are usually associated with clinically evident myoclonic or dystonic activity. MRI may be normal or may show early changes of increased signal on T2-weighted sequences, frequently involving the periventricular or subcortical white matter in the frontal, temporal, and occipital white matter; late changes include significant white matter loss, approximately 30% of patients show basal ganglia changes, while 25% have cortical changes. Fifty percent of patients who develop SSPE had measles (rubeola) before two years of age, and 80% before age four years. Five percent of patients survive three months or less and 20% survive four or more years, with a mean survival of only 18 months. Death occurs in stage IV, often the result of intercurrent illnesses such as pneumonia. MS (visual changes, oligoclonal bands) is often considered in the differential diagnosis of SSPE. Treatment is disappointing. The most promising results to date have used a combination of inosiplex, an antiviral agent, and intraventricular or intrathecal alpha-interferon as an immunomodulator, with stabilization or improvement in some patients. Early childhood measles vaccinations remain critical in limiting the incidence of SSPE.