Huntington Disease a nd Other Choreas Francisco Cardoso, MD, PhD KEYWORDS  Chorea  Ballism  Huntington disease  Neuroacanthocytosis  Sydenham chorea  Vascular chorea

Chorea is a syndrome characterized by brief, abrupt involuntary movements resulting from a continuous flow of random muscle contractions. The pattern of movement may sometimes seem playful, conveying a feeling of restlessness to the observer. When choreic movements are more severe, assuming a flinging, sometimes violent, character, they are called ballism. Regardless of its cause, chorea has the same features.1 There are genetic and nongenetic causes of chorea, listed in Box 1. Nongenetic causes include vascular choreas, autoimmune choreas, metabolic and toxic choreas, and drug-induced choreas. Although there are few community-based studies available regarding the prevalence and incidence of choreas, there is information regarding the situation in tertiary care centers. Huntington disease (HD) is the most frequent cause of genetic chorea with reported prevalence rates in North America and Europe ranging from 3 to 7 per 100,000.1 The other genetic conditions causing chorea are rare. According to a recent study from Pennsylvania, Sydenham chorea (SC) accounts for almost 100% of acute cases of chorea seen in children.2 In contrast, the situation is more distinct in adult patients. Although no published data are available, it is likely that levodopa-induced chorea in patients with Parkinson disease (PD) is the most common cause of chorea seen by neurologists. One study of consecutive patients seen at a tertiary hospital found that stroke accounted for 50% of all cases, drug abuse was identified in one third of the patients, and the remaining patients had chorea related to AIDS and other infections and metabolic problems.3 The aim of this article is to provide an overview of the main causes of chorea. The clinical features, causes, pathogenesis, and management are discussed. HUNTINGTON DISEASE

HD is an autosomal-dominant, progressive neurodegenerative disorder typically characterized by a movement disorder, including chorea, cognitive decline, and behavioral changes leading to relentlessly increasing disability and ultimately death. Patients usually develop the first symptoms in their mid-30s to mid-40s. However, the onset

Internal Medicine Department, The Federal University of Minas Gerais, Av Pasteur 89/1107, 30150-290 Belo Horizonte, MG, Brazil E-mail address: [email protected] Neurol Clin 27 (2009) 719–736 doi:10.1016/j.ncl.2009.04.001 neurologic.theclinics.com 0733-8619/09/$ – see front matter ª 2009 Elsevier Inc. All rights reserved.

720

Cardoso

Box 1 Causes of Chorea Genetic causes  Huntington disease  Huntington disease-like illnesses  Neuroacanthocytosis  McLeod syndrome  Wilson disease  Benign hereditary chorea (BHC)  Spinocerebellar atrophy type 2  Spinocerebellar atrophy type 3  Spinocerebellar atrophy type 17  Dentatorubropallidoluysian degeneration  Ataxia-telangiectasia  Ataxia associated with oculomotor apraxia  Neuroferritinopathy  Pantothenate kinase associated degeneration  Leigh disease and other mitochondriopathies  Lesch-Nyhan disease Immunologic  Sydenham chorea (SC) and variants (chorea gravidarum and contraceptive-induced chorea)  Systemic lupus erythematosus  Antiphospholipid antibody syndrome  Paraneoplastic syndromes  Acute disseminated encephalomyelopathy  Celiac disease Drug-related  Amantadine  Amphetamine  Anticonvulsants  Carbon monoxide  Central nervous system (CNS) stimulants (methylphenidate, pemoline, cyproheptadine)  Cocaine  Dopamine agonists  Dopamine-receptor blockers  Ethanol  Levodopa  Levofloxacin  Lithium  Sympathomimetics  Theophylline

Choreas

 Tricyclic antidepressants  Withdrawal emergent syndrome Infections  AIDS-related (toxoplasmosis, progressive multifocal leukoencephalopathy, HIV encephalitis)  Bacteria - Diphtheria - Scarlet fever - Whooping cough  Encephalitis - B19 parvovirus - Japanese encephalitis - Measles - Mumps - West Nile River encephalitis - Others  Parasites - Neurocysticercosis  Protozoan - Malaria - Syphilis Endocrine-metabolic dysfunction  Adrenal insufficiency  Hyper/hypocalcemia  Hyper/hypoglycemia  Hypomagnesemia  Hypernatremia  Liver failure Vascular  Post-pump chorea (cardiac surgery)  Stroke  Subdural hematoma Miscellaneous  Anoxic encephalopathy  Cerebral palsy  Kernicterus  Multiple sclerosis  Normal maturation (less than 12 months old)  Nutritional (eg, B12 deficiency)  Posttraumatic (brain injury)

721

722

Cardoso

in a small proportion of subjects is before the age of 20 years (Westphal variant) or after the age of 70 years.1 Clinical Features

HD is characterized by a triad of movement disorder, cognitive decline, and behavioral changes. Although chorea is the prototypical movement disorder in HD and is usually present with middle-age or elderly onset, the full spectrum of motor impairment in HD includes eye movement abnormalities, parkinsonian features and dystonia (particularly in juvenile HD), myoclonus, tics, ataxia, dysarthria and dysphagia, and spasticity with hyperreflexia and extensor plantar responses.4–8 With progressing illness, chorea is often superseded by dystonia or akineto-rigid parkinsonian features. One study demonstrated that dystonia is found in more than 90% of patients with HD,9 although rarely it becomes as prominent as in idiopathic dystonias. A recent study demonstrated that falls are an important clinical problem in HD, occurring in 60% of patients, and are correlated with motor deficits, cognitive decline, and behavioral changes.10 Behavioral impairment is universal in HD and may occasionally antedate motor manifestations. Major depression is common, diagnosed in more than 40% of subjects, and responsible for increased suicide rates in HD. The spectrum of behavioral abnormalities in HD is broad and includes anxiety or panic attacks, obsessive compulsive symptoms, manic features, psychosis, irritability and aggressive behavior, sexual disinhibition, and apathy.11–17 In a prospective study of a large cohort (681) of subjects with presymptomatic HD, significantly more psychiatric symptoms (specially depression, anxiety, and obsessive-compulsiveness) were reported than for the controls.18 Similarly, psychiatric difficulties are indicators of juvenile HD onset.19 Patients with HD universally go through cognitive decline, mental slowing, impaired problem-solving abilities, and other signs of a frontal dysexecutive syndrome, and they eventually become demented. These patients present with the prototype of socalled subcortical dementia.20–22 Cognitive decline also heralds the juvenile onset of HD.19 A recent investigation has demonstrated that asymptomatic carriers of the HD gene have decreased phonemic fluency.23 HD is relentlessly progressive with death occurring 15 to 20 years after symptom onset with particularly rapid progression in the juvenile Westphal variant. Patients with end-stage HD are typically rigid and akinetic, demented, and mute. Immobility and dysphagia often lead to aspiration pneumonia, the most common cause of death in these patients.24–26 Etiology and Pathogenesis

HD is caused by a trinucleotide (CAG) repeat expansion in the gene encoding for huntingtin on chromosome 4p16.3; the exact function of normal huntingtin is still unknown, and it is widely expressed in the human brain.27,28 The normal CAG repeat length in the HD gene is 35 or lower; expansions of 40 or more cause HD with complete penetrance. Individuals with 36 to 39 repeats may also develop HD but penetrance is incomplete.29 A CAG repeat range between 27 and 35 is considered normal allele with particular risk for expansion into the HD range in the paternal germline.30,31 However, there is a report showing that 1 patient with 34 repeats developed HD.32 The mutant protein has been shown to form nuclear aggregates but how this leads to neurodegeneration remains unclear. Current evidence suggests that formation of aggregates of huntingtin is not primarily responsible for neuronal loss in HD. Alternative hypotheses suggested include transcriptional dysregulation, excitotoxicity, altered energy metabolism, impaired axonal transport, and altered synaptic transmission.33,34 Neurodegeneration in HD affects most prominently the striatum with loss

Choreas

of medium spiny neurons and layers III, IV, and V of the cortex with loss of large neurons, and is characterized by the presence of intranuclear inclusion bodies consisting of amyloid-like fibrils that contain mutant huntingtin, ubiquitin, synuclein, and other proteins.35–37 Management

To date there is no effective treatment to modify the relentlessly progressive course of HD.38 Symptomatic treatment of chorea is needed if it causes functional disability or social embarrassment. One principle that generally guides the choice of antichoreic agents is their ability to powerfully block D2 receptors. With the exception of amantadine (see later discussion), all drugs effective in providing symptomatic improvement of chorea have high affinity toward this family of dopamine receptors, which explains why atypical agents, such as quetiapine and clozapine, often used to treat psychosis in patients with movement disorders, are usually ineffective in controlling chorea. Atypical antipsychotics such as olanzapine, quetiapine or risperidone may sufficiently and at least transiently reduce choreic movements but are generally less potent than typical neuroleptics. If the neuroleptics are effective in reducing chorea, they are often associated with unacceptable side effects such as sedation, acute dystonic reaction, tardive dyskinesia, and parkinsonism. Parkinsonism can be a problem in patients with HD; with progression of the illness there is a tendency for development of rigidity and dystonia.39 Mild to moderate chorea in HD may also respond to glutamate antagonists such as amantadine.40,41 Recent controlled data have confirmed that tetrabenazine, a presynaptic dopamine depletory, is efficacious in controlling chorea in HD.42,43 This agent has now been approved by the Food and Drug Administration for symptomatic control of chorea in HD. In a recent open-label study, aripiprazole was found to have efficacy comparable to tetrabenazine in the control of chorea in HD. Further studies are required to confirm this observation.44 Levodopa may be required in patients with Huntington disease with advanced illness and severe rigidity.38 Atypical neuroleptics may also be useful in the management of emotional irritability, aggressiveness, and other forms of erratic behavior.17,45 Depression may respond to classic antidepressants such as selective serotonin reuptake inhibitors (SSRIs) or antimuscarinic drugs, or to newer antidepressants such as mirtazapine, reboxatine, or venlafaxin, but there are no formal trial data to assess the relative efficacy and safety of these agents in HD.17 Occasional reports have claimed mild beneficial effects of treatment with cholinesterase inhibitor to reduce cognitive dysfunction in HD, but there are no adequate studies to support their use.46,47 Surgery to treat chorea is rarely needed. Pallidotomy and pallidal stimulation have also been used in a few patients with HD.48,49 Several patients with Huntington disease have been treated with fetal cell implantation in the striatum. Despite a few positive reports, in most cases no improvement has been observed. Autopsy studies have shown that the grafts survive but do not integrate with host striatum.50,51 OTHER GENETIC CHOREAS

Approximately 3% of patients with an HD phenotype test negative for this condition. Cohort studies have established that, although most phenocopy patients remain undiagnosed, in those patients in whom a genetic diagnosis is reached the commonest causes are neuroacanthocytosis, SCA17, Huntington disease-like syndrome 2, familial prion disease, and Friedreich ataxia. Other causes of HD phenocopies include Huntington disease-like syndrome 1, Huntington disease-like syndrome 3, other spinocerebellar ataxias, dentatorubral-pallidoluysian atrophy, and iron accumulation disorders.52,53

723

724

Cardoso

Neuroacanthocytosis causes chorea combined with dystonia (especially a selfmutilating oro-mandibullingual dyskinesia), tics, parkinsonism, dementia, seizures, and head of caudate atrophy on neuroimaging studies.54 Several conditions can cause the combination of chorea and acanthocytosis: autosomal recessive choreaacanthocytosis, X-linked McLeod syndrome, Huntington disease-like 2, panthotenate kinase–associated neurodegeneration, and Bassen-Kornzweig disease.55 A study of several patients with McLeod syndrome, including the subject of the original report, demonstrated that their phenotype is similar to the clinical features of patients with HD, with the myopathic findings overtaken by chorea and dementia.56 Another genetic cause of chorea that has received increased attention is benign hereditary chorea (BHC). Not long ago, the existence of this condition was questioned.57 Now it is well established as an autosomal dominant illness, with a mutation in the TITF-1 gene, which codes for a transcription factor essential for the organogenesis of the lungs, thyroid, and basal ganglia.58 The clinical picture of these patients is characterized by a variable combination of chorea, mental retardation, congenital hypothyroidism, and chronic lung disease, hence the term brain-thyroid-lung syndrome, proposed for this disease.59,60 The movement disorder of these patients is differentiated from the hyperkinesia seen in myoclonus dystonia by its continuous nature; in myoclonus dystonia the movements are triggered by motion.61 New studies with clinical-genetic correlation have helped to demonstrate that the clinical spectrum of BHC is wider than previously believed, and includes psychosis and short stature.62,63 The phenotype of BHC and hypothyroidism has been shown to be caused by a novel NKX2.1 mutation.64 Moreover, a new locus on 8q21.3 q23.3 is associated with adult-onset, pure, slowly progressive chorea.65 The list of genetic causes of chorea is long and growing.1 It is beyond the scope of this article to review all of them. Recently, however, there has been interest in a few additional conditions in which progress has been made. For example, paroxysmal nonkinesigenic dyskinesia, Mount-Reback Syndrome, is now known to be caused by mutations of myofibrillogenesis regulator 1 (MR-1) gene mutations, located on 2q35.66,67 Patients with this condition develop episodes of chorea or other movement disorders unrelated to exercise but often in association with the use of nicotine and alcohol.68 A new study showed that there is a defect in the MR-1 mitochondrial targeting sequence.69 Other paroxysmal dyskinesias in which chorea is part of the clinical picture map to genes on 16p12-q12 and 10q22.70 There are no controlled studies of treatment of other genetic causes of chorea. Overall, the principles discussed for HD apply to these conditions. However, there are peculiarities in some cases. A substantial proportion of patients with chorea-acanthocytosis present with a self-mutilating tongue-biting dystonia. This dyskinesia can be disabling, preventing these patients from eating properly and resulting in severe injuries. In the author’s experience, injections of botulinum toxin in the genioglossus muscle can provide substantial and lasting relief. Another clinical feature common in this condition is seizure disorder, requiring the use of antiepileptic drugs. The kinesigenic paroxysmal dyskinesias are sensitive to low doses of antepileptic drugs, whereas Mount-Reback syndrome responds to benzodiazepines.68,71 Finally, there is one report suggesting that levodopa can be effective in the treatment of BHC.72 SYDENHAM CHOREA

SC, the most common form of autoimmune chorea worldwide, is a major feature of acute rheumatic fever (ARF), a nonsuppurative complication of group A b-hemolytic Streptococcus infection. Despite the decline of ARF, it remains the most common

Choreas

cause of acute chorea in children in the United States and a major public health problem in developing areas of the world. Clinically, it is characterized by a combination of chorea, other movement disorders, behavioral abnormalities, and cognitive changes.1,2 Clinical Features

The usual age at onset of SC is 8 to 9 years, but there are reports of patients who developed chorea during the third decade of life. In most series, there is a female preponderance.73 Typically, patients develop this disease 4 to 8 weeks after an episode of group A b-hemolytic streptococcal pharyngitis. It does not occur after streptococcal infection of the skin. The chorea spreads rapidly and becomes generalized, but hemichorea persists in 20% of patients.73,74 Patients display motor impersistence, particularly noticeable during tongue protrusion and ocular fixation. The muscle tone is usually decreased; in severe and rare cases (8% of all patients seen at the Movement Disorders of the Federal University of Minas Gerais, Brazil), this is so pronounced that the patient may become bedridden (chorea paralytica). Patients often display other neurologic and nonneurologic symptoms and signs. There are reports that tics are a common occurrence in SC. However, it is virtually impossible to distinguish simple tics from fragments of chorea. Even vocal tics, found in 70% or more of patients with SC in one study, are not a simple diagnosis in patients with hyperkinesias.75 In a cohort of 108 patients with SC who were carefully followed up at our unit, vocalizations were identified in just 8% of subjects. The term ‘‘tic’’ was avoided because there was no premonitory sign or complex sound and, conversely, the vocalizations were associated with severe cranial chorea. These findings suggest that involuntary sounds present in a few patients with SC result from choreic contractions of the upper respiratory tract muscles rather than true tics.76,77 There is evidence that many patients with active chorea have hypometric saccades, and a few also show oculogyric crisis. Dysarthria and impairment of verbal fluency are common. In a case– control study of patients, a pattern of decreased verbal fluency was described that reflected reduced phonetic, but not semantic, output.78 This result is consistent with dysfunction of the dorsolateral prefrontal basal ganglia circuit. Studying adults with SC, the authors have extended this finding, showing that many functions dependent on the prefrontal area are impaired in these patients. The conclusion of this study is that SC should be included among the causes of dysexecutive syndrome.79 The prosody is also affected in SC. In an investigation of 20 patients with SC, decreased vocal tessitura and increased duration of the speech were shown.80,81 These findings are similar to those observed in Parkinson disease.82 In a recent survey of 100 patients with rheumatic fever, half of whom had chorea, migraine was found to be more frequent in SC (21.8%) than in normal controls (8.1%, P 5 .02).83 This is similar to what has been described in Tourette syndrome (TS).84 In the older literature, there are also references to papilledema, central retinal artery occlusion, and seizures in a few patients with Sydenham chorea. Attention has also been drawn to behavioral abnormalities. Swedo and colleagues85 found obsessive-compulsive behavior in 5 of 13 SC patients, 3 of whom met criteria for obsessive-compulsive disorder, whereas no patient of the rheumatic fever group presented with obsessive-compulsive behavior. In another study of 30 patients with SC, Asbahr and colleagues86 demonstrated that 70% of the subjects presented with obsessions and compulsions, whereas 16.7% of them met criteria for obsessive-compulsive disorder. None of the 20 patients with ARF without chorea had obsessions or compulsions. These results were roughly replicated by a more recent study in which patients with ARF without chorea were found to have more obsessions

725

726

Cardoso

and compulsions than healthy controls.87 This study also tackled the issue of hyperactivity and attention deficit disorder in SC and found that 45% of their 22 patients met criteria for this condition. Recently, Maia and colleagues88 investigated behavioral abnormalities in 50 healthy subjects, 50 patients with rheumatic fever without chorea, and 56 patients with Sydenham chorea. The investigators found that obsessivecompulsive behavior, obsessive-compulsive disorder, and attention deficit and hyperactivity disorder were more frequent in the SC group (19%, 23.2%, 30.4%) than in the healthy controls (11%, 4%, 8%) or in the patients with ARF without chorea (14%, 6%, 8%). In this study, the investigators demonstrated that obsessive-compulsive behavior displays little degree of interference in the performance of the activities of daily living. Another study compared the phenomenology of obsessions and compulsions of patients with SC with subjects diagnosed with tic disorders. The investigators demonstrated that the symptoms observed among the SC patients were different from those reported by patients with tic disorders but were similar to those previously noted among samples of pediatric patients with primary obsessive-compulsive disorder.89 A recent investigation comparing healthy controls with patients with rheumatic fever showed that obsessive-compulsive behavior is more commonly seen in patients with Sydenham chorea with relatives who also have obsessions and compulsions.90 This study makes clear that there is interplay between genetic factors and the environment in the development of behavioral problems in SC. The authors recently reported that, although rare, SC may induce psychosis or trichotillomania during the acute phase of the illness.91,92 An investigation demonstrated that the peripheral nervous system is not targeted in Sydenham chorea.93 SC is a major manifestation of rheumatic fever. Sixty percent to 80% of patients display cardiac involvement, particularly mitral valve dysfunction, in SC, whereas the association with arthritis is less common, seen in 30% of patients; however, in approximately 20% of patients, chorea is the sole finding.73,94 A prospective follow-up of patients with SC with and without cardiac involvement in the first episode of chorea suggests that the heart remains spared in those without lesion at the onset of the rheumatic fever.95 The current diagnostic criteria of SC are a modification of the Jones criteria: chorea with acute or subacute onset and lack of clinical and laboratory evidence of an alternative cause are mandatory findings. The diagnosis is further supported by the presence of additional major or minor manifestations of ARF.78,96,97 The first validated scale to rate SC was published recently. The Universidade Federal de Minas Gerais Sydenham Chorea Rating Scale was designed to provide a detailed quantitative description of the performance of the activities of daily living, behavioral abnormalities, and motor function of patients with SC. It comprises 27 items, and each is scored from 0 (no symptom or sign) to 4 (severe disability or finding).98 Etiology and Pathogenesis

Taranta and Stollerman established the casual relationship between infection with group A b-hemolytic streptococci and the occurrence of SC.99 Based on the assumption of molecular mimicry between streptococcal and central nervous system antigens, it has been proposed that the bacterial infection in genetically predisposed subjects leads to formation of cross-reactive antibodies that disrupt the basal ganglia function. Several studies have demonstrated the presence of such circulating antibodies in 50% to 90% of patients with Sydenham chorea.100,101 A specific epitope of streptococcal M proteins that cross-reacts with basal ganglia has been identified.102 In one study, all patients with active SC had antibasal ganglia antibodies demonstrated by ELISA and Western blot. In subjects with persistent SC (duration

Choreas

of disease greater than 2 years despite best medical treatment), positivity was about 60%.103 Recently, neuronal tubulin was found to be the target of antineuronal antibodies.104 The biologic value of the antibasal ganglia antibodies remains to be determined. One study suggests that they may interfere with neuronal function, however. Kirvan and colleagues105 demonstrated that IgM of 1 patient with Sydenham chorea induced expression of calcium-dependent calmodulin in a culture of neuroblastoma cells. Our finding that there is a linear correlation between the increase in intracellular calcium levels in PC12 cells and antibasal ganglia antibody titer in the serum from SC patients further strengthens the hypothesis that these antibodies have a pathogenic value.106 Although some investigations suggest that susceptibility to rheumatic chorea is linked to human leukocyte antigen-linked antigen expression,107 some studies have failed to identify any relationship between SC and human leukocyte antigen class I and II alleles.108 However, an investigation has shown that there is an association between HLA-DRB1*07 and recurrent streptococcal pharyngitis and rheumatic heart disease.109 The genetic marker for ARF and related conditions would be the B-cell alloantigen D8/17.110 Despite repeated reports of the group who developed the assay claiming its high specificity and sensitivity,111,112 findings of other investigators suggest that the D8/17 marker lacks specificity and sensitivity.1 Another suggested genetic risk factor for development of ARF but not SC are polymorphisms within the promoter region of the tumor necrosis factor-a gene.113 Because of the difficulties with the molecular mimicry hypothesis in accounting for the pathogenesis of SC, some studies have addressed the role of immune cellular mechanisms in this condition. Investigating sera and cerebrospinal fluid (CSF) samples from patients of the Movement Disorders of the Federal University of Minas Gerais, Church and colleagues114 found elevation of cytokines that take part in the Th2 (antibody-mediated) response, interleukins 4 (IL-4) and 10 (IL-10), in the serum of patients with acute SC in comparison with persistent SC. They also described interleukin 4 in the CSF of 31% of patients with acute SC, whereas just interleukin 4 was raised in the CSF of patients with persistent SC. The investigators concluded that SC is characterized by a Th2 response. However, as they have found elevated levels of interleukin 12 in patients with acute SC and, more recently, Teixeira and colleagues described an increased concentration of chemokines CXCL9 and CXCL10 in the serum of patients with acute SC,115 it can be concluded that Th1 (cell-mediated) mechanisms may also be involved in the pathogenesis of this disorder. Currently, the evidence suggests that the pathogenesis of SC is related to circulating cross-reactive antibodies. Streptococcus-induced antibodies have been shown to be associated with a form of acute disseminated encephalomyelitis characterized by a high frequency of dystonia and other movement disorders as well as basal ganglia lesions on neuroimaging.116 Antineural and antinuclear antibodies have also been found in patients with TS but their relationship with prior streptococcus infection remains equivocal.117 Management

In the past, physicians emphasized the need for bed rest for the treatment of SC. Currently there is no place for this measure. Because SC results from autoimmune, and not direct bacterial attack against the CNS, quarantine to prevent contamination of others is usually unnecessary.118 The first aim of the treatment of SC is to provide control of the chorea and behavioral problems often associated with this condition. Regardless of the choice of agent for symptomatic control, the physician should attempt a gradual decrease in the dosage

727

728

Cardoso

of the medication (25% reduction every 2 weeks) after the patient remains free of the symptom for at least 1 month. In some patients symptoms are so mild that they do not cause meaningful disability. In these cases, it is possible to avoid any pharmacologic intervention, because spontaneous remission of SC is the rule.97,119 The second aim is prophylaxis of new bouts of ARF. Although it remains unproved whether prophylaxis of streptococcus infection prevents recurrences of SC,120 clearly it decreases the development of new cardiac lesions, which are the source of the most important disability in rheumatic fever. There are no controlled studies of symptomatic treatment of SC and all the recommendations mentioned are off-label use of the cited drugs.118 The first choice is valproic acid at an initial dosage of 250 mg/d that is increased over a 2-week period to 250 mg 3 times a day. If the response is not satisfactory, dosage can be increased gradually up to 1500 mg/d. As this drug has a slow onset of action, a period of 2 weeks should elapse before concluding that the regimen is ineffective. Valproic acid is usually well tolerated although some patients may develop dyspepsia and diarrhea at the beginning of the treatment. Chronic exposure may be associated with action tremor of the hands and, more rarely, liver toxicity. An open-label study demonstrated that carbamazepine (15 mg/kg/d) is as effective as valproic acid (20–25 mg/kg/d) to induce remission of chorea.121 If the patient fails to respond to valproic acid, or, as first line treatment in patients who present with chorea paralytica, the next option is to prescribe neuroleptics. Risperidone, a potent dopamine D2 receptor blocker, is usually effective in controlling the chorea. The initial regimen is usually 1 mg twice a day. If, 2 weeks later, the chorea is still troublesome, the dosage can be increased to 2 mg twice a day. Haloperidol and pimozide are also occasionally used in the management of chorea in SC. However, they are less well tolerated than risperidone. Dopamine D2 receptor blockers must be used with great caution in patients with SC. After observation of development of parkinsonism, dystonia, or both in patients treated with neuroleptics, we performed a case–control study comparing the response to these drugs in patients with SC and TS. Five percent of 100 patients with chorea developed extrapyramidal complications, whereas these findings were not seen among patients with tics matched for age and dosage of neuroleptics.121 Other potential side effects of these agents are sedation, depression, and tardive dyskinesia. There are no published guidelines concerning the discontinuation of antichoreic agents. Our policy is to attempt a gradual decrease of the dosage (25% reduction every 2 weeks) after the patient remains at least free of chorea for 1 month. Finally, the most important measure in the treatment of patients with SC is secondary prophylaxis. Because of the presumably autoimmune origin of SC, there have been attempts to treat patients with rheumatic chorea with corticosteroids. However, this is a controversial area. Despite mentions of effectiveness of prednisone in suppressing chorea, this drug is only used when there is associated severe carditis. We recently reported that methylprednisolone 25 mg/kg/d in children and 1 g/d in adults for 5 days followed by prednisone 1 mg/kg/d is an effective and well-tolerated treatment regimen for patients with SC refractory to conventional treatment with antichoreic drugs and penicillin.98,122 At least one other group has replicated our findings of a good response to steroids in selected patients with SC.123 In one of the few randomized controlled trials in SC, the investigators compared oral prednisone (2 mg/kg/d) and placebo in a double-blind fashion. Simultaneous use of haloperidol was allowed. They concluded that steroid accelerates the recovery but the rate of remission and recurrence is similar in both groups.124 However, this study has some limitations: haloperidol use was not controlled in both groups; it remains uncertain whether the development of side

Choreas

effects such as weight gain and moon face in the steroid group could have potentially compromised the blinding of the study (this is of particular concern considering the high dosage of prednisone); the investigators used a nonvalidated scale to rate the severity of chorea. The current recommendation is to reserve steroids for patients with persistent disabling chorea refractory to antichoreic agents or those who develop unacceptable side effects with other agents. Finally, one open, controlled study of a small number of patients reported that plasma exchange or intravenous immunoglobulin are as effective as oral prednisone to control the severity of chorea in SC.125 Surprisingly, the investigators report the lack of side effects in all groups. Because of the lack of additional studies to confirm the safety and effectiveness of these treatments, their high cost and existence of alternative efficacious therapeutic options, plasmapheresis and immunoglobulin are presently considered as investigational, and do not have a place in routine medical practice. OTHER AUTOIMMUNE CHOREAS

Other immunologic causes of chorea are systemic lupus erythematosus (SLE), primary antiphospholipid antibody syndrome (PAPS), vasculitis, and paraneoplastic syndromes. SLE or PAPS are classically described as the prototypes of autoimmune choreas.126 However, several reports show that chorea is seen in no more than 1% to 2% of large series of patients with these conditions.127,128 Autoimmune chorea has rarely been reported in the context of paraneoplastic syndromes associated with CV2/CRMP5 antibodies in patients with small-cell lung carcinoma or malignant thymoma.129 As these disorders are rare, chorea caused by them is uncommon. Chorea associated with SLE or PAPS has been treated with immunosuppressive measures, especially intravenous methylprednisolone following a dosage regimen as described for SC, and intravenous immunoglobulin.130 As it is accepted that neurologic complications, including chorea, in PAPS are related to ischemic events, antiplatelet agents and even anticoagulants are often prescribed to treat chorea in this condition.131 However, these recommendations are based on reports of openlabel studies involving small numbers of patients and the clinical experience of the physicians.1 VASCULAR CHOREAS

A study in a tertiary referral center showed that cerebrovascular disease was the most common cause of nongenetic chorea, accounting for 21 out of 42 cases.3 Conversely, chorea is an unusual complication of acute vascular lesions, seen in less than 1% of patients with acute stroke. Vascular hemichorea, or hemiballism, is usually related to ischemic or hemorrhagic lesions of the basal ganglia and adjacent white matter in the territory of the middle or the posterior cerebral artery. In contrast to the classic textbook concepts of hemiballism, most patients with vascular chorea have lesions outside the subthalamus.132 Although spontaneous remission is the rule, treatment with antichoreic drugs such as neuroleptics or dopamine depletors may be necessary in the acute phase. In a few patients with vascular chorea, the movement disorder may persist. These patients can be treated effectively with stereotactic surgery such as thalamotomy or posteroventral pallidotomy.133,134 An uncommon cause of chorea is Moyamoya disease, an intracranial vasculopathy that presents with an ischemic lesion or, less commonly, hemorrhagic stroke of the basal ganglia.135 Another rare form of vascular chorea is ‘‘postpump chorea,’’ a complication of extracorporeal circulation. The pathogenesis of this movement disorder is believed to be related to vascular insult of the basal ganglia during the

729

730

Cardoso

surgical procedure. The current evidence supports the notion that the long-term prognosis of PC is poor. In 1 series of 8 patients, for example, 5 subjects had persistent chorea and 1 of them died. In another study, there was a clear distinction between those 8 patients with onset at earlier age (median 4.3 months), all of whom recovered fully, and 11 others, who were older at onset (median age 16.8 months). Among the latter, 4 died and only 1 of the survivors made a complete neurologic recovery.136 SUMMARY

Huntington disease (HD), an autosomal dominant degenerative disease, is the most common genetic cause of chorea. HD, a relentlessly progressive illness, is characterized by a combination of movement disorder, cognitive decline, and behavioral abnormalities. There is no treatment capable of stopping its progression. The most common conditions that mimic HD are neuroacanthocytosis, SCA17, Huntington disease-like syndrome 2, familial prion disease, and Friedreich ataxia. Sydenham chorea (SC) is the most common cause of chorea in children worldwide. Patients with SC present with a variable combination of chorea, obsessive-compulsive behavior, other behavioral abnormalities, and carditis. Management of SC involves prophylaxis of Streptococcus infections with penicillin and antichoreic agents. Stroke is the most common sporadic cause of chorea in adults. Vascular chorea, usually a complication of diabetes mellitus, is often a self-limited condition. REFERENCES

1. Cardoso F, Seppi K, Mair KJ, et al. Seminar on choreas. Lancet Neurol 2006;5: 589–602. 2. Zomorrodi A, Wald ER. Sydenham’s chorea in western Pennsylvania. Pediatrics 2006;117:e675–9. 3. Piccolo I, Defanti CA, Soliveri P, et al. Cause and course in a series of patients with sporadic chorea. J Neurol 2003;250:429–35. 4. Leigh RJ, Newman SA, Folstein SE, et al. Abnormal ocular motor control in Huntington’s disease. Neurology 1983;33:1268–75. 5. Carella F, Scaioli V, Ciano C, et al. Adult onset myoclonic Huntington’s disease. Mov Disord 1993;8:201–5. 6. Jankovic J, Ashizawa T. Tourettism associated with Huntington’s disease. Mov Disord 1995;10:103–5. 7. Reuter I, Hu MT, Andrews TC, et al. Late onset levodopa responsive Huntington’s disease with minimal chorea masquerading as Parkinson plus syndrome. J Neurol Neurosurg Psychiatr 2000;68:238–41. 8. Tan EK, Jankovic J, Ondo W. Bruxism in Huntington’s disease. Mov Disord 2000; 15:171–3. 9. Louis ED, Lee P, Quinn L, et al. Dystonia in Huntington’s disease: prevalence and clinical characteristics. Mov Disord 1999;14:95–101. 10. Grimbergen YA, Knol MJ, Bloem BR, et al. Falls and gait disturbances in Huntington’s disease. Mov Disord 2008;23(7):970–6. 11. Caine ED, Shoulson I. Psychiatric syndromes in Huntington’s disease. Am J Psychiatry 1983;140:728–33. 12. Mendez MF. Huntington’s disease: update and review of neuropsychiatric aspects. Int J Psychiatry Med 1994;24:189–208. 13. Schoenfeld M, Myers RH, Cupples LA, et al. Increased rate of suicide among patients with Huntington’s disease. J Neurol Neurosurg Psychiatry 1984;47: 1283–7.

Choreas

14. Shiwach R. Psychopathology in Huntington’s disease patients. Acta Psychiatr Scand 1994;90:241–6. 15. Rosenblatt A, Leroi I. Neuropsychiatry of Huntington’s disease and other basal ganglia disorders. Psychosomatics 2000;41:24–30. 16. Rosenblatt A, Anderson K, Goumeniouk AD, et al. Clinical management of dard MA, aggression and frontal syndromes in Huntington’s Disease. In: Be Agid Y, Chouinard S, Fahn S, Korczyn AD, Lesperance P, editors. Mental and behavioral dysfunction in movement disorders. Totowa (NJ): Humana Press; 2003. p. 427–41. 17. Guttman M, Alpay M, Chouinard S, et al. Clinical management of psychosis and dard MA, Agid Y, Chouinard S, mood disorders in Huntington’s disease. In: Be Fahn S, Korczyn AD, Lesperance P, editors. Mental and behavioral dysfunction in movement disorders. Totowa (NJ): Humana Press; 2003. p. 409–26. 18. Duffin K, Paulsen JS, Beglinger LJ, et al. Psychiatric symptoms in Huntington’s disease before diagnosis: the predict-HD study. Biol Psychiatry 2007;62:1341–6. 19. Ribaı¨ P, Nguyen K, Hahn-Barma V, et al. Psychiatric and cognitive difficulties as indicators of juvenile Huntington disease onset in 29 patients. Arch Neurol 2007; 64(6):813–9. 20. Ho AK, Sahakian BJ, Brown RG, et al. Profile of cognitive progression in early Huntington’s disease. Neurology 2003;61:1702–6. 21. Lawrence AD, Sahakian BJ, Hodges JR, et al. Executive and mnemonic functions in early Huntington’s disease. Brain 1996;119(Pt 5):1633–45. 22. Kirkwood SC, Su JL, Conneally P, et al. Progression of symptoms in the early and middle stages of Huntington disease. Arch Neurol 2001;58:273–8. 23. Larsson MU, Almkvist O, Luszcz MA, et al. Phonemic fluency deficits in asymptomatic gene carriers for Huntington’s disease. Neuropsychology 2008;22(5): 596–605. 24. Marshall F. Clinical features and treatment of Huntington’s disease. In: Watts RL, Koller WC, editors. Movement disorders: neurological principles and practice. New York: McGraw-Hill; 2004. p. 589–601. 25. Sorensen SA, Fenger K. Causes of death in patients with Huntington’s disease and in unaffected first degree relatives. J Med Genet 1992;29:911–4. 26. Lanska DJ, Lanska MJ, Lavine L, et al. Conditions associated with Huntington’s disease at death. A case-control study. Arch Neurol 1988;45:878–80. 27. The Huntington’s Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. The Huntington’s Disease Collaborative Research Group. Cellule 1993;72:971–83. 28. Biglan KM, Shoulson I. Huntington’s disease. In: Jankovic JJ, Tolosa E, editors. Parkinson’s disease and movement disorders. Philadelphia: Lippincott Williams & Wilkins; 2002. p. 212–27. 29. Rubinsztein DC, Leggo J, Coles R, et al. Phenotypic characterization of individuals with 30-40 CAG repeats in the Huntington disease (HD) gene reveals HD cases with 36 repeats and apparently normal elderly individuals with 36-39 repeats. Am J Hum Genet 1996;59:16–22. 30. Ranen NG, Stine OC, Abbott MH, et al. Anticipation and instability of IT-15 (CAG)n repeats in parent-offspring pairs with Huntington disease. Am J Hum Genet 1995;57:593–602. 31. Laccone F, Engel U, Holinski-Feder E, et al. DNA analysis of Huntington’s disease: five years of experience in Germany, Austria, and Switzerland. Neurology 1999;53:801–6.

731

732

Cardoso

32. Andrich J, Arning L, Wieczorek S, et al. Huntington’s disease as caused by 34 CAG repeats. Mov Disord 2008;23(6):879–81. 33. Roze E, Saudou F, Caboche J. Pathophysiology of Huntington’s disease: from huntingtin functions to potential treatments. Curr Opin Neurol 2008;21(4): 497–503. 34. Truant R, Atwal RS, Desmond C, et al. Huntington’s disease: revisiting the aggregation hypothesis in polyglutamine neurodegenerative diseases. FEBS J 2008; 275(17):4252–62. 35. Ferrante RJ, Kowall NW, Beal MF, et al. Selective sparing of a class of striatal neurons in Huntington’s disease. Science 1985;230(4725):561–3. 36. Hedreen JC, Peyser CE, Folstein SE, et al. Neuronal loss in layers V and VI of cerebral cortex in Huntington’s disease. Neurosci Lett 1991;133:257–61. 37. Margolis RL, Ross CA. Diagnosis of Huntington disease. Clin Chem 2003; 49(10):1726–32. 38. Bonelli RM, Wenning GK. Pharmacological management of Huntington’s disease: an evidence-based review. Curr Pharm Des 2006;12:2701–20. 39. Deng YP, Albin RL, Penney JB, et al. Differential loss of striatal projection systems in Huntington’s disease: a quantitative immunohistochemical study. J Chem Neuroanat 2004;27:143–64. 40. Lucetti C, Del Dotto P, Gambaccini G, et al. IV amantadine improves chorea in Huntington’s disease: an acute randomized, controlled study. Neurology 2003; 60:1995–7. 41. O’Suilleabhain P, Dewey RB Jr. A randomized trial of amantadine in Huntington disease. Arch Neurol 2003;60:996–8. 42. Huntington Study Group. Tetrabenazine as antichorea therapy in Huntington disease: a randomized controlled trial. Neurology 2006;66:366–72. 43. Kenney C, Hunter C, Davidson A, et al. Short-term effects of tetrabenazine on chorea associated with Huntington’s disease. Mov Disord 2007a;22:10–3. 44. Brusa L, Orlacchio A, Moschella V, et al. Treatment of the symptoms of Huntington’s disease: preliminary results comparing aripiprazole and tetrabenazine. Mov Disord 2009;24(1):126–9. 45. Cardoso F. Chorea. In: Hallett Mark, Poewe Werner, editors. Therapeutics of Parkinson’s disease and other movement disorders. Philadelphia: John Wiley & Sons; 2008. p. 212–27. 46. de Tommaso M, Specchio N, Sciruicchio V, et al. Effects of rivastigmine on motor and cognitive impairment in Huntington’s disease. Mov Disord 2004; 19:1516–8. 47. Rot U, Kobal J, Sever A, et al. Rivastigmine in the treatment of Huntington’s disease. Eur J Neurol 2002;9:689–90. 48. Cubo E, Shannon KM, Penn RD, et al. Internal globus pallidotomy in dystonia secondary to Huntington’s disease. Mov Disord 2000;15:1248–51. 49. Moro E, Lang AE, Strafella AP, et al. Bilateral globus pallidus stimulation for Huntington’s disease. Ann Neurol 2004;56:290–4. 50. Keene CD, Sonnen JA, Swanson PD, et al. Neural transplantation in Huntington disease: long-term grafts in two patients. Neurology 2007;68(24):2093–8. 51. Clelland CD, Barker RA, Watts C. Cell therapy in Huntington disease. Neurosurg Focus 2008;24(3–4):E9. 52. Wild EJ, Tabrizi SJ. Huntington’s disease phenocopy syndromes. Curr Opin Neurol 2007;20(6):681–7. 53. Wild EJ, Mudanohwo EE, Sweeney MG, et al. Huntington’s disease phenocopies are clinically and genetically heterogeneous. Mov Disord 2008;23(5):716–20.

Choreas

54. Walker RH, Danek A, Dobson-Stone C, et al. Developments in neuroacanthocytosis: expanding the spectrum of choreatic syndromes. Mov Disord 2006;21: 1794–805. 55. Walker RH, Jung HH, Dobson-Stone C, et al. Neurologic phenotypes associated with acanthocytosis. Neurology 2007;68(2):92–8. 56. Hewer E, Danek A, Schoser BG, et al. McLeod myopathy revisited: more neurogenic and less benign. Brain 2007;130(Pt 12):3285–96. 57. Schrag A, Quinn NP, Bhatia KP, et al. Benign hereditary chorea – entity or syndrome? Mov Disord 2000;15(2):280–8. 58. Kleiner-Fisman G, Rogaeva E, Halliday W, et al. Benign hereditary chorea: clinical, genetic, and pathological findings. Ann Neurol 2003;54:244–7. 59. Willemsen MA, Breedveld GJ, Wouda S, et al. Brain-Thyroid-Lung syndrome: a patient with a severe multi-system disorder due to a de novo mutation in the thyroid transcription factor 1 gene. Eur J Pediatr 2005;164:28–30. 60. Devos D, Vuillaume I, de Becdelievre A, et al. New syndromic form of benign hereditary chorea is associated with a deletion of TITF-1 and PAX-9 contiguous genes. Mov Disord 2006;21:2237–40. 61. Asmus F, Devlin A, Munz M, et al. Clinical differentiation of genetically proven benign hereditary chorea and myoclonus-dystonia. Mov Disord 2007;22(14): 2104–9. 62. Kleiner-Fisman G, Lang AE. Benign hereditary chorea revisited: a journey to understanding. Mov Disord 2007;22:2297–305. 63. Glik A, Vuillaume I, Devos D, et al. Psychosis, short stature in benign hereditary chorea: a novel thyroid transcription factor-1 mutation. Mov Disord 2008;23: 1744–7. 64. Ferrara AM, De Michele G, Salvatore E, et al. A novel NKX2.1 mutation in a family with hypothyroidism and benign hereditary chorea. Thyroid 2008;18:1005–9. 65. Shimohata T, Hara K, Sanpei K, et al. Novel locus for benign hereditary chorea with adult onset maps to chromosome 8q21.3 q23.3. Brain 2007;130(Pt 9): 2302–9. 66. Lee HY, Xu Y, Huang Y, et al. The gene for paroxysmal non-kinesigenic dyskinesia encodes an enzyme in a stress response pathway. Hum Mol Genet 2004;13:3161–70. 67. Rainier S, Thomas D, Tokarz D, et al. Myofibrillogenesis regulator 1 gene mutations cause paroxysmal dystonic choreoathetosis. Arch Neurol 2004;61(7):1025–9. 68. Bruno MK, Lee HY, Auburger GW, et al. Genotype-phenotype correlation of paroxysmal nonkinesigenic dyskinesia. Neurology 2007;68(21):1782–9. 69. Ghezzi D, Viscomi C, Ferlini A, et-al. Paroxysmal non-kinesigenic dyskinesia is caused by mutations of the MR-1 mitochondrial targeting sequence. Hum Mol Genet 2009;18(6):1058–64. 70. Rochette J, Roll P, Szepetowski P. Genetics of infantile seizures with paroxysmal dyskinesia: the infantile convulsions and choreoathetosis (ICCA) and ICCA-related syndromes. J Med Genet 2008;45(12):773–9. 71. Demirkiran M, Jankovic J. Paroxysmal dyskinesias: clinical features and classification. Ann Neurol 1995;38:571–9. 72. Asmus F, Horber V, Pohlenz J, et al. A novel TITF-1 mutation causes benign hereditary chorea with response to levodopa. Neurology 2005;64:1952–4. 73. Cardoso F, Silva CE, Mota CC. Sydenham’s chorea in 50 consecutive patients with rheumatic fever. Mov Disord 1997;12:701–3. 74. Nausieda PA, Grossman BJ, Koller WC, et al. Sydenham’s chorea: an update. Neurology 1980;30:331–4.

733

734

Cardoso

75. Mercadante MT, Campos MC, Marques-Dias MJ, et al. Vocal tics in Sydenham’s chorea. J Am Acad Child Adolesc Psychiatry 1997;36:305–6. 76. Jankovic J. Differential diagnosis and etiology of tics. Adv Neurol 2001;85: 15–29. 77. Teixeira AL Jr, Cardoso F, Maia DP, et al. Frequency and significance of vocalizations in Sydenham’s chorea. Parkinsonism Relat Disord 2009;15:62–3. 78. Cunningham MC, Maia DP, Teixeira AL Jr, et al. Sydenham’s chorea is associated with decreased verbal fluency. Parkinsonism Relat Disord 2006;12(3): 165–7. 79. Cardoso F, Beato R, Siqueira CF, et al. Neuropsychological performance and brain SPECT imaging in adult patients with Sydenham’s chorea. Neurology 2005;64(Suppl 1):A76. 80. Cardoso F, Oliveira PM, Reis CC, et al. Prosody in Sydenham chorea – I: Tessitura. Mov Disord 2006;21:S359–60. 81. Cardoso F, Oliveira PM, Reis CC, et al. Prosody in Sydenham chorea – II: duration of statements. Mov Disord 2006;21:S360. 82. Azevedo LL, Cardoso F, Reis C. Acoustic analysis of prosody in females with Parkinson’s disease: comparison with normal controls. Arq Neuropsiquiatr 2003;61:999–1003. 83. Teixeira AL Jr, Meira FC, Maia DP, et al. Migraine headache in patients with Sydenham’s chorea. Cephalalgia 2005;25(7):542–4. 84. Kwack C, Vuong KD, Jankovic J. Migraine headache in patients with Tourette syndrome. Arch Neurol 2003;60:1595–8. 85. Swedo SE, Leonard HL, Garvey M, et al. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: clinical description of the first 50 cases. Am J Psychiatry 1988;155:264–71. 86. Asbahr FR, Negrao AB, Gentil V, et al. Obsessive-compulsive and related symptoms in children and adolescents with rheumatic fever with and without chorea: a prospective 6-month study. Am J Psychiatry 1998;155:1122–4. 87. Mercadante MT, Busatto GF, Lombroso PJ, et al. The psychiatric symptoms of rheumatic fever. Am J Psychiatry 2000;157:2036–8. 88. Maia DP, Teixeira AL Jr, Quintao Cunningham MC, et al. Obsessive compulsive behavior, hyperactivity, and attention deficit disorder in Sydenham chorea. Neurology 2005;64(10):1799–801. 89. Asbahr FR, Garvey MA, Snider LA, et al. Obsessive-compulsive symptoms among patients with Sydenham chorea. Biol Psychiatry 2005;57:1073–6. 90. Hounie AG, Pauls DL, do Rosario-Campos MC, et al. Obsessive-compulsive spectrum disorders and rheumatic fever: a family study. Biol Psychiatry 2007; 61:266–72. 91. Kummer A, Maia DP, Cardoso F, et al. Trichotillomania in acute Sydenham’s chorea. Aust NZ J Psychiatry 2007;41:1013–4. 92. Teixeira AL Jr, Maia DP, Cardoso F. Psychosis following acute Sydenham’s chorea. Eur Child Adolesc Psychiatry 2007;16(1):67–9. 93. Cardoso F, Dornas L, Cunningham M, et al. Nerve conduction study in Sydenham’s chorea. Mov Disord 2005;20:360–3. 94. Vijayalakshmi IB, Mithravinda J, Deva AN. The role of echocardiography in diagnosing carditis in the setting of acute rheumatic fever. Cardiol Young 2005;15: 583–8. 95. Panamonta M, Chaikitpinyo A, Auvichayapat N, et al. Evolution of valve damage in Sydenham’s chorea during recurrence of rheumatic fever. Int J Cardiol 2007; 119(1):73–9.

Choreas

96. Guidelines for diagnosis of rheumatic fever. Jones criteria, 1992 update. Special Writing Group of the Committee of Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardio-Vascular Disease of the Young of the American Heart Association. Guidelines for the diagnosis of rheumatic fever. JAMA 1992; 268:2069–73. 97. Cardoso F, Vargas AP, Oliveira LD, et al. Persistent Sydenham’s chorea. Mov Disord 1999;14:805–7. 98. Teixeira AL Jr, Maia DP, Cardoso F. UFMG Sydenham’s chorea rating scale (USCRS): reliability and consistency. Mov Disord 2005b;20(5):585–91. 99. Taranta A, Stollerman GH. The relationship of Sydenham’s chorea to infection with group A streptococci. Am J Med 1956;20:170–5. 100. Husby G, Van De Rijn U, Zabriskie JB, et al. Antibodies reacting with cytoplasm of subthalamic and caudate nuclei neurons in chorea and acute rheumatic fever. J Exp Med 1976;144:1094–110. 101. Cardoso F. Chorea gravidarum. Arch Neurol 2002;59(5):868–70. 102. Bronze MS, Dale JB. Epitopes of streptococcal M proteins that evoke antibodies that cross-react with human brain. J Immunol 1993;151:2820–8. 103. Church AJ, Cardoso F, Dale RC, et al. Anti-basal ganglia antibodies in acute and persistent Sydenham’s chorea. Neurology 2002;59:227–31. 104. Kirvan CA, Cox CJ, Swedo SE, et al. Tubulin is a neuronal target of autoantibodies in Sydenham’s chorea. J Immunol 2007;178(11):7412–21. 105. Kirvan CA, Swedo SE, Heuser JS, et al. Mimicry and autoantibody-mediated neuronal cell signaling in Sydenham chorea. Nat Med 2003;9(7):914–20. 106. Teixeira AL Jr, Guimaraes MM, Romano-Silva MA, et al. Serum from Sydenham’s chorea patients modifies intracellular calcium levels in PC12 cells by a complement-independent mechanism. Mov Disord 2005a;20(7):843–5. 107. Ayoub EM, Barrett DJ, Maclaren NK, et al. Association of class II human histocompatibility leukocyte antigens with rheumatic fever. J Clin Invest 1986;77: 2019–26. 108. Donadi EA, Smith AG, Louzada-Junior P, et al. HLA class I and class II profiles of patients presenting with Sydenham’s chorea. J Neurol 2000;247:122–8. 109. Haydardedeoglu FE, Tutkak H, Kose K, et al. Genetic susceptibility to rheumatic heart disease and streptococcal pharyngitis: association with HLA-DR alleles. Tissue Antigens 2006;68:293–6. 110. Feldman BM, Zabriskie JB, Silverman ED, et al. Diagnostic use of B-cell alloantigen D8/17 in rheumatic chorea. J Pediatr 1993;123:84–6. 111. Eisen JL, Leonard HL, Swedo SE, et al. The use of antibody D8/17 to identify B cells in adults with obsessive-compulsive disorder. Psychiatry Res 2001;104: 221–5. 112. Harel L, Zeharia A, Kodman Y, et al. Presence of the d8/17 B-cell marker in children with rheumatic fever in Israel. Clin Genet 2002;61:293–8. 113. Ramasawmy R, Fae KC, Spina G, et al. Association of polymorphisms within the promoter region of the tumor necrosis factor-alpha with clinical outcomes of rheumatic fever. Mol Immunol 2007;44:1873–8. 114. Church AJ, Dale RC, Cardoso F, et al. CSF and serum immune parameters in Sydenham’s chorea: evidence of an autoimmune syndrome? J Neuroimmunol 2003;136(1–2):149–53. 115. Teixeira AL Jr, Cardoso F, Souza AL, et al. Increased serum concentrations of monokine induced by interferon-gamma/CXCL9 and interferon-gamma-inducible protein 10/CXCL-10 in Sydenham’s chorea patients. J Neuroimmunol 2004;150(1–2):157–62.

735

736

Cardoso

116. Dale RC, Church AJ, Cardoso F, et al. Poststreptococcal acute disseminated encephalomyelitis with basal ganglia involvement and auto-reactive antibasal ganglia antibodies. Ann Neurol 2001;50:588–95. 117. Morshed SA, Parveen S, Leckman JF, et al. Antibodies against neural, nuclear, cytoskeletal, and streptococcal epitopes in children and adults with Tourette’s syndrome, Sydenham’s chorea, and autoimmune disorders. Biol Psychiatry 2001;50:566–77. 118. Cardoso F. Sydenham’s chorea. Curr Treat Options Neurol 2008;10:230–5. 119. Tumas V, Caldas CT, Santos AC, et al. Sydenham’s chorea: clinical observations from a Brazilian movement disorder clinic. Parkinsonism Relat Disord 2007; 13(5):276–83. 120. Korn-Lubetzki I, Brand A, Steiner I. Recurrence of Sydenham chorea: implications for pathogenesis. Arch Neurol 2004;61:1261–4. 121. Teixeira AL, Cardoso F, Maia DP, et al. Sydenham’s chorea may be a risk factor for drug induced parkinsonism. J Neurol Neurosurg Psychiatry 2003;74(9): 1350–1. 122. Cardoso F, Maia D, Cunningham MC, et al. Treatment of Sydenham chorea with corticosteroids. Mov Disord 2003;18:1374–7. 123. Barash J, Margalith D, Matitiau A. Corticosteroid treatment in patients with Sydenham’s chorea. Pediatr Neurol 2005;32:205–7. 124. Paz JA, Silva CA, Marques-Dias MJ. Randomized double-blind study with prednisone in Sydenham’s chorea. Pediatr Neurol 2006;34:264–9. 125. Garvey MA, Snider LA, Leitman SF, et al. Treatment of Sydenham’s chorea with intravenous immunoglobulin, plasma exchange, or prednisone. J Child Neurol 2005;20:424–9. 126. Quinn N, Schrag A. Huntington’s disease and other choreas. J Neurol 1998;245: 709–16. 127. Asherson RA, Cervera R. The antiphospholipid syndrome: multiple faces beyond the classical presentation. Autoimmun Rev 2003;2(3):140–51. 128. Avcin T, Benseler SM, Tyrrell PN, et al. A followup study of antiphospholipid antibodies and associated neuropsychiatric manifestations in 137 children with systemic lupus erythematosus. Arthritis Rheum 2008;59(2):206–13. 129. Honnorat J, Cartalat-Carel S, Ricard D, et al. Onco-neural antibodies and tumor type determine survival and neurological symptoms in paraneoplastic neurological syndromes with Hu or CV2/CRMP5 antibodies. J Neurol Neurosurg Psychiatry 2009;80(4):412–6. 130. Lazurova I, Macejova Z, Benhatchi K, et al. Efficacy of intravenous immunoglobulin treatment in lupus erythematosus chorea. Clin Rheumatol 2007;26(12):2145–7. 131. Levine SR, Brey RL. Neurological aspects of antiphospholipid antibody syndrome. Lupus 1996;5:347–53. 132. Ghika-Schmid F, Ghika J, Regli F, et al. Hyperkinetic movement disorders during and after acute stroke: the Lausanne Stroke Registry. J Neurol Sci 1997;146:109–16. 133. Cardoso F, Jankovic J, Grossman RG, et al. Outcome after stereotactic thalamotomy for dystonia and hemiballismus. Neurosurgery 1995;36:501–7. 134. Choi SJ, Lee SW, Kim MC, et al. Posteroventral pallidotomy in medically intractable postapoplectic monochorea: case report. Surg Neurol 2003;59:486–90. 135. Gonzalez-Alegre P, Ammache Z, Davis PH, et al. Moyamoya-induced paroxysmal dyskinesia. Mov Disord 2003;18:1051–6. 136. Medlock MD, Cruse RS, Winek SJ, et al. A 10-year experience with postpump chorea. Ann Neurol 1993;34:820–6.