A system implementation study: management commitment to project management

A system implementation study: management commitment to project management

Review Article Address correspondence to Dr Tiago A. Mestre, Parkinson’s Disease and Movement Disorders Centre, Civic Campus, The Ottawa Hospital, 105...

765KB Sizes 11 Downloads 62 Views

Review Article Address correspondence to Dr Tiago A. Mestre, Parkinson’s Disease and Movement Disorders Centre, Civic Campus, The Ottawa Hospital, 1053 Carling Ave, Rm 2174, Ottawa, ON K1Y 4E9, Canada, [email protected] Relationship Disclosure: Dr Mestre receives personal compensation for serving on the scientific advisory board of AbbVie, for speaking engagements for Teva Pharmaceutical Industries Ltd, and for educational events for WebMD. Dr Mestre receives grant support from the Parkinson Study Group/Parkinson Disease Foundation. Unlabeled Use of Products/Investigational Use Disclosure: Dr Mestre reports no disclosure. * 2016 American Academy of Neurology.

Chorea Tiago A. Mestre, MSc, MD ABSTRACT Purpose of Review: This article reviews the clinical approach to the diagnosis of adult patients presenting with chorea, using Huntington disease (HD) as a point of reference, and presents the clinical elements that help in the diagnostic workup. Principles of management for chorea and some of the associated features of other choreic syndromes are also described. Recent Findings: Mutations in the C9orf72 gene, previously identified in families with a history of frontotemporal dementia, amyotrophic lateral sclerosis, or both, have been recognized as one of the most prevalent causes of HD phenocopies in the white population. Summary: The diagnosis of chorea in adult patients is challenging. A varied number of associated causes require a physician to prioritize the investigations, and a detailed history of chorea and associated findings will help. For chorea presenting as part of a neurodegenerative syndrome, the consideration of a mutation in the C9orf72 gene is a new recommendation after excluding HD. There are no new treatment options for chorea, aside from dopamine blockers and tetrabenazine. There are no disease-modifying treatments for HD or other neurodegenerative choreic syndromes. Continuum (Minneap Minn) 2016;22(4):1186–1207.

Supplemental digital content: Videos accompanying this article are cited in the text as Supplemental Digital Content. Videos may be accessed by clicking on links provided in the HTML, PDF, and app versions of this article; the URLs are provided in the print version. Video legends begin on page 1204.


INTRODUCTION Huntington disease (HD) is the most frequent cause of a hereditary neurodegenerative choreic syndrome. HD has a worldwide distribution with some geographic variability in its prevalence. In North America and Europe, the average prevalence is 5 per 100,000 inhabitants.1 In patients with HD, the initial symptoms occur more frequently between the ages of 30 and 50, although onset can range from childhood/adolescence (juvenile form, also known as the Westphal variant) to individuals older than 70 years of age. HD can present to the clinician with one of three symptom complexes classically described in this condition (motor, cognitive, and neuropsychiatric) or in combination. The motor symptoms include chorea, dystonia, and tics. Chorea has been classically used as the reference manifestation for a clin-

ical diagnosis. Parkinsonism usually develops later in the course of the disease. The juvenile form of HD presents as a predominantly hypokinetic movement disorder with parkinsonism but also myoclonus. Of importance, as many as 7% of subjects with a clinical presentation compatible with HD are found to have a negative genetic test for HD and have been coined ‘‘HD 2 phenocopies.’’ Spinocerebellar ataxia (SCA) type 17 (SCA17), also referred to as Huntington diseaseYlike (HDL) syndrome type 4 (HDL4), and C9orf72related HD phenocopy in populations of white individuals are considered the 3,4 most frequent alternative diagnoses. The motor and nonmotor elements that help in the diagnostic workup of HD phenocopies in the adult will be discussed later in this article, and a core description of neurodegenerative choreic syndromes is provided in Table 8-1.


Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

August 2016

TABLE 8-1 Clues for Diagnosis and Investigations of Adult-Onset Neurodegenerative Diseases With Chorea Neurodegenerative Conditions

Relevant Demographics

Core Features

Useful Investigations

Most common neurodegenerative choreic syndromes Huntington disease (HD)

Estimated prevalence is 5/100,000 (with geographic variation); modal age group for onset is 30Y50 years of age

Chorea (onset); depression, apathy, irritability, cognitive impairment, parkinsonism, and dystonia (later stages)

Caudate atrophy (MRI), genetic test (HTT gene, CAG repeat expansion 935)

Huntington diseaseYlike (HDL) syndrome type 4 (HDL4)/ Spinocerebellar ataxia (SCA) type 17 (SCA17)

Common cause for HD-negative neurodegenerative chorea (white populations)

Ataxia in an HD phenocopy

Caudate and cerebellar atrophy, putaminal rim enhancement (MRI), genetic test (TBP gene, CAA/CAG repeat expansion 942)

C9orf72-related HD phenocopy

Common cause for HD-negative neurodegenerative chorea (white populations)

HD phenocopy, ataxia, parkinsonism, and upper motor neuron signs, phenotypic heterogeneity in families

Genetic test (C9orf72 gene, GGGGCC/G4C2 hexanucleotide repeat expansion 960 are definitely pathogenic)


Exclusive to sub-Saharan African descendants

HD phenocopy

Caudate atrophy (MRI), acanthocytosis (fresh blood film) in about 10% of patients, genetic test (JPH3 gene, CTG repeat expansion 940, fully penetrant)

Rare neurodegenerative syndromes, chorea as a classic prominent feature Chorea-acanthocytosis (Levine-Critchley syndrome)

Estimated prevalence of 1000 cases worldwide; young adult onset

Chorea, dystonia (orofacial involvement, tongue protrusion), tics, self-mutilation, seizures, sensorimotor axonal polyneuropathy, hepatomegaly, splenomegaly

Acanthocytosis (fresh blood film), elevated creatine kinase, chorein absent in red blood cells, predominant atrophy of the head of caudate (MRI), genetic test (VPS13A gene)

McLeod syndrome

Rarer than chorea-acanthocytosis; exclusive to males and with a later onset (after fourth decade)

Chorea, dystonia, parkinsonism, psychiatric features, seizures, sensorimotor axonal neuropathy, cardiomyopathy, hepatosplenomegaly, hemolytic anemia

Acanthocytosis (fresh blood film), antigen Kell absent/ reduced in red blood cells, elevated creatine kinase and liver function test, genetic test (XK gene)

Continued on page 1188

Continuum (Minneap Minn) 2016;22(4):1186–1207


Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.



TABLE 8-1 Clues for Diagnosis and Investigations of Adult-Onset Neurodegenerative Diseases With Chorea Continued from page 1187 Neurodegenerative Conditions

Relevant Demographics

Core Features

Useful Investigations


Very rare (four families reported5)

Chorea, ataxia, prominent psychiatric features, myoclonus, seizures

Atrophy of basal ganglia, cerebellum, frontal and temporal lobes (MRI), genetic test (PRNP gene, eight octapeptide repeat insertions)

Dentatorubralpallidoluysian atrophy

Most common in Japan (1/208,000), rare in non-Japanese populations

Ataxia, chorea, myoclonus, dementia, seizures

Atrophy of cerebellum, brainstem, cerebrum; hyperintensity in periventricular white matter (MRI), genetic test (ATN1 gene, CAG repeat expansion 947, fully penetrant)


Reported in Cumbria, United Kingdom, and France; estimated prevalence of G1/1 million (very rare)

Chorea/dystonia with orofacial involvement, nontremulous parkinsonism (less frequent), maintained asymmetrical features, ataxia (rarer), late neuropsychiatric and cognitive symptoms (later feature)

Hypointensity in dentate nuclei, red nuclei, basal ganglia, thalami, rolandic cortex (T2*), bilateral pallidal necrosis with cystic degeneration (MRI), low serum ferritin, genetic test (FTL gene)


Estimated prevalence of 1/1 million to 1/1.2 million (very rare); onset at middle age

Dystonia (craniocervical), parkinsonism, chorea and ataxia, depression, cognitive dysfunction, anemia, diabetes mellitus, retinal degeneration preceding neurologic manifestations

Low serum ceruloplasmin and high ferritin, hypointensity in the striatum, thalamus, and dentate nucleus (T2* MRI), genetic test (CP gene)

Neurodegenerative syndromes, chorea as a rare manifestation SCA1

Rare chorea-athetosis, ataxia, dystonia, dementia, early hyperreflexia, late neuropathy

Cerebellar atrophy (MRI), genetic test (ATXN1 gene, triplet repeat expansion 939, fully penetrant)


Rare chorea-athetosis, ataxia, hyperreflexia, earlier slow saccades, levodopa-responsive, parkinsonism, dystonia, dementia, early neuropathy

Cerebellar atrophy (MRI), genetic test (ATXN2 gene, CAG/CAA repeat expansion 932, fully penetrant)

Continued on page 1189



Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

August 2016

TABLE 8-1 Clues for Diagnosis and Investigations of Adult-Onset Neurodegenerative Diseases With Chorea Continued from page 1188 Neurodegenerative Conditions

Relevant Demographics

Core Features

Useful Investigations


Rare chorea-athetosis, ataxia, levodopa-responsive, parkinsonism, dystonia, hyperreflexia/spasticity, late neuropathy

Cerebellar atrophy (MRI), genetic test (ATXN3 gene, triplet repeat expansion 951, fully penetrant)

Wilson disease

Chorea is relatively rare, predominantly parkinsonism and dystonia (with risus sardonicus), ataxia, psychiatric symptoms, seizures can occur (G10%), KayserYFleischer rings, arthropathy, hemolytic anemia

Kayser-Fleischer rings (slit-lamp examination), eye-of-the-panda sign, variable white matter lesions in brainstem, cerebellum (MRI), low serum ceruloplasmin, high urine copper (24-hour urine), high liver copper content on biopsy, genetic test (CP gene)

Pantothenate kinaseYassociated neurodegeneration

Single case with chorea reported, onset at age 766

Head and upper limb chorea with later generalization, imbalance

Bilateral hypointensity in the putamen, caudate, substantia nigra, and dentate nuclei, eye-of-the-tiger signa (MRI), acanthocytosis (fresh blood film) in about 10% of patients,a genetic test (PANK2 gene)a

Friedreich ataxia

Single case with chorea reported3

Ataxia, chorea, cognitive impairment (at presentation), dysphagia and dysarthria (later stages)

Genetic test (FXN gene, GAA repeat expansion 965, fully penetrant)

Pallidonigroluysian atrophy

Very rare7

Chorea (20% of cases), gait or balance disturbance

Postmortem diagnosis

Lubag disease (TAF1)

Filipino origin

Dystonia-parkinsonism, chorea is a very rare feature (also reported in female carriers)

Genetic test (TAF1 gene)

MRI = magnetic resonance imaging. a Diagnostic features of pantothenate kinaseYassociated neurodegeneration, but not documented in the case report.

Acquired causes of chorea are important to take into consideration since a few can be treated. Certain elements in the clinical presentation of acquired causes of chorea help in the differential diagnosis. Chorea secondary to stroke and drug-induced chorea are among the most prevalent causes of sporadic Continuum (Minneap Minn) 2016;22(4):1186–1207

chorea that a clinician should consider in the appropriate setting.8 Other sporadic forms of chorea are broadly divided into immune-mediated, infectious, metabolic/endocrine, vascular, and others causes (Table 8-2). This article covers the approach to adult-onset chorea. As such, conditions with a classic www.ContinuumJournal.com

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.



TABLE 8-2 Nongenetic Causes of Chorea b Drugs Antiemetics (dopamine antagonists) Antiepileptic drugs (eg, phenytoin, carbamazepine, valproic acid) Antihistamines Baclofen Calcium channel blockers Digoxin Fluoroquinolones Levodopa, dopamine agonists (levodopa-induced dyskinesia) Lithium Methotrexate, cyclosporine Neuroleptics (tardive dyskinesia) Oral contraceptives, estrogen replacement therapy (often with a history of previous Sydenham chorea) Psychostimulants (eg, cocaine, amphetamines) Steroids Theophylline Tricyclic antidepressants b Immune Mediated Antibody associated (paraneoplastic or idiopathic)9 Associated with neoplasia: collapsin response mediator protein-5 (CRMP5) (small cell lung carcinoma and thymoma), Hu (small cell lung carcinoma), Yo, antineuronal nuclear antibody (ANNA) type 1 and type 2, N-methyl-Daspartate (NMDA) subunit NR1 (ovarian tumor) Idiopathic: NMDA subunit NR1 (45% of cases), leucine-rich, glioma inactivated 1 (LgI1), contactin-associated proteinlike 2 (CASPR2), glutamic acid decarboxylase 65 (GAD65), IgLON family member 5 (IgLON5), pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) Behçet disease Celiac disease Demyelinating disease (rare, hemiballismus reported)10 Sjo¨gren syndrome Systemic lupus erythematosus/antiphospholipid syndrome

Continued on page 1191



Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

August 2016

TABLE 8-2 Nongenetic Causes of Chorea Continued from page 1190 b Infectious Encephalitis (West Nile virus, mumps, measles, varicella zoster) Human immunodeficiency virus (HIV) (eg, secondary focal lesion due to toxoplasmosis, primary central nervous system lymphoma, HIV encephalitis) Tuberculosis, cysticercosis, borreliosis, neurosyphilis, diphtheria Variant Creutzfeldt-Jakob disease b Metabolic/Endocrine Acquired hepatolenticular degeneration (advanced liver disease) Electrolyte imbalance (hypoglycemia/hypercalcemia, hypomagnesemia, hyponatremia) Hyperthyroidism Hypoglycemia/hyperglycemia (nonketotic) Vitamin B12 deficiency (more frequently found as a cause of chorea in children) b Vascular Essential thrombocythemia (one case reported)11 Ischemic/hemorrhagic stroke Polycythemia rubra vera (elderly, primarily females) Posterior reversible encephalopathy syndrome Postpump chorea (more frequent in children) b Other Causes Carbon monoxide intoxication Hydrocephalus Postanoxic/cerebral palsy Psychogenic chorea

onset in the pediatric age group will not be discussed in detail, and brief references will be given when pertinent. Examples of these conditions include acquired postinfectious Sydenham chorea, benign hereditary chorea, pantothenate kinaseYassociated neurodegeneration, Lesch-Nyhan syndrome, and autosomal recessive ataxias in which chorea has also been described, such as apraxia with oculomotor apraxia type 1 and 2 and ataxia telangiectasia. Continuum (Minneap Minn) 2016;22(4):1186–1207

CLINICAL APPROACH TO AN ADULT PATIENT WITH CHOREA Physicians treating adult patients presenting with chorea should carry out a detailed and focused history and examination that consider the multiple causes of chorea and its presentations. The data collected by the physician give important clues toward the most likely cause of the presenting chorea and the selection of the more pertinent investigations. www.ContinuumJournal.com

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.



h Chorea may present as an isolated symptom or as a syndrome with a variable combination of a mixed movement disorder, behavioral and cognitive symptoms, seizures, or polyneuropathy.

h Most of the cases of senile chorea correspond to cases of late-onset Huntington disease.

Chorea as Symptom Chorea can present as an isolated symptom or a mixed movement disorder and can be associated with behavioral and cognitive symptoms, seizures, or symptoms suggestive of polyneuropathy. The different symptom complexes identified with a clinical interview can give the first clues for a diagnosis and prioritization of investigations. Chorea is frequently noticed first by a third person and not by the patient; consequently, the information provided by a caregiver or family member is particularly important for a more rigorous history of chorea. As with other neurologic symptoms, the age of onset (adult versus elderly), the acute versus progressive mode of onset, and the type of disease course (remitting, paroxysmal, or continuous) can favor a specific syndrome. In terms of age of onset, there is the particular case of senile chorea defined as an idiopathic sporadic form of chorea with onset in the elderly in the absence of dementia

(Supplemental Digital Content 8-1, links.lww.com/CONT/A188).12 The advent of a genetic diagnosis for HD has shown that most of these cases are, in fact, late-onset HD (Case 8-1).13 In terms of mode of onset, a relatively acute onset of chorea can be the manifestation of stroke, and also other causes such as nonketotic hyperglycemia, chorea gravidarum, or drug-induced chorea (Table 8-2). A subacute course over a few days or weeks may be the manifestation of infectious process or autoimmune chorea, including a paraneoplastic syndrome, but does not exclude a metabolic cause.14 In some cases of drug-induced chorea, a gradual onset may occur, such as in levodopainduced dyskinesia in Parkinson disease (Supplemental Digital Content 8-2, links.lww.com/CONT/A189) or neuroleptic-induced dyskinesia.15 A more protracted course of months to years is usually associated with a neurodegenerative condition. In terms of the time course of chorea, a slowly

Case 8-1 An 88-year-old woman presented with a 6- to 8-year history of progressive involuntary movements and imbalance, for which she had to use a walker. The involuntary movements were described as ‘‘shaking’’ and were increasingly embarrassing to the patient. She had also noticed swallowing air when eating. The patient did not endorse cognitive or mood symptoms, and she lived independently at a retirement home. The patient did not have a family history of chorea. Her examination was remarkable for pronounced generalized chorea involving the limbs, trunk, and face, as well as an inability to walk unaided. A diagnosis of senile chorea was made. The investigations at that time included a head CT, renal and liver function tests, serum glucose, thyroid-stimulating hormone (TSH), as well as anticardiolipin, antiphospholipid, and antinuclear antibodies. All investigations were normal. Genetic testing for Huntington disease (HD) showed a CAG repeat of 39, confirmatory of a diagnosis of late-onset HD. Two years later, the patient died at age 90 with complications from dysphagia and dehydration. Comment. This case is demonstrative of how to approach a case of senile chorea and how late in life a diagnosis of HD can be made. In a case of senile chorea, a diagnosis of HD has implications for a patient’s children, who are at risk of developing HD and may consider predictive genetic testing.



Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

August 2016

remitting hemichorea is often a case of vascular chorea secondary to a stroke or nonketotic hyperglycemia. The particular case of paroxysmal recurrent chorea suggests a completely different set of diagnoses with consideration of paroxysmal dyskinesias when multiple and short-lived episodes of chorea are reported. Three forms are classically described: paroxysmal kinesigenic dyskinesia, paroxysmal nonkinesigenic dyskinesia, and paroxysmal exertion-induced (or exercise-induced) dyskinesia. Although chorea can present in isolation, the paroxysmal dyskinesias manifest most commonly with both dystonia and chorea in about 60% to 65% of genetically proven cases of paroxysmal kinesigenic dyskinesia (Supplemental Digital Content 8-3, links.lww.com/ CONT/A190) and paroxysmal nonkinesigenic dyskinesia and in about 95% of genetically proven cases of paroxysmal exertion-induced dyskinesia.16 These conditions have been distinguished on a clinical basis, mainly with respect to the trigger of the episodes, and have been further characterized by the age of onset, duration and frequency of episodes, and response to treatment. In recent years, there has been a significant breakthrough in finding the genetic basis of these conditions (for more information, refer to the following section on investigations and Table 8-3). Psychogenic chorea is rarely reported as a cause of psychogenic movement disorders and typically presents in the form of a paroxysmal movement disorder.17 Recurrent chorea can also occur in patients with a history of chorea gravidarum or Sydenham chorea who develop chorea when exposed to drugs such as oral contraceptives or phenytoin, although these cases can assume a distinctive pattern of longerlasting episodes separated, at times, by Continuum (Minneap Minn) 2016;22(4):1186–1207

years.18 The presence of chorea in specific body regions also provides important clues for the differential diagnosis. In forms of neurodegenerative chorea, orofacial chorea frequently associated with dystonia is suggestive of a classic neuroacanthocytosis syndrome (ie, chorea-acanthocytosis (Case 8-2 and Supplemental Digital Content 8-4, links.lww.com/CONT/A191) and, less commonly, McLeod syndrome).19 Orofacial chorea can also be an early feature of the rare neuroferritinopathy, a late-onset form of neurodegeneration with brain iron accumulation.20 The dystonic protrusion of the tongue with an associated difficulty maintaining ingested food in the mouth (feeding dystonia) has been classically described in choreaacanthocytosis, but can also be found in other conditions considered in the differential diagnosis of chorea, such as McLeod syndrome, tardive dyskinesia, pantothenate kinaseYassociated neurodegeneration, and Lesch-Nyhan syndrome.21 In addition, the presence of head drops and truncal/cervical extension is recognized as a distinctive feature of advanced choreaacanthocytosis, but is also described in McLeod syndrome and advanced HD.22Y24 The presence of tics can be found in HD, but also in the classic neuroacanthocytosis syndromes, particularly in chorea-acanthocytosis. The presence of significant behavioral symptoms in addition to cognitive deterioration strongly suggests a neurodegenerative choreic syndrome, namely HD. In an HD population, apathy is considered the most prevalent behavioral symptom (28.1%), followed by depression, irritability/aggressiveness, and obsessive/compulsive behaviors.25 Psychosis is less prevalent and can affect as little as 1.2% of the HD population.25 Behavioral symptoms can precede the onset of motor symptoms and, at the


h Chorea secondary to stroke has an acute onset and will, most often, improve over time.

h Recurrent episodes of chorea, frequently in association with dystonia, suggest a form of paroxysmal dyskinesia.

h Orofacial chorea is suggestive of a classic neuroacanthocytosis syndrome.


Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.



a TABLE 8-3 Clinical Features of Paroxysmal Dyskinesia

Paroxysmal Kinesigenic Dyskinesia

Paroxysmal Nonkinesigenic Dyskinesia

Paroxysmal Exertion-Induced Dyskinesia

Childhood/adolescence (majority of cases)

Childhood/adolescence (majority of cases)

Variable (depending on cause)


Sudden movements or intention to move

Coffee, tea, alcohol (more consistent), anxiety, excitement, fatigue

Prolonged exertion (more frequently), fasting, stress, anxiety


Brief, majority of episodes G1 minute

Typically more prolonged, 10 minutes to 4 hours

Episode ends with rest


Up to hundreds of episodes a dayb

Weekly episodes more commonb

Dependent on triggers


Good response to antiepileptics; carbamazepine is drug of choice

Avoid triggering factors; poor response to benzodiazepines, phenytoin, acetazolamide, levodopa

Avoid triggering factors, treat underlying cause when applicable

Gene associated with primary formc

Proline-rich transmembrane protein 2 (PRRT2)

Myofibrillogenesis regulator 1 (MR-1)d

Glucose transporter 1 (SLC2A1)e (in 20Y25% of cases)

Secondary causes

Secondary to brain injury (vascular, trauma, multiple sclerosis)

Secondary to brain injury, symptomatic cases are rare

Parkinson disease, dopa-responsive dystonia

Age of onset Episodes



Data from Erro R, et al, Mov Disord.16 onlinelibrary.wiley.com/doi/10.1002/mds.25933/abstract. Frequency has a tendency to decrease with age. c Genotype-phenotype correlation is incomplete, and overlap of forms of paroxysmal dyskinesia may exist. d Potassium calcium-activated channel, subfamily M alpha member 1 (KCNMA1) has been described in one family with cases of paroxysmal nonkinesigenic dyskinesia and epilepsy. e Mutations in the gene SLC2A1 can also cause benign familial infantile seizures, familial infantile convulsions with paroxysmal choreoathetosis, and hemiplegic migraine. b

Case 8-2 A 28-year-old man presented with a 1-year history of difficulty chewing and abnormal gait. In order to eat, the patient swallowed food in big chunks without chewing it. There was no history of seizures, and he was otherwise healthy. There was a known family history of chorea-acanthocytosis in his brother and two paternal cousins. Examination was remarkable for a left gum ulcer, dystonic protrusion of the tongue when ingesting food or speaking, as well as jaw-opening dystonia and recurrent sniffing. He had mild generalized chorea and slight weakness in his hands and feet. Ankle reflexes were absent. Gait was abnormal with hesitations, namely with turns. The investigations identified elevated creatine kinase (422 units/L) and acanthocytes (more than 10%) in the blood. He was started on

Continued on page 1195



Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

August 2016


Continued from page 1194 trihexyphenidyl for jaw-opening dystonia with benefit. The patient did not return for follow-up. Comment. This case shows features suggestive of chorea-acanthocytosis, including the presence of oromandibular dyskinesia with feeding dystonia, tics, as well as signs of peripheral neuropathy. The documented family history of chorea-acanthocytosis and the laboratory findings of elevated creatine kinase and presence of more than 10% of acanthocytes in the blood facilitated the diagnosis.

time of a diagnosis based on motor features, deficits in cognitive function can be elicited in formal testing.26 Suicidal ideation is relatively frequent (8% to 10%) and should be actively looked for, especially in patients with active depression and a previous suicidal attempt.27 HD phenocopies in which behavioral or cognitive symptoms are part of the clinical presentation include HDL2, chorea-acanthocytosis, and dentatorubral-pallidoluysian atrophy (DRPLA).28Y30 In McLeod syndrome, behavioral problems are more common and cognitive difficulties are milder.29 Self-mutilation of the lip and tongue is a clinical manifestation of chorea-acanthocytosis, but is uncommon in McLeod syndrome.31 LeschNyhan syndrome is an X-linked genetic condition in which patients can have self-mutilating behaviors but the onset occurs in childhood. Chorea gravidarum, antiphospholipid syndrome, or systemic lupus erythematosus are among nondegenerative causes of chorea that can present with concomitant behavioral symptoms, including personality changes, depression, psychotic symptoms, and cognitive impairment.18 The occurrence of seizures is a differentiating feature of some HD phenocopies, occurring in about 50% of the cases in chorea-acanthocytosis (30% as presenting feature) and McLeod syndrome, as well as in DRPLA and HDL1, an exceedingly rare entity Continuum (Minneap Minn) 2016;22(4):1186–1207

h In chorea-acanthocytosis, seizures can occur in about 50% of cases.

h Huntington diseaseYlike syndrome type 2 is most prevalent in patients with a sub-Saharan African ancestry.

in which the majority of the cases have seizures.5,19,30,32 In DRPLA, it is useful to recognize that when the age of onset overlaps the mean age of onset of the adult form of HD, seizures rarely occur, and more common presenting features are chorea, in addition to dystonia, parkinsonism, and psychosis. When the clinician is considering a genetic choreic syndrome, it is helpful to recognize that certain causes have a higher incidence, in particular, geographic areas or ethnic origins and, thus, should be prioritized whenever applicable. For example, HDL2 has been reported almost exclusively in subjects with a sub-Saharan African ancestry, namely African Americans and black South Africans, and in the rare cases of a presumed non-African origin, an African ancestor could not be ruled out.33 Neuroferritinopathy has been mostly described in families from the United Kingdom (Cumbria region), with a few cases reported in France and one single case in North America.34 DRPLA is most frequent in Japan, although it is not exclusive to that country, with rare cases reported in European and North American populations of non-Japanese ancestry.35 The Haw River syndrome corresponds to a family of African Americans originally from North Carolina, and has been reported as a form of DRPLA.36 Past Medical History The presence of acute hemichorea or hemiballismus in a patient with www.ContinuumJournal.com

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.



h In the Western world, chorea gravidarum has become a rare cause of chorea.

h In C9orf72-related Huntington disease, phenocopies present with significant phenotypic heterogeneity and have, in most of the cases, a positive family history.

significant vascular risk factors suggests stroke as a cause, while in a patient with diabetes mellitus, a primary diagnosis of nonketotic hyperglycemia has to be considered in addition. Recurrent miscarriages, migraine, and thrombotic events are a clue for the presence of an antiphospholipid syndrome or systemic lupus erythematosus. Hemodialysis, alcoholism, and malnutrition can point to extrapontine myelinolysis, and the presence of human immunodeficiency virus (HIV) risk factors provide clues to the clinician for HIV-associated causes of chorea (eg, opportunistic infections including toxoplasmosis, progressive multifocal leukoencephalopathy, and HIV encephalitis). The occurrence of chorea in a pregnant woman should raise the possibility of chorea gravidarum. In the Western world, chorea gravidarum is increasingly rare; currently, its most common causes are antiphospholipid syndrome and systemic lupus erythematosus.18 In the past, rheumatic fever was the most prevalent cause for chorea gravidarum, but it decreased sharply with the widespread use of penicillin.18 Family History A clear pattern of inheritance will help the clinician prioritize genetic causes of chorea in the differential diagnosis. However, it is important to recognize that the absence of a family history does not exclude a genetic disorder for many possible reasons, including nonpaternity, de novo mutations (including unstable trinucleotide repeats), premature death of asymptomatic carriers, as well as partial penetrance and phenotypic variability. In fact, genetic causes for chorea are frequently found in sporadic cases (Case 8-1). In the presence of a family history, an autosomal dominant inheritance pattern is compatible with HD,


SCA17, C9orf72-related HD phenocopy, HDL2, as well as DRPLA, neuroferritinopathy, SCA1, SCA2, SCA3, SCA7, and HDL1.37 In SCA17, most of the cases reported are sporadic or isolated subjects in a family with an ataxic syndrome. Although a family with a SCA17 mutation and multiple members presenting an HD-like phenotype show that phenotypic homogeneity may exist, this is exceedingly rare.38 For C9orf72-related HD phenocopies, available data suggest a higher prevalence of a positive family history, although with phenotypic heterogeneity within the known spectrum of C9orf72-related clinical presentations.4 The prevalence of C9orf72-related HD phenocopies should be further assessed as in the initial case series, only three of the 10 cases reported had chorea in their presentation.4 An autosomal recessive inheritance pattern is compatible with choreaacanthocytosis and aceruloplasminemia. HDL3 also has an autosomal recessive inheritance pattern but has only been described in a Saudi Arabian family. The onset of symptoms is in early childhood, and its presentation resembles the HD Westphal variant.39 An X-linked recessive inheritance pattern is compatible with McLeod syndrome, although rare female cases have been reported.40 EXAMINATION The observation of chorea, other movement disorders, and additional neurologic or systemic signs provides clues for the differential diagnosis. Phenomenology of Chorea and Related Movement Disorders Chorea is one of the hyperkinetic movement disorders. Chorea (derived from the Greek word horos, meaning dance) is characterized by involuntary, brief, irregular, random movements


Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

August 2016

(Supplemental Digital Content 8-5, links.lww.com/CONT/A192; Supplemental Digital Content 8-6, links. lww.com/CONT/A193). Ballismus (derived from the Greek word ballismos, meaning jumping about) is considered a form of chorea characterized by highamplitude movement of a limb in a flinging or flailing motion, including the most proximal segments (Supplemental Digital Content 8-7, links.lww. com/CONT/A194). Athetosis (derived from the Greek word athetos, meaning not fixed) is classically a slow, random, involuntary, writhing movement of the distal region of the limbs and is now recognized to be a manifestation of underlying dystonia, namely in cases of cerebral palsy, and will not be addressed in this article (Supplemental Digital Content 8-8, links.lww. com/CONT/A195). Chorea Distribution Particular locations of chorea are suggestive of specific etiologies; aside from the diagnostic value of prominent orolingual and truncal/cervical chorea-dystonia previously described, the presence of hemichorea or hemiballismus suggests a focal structural brain lesion secondary to a vascular event, nonketotic hyperglycemia, and, more rarely, an opportunistic infection in HIV. Nevertheless, instances occur in which hemichorea is a presenting feature of other conditions without a documentable focal brain lesion, examples of which are autoimmune chorea including Sydenham chorea and paraneoplastic syndromes as well as variant Creutzfeldt-Jakob disease.9,15,41 Conversely, conditions such as nonketotic hyperglycemia can present as generalized chorea42 (Case 8-3). Other Movement Disorders The presence of other movement disorders can help with the diagnosis of a Continuum (Minneap Minn) 2016;22(4):1186–1207

particular chorea syndrome. Dystonic features can be present in HD and in the most prevalent HD phenocopies such as HDL2, SCA17, but also in chorea-acanthocytosis, DRPLA, and neuroferritinopathy (orofacial dystonia), among others. Parkinsonism is a late feature of adult-onset HD at a stage in which chorea is less intense. Nontremulous parkinsonism has been described in neuroferritinopathy, but it is a less common presenting feature (7.5%) compared with chorea (50%) and focal limb dystonia (47.5%).20 More prominent ataxic features, including eye movement abnormalities (saccadic pursuit, dysmetric saccades, gaze-evoked nystagmus), limb incoordination, and wide-based gait with imbalance should make the clinician suspect an SCA, SCA17 being a more frequent cause. DRPLA can also be considered, and, more rarely, Wilson disease can be considered when ataxia is part of a chorea syndrome. In SCA17, although ataxia is most often present, marked phenotypic heterogeneity occurs, and the presence of a pure choreic syndrome does not exclude this diagnosis.38 It is worthwhile mentioning that choreic movements are exceptional in other SCAs, such as the example of SCA1, SCA2, SCA3, and SCA7.37,44 In these cases, ataxia is predominant, and the description of chorea best fits with choreoathetosis. Very rare reports of chorea in other SCAs can be found in the literature: hand choreic movements have been described in SCA14 (PRKCG gene) and in SCA8 (ATXN8/ ATXN8OS gene) gene expansion, although the pathologic role of an expansion in the ATXN8/ATXN8OS gene remains a matter of discussion.45,46 Apart from eye movement abnormalities consistent with an ataxia syndrome, other changes can be documented when examining a patient with chorea. Difficulty


h Hemichorea or hemiballismus suggest the presence of a focal brain lesion.

h The combination of other movement disorders can help with the diagnosis of a particular chorea syndrome.


Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.



Case 8-3 A 73-year-old woman presented to the emergency department with an 8-day history of generalized chorea with an acute onset. There was no relevant past medical history, no family history of chorea, and no known use of neuroleptic drugs. Her examination was remarkable for orofacial dyskinesias and generalized chorea. The investigations for vascular and metabolic cases of chorea were remarkable for severe hyperglycemia on admission (more than 500 mg/L). The brain MRI showed bilateral putaminal hyperintensity in T1-weighted imaging (Figure 8-143). Chorea persisted beyond the normalization of the patient’s hyperglycemia. She died 32 days after admission as a result of unresolved sepsis. Comment. This case shows that nonketotic hyperglycemia may be a cause of acute-onset chorea presenting in a generalized form. The MRI findings highlighted in this case are typical of the syndrome of chorea in the setting of nonketotic hyperglycemia. The MRI findings can be unilateral or bilateral consistent with the side(s) of the body presenting with chorea.

Brain MRI of the patient in Case 8-3 with bilateral chorea-related nonketotic hyperglycemia exhibiting putaminal hyperintensity in T1-weighted imaging.


Reprinted with permission from Mestre TA, et al. J Neurol Neurosurg Psychiatry.43 B 2007 BMJ Publishing Group Ltd. jnnp.bmj.com/content/ 78/5/549.extract.

Case modified with permission from Mestre TA, et al, J Neurol Neurosurg Psychiatry.43 B 2007 BMJ Publishing Group Ltd. jnnp.bmj.com/content/78/5/549.extract.

in initiating saccades is classically described in HD. Other associated neurologic signs may suggest a particular diagnosis: In chorea-acanthocytosis (Case 8-2) and McLeod syndrome, areflexia (Achilles reflex absent in 90% of patients) and limb weakness together with muscle wasting are suggestive of an axonal polyneuropathy and, in some cases, a myopathy has also been documented.19,47 Patients with SCA1, SCA2, and SCA3 can also have a polyneuropathy. In paraneoplastic syndromes, more commonly there will be other neurologic signs, including peripheral neuropathy, visual disturbances, ataxia, oculomotor


disturbances, and behavioral changes with a subacute presentation.9,48 Systemic Features in Choreic Syndromes Classic neuroacanthocytosis syndromes are recognized as multisystemic disorders. McLeod syndrome is associated with a cardiomyopathy with atrial fibrillation in 60% of the cases, in addition to hemolytic anemia, hepatomegaly, and splenomegaly. 1 9 In choreaacanthocytosis, hepatomegaly and splenomegaly are also found.32 The presence of a photosensitive malar rash and arthritis is suggestive of systemic lupus erythematosus. Signs of thyroid


Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

August 2016

disease suggest the presence of underlying thyroid dysfunction. Anemia, diabetes mellitus, and retinal degeneration are found in aceruloplasminemia. Stigma of chronic liver failure can suggest acquired hepatocerebral degeneration, in which patients can present with orobuccal chorea resembling tardive dyskinesia, in addition to dystonia, parkinsonism, and ataxia, as well as cognitive and behavioral problems.49 Kayser-Fleischer rings are observed in Wilson disease. INVESTIGATIONS An initial panel of investigations should be used to consider treatable causes of chorea and include routine hematology and blood biochemistry tests, in addition to brain MRI and autoantibody testing to identify antiphospholipid syndrome and systemic lupus erythematosus (Table 8-4). Most of these treatable causes have an acute or subacute onset, which is in striking contrast with a more protracted course of HD and HD phenocopies. As HD is the most prevalent genetic cause of chorea, testing for a pathologic repeat expansion in the HTT gene should be

considered, including cases without a known family history for chorea and without an apparent cause after a first round of investigations. In the presence of a symptom complex that points to a specific, albeit rare, cause of chorea, these neurodegenerative conditions can also be considered in a first round of investigations (Table 8-1). For HD, a trinucleotide cytosineadenosine-guanine (CAG) equal to or greater than 36 repeats is diagnostic in the presence of characteristic symptoms. In the special case of asymptomatic carriers, a result between 36 and 39 CAG repeats corresponds to incomplete penetrance and uncertainty about phenoconversion in life. As with other neurodegenerative conditions caused by a trinucleotide expansion, a larger number of repeats is associated with an earlier age of onset, and a tendency exists for the number of repeats to increase from generation to generation, manifesting in the form of an anticipation phenomenon for the age of onset. CAG repeats in the intermediate range of 27 and 35 CAG repeats that have been described in rare case reports compatible with symptomatic


h In neuroacanthocytosis syndromes, the clinical multisystemic involvement is characteristic and has diagnostic and management implications.

h Huntington disease is the most frequent genetic cause of chorea.

TABLE 8-4 Initial Panel of Investigations in Patients With Chorea 1. Test for thyroid function, renal and liver function, electrolytes, erythrocyte sedimentation rate, antinuclear antibodies, antiYdouble-stranded DNA antibodies, anticardiolipin antibodies, and lupus anticoagulant. 2. Perform brain MRI. 3. If inconclusive or known family history of chorea, perform genetic test for Huntington disease. If the latter genetic test is negative, consider spinocerebellar ataxia type 17 and C9orf72 in white individuals, and Huntington diseaseYlike syndrome type 2 in subjects with black African ancestry. 4. Test for acanthocytes in peripheral fresh blood film. A single negative test is not sufficient to rule out the presence of acanthocytes and should be done in a laboratory with appropriate expertise; perform three assays. DNA = deoxyribonucleic acid; MRI = magnetic resonance imaging.

Continuum (Minneap Minn) 2016;22(4):1186–1207


Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.



h The vast majority of Huntington disease phenocopies remain undiagnosed.

h Spinocerebellar ataxia type 17 and C9orf7-related Huntington disease phenocopy are the most frequent causes for a Huntington disease phenocopy.

h Caudate atrophy can be found in Huntington disease phenocopies, namely in Huntington diseaseYlike syndrome type 2, chorea-acanthocytosis, and McLeod syndrome.


HD are associated with significant behavioral abnormalities, with implications for genetic counseling.50,51 Genetic testing in HD and other neurodegenerative conditions with an adult onset not only impacts the life of the individual being tested, but also his or her family, especially children. For family members at risk, the consideration of predictive testing is usually prompted by wishing to know the carrier status but also for a need to inform life decisions including marriage, parenthood, or a professional career. Genetic counseling is fundamental in order for patients to make a decision about predictive testing in a fully informed and free manner. Risks that are associated with positive predictive testing need to be discussed, including the potential issues of discrimination at work or for insurance purposes, tension in family and personal relations, as well as stress on the patient. Legislation on protection against genetic discrimination exists but varies from country to country and, in the United States, can change from state to state. A significant proportion of patients presenting as an HD phenocopy currently remain undiagnosed. An alternative diagnosis is found in as low as 2.8% of the cases in tertiary movement disorders centers.3 In an attempt to prioritize investigations, elements related with differentiating clinical features, ethnic/geographic origin, and family history should be considered as described previously. Available clinical data from case series in tertiary HD centers from Western Europe suggest that SCA17 and C9orf72 gene mutations should be prioritized, particularly in white individuals.4 HDL2 should be strongly considered in African Americans. Of note, HDL2 may resemble HD more than any other known disease.52 In a Brazilian cohort, HDL2 and SCA2 were the diagnoses found for HD

phenocopies, and there was no diagnosis of SCA17. 53 Among rare genetic entities that have been reported to present as an HD phenocopy and have an available diagnostic test, Friedreich ataxia was reported as an adult-onset choreic syndrome in the sixth decade of life, in association with cerebellar ataxia, and a single case of adult-onset chorea was found to have typical pathology of pantothenate kinaseYassociated neurodegeneration.3,6 In more recent years, there has been a significant breakthrough in the genetic basis of paroxysmal dyskinesia: the myofibrillogenesis regulator 1 (MR-1) gene and the much less frequent potassium calcium-activated channel subfamily M alpha 1 (KCNMA1) gene were identified in paroxysmal nonkinesigenic dyskinesia, the prolinerich transmembrane protein 2 (PRRT2) gene was identified in paroxysmal kinesigenic dyskinesia, and the glucose 1 transporter (SLC2A1 gene) was identified in paroxysmal exertion-induced (exercise-induced) dyskinesia. MRI can be helpful in the differential diagnosis of a suspected neurodegenerative choreic syndrome, with attention to patterns of atrophy, presence of signal changes in T1, T2, and fluidattenuated inversion recovery (FLAIR) weighted images, and iron susceptibility imaging. The hallmark feature in clinical MRIs found in adult-onset HD is caudate atrophy (Figure 8-2). It is important to emphasize that a few adult-onset neurodegenerative HD phenocopies may not be differentiated from HD based on MRI findings, examples of which include HDL2, choreaacanthocytosis, and McLeod syndrome. Nevertheless, in chorea-acanthocytosis and McLeod syndrome, T2-weighted hyperintensity in the striatum, mild generalized cortical atrophy (less in McLeod syndrome), and hippocampal sclerosis and atrophy (in chorea-acanthocytosis)


Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

August 2016


Caudate atrophy in a patient with Huntington disease documented on T2-weighted MRI.

have been described.54 Cerebellar atrophy occurs earlier and more severely in SCAs; in HD, cerebellar atrophy is a late and mild feature.55 In DRPLA, brainstem and cerebellar atrophy can be found in addition to diffuse T2-weighted hyperintensities in the deep subcortical white matter, and increased iron susceptibility is found in the cerebellum, dentate nuclei, and basal ganglia.56,57 The presence of a distinctive pattern of iron deposition can suggest and, at times, be diagnostic of neurodegeneration with brain iron accumulation (Figure 8-358). In neuroferritinopathy, hypointensities in the dentate nuclei, red nuclei, basal ganglia, thalami, and the rolandic cortex are found even in nonmanifesting carriers.20 With disease progression, a distinctive bilateral pallidal necrosis with cystic degeneration is observed (Figure 8-3).20 MRI is also helpful to raise the suspicion or Continuum (Minneap Minn) 2016;22(4):1186–1207

be confirmatory of a diagnosis in sporadic forms of chorea; in patients with chorea due to stroke, a vascular lesion in the subthalamic nucleus is classically described, but chorea can also be associated with strokes in other basal ganglia locations, thalamus, and internal capsule.59 In the variant CreutzfeldtJakob disease, the bilateral hyperintensity in the pulvinar of the thalamus (hockey stick sign), more frequently found in FLAIR sequences, is almost pathognomonic.60 In nonketotic hyperglycemia, T1-hyperintense lesions in the putamen are observed.43 In acquired hepatocerebral degeneration, T1 hyperintense lesions are found in the putamen and also in the internal capsule, the mesencephalon, and the cerebellum, in addition to cavitations of the basal ganglia, all thought to be secondary to the deposition of manganese via a portosystemic shunt.49 The presence www.ContinuumJournal.com

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.



h The treatment of chorea should aim at reducing related disability and improving overall function.

MRI findings in neuroferritinopathy with hypointensity in T2*-weighted image involving the globus pallidus, putamen, caudate nuclei, thalami (A), and dentate nuclei (not shown). Hyperintensity in the putamen and pallidum in T2-weighted fast spin echoYweighted image found at a later disease stage due to cystic degeneration (B).



Reprinted with permission from McNeill A, et al. Neurology. www.neurology.org/content/70/18/1614.short.

of brain calcification, better documented with a head CT, suggests idiopathic basal ganglia calcification once secondary causes are excluded; however, chorea is a rare presentation.61 Other investigations are to be specifically considered for certain sporadic and genetic causes (refer to Table 8-1 and Table 8-2), including an antibody panel and search of an occult neoplasm in paraneoplastic chorea. MANAGEMENT When chorea is the manifestation of a treatable condition, the main goal of management is treatment of the underlying condition rather than of the chorea itself. This includes removal of the offending drug, normalization of glycemia, immunomodulatory therapy for autoimmune chorea, or removal of an underlying neoplasm. When these approaches prove to be insufficient or a treatable cause is not found, symptomatic treatment is considered for chorea. Establishing clinical criteria for treatment is the first


B 2008 American Academy of Neurology.

step in the management of chorea. The clinician should assess the degree of functional incapacity or social embarrassment caused by chorea in a particular individual. However, the lack of insight frequently shown by a patient with chorea relative to the severity of his or her own symptoms can be a limitation for an accurate assessment. In fact, relatives often request treatment. Regardless of the decision, antichoreic medication should be used judiciously as no drug has proven to have a dramatic effect, and adverse effects may have an impact on the functional capacity of patients. Classically, neuroleptics have been used to treat chorea, although the evidence supported by randomized controlled trials is scarce. The only treatment shown to effectively treat chorea, including HD, is the monoamine depleter tetrabenazine.62 Due to the cost and tolerability profile of this drug, it may be chosen as a secondline drug after the unsuccessful trial of an atypical neuroleptic. Monitoring


Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

August 2016

of depression, suicidal ideation, akathisia, and parkinsonism are mandatory with tetrabenazine. Pallidal deep brain stimulation (DBS) has been considered as an option for the treatment of pharmacoresistant chorea or ballismus in cases with significant disability, as well as for head drops in chorea-acanthocytosis, with a suggestion of efficacy in HD and chorea-acanthocytosis.22,63 The treatment of other symptoms in HD phenocopies deserves a special comment. For severe tongue protrusion, it is important to recognize that swallowing and breathing difficulties may be life-threatening. Botulinum toxin injections have been considered in these cases with success, in spite of the risk of temporary dysphagia.21 Tongue or lip biting can also be treated with botulinum toxin injections or with the use of mouth guards.21,64 In McLeod syndrome, orthoses may be useful in patients with severe peripheral neuropathy. Patients with head drops such as those found in choreaacanthocytosis (but also in McLeod syndrome and advanced HD) can use head protective gear. Mood symptoms are generally treated as in general psychiatry, since there are no medications specifically approved for mood disorders in HD and other choreic syndromes. There are no cognitive-enhancing medications with proven efficacy for HD and other choreic syndromes. For the conditions presenting with seizures, general principles for the treatment for epilepsy apply. In the choreic syndromes that are part of a multisystem disorder, management requires the involvement of different medical specialties. An important example is McLeod syndrome, which requires periodic cardiac assessment due to the presence of cardiomyopathy and the risk of cardiac sudden death. Continuum (Minneap Minn) 2016;22(4):1186–1207

No disease-modifying therapies are available for HD (although several trials are ongoing) and other neurodegenerative choreic syndromes. In aceruloplasminemia, anecdotal evidence suggests that the use of iron chelators may modify disease biology.65


h In Huntington disease and Huntington disease phenocopies, a multidisciplinary management plan is required.

CONCLUSION Chorea is a hyperkinetic movement disorder with a vast list of causes. Aside from sporadic causes, the most prevalent cause of chorea in the adult is HD. The rigorous characterization of the phenomenology and associated neurologic and systemic features will help the clinician prioritize the investigations for the differential diagnosis of choreic syndromes. HD phenocopies represent a challenging diagnostic group; SCA17, C9orf72 in white individuals, and HDL2 in people of sub-Saharan African ancestry, including African Americans, are the most frequent diagnoses, and apart from a few other entities, the vast majority of patients currently remain without a diagnosis. The management of chorea represents a challenge, and the clinician should be able to identify the disability secondary to chorea as the appropriate indication for treatment. When a treatable cause of chorea is present, identification of that cause is mandatory. ACKNOWLEDGMENTS The author would like to acknowledge David Grimes, MD, FRCPC, for providing Supplemental Digital Content 8-3 and Supplemental Digital Content 8-4, as well insightful comments. The author would also like to acknowledge Anthony E. Lang, OC, MD, FRCPC, FAAN, FCAHS, FRSC, for providing Supplemental Digital Content 8-6 and Joaquim J. Ferreira, MD, PhD, for p r o v i d i n g S u p p l e m e n t a l Di g i tal Content 8-5, Supplemental Digital Content 8-7, and Supplemental Digital Content 8-8. www.ContinuumJournal.com

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.



VIDEO LEGENDS Supplemental Digital Content 8-1 Senile chorea. Video shows a man in his seventies with a clinical diagnosis of senile chorea and who was found to have genetically proven Huntington disease. Mild chorea is seen in the trunk, neck, and orofacial regions, and an exaggerated pout and grimace is seen in the orofacial region. links.lww.com/CONT/A188 B 2016 American Academy of Neurology.

Supplemental Digital Content 8-2 Levodopa-induced dyskinesia in Parkinson disease. Video shows a 62year-old woman with a 10-year history of Parkinson disease who now has severe, refractory levodopa-induced dyskinesia. After an acute administration of levodopa, she exhibits predominantly choreic dyskinesia that involves the lower limbs, trunk, and, to a lesser extent, the upper limbs. links.lww.com/CONT/A189 B 2016 American Academy of Neurology.

Supplemental Digital Content 8-3 Paroxysmal kinesigenic dyskinesia. Video shows a man with paroxysmal kinesigenic dyskinesia (PRRT2 gene positive) presenting with chorea and dystonia. Upon standing, a 10-second episode occurs involving the left upper limb with arm adduction, elbow flexion, hand clenching, and choreic movements of the fingers. links.lww.com/CONT/A190 Courtesy of David Grimes, MD, FRCPC.

Supplemental Digital Content 8-4 Chorea-acanthocytosis. Video shows a 28-year-old man exhibiting jaw-


opening dystonia, chorea of the trunk and neck, and dystonic protrusion of the tongue when eating or speaking, but not impaired drinking. Mild bradykinesia and sniffing with nose clearing are also observed. links.lww.com/CONT/A191 Courtesy of David Grimes, MD, FRCPC.

Supplemental Digital Content 8-5 Chorea in Huntington disease. Video shows florid choreic movements in a man with genetically proven Huntington disease. He exhibits brief, irregular, random, purposeless, involuntary movements flowing from one muscle group to the next, which are superimposed on voluntary motor activity, namely walking. links.lww.com/CONT/A192 Courtesy of Joaquim J. Ferreira, MD, PhD.

Supplemental Digital Content 8-6 Chorea of the hands in Huntington disease. Video shows focal chorea localized to the hands of a man with Huntington disease. He exhibits random piano-playing movements of the fingers that are brought about by finger tapping and counting backward. links.lww.com/CONT/A193 Courtesy of Anthony E. Lang, OC, MD, FRCPC, FAAN, FCAHS, FRSC.

Supplemental Digital Content 8-7 Ballismus. Video shows a man with right upper limb unilateral ballismus. He exhibits characteristic high-amplitude involuntary flinging movements involving the most proximal segment of the upper limb. links.lww.com/CONT/A194 Courtesy of Joaquim J. Ferreira, MD, PhD.


Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

August 2016

Supplemental Digital Content 8-8 Athetosis. Video shows a woman with cerebral palsy and athetosis of the right hand. She exhibits characteristic, slow involuntary writhing movements of the distal limb region. Underlying dystonia is evident with prominent lateral deviation and flexion of the wrist and finger extension. links.lww.com/CONT/A195 Courtesy of Joaquim J. Ferreira, MD, PhD.

REFERENCES 1. Pringsheim T, Wiltshire K, Day L, et al. The incidence and prevalence of Huntington’s disease: a systematic review and meta-analysis. Mov Disord 2012;27(9):1083Y1091. doi:10.1002/ mds.25075. 2. Stevanin G, Camuzat A, Holmes SE, et al. CAG/CTG repeat expansions at the Huntington’s disease-like 2 locus are rare in Huntington’s disease patients. Neurology 2002;58(6):965Y967. doi:10.1212/WNL.58.6.965. 3. Wild EJ, Mudanohwo EE, Sweeney MG, et al. Huntington’s disease phenocopies are clinically and genetically heterogeneous. Mov Disord 2008;23(5):716Y720. doi:10.1002/ mds.21915. 4. Hensman Moss DJ, Poulter M, Beck J, et al. C9orf72 expansions are the most common genetic cause of Huntington disease phenocopies. Neurology 2014;82(4):292Y299. doi:10.1212/WNL.0000000000000061.

2013;80(12):1133Y1144. doi:10.1212/ WNL.0b013e3182886991. 10. Riley D, Lang AE. Hemiballism in multiple sclerosis. Mov Disord 1988;3(1):88Y94. doi:10.1002/mds.870030111. 11. Venkatesan EP, Ramadoss K, Balakrishnan R, Prakash B. Essential thrombocythemia: rare cause of chorea. Ann Indian Acad Neurol 2014;17(1):106Y107. doi:10.4103/ 0972-2327.128569. 12. Critchley M. The neurology of old age. Lancet 1931;217(5621):1119Y1127. doi:10.1016/S0140-6736(00)90705-0. 13. Garcia Ruiz PJ, Go´mez-Tortosa E, del Barrio A, et al. Senile chorea: a multicenter prospective study. Acta Neurol Scand 1997;95(3):180Y183. doi:10.1111/ j.1600-0404.1997.tb00092.x. 14. Rana AQ, Yousuf MS, Hashmi MZ, Kachhvi ZM. Hemichorea and dystonia due to frontal lobe meningioma. J Neurosci Rural Pract 2014;5(3):290Y292. doi:10.4103/ 0976-3147.133611. 15. Cardoso F, Seppi K, Mair KJ, et al. Seminar on choreas. Lancet Neurol 2006;5(7):589Y602. doi:10.1016/S1474-4422(06)70494-X. 16. Erro R, Sheerin UM, Bhatia KP. Paroxysmal dyskinesias revisited: a review of 500 genetically proven cases and a new classification. Mov Disord 2014;29(9): 1108Y1116. doi:10.1002/mds.25933. 17. Edwards MJ, Schrag A. Hyperkinetic psychogenic movement disorders. Handb Clin Neurol 2011;100:719Y729. doi:10.1016/ B978-0-444-52014-2.00051-3. 18. Robottom BJ, Weiner WJ. Chorea gravidarum. Handb Clin Neurol 2011;100:231Y235. doi:10.1016/B978-0-444-52014-2.00015-X.

5. Paucar M, Xiang F, Moore R, et al. Genotype-phenotype analysis in inherited prion disease with eight octapeptide repeat insertional mutation. Prion 2013;7(6):501Y510. doi:10.4161/pri.27260.

19. Danek A, Rubio JP, Rampoldi L, et al. McLeod neuroacanthocytosis: genotype and phenotype. Ann Neurol 2001;50(6): 755Y764. doi:10.1002/ana.10035.

6. Grimes DA, Lang AE, Bergeron C. Late adult onset chorea with typical pathology of Hallervorden-Spatz syndrome. J Neurol Neurosurg Psychiatry 2000;69(3):392Y395. doi:10.1136/jnnp.69.3.392.

20. Chinnery PF, Crompton DE, Birchall D, et al. Clinical features and natural history of neuroferritinopathy caused by the FTL1 460InsA mutation. Brain 2007; 130(pt 1):110Y119. doi:10.1093/ brain/awl319.

7. Wong JC, Armstrong MJ, Lang AE, Hazrati LN. Clinicopathological review of pallidonigroluysian atrophy. Mov Disord 2013;28(3):274Y281. doi:10.1002/mds.25232. 8. Piccolo I, Defanti CA, Soliveri P, et al. Cause and course in a series of patients with sporadic chorea. J Neurol 2003;250(4): 429Y435. doi:10.1007/s00415-003-1010-76. 9. O’Toole O, Lennon VA, Ahlskog JE, et al. Autoimmune chorea in adults. Neurology Continuum (Minneap Minn) 2016;22(4):1186–1207

21. Schneider SA, Aggarwal A, Bhatt M, et al. Severe tongue protrusion dystonia: clinical syndromes and possible treatment. Neurology 2006;67(6):940Y943. doi:10.1212/01.wnl.0000237446.06971.72. 22. Schneider SA, Lang AE, Moro E, et al. Characteristic head drops and axial extension in advanced chorea-acanthocytosis. Mov Disord 2010;25(10):1487Y1491. doi:10.1002/ mds.23052. www.ContinuumJournal.com

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.



23. Chauveau M, Damon-Perriere N, Latxague C, et al. Head drops are also observed in McLeod syndrome. Mov Disord 2011;26(8): 1562Y1563. doi:10.1002/mds.23605. 24. Spampinato U, Debruxelles S, Rouanet M, et al. Head drops are also observed in advanced Huntington disease. Parkinsonism Relat Disord 2013;19(5):569Y570. doi:10.1016/ j.parkreldis.2013.01.012. 25. van Duijn E, Craufurd D, Hubers AA, et al. Neuropsychiatric symptoms in a European Huntington’s disease cohort (REGISTRY). J Neurol Neurosurg Psychiatry 2014;85(12): 1411Y1418. doi:10.1136/jnnp-2013-307343. 26. Tabrizi SJ, Langbehn DR, Leavitt BR, et al. Biological and clinical manifestations of Huntington’s disease in the longitudinal TRACK-HD study: cross-sectional analysis of baseline data. Lancet Neurol 2009;8(9): 791Y801. doi:10.1016/S1474-4422(09)70170-X. 27. Hubers AA, van Duijn E, Roos RA, et al. Suicidal ideation in a European Huntington’s disease population. J Affect Disord 2013;151(1): 248Y258. doi:10.1016/j.jad.2013.06.001. 28. Fischer CA, Licht EA, Mendez MF. The neuropsychiatric manifestations of Huntington’s disease-like 2. J Neuropsychiatry Clin Neurosci 2012;24(4):489Y492. doi:10.1176/appi.neuropsych.11120358.

36. Burke JR, Wingfield MS, Lewis KE, et al. The Haw River syndrome: dentatorubropallidoluysian atrophy (DRPLA) in an African-American family. Nat Genet 1994;7(4):521Y524. doi:10.1038/ng0894-521. 37. Pedroso JL, de Freitas ME, Albuquerque MV, et al. Should spinocerebellar ataxias be included in the differential diagnosis for Huntington’s diseases-like syndromes? J Neurol Sci 2014;347(1Y2):356Y358. doi:10.1016/j.jns.2014.09.050. 38. Schneider SA, van de Warrenburg BP, Hughes TD, et al. Phenotypic homogeneity of the Huntington disease-like presentation in a SCA17 family. Neurology 2006;67(9):1701Y1703. doi:10.1212/ 01.wnl.0000242740.01273.00. 39. Al-Tahan AY, Divakaran MP, Kambouris M, et al. A novel autosomal recessive ‘‘Huntington’s disease-like’’ neurodegenerative disorder in a Saudi family. Saudi Med J 1999;20(1):85Y89. 40. Hardie RJ, Pullon HW, Harding AE, et al. Neuroacanthocytosis. A clinical, haematological and pathological study of 19 cases. Brain 1991;114(pt 1A):13Y49. doi:13-49.

29. Walterfang M, Evans A, Looi JC, et al. The neuropsychiatry of neuroacanthocytosis syndromes. Neurosci Biobehav Rev 2011;35(5):1275Y1283. doi:10.1016/ j.neubiorev.2011.01.001.

41. Bowen J, Mitchell T, Pearce R, Quinn N. Chorea in new variant Creutzfeldt-Jacob disease. Mov Disord 2000;15(6):1284Y1285. doi:10.1002/1531-8257(200011) 15:6G1284::AID-MDS104393.0.CO;2-Y.

30. Rajput A. Dentatorubral pallidoluysian atrophy. Handb Clin Neurol 2011;100:153Y159. doi:10.1016/B978-0-444-52014-2.00008-2.

42. Mestre T, Ferreira J, Pimentel J. Putaminal petechial haemorrhage as the cause of non-ketotic hyperglycaemic chorea: a neuropathological case correlated with MRI findings. BMJ Case Reports 2009;2009. pii: bcr08.2008.0785. doi:10.1136/ bcr.08.2008.0785.

31. Hewer E, Danek A, Schoser BG, et al. McLeod myopathy revisited: more neurogenic and less benign. Brain 2007;130(pt 12):3285Y3296. doi:10.1093/brain/awm269 3285-3296. 32. Jung HH, Danek A, Walker RH. Neuroacanthocytosis syndromes. Orphanet J Rare Dis 2011;6:68. doi:10.1186/1750-1172-6-68. 33. Rodrigues GG, Teive HA, Tumas V. Huntington’s disease-like 2 and apparent ancestry. Clin Genet 2009;75(2):207; author reply 8. doi:10.1111/ j.1399-0004.2008.01055.x. 34. Ondo WG, Adam OR, Jankovic J, Chinnery PF. Dramatic response of facial stereotype/tic to tetrabenazine in the first reported cases of neuroferritinopathy in the United States. Mov Disord 2010;25(14):2470Y2472. doi:10.1002/mds.23299. 35. Becher MW, Rubinsztein DC, Leggo J, et al. Dentatorubral and pallidoluysian atrophy (DRPLA). Clinical and neuropathological findings in genetically confirmed


North American and European pedigrees. Mov Disord 1997;12(4):519Y530. doi:10.1002/ mds.870120408.

43. Mestre TA, Ferreira JJ, Pimentel J. Putaminal petechial haemorrhage as the cause of non-ketotic hyperglycaemic chorea: a neuropathological case correlated with MRI findings. J Neurol Neurosurg Psychiatry 2007;78(5):549Y550. doi:10.1136/jnnp. 2006.105387. 44. Namekawa M, Takiyama Y, Ando Y, et al. Choreiform movements in spinocerebellar ataxia type 1. J Neurol Sci 2001;187(1Y2): 103Y106. doi:10.1016/S0022-510X(01)00527-5. 45. Stevanin G, Hahn V, Lohmann E, et al. Mutation in the catalytic domain of protein kinase C gamma and extension of the phenotype associated with spinocerebellar ataxia type 14. Arch Neurol 2004;61(8): 1242Y1248. doi:10.1001/archneur.61.8.1242.


Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

August 2016

46. Koutsis G, Karadima G, Pandraud A, et al. Genetic screening of Greek patients with Huntington’s disease phenocopies identifies an SCA8 expansion. J Neurol 2012;259(9): 1874Y1878. doi:10.1007/s00415-012-6430-9. 47. Rampoldi L, Danek A, Monaco AP. Clinical features and molecular bases of neuroacanthocytosis. J Mol Med (Berl) 2002; 80(8):475Y491. doi:10.1007/s00109-002-0349-z. 48. Dalmau J, Rosenfeld MR. Paraneoplastic syndromes causing movement disorders. Handb Clin Neurol 2011;100:315Y321. doi:10.1016/B978-0-444-52014-2.00024-0. 49. Meissner W, Tison F. Acquired hepatocerebral degeneration. Handb Clin Neurol 2011;100:193Y197. doi:10.1016/B978-0-444-52014-2.00011-2. 50. Killoran A, Biglan KM, Jankovic J, et al. Characterization of the Huntington intermediate CAG repeat expansion phenotype in PHAROS. Neurology 2013;80(22):2022Y2027. doi:10.1212/ WNL.0b013e318294b304. 51. Semaka A, Hayden MR. Evidence-based genetic counselling implications for Huntington disease intermediate allele predictive test results. Clin Genet 2014;85(4):303Y311. doi:10.1111/cge.12324. 52. Schneider SA, Bhatia KP. Huntington’s disease look-alikes. Handb Clin Neurol 2011;100: 101Y112. doi:10.1016/B978-0-444-52014-2.00005-7. 53. Castilhos RM, Souza AF, Furtado GV, et al. Huntington disease and Huntington disease-like in a case series from Brazil. Clin Genet 2014;86(4):373Y377. doi:10.1111/cge.12283. 54. Scheid R, Bader B, Ott DV, et al. Development of mesial temporal lobe epilepsy in chorea-acanthocytosis. Neurology 2009;73(17): 1419Y1422. doi:10.1212/WNL.0b013e3181bd80d4. 55. Martino D, Stamelou M, Bhatia KP. The differential diagnosis of Huntington’s disease-like syndromes: ‘red flags’ for the clinician. J Neurol Neurosurg Psychiatry 2013;84(6):650Y656. doi:10.1136/ jnnp-2012-302532. 56. Simpson M, Smith A, Kent H, Roxburgh R. Neurological picture. Distinctive MRI abnormalities in a man with dentatorubral-pallidoluysian atrophy. J Neurol Neurosurg Psychiatry 2012;83(5): 529Y530. doi:10.1136/jnnp-2011-301612.

Continuum (Minneap Minn) 2016;22(4):1186–1207

57. Koide R, Onodera O, Ikeuchi T, et al. Atrophy of the cerebellum and brainstem in dentatorubral pallidoluysian atrophy. Influence of CAG repeat size on MRI findings. Neurology 1997;49(6):1605Y1612. doi:10.1212/WNL.49.6.1605. 58. McNeill A, Birchall D, Hayflick SJ, et al. T2* and FSE MRI distinguishes four subtypes of neurodegeneration with brain iron accumulation. Neurology 2008;70(18):1614Y1619. doi:10.1212/ 01.wnl.0000310985.40011.d6. 59. Ghika-Schmid F, Ghika J, Regli F, Bogousslavsky J. Hyperkinetic movement disorders during and after acute stroke: the Lausanne Stroke Registry. J Neurol Sci 1997;146(2):109Y116. doi:10.1016/ S0022-510X(96)00290-0. 60. Collie DA, Summers DM, Sellar RJ, et al. Diagnosing variant Creutzfeldt-Jakob disease with the pulvinar sign: MR imaging findings in 86 neuropathologically confirmed cases. AJNR Am J Neuroradiol 2003;24(8):1560Y1569. 61. Nicolas G, Pottier C, Charbonnier C, et al. Phenotypic spectrum of probable and genetically-confirmed idiopathic basal ganglia calcification. Brain 2013;136(pt 11): 3395Y3407. doi:10.1093/brain/awt255. 62. Armstrong MJ, Miyasaki JM; American Academy of Neurology. Evidence-based guideline: pharmacologic treatment of chorea in Huntington disease: report of the guideline development subcommittee of the American Academy of Neurology. Neurology 2012;79(6):597Y603. doi:10.1212/ WNL.0b013e318263c443. 63. Miquel M, Spampinato U, Latxague C, et al. Short and long term outcome of bilateral pallidal stimulation in chorea-acanthocytosis. PLoS One 2013;8(11):e79241. doi:10.1371/ journal.pone.0079241. 64. Fontenelle LF, Leite MA. Treatment-resistant self-mutilation, tics, and obsessive-compulsive disorder in neuroacanthocytosis: a mouth guard as a therapeutic approach. J Clin Psychiatry 2008;69(7):1186Y1187. 65. Miyajima H, Takahashi Y, Kamata T, et al. Use of desferrioxamine in the treatment of aceruloplasminemia. Ann Neurol 1997;41(3): 404Y407. doi:10.1002/ana.410410318.


Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.