Chorea.pptx

Contd....
• Chorea refers to involuntary random, irregular, purposeless
movements that flow from one body part to the next.
• The unpredictable fragmented movements may involve the limbs,
trunk, neck, face, and tongue.

Contd....
• The velocity of chorea can vary from fast (which may make it difficult
to differentiate from myoclonus) to slow (which may make it difficult
to differentiate from dystonia).

Contd....
• The intensity, frequency, and amplitude of chorea may vary from
subtle low-amplitude movements of varying frequency in the upper
face to severe large-amplitude movements in the limbs and trunk.
• Chorea may initially manifest as fidgeting and go unnoticed or denied
by patients, despite usually being detectable by others.

Contd....
• Some patients disguise chorea by incorporating it into a voluntary
movement.
• Motor impersistence is another common associated feature of chorea
and is demonstrated by the inability to maintain a grasp on the
examiner’s hand (ie, milkmaid’s grip) or sustain tongue protrusion.

CHOREA VERSUS OTHER HYPERKINETIC MOVEMENTS
• Differentiating chorea from other hyperkinetic movements can be
challenging, especially when various movements coexist.
• Recognizing the phenomenology of the movements observed can
direct the diagnostic approach and treatment strategy.

Dystonia
• Dystonia is defined by sustained muscle contractions and abnormal
postures that are repetitive, patterned, twisting, and sometimes
tremulous.
• Compared to chorea, dystonic movements are generally slower.
• Dystonia may occur at rest; however, it is typically triggered by
voluntary actions.

Contd....
• Unique features of dystonia include an alleviating maneuver
(previously described as a sensory trick), a null point, and mirror
movements.
• Of note, dystonic movements can coexist with chorea.

Dyskinesia
• Dyskinesia is a general term for abnormal movements, one of which is
chorea.
• The term is most frequently used for specific medication-induced
hyperkinetic conditions, such as
levodopa-induced dyskinesia in PD or
tardive dyskinesia induced by neuroleptic medications

Contd....
• Chorea and choreoathetoid movements are the most common forms
of levodopa-induced dyskinesia ; however, dyskinesia is not
synonymous with chorea.

Myoclonus
• Myoclonus is a brief lightninglike jerk that is usually described as the
quickest movement a body part can produce, ranging from
approximately 50 to 200 milliseconds.
• This movement disorder can be caused by muscle contraction
(positive myoclonus) or sudden interruption of muscle activity
(negative myoclonus).

Contd....
• Asterixis, which often appears in metabolic encephalopathies, is a
form of negative myoclonus.
• Chorea also has fast movement fragments, but, unlike in myoclonus,
the movements occur together with slower movements to produce a
flowing quality.

Tremor
• Rhythmicity, oscillation,and predictability are important factors that
distinguish tremor from chorea.
• Tremors are generally classified by their location, the posture in which
they occur, amplitude, and frequency.
• Tremors may accompany other movement disorders, such as
dystonia.

Tics
• Tics are nonrhythmic, recurrent, patterned movements or
vocalizations usually associated with a premonitory urge and some
degree of suppressibility.
• Tics may be simple or complex and can vary in type, severity, and
anatomic location.
• The repetitiveness, accompanying urge, and suppressibility of tics
differentiate them from chorea.

Ballism
• Ballism, or ballismus, is a high-amplitude movement that usually
involves proximal parts of the limbs (ie, shoulder or hip), often
described as a flinging or kicking movement.

Athetosis
• Athetosis is of lower amplitude than chorea and often distal.
• Although it may involve the trunk.
• It is a writhing movement with slow continuous flow rather than the
fragmented sequence seen in chorea.
• Chorea may coexist with athetosis.

EVALUATING CHOREA
• In addition to associated neurologic signs, the location or distribution
of chorea can be an important clue when narrowing the differential
diagnosis.
Body Distribution
• Chorea is generalized in many cases; however, its localized
distribution may act as an important diagnostic factor to determine
the underlying etiology.

HEMICHOREA
• Hemichorea has been classically associated with focal vascular lesions
of the contralateral subthalamic nucleus or basal ganglia.
• However, vascular lesions in other territories, such as the thalamus or
temporoparietal cortex, have also been implicated in causing chorea.

Contd....
• Other etiologies that may cause hemichorea with focal lesions are
nonketotic hyperglycemia and
opportunistic infections in the setting of HIV and AIDS.

Contd....
• Some conditions may cause hemichorea in the absence of an
apparent brain lesion.
• Examples include autoimmune chorea (eg, Sydenham chorea),
paraneoplastic syndromes, and variant Creutzfeldt-Jakob disease.
• However, these conditions may also present as generalized chorea.

OROBUCCOLINGUAL CHOREA
• It may present in several conditions, with the most common being tardive
syndromes.
• Involvement of the orobuccolingual muscles may occur in paraneoplastic
syndromes:
N-methyl- D -aspartate [NMDA] receptor encephalitis)
polycythemia vera, and
chorea-acanthocytosis

Contd....
• In chorea-acanthocytosis, chorea is frequently accompanied by
oromandibular and lingual dystonia, leading to tongue protrusion and
feeding dystonia.
• Other etiologies of chorea may present with oromandibular dystonia.
• Some examples are Lesch-Nyhan syndrome, Lubag disease (X-linked
dystonia-parkinsonism), Wilson disease, and pantothenate kinase–
associated neurodegeneration (PKAN).

FACIAL OR FOREHEAD CHOREA
• Chorea involving the forehead/upper face, manifested by frontalis
contraction, intermittently widened palpebral fissures, and irregular
blinking, is common in Huntington disease (HD).
• This is not a pathognomonic feature of HD but is far less common in
tardive syndromes and can therefore help when seen in addition to
delayed ocular saccade initiation and velocity or other features
common in HD.

• Evaluation
• Observation throughout the encounter is of utmost importance when evaluating
• an individual with chorea. Multiple scales are available to rate chorea severity;
• however, if a rating scale is not used, describing the location and severity of the
• chorea is sufficient. One of the most widely recognized validated scales is the
• UnifiedHuntington’sDiseaseRatingScale(UHDRS),inwhichthetotalmaximal
• chorea score within the motor section of the scale is used to measure the severity
• of chorea ranging from absent to severe.

• The chorea is rated in seven body
• regions: the face, orobuccolingual, trunk, and each limb
independently. 33 The
• Abnormal Involuntary Movement Scale (AIMS) is another commonly
used scale
• to evaluate chorea in the setting of tardive dyskinesia and assess
chorea severity
• in various locations.

• When evaluating chorea, the entire body should be visible, including the feet
• (without socks),with the patient sittingon an examination table.It isimperative
• to evaluate the chorea throughout the encounter, as the severity can fluctuate
• with distraction. 33 Like most hyperkinetic movements, the severity may
increase
• with heightened emotion. Observing gait (more specifically, tandem gait) can
• illuminate the severity of the chorea.

• Although mild chorea may go unnoticed by patients and their caregivers,
• moderate chorea is typically more apparent. In HD, anosognosia is common;
• therefore, individuals may be unaware of even severe chorea. Chorea usually
• affects the limbs, trunk, and face. Less frequently, it can interfere with
• respiration and phonation, presenting with slurred speech or involuntary
• vocalizations (eg, grunting, humming). Chorea usually presents at rest,
• disappears during sleep, and may increase with distracting maneuvers such as
• counting backward. Chorea may be partially suppressible or camouflaged by

• the patient. Motor impersistence, as mentioned above, is a common
• phenomenon in individuals with chorea. This can bedemonstrated by
asking the
• patient to squeeze the examiner’s finger or sustain tongue protrusion
for
• 10 seconds

• Clues to differentiate inherited choreas from acquired choreas include
• the timeline (acute, subacute, or chronic [>1 year]) and course (static,
paroxysmal, or progressive).

• PATHOPHYSIOLOGY
• The pathophysiology of chorea is linked to the neural network connecting the
• thalamus to the basal ganglia, including the striatum, globus pallidus externus,
• andglobuspallidusinternusaswellasrelatednuclei(eg,thesubthalamicnucleus
• and substantia nigra). The classic model of basal ganglia function describes the
• direct and indirect pathways that originate from striatal medium spiny neurons.

• According to this model, a cortical impulse activates medium spiny
neurons
• with the release of glutamate. Medium spiny neurons control
downstream
• pathways with γ-aminobutyric acid (GABA), a naturally inhibitory
signal. In the

• direct pathway, the inhibition of the globus pallidus internus, which is also
• γ-aminobutyric acid–mediated (GABAergic), results in disinhibition of the
• thalamus and locomotor activation. Conversely, the indirect pathway activates
• theglobuspallidusinternuswithinhibitionoftheexcitatorysubthalamicnucleus
• and ultimately reduces locomotion. In addition to the cortical impulses, the
• substantia nigra pars compacta controls mediumspiny neurons and downstream
• pathways byreleasing dopamine. Although choreahas differentetiologies,many
• of its various forms can be explained by decreased inhibitory input of the globus
• pallidus internus to the thalamus, resulting in facilitation of thalamocortical
• motor drive. 23,37

• However, some discrepancies exist. For example, internal pallidal ablation
• (globus pallidus internus pallidotomy) has been successfully used in treating
• some forms of chorea, whereas according to the classic model, it should actually
• increase thalamocortical motor drive and worsen chorea. In another example,
• findingsonpositronemissiontomography(PET)haveshownevidenceofstriatal
• hypometabolism in HD and some other causes of chorea, which correlates with
• neuronal loss.

• Conversely, in patients with hyperthyroidism, polycythemia vera,
• and Sydenham chorea, hypermetabolism of the striatum was found.
These
• inconsistencies suggest a more complex mechanism and even
different
• pathophysiology among variants of chorea.

Hereditary Choreas
• HD is the most common cause of adult-onset hereditary chorea, but
even in
• HD, 5% of cases represent a de novo HTT pathogenic variant or
expansions in
• the nonpathogenic but mutable range (ie, CAG repeats may expand in
• successive generations into the pathogenic range), and family history
may be
• incomplete, incorrect, or unknown. 42

• Among other hereditary causes, some
• share phenotypic characteristics with HD and are considered HD
mimics or
• phenocopies and others have different inheritance patterns and
unique
• features that may lead to their consideration, but all are considered
rarer than
• HD and therefore considered only after a negative test for the HTT
• pathogenic variant.

• HUNTINGTON DISEASE. HD is the most common cause of adult-onset hereditary
• chorea ( VIDEO 8-1 and VIDEO 8-2 ), affecting approximately 5 per 100,000 to 12
• per 100,000 people. 43 It is caused by an autosomal dominant trinucleotide
• repeat expansion (CAG) in the huntingtin gene (HTT) on chromosome 4p16.3.
• Repeat lengths of 40 and above have full penetrance, with a phenotype
• consisting of progressive motor, cognitive, and behavioral changes. The precise
• mechanism for the degenerative changes in HD is unclear, but mutant
• huntingtin protein forms nuclear aggregates in the striatum, particularly leading
• to loss of medium spiny neurons. A CAG repeat length of 26 or lower is
• considered normal ( TABLE 8-1 44 ). Individuals who have 36 to 39 CAG repeats are
• considered to have reduced penetrance but can still develop the disease. In those
• with 27 to 35 CAG repeats, the phenomenon of “anticipation” via paternal
• inheritancecan poserisk forexpansion intothe HDrangeinthe next generation.

• Although HD symptom onset can occur at any age, the average age of onset
• is in the third or fourth decade of life, and the average lifespan is approximately
• 15to20yearsaftersymptomonset.Theageofmotoronsetisinverselycorrelated
• with the number of CAG repeats; however, this only accounts for approximately
• 50% to 70% of the variance. 45 Through genome-wide association studies
• evaluating large cohorts, the Genetic Modifiers of Huntington’s Disease
• (GeM-HD) Consortium has identified genes involved in DNA maintenance and
• repair that have been implicated in modifying motor symptom onset by likely
• influencing somatic expansion of the HTT CAG repeat. 46,47 The GeM-HD
• Consortium and others determined that the uninterrupted CAG repeat length

• is more influential in contributing to the age of motor onset than the
• polyglutamine length. 47
• Prodromal HD can occur approximately 10 years before a clinical
• diagnosis. 46 During this period, subtle motor and nonmotor symptoms maybe
• be present but are not significant enough to warrant a clinical diagnosis.
• A clinical diagnosis of HD has historically been based on motor symptoms.
• However, cognitive and behavioral symptoms can be deleterious and may
• precede significant motor symptoms. Reilmann and colleagues 48 proposed a
• revision of the diagnostic criteria to include nonmotor features, more
• specifically cognitive symptoms, when making a diagnosis. Subsequently, a
• Movement Disorder Society task force proposed a refinement of the clinical
• diagnostic criteria. 49,50 Efforts are under way to expand upon this for both
• clinical and research purposes.

• Juvenile HD (also known as the Westphal variant) occurs before the age of 20
• and is associated with CAG repeat lengths higher than 55; it phenotypically can
• present with akinesia, parkinsonism, and seizures rather than chorea. Although
• chorea isthe mostcommon and prototypicalmovement disorder associated with
• HD, especially among those with onset in middle age or older adult life, other
• movements often seen include ataxia, dystonia, parkinsonism, tics, dysarthria,
• dysphagia, and impaired ocular saccade initiation and velocity. 43 In fact, delayed
• ocular saccade initiation can be a helpful clue when trying to differentiate HD
• from other causes of chorea. 43

• Cognitive decline eventually occurs in all individuals with HD. Executive
• dysfunction is common, including impairments in planning, working memory,
• and attention. The cognitive symptoms are progressive and lead to functional
• declineanddependence.Behavioralfeaturesarevariableamong individualswith
• HD. Depression, irritability, anxiety, and impulsivity are among the most
• common psychiatricsymptomsand can contribute tothehighsuiciderate inthis
• population. Obsessive-compulsive symptoms and apathy are not uncommon,
• and, unlike other neuropsychiatric features, apathy longitudinally worsens
over
• time. Psychosis can also be seen, albeit rarely.

• BENIGN HEREDITARY CHOREA. Familial forms of chorea that have an onset in
• childhood and remain fairly stable or only mildly progressive are suggestive of
• benign hereditary chorea. Although many cases are truly benign, some are
• associated with increased risk of malignancy and with pulmonary or thyroid
• disorders—a triad known as the brain-lung-thyroid disease—depending on the
• severity of the pathogenic variant in the thyroid transcription factor 1 gene
• (TITF1/NKX2-1). The pattern of inheritance is typically autosomal dominant.
• In the first few years of life, some individuals with benign hereditary chorea
• will experience hypotonia and some delay in motor milestones, but it is
• generally stable after the first decade of life. Unlike other forms of hereditary
• chorea, cognitive decline is less common

• PAROXYSMAL KINESIGENIC AND NONKINESIGENIC DYSKINESIA. Paroxysmal
• kinesigenic dyskinesia and paroxysmal nonkinesigenic dyskinesia are
• hereditary paroxysmal or episodic movement disorders that occur in
• childhood and are most commonly associated with chorea or dystonia. Unlike
• other conditions described here, individuals typically have a normal
• neurologic examination between episodes, and the disorders can often be
• confused with functional movement disorders. In paroxysmal kinesigenic
• dyskinesia (also known as DYT10), episodes typically last seconds to minutes

• and can occur countless times per day. Episodes are triggered by movement, but
• individuals will often describe a prodromal sensation before an episode. The
• choreiform movements can affect any body region but are often asymmetric,
• andtheytypically respondwelltocarbamazepine.In paroxysmal nonkinesigenic
• dyskinesia (also known as DYT8), episodes are typically longer, lasting minutes
• to hours. Episodes are also less frequent than in paroxysmal kinesigenic
• dyskinesia and are not triggered by movement but rather by stress, extremes of
• temperature, alcohol, or excitement. Paroxysmal nonkinesigenic dyskinesia is

• less responsive to pharmacotherapy than paroxysmal kinesigenic dyskinesia.
• Paroxysmal kinesigenic dyskinesia is associated with autosomal dominant
• pathogenic variants in the proline-rich transmembrane protein 2 gene
(PRRT2);
• the same gene has been associated with other conditions such as hemiplegic
• migraine and episodic ataxia. Paroxysmal nonkinesigenic dyskinesia is also an
• autosomal dominant disorder, due to a pathogenic variant in the
• myofibrillogenesis regulator 1 gene (MR-1). Another related condition,
• paroxysmal exercise-induced chorea, is associated with a deficiency in the
• glucose-transporter 1 (GLUT-1).

SLE AND OTHER AUTOIMMUNE-RELATED CHOREAS
• Chorea is a rare manifestation of SLE but rarely (1% to 4% of cases of
systemic lupus erythematosus) may be seen as a presenting
manifestation of the disease.
• This may be related to circulating antiphospholipid and anticardiolipin
antibodies, although vascular phenomena have also been proposed.

• Behçet disease, Sjögren syndrome, and celiac disease are all systemic
autoimmune conditions with antibodies that can be rarely associated
with chorea.
• Anti-NMDA receptor encephalitis is a known cause of autoimmune
encephalitis. Like other forms of limbic encephalitis, it can be
associated with epilepsy and behavioral changes.

Contd....
• Other neurobehavioral features, including chorea and catatonia, are
seen commonly with NMDA receptor encephalitis.
• In some patients, particularly in young women, NMDA receptor
antibodies can be paraneoplastic related to ovarian teratomas.

• Immunoglobulin like cell adhesion molecule 5 (IgLON5) is an antibody
that has been discovered recently in association with parasomnias
but can be associated with cognitive impairment, gaze palsies, and
chorea.

PARANEOPLASTIC CHOREA
• Paraneoplastic causes of chorea should be considered in adults,
particularly when the onset is subacute and associated with other
systemic findings such as weight loss.
• Chorea often develops before tumor diagnosis, and early recognition
may lead to detection of occult malignancies.

• Antibodies to nuclear and cytoplasmic antigens, such as anti-Hu and
anti–collapsin response mediator protein 5 (CRMP-5) antibodies,
associated with small cell lung cancer are among the most common
to cause chorea.
• Additional antibodies targeting intracellular antigens include anti-Ma
and antibodies directed at P/Q calcium channels.

• These antibodies indicate a T-cell–mediated immune response and may be
less responsive to immunotherapy.
• Antibodies to cell surface proteins, including leucine-rich glioma inactivated
protein 1 (LGI1), contactin-associated proteinlike 2 (CASPR2), and NMDA
antibodies, may be more likely to improve with immunotherapy.
• As noted above, anti-NMDA antibodies have been associated with ovarian
teratomas but may also be seen as described above without a neoplasm.

STRUCTURAL/LESIONAL CHOREA
• Any structural lesion involving the basal ganglia has the potential to
cause chorea.
• In the perinatal period, vascular phenomena leading to cerebral palsy
can frequently cause choreiform and dystonic movements.
• Dyskinetic cerebral palsy represents 14% of all cases of cerebral palsy.

• Although imaging may show periventricular leukomalacia or thalamic
and basal ganglia lesions, normal structural imaging is also common
in these cases.
• Focal lesions occurring at any age, including ischemic strokes,
hemorrhages, demyelinating lesions, and space-occupying lesions (ie,
neoplasms), can cause chorea in the contralateral limbs when
involving basal ganglia structures.

• Of hemorrhagic or ischemic strokes, 1% to 4% have been associated
with movement disorders contralateral to the side of the injury, with
movements including chorea, hemiballismus, and dystonia.
• The onset can be acute at the time of the stroke or delayed.

• Lesions in the caudate, putamen, globus pallidus, subthalamic
nucleus, or thalamus can all be associated with chorea.
• Polycythemia vera, a myeloproliferative disorder, has also been
associated with chorea.

• It has been suggested to occur as a result of hyperviscosity impacting
blood flow to the basal ganglia, although an underlying molecular
explanation has also been proposed.
• Imaging the brain to look for a structural lesion is the first step in
diagnosis whenever a patient presents with hemibody or focal-onset
chorea.

PARAINFECTIOUS CHOREA
• Chorea can be caused by viral infections, either as a result of a
cytotoxic effect of the virus or by a cytokine-mediated or
parainfectious mechanism.
• When chorea occurs in the setting of a viral infection, it typically has
an acute or subacute onset and develops over the course of the
infection itself.

• It is often associated with encephalopathy and other signs of systemic
illness.
• It can be unilateral or generalized and typically improves over days to
weeks as the infection is treated.

• Viruses associated with chorea include measles, mumps, rubella,
varicella-zoster, influenza, herpesvirus, Epstein-Barr virus, tick-borne
encephalitis, West Nile encephalitis, cytomegalovirus, Japanese B
encephalitis, and HIV.

• In HIV, chorea can be the direct result of the virus or due to other
opportunistic infections (eg, toxoplasmosis, syphilis).
• Most TORCH infections can also cause chorea.

TOXIC/METABOLIC CAUSES OF CHOREA
• Medication-induced chorea is common and frequently encountered
in neurologic practice.
• ‘Levodopa-induced dyskinesia in patients with PD and tardive
dyskinesia from chronic neuroleptic exposure are among the most
common causes of chorea.

• Levodopa-induced dyskinesia occurs in approximately 50% of people
with PD at 5 years and correlates with
• disease duration
• higher doses of levodopa
• lower weight
• female sex, and
• younger age at onset

• Multiple pathogenic mechanisms have been described, including
pulsatile, nonphysiologic stimulation of dopamine receptors.
• Prolonged exposure to dopamine-receptor blocking agents, such as
many antipsychotic and antiemetic medications, leads to dopamine
receptor hypersensitivity.

• The result is often a characteristic
buccolingual masticatory chorea,
although any region of the body can be
involved.
• Other pharmacologic agents that have
been reported to cause chorea include:
CNS stimulants (eg, amphetamines),
anticholinergics
antihistamines
antidepressants
antiseizure medications, and
oral contraceptives.

• In most cases, the chorea remits with removal of the offending agent,
• But with tardive dyskinesia, movements may sometimes persist or
worsen even once the offending agent is discontinued.

• Various metabolic derangements have been associated with chorea,
• The most common of which is acute-onset chorea secondary to
nonketotic hyperglycemia,
• in which a characteristic hyperintense T1 signal is often seen in the
contralateral putamen.

• Additional endocrinologic changes associated with chorea include
hypocalcemia, hypoparathyroidism, hyponatremia or hypernatremia,
hypomagnesemia, and uremia.
• Toxins, including carbon monoxide, manganese, organophosphates,
and mercury, have also been associated with basal ganglia injury and
subsequent chorea.

APPLYING FOUR FEATURES IN THE DIAGNOSIS OF
CHOREA
• Various algorithms can guide the assessment of a patient with chorea.
• Considering the time course, age of onset, comorbid
history/examination findings, and comorbid data findings may aid the
clinician in distinguishing between causes of chorea and developing a
more targeted diagnostic plan.

• Hereditary causes are more often insidious and chronic, whereas
acquired causes may have a more subacute presentation.
• Static and paroxysmal causes have also been discussed.
• Episodic chorea can be seen in paroxysmal kinesigenic and
nonkinesigenic dyskinesia.
• Static chorea is more likely due to an acquired cause such as a vascular
lesion.

• Childhood onset often raises suspicion for Sydenham chorea.
• Adult onset should raise suspicion for HD and HD mimics.
• Further inquiry into ethnicity; inheritance pattern; drug exposures;
location of the chorea (eg, focal, diffuse, orobuccolingual); and
comorbid neurologic, psychiatric, systemic, and cognitive features
may guide diagnosis.

• Finally, bloodwork and imaging may aid in the diagnosis of select
hereditary, structural, autoimmune, or metabolic causes.
• In adults, genetic counseling followed by an HD gene test remains the
most appropriate first step when hereditary chorea is suspected given
the prevalence of HD compared to other hereditary conditions.

• If the HD test is negative, additional workup can be guided by the
clinical phenotype, presumed inheritance pattern, and additional test
results.
• Among HD phenocopies, Wild and colleagues reported that SCA17
accounts for 1.1% of HD phenocopies, HDL2 for 0.7%, Friedreich
ataxia (JPH3) for 0.35%, and inherited prion disease (PRNP) for 0.24%.

• Testing for these pathogenic variants can now be performed via a
single panel, or targeted assessments can be done based on features
described of each above.

• In a 2014 review of 514 HD phenocopies, 1.95% were found to have
the C9orf72 expansion, leading the authors to propose this
pathogenic variant as the most common phenocopy to test for after
an HD gene test is negative.
• Regardless, the majority of patients with HD phenocopies still do not
attain a formal genetic diagnosis.

Differential Diagnosis of Hereditary Chorea

Differential Diagnosis of Acquired Chorea

Dentatorubral-Pallidoluysian Atrophy
• Dentatorubral-pallidoluysian atrophy is an inherited
neurodegenerative disease that appears to be rare outside Japan but
has been found to be relatively common in North Carolina: hence the
alternative term Haw River syndrome.
• Typical symptoms of DRPLA include chorea, ataxia, myoclonic
epilepsy, dystonia, parkinsonism, psychosis, and dementia.

• Onset is usually in the 20s, with death about 20 years later.
• Anticipation occurs with paternal transmission of the gene.
• The pathology of DRPLA includes degeneration of the dentate and red
nuclei, the GP, and the STN.
• Neurodegeneration may also be found in the cerebral white matter,
putamen, medulla oblongata, and spinal cord.

• Neuronal nuclear inclusions stain for ubiquitin and atrophin-1.
• There is also evidence for aberrant phosphorylation of the DRPLA
protein complex and the nuclear membrane.
• DRPLA is associated with an expansion of CAG trinucleotide repeat in
a gene on chromosome 12.

• In this region of the genome, the normal trinucleotide repeat length
is 7–23.
• In DRPLA, the CAG repeat length is between 49 and 75.
• Because of the polyglutamine stretch in the mutant protein,
neurodegeneration likely relates to interactions between the protein,
other cellular components, and cellular proteins.

• The Haw River syndrome, described in a multigenerational African American
family, is caused by the same repeat expansion as DRPLA.
• Clinical differences include lack of myoclonic epilepsy and the presence of
subcortical white-matter demyelination, basal ganglia calcifications, and
neuroaxonal dystrophy.
• No information is available about the treatment of DRPLA, but as in HD, the
clinician should be guided by the nature and severity of symptoms.

Neuroacanthocytosis and McLeod Syndrome
• The term acanthocyte is derived from the Greek word for “thorn.”
• Acanthocytes are contracted erythrocytes with unevenly distributed
thorny projections, often with terminal bulbs.

• Acanthocytes are seen in peripheral blood smears in patients with
three neurological syndromes: abetalipoproteinemia,
neuroacanthocytosis, and McLeod syndrome.
• A broad spectrum of movement disorders is seen in
neuroacanthocytosis and McLeod syndrome.

• All forms of neuroacanthocytosis are rare disorders.
• Autosomal recessive neuroacanthocytosis is characterized by onset at
around age 35 years of a progressive syndrome that includes a
movement disorder and behavioral and cognitive changes.
• The movement disorder predominantly consists of chorea, dystonia,
and tics; parkinsonism may occur in more advanced stages.

• There is also prominent orofacial dystonia with dystonic tongue
protrusion interfering with eating.
• In addition, many patients exhibit lip and tongue biting and
prominent dysarthria and dysphagia.

• Behavioral changes resemble those seen in HD: anxiety, depression,
obsessive-compulsive disorder, and emotional lability.
• Subcortical dementia is a late feature.
• Seizures develop in approximately 50% of patients.

• There may be myopathy or axonal neuropathy, and the creatine
kinase level is elevated.
• In patients with neuroacanthocytosis, acanthocytes usually make up
5%–20% of peripheral blood erythrocytes.
• Autopsy changes include atrophy of the caudate, putamen, GP, and
SN, with marked neuronal loss and gliosis.

• The cerebral cortex is relatively spared.
• Mutations in the CHAC gene (recently renamed VPS13A) on
chromosome 9 that lead to the production of chorein, a truncated
protein of unknown function, have been found in this syndrome.
• Homologous proteins in animals seem important in intracellular
trafficking.

• McLeod syndrome is an X-linked recessive disorder linked to a
number of mutations in the XK gene, a gene for the Kell group of
erythrocyte membrane glycoprotein antigens on the X chromosome.
• McLeod syndrome usually begins around age 50 and has a slowly
progressive course.
• The most common clinical feature is an axonal peripheral neuropathy.

• Some patients have evidence of myopathy as well, and all have
elevations in serum creatine kinase level.
• The CNS illness is characterized by limb chorea.
• Oral movements and lip and tongue biting are less common than in
neuroacanthocytosis.

• Facial tics are common, and some patients have dystonia.
• Seizures may be seen.
• Subcortical dementia and behavioral changes occur later in the
disease course in approximately 50% of patients.
• Cardiomyopathy and hemolytic anemia are other common
manifestations.

• Neuroimaging studies may show caudate atrophy with secondarily
enlarged lateral ventricles.
• Increased T2-weighted signals in the lateral putamen may be seen on
MRI scans.
• Pathological changes include intense caudate atrophy, loss of small
cells, and gliosis in the dorsolateral putamen, with less severe
changes in the GP.

• Milder changes may be present in the thalamus, SN, and anterior
horns of the spinal cord.
• Neurons in the cerebral cortex, STN, and cerebellum are spared.
• The reported mutations in the XK gene result in absence or truncation
of the protein product.
• Kell is an endothelin processing enzyme.

• Endothelins are important in proliferation and development of neural
crest–derived cells and are thought to be important in
neurotransmitter release in dopaminergic neurons.
• No information is available about treatment of neuroacanthocytosis,
but the physician should be guided by the clinical manifestations.

Sydenham Chorea and Other Autoimmune
Choreas
• Sydenham chorea (SC), one of the major manifestations of rheumatic
fever, typically appears months after the initial streptococcal
infection.
• Because of the widespread availability of antistreptococcal therapy,
SC is now extremely rare in developed countries.

• It is a disorder of children, mainly girls, between ages 5 and 15, with a
mean age at onset of 8.4 years.
• The chorea begins insidiously, but progresses over a period of weeks,
and it generally resolves within about 6 months.
• Choreic movements are usually generalized, but asymmetric and
hemichorea may also be seen.

• Behavioral accompaniments such as restlessness, irritability, and
obsessive-compulsive traits are common.
• It is a self-limited disorder, usually lasting up to 6 months.
• Approximately 20% of cases recur, but multiple recurrences are rare.

• Mild enlargement of the basal ganglia may be seen on MRI brain scan.
• Pathologically, SC is characterized by inflammation of the cortex and
basal ganglia.
• Anti–basal ganglia antibodies can be detected by enzyme-linked
immunosorbent assay and Western immunoblot.

• The mechanism of basal ganglia damage is likely molecular mimicry,
with cross-reaction between antibodies directed against streptococcal
and striatal antigens.
• Because it is often self-limited, the decision to treat SC depends on
the magnitude of each patient’s disability.
• A recent comparative trial suggested that valproic acid is the most
effective treatment, followed by carbamazepine and haloperidol.

Contd....
• The typical neuroleptics, such as haloperidol, however, are now rarely
used in the treatment of chorea and instead VMAT2 inhibitors, such
as tetrabenazine, deutetrabenazine, and valbenazine are now
considered the drugs of choice.

• Because SC tends to be self-limited, periodic attempts should be
made to wean from therapy.
• Intravenous methylprednisolone followed by oral prednisone may be
useful in refractory cases.

• Later in life, people who have survived SC may have a recrudescence
of chorea in the presence of hormonal stresses like pregnancy (chorea
gravidarum) or estrogen treatment.
• Besides SC, there are many other autoimmune choreas, including
systemic lupus erythematosus and paraneoplastic choreas and
NMDAR encephalitis.

Etiology of Hemiballism
• Structural Lesions
• Cerebrovascular Disease
Infarction
Transient ischemic attack
Hemorrhage
Arteriovenous malformation
Subarachnoid hemorrhage
Subclavian steal syndrome

Infection
• Syphilis
• Tuberculoma
• Toxoplasmosis
• AIDS
• Influenza A
Tumor
• Pituitary microadenoma
• Metastasis

Immune-Mediated
• Systemic lupus erythematosus
• Sydenham chorea
• Behçet disease
• Scleroderma
Other
• Static encephalopathy
• Head injury
• Demyelinating disease
• Thalamotomy
• Heredodegenerative disease

Metabolic
• Nonketotic hyperosmolar
hyperglycemia
Drug-Induced
• Phenytoin and other
anticonvulsants
• Oral contraceptives
• Neuroleptics (tardive)

Ballism
• Ballism is usually a high-amplitude proximal ballistic flinging
movement that most commonly affects the limbs on one side of the
body (HB), but involvement in both legs (paraballism) or both sides of
the body (biballism) is also possible.

• Ballism overlaps with choreas, and both movements may coexist.
• Acute-onset ballism often evolves into and is replaced by chorea.
• Animal models with lesions in the STN result in a mixture of choreic
and ballistic movements.

• The development of ballism varies with the underlying etiology.
• HB related to stroke appears suddenly or emerges more slowly in a
recovering plegic limb.
• Approximately 20% of cases relate to structural lesions within the
contralateral STN and in 20% of cases no lesion can be demonstrated
by MRI.

• In other cases, the lesion is usually found in the afferent or efferent
projections of the STN.
• Rarely, other etiologies, even ipsilateral to the movement, have been
described.
• Although the underlying lesion is usually cerebrovascular disease in the
elderly and infectious or inflammatory disease in younger patients, any type
of structural lesion, appropriately placed, can produce the characteristic
movement.

• Metabolic disorders such as nonketotic hyperglycemia and drug
exposure may also cause HB.
• The mechanism of ballism is not well understood but loss of STN
excitation of the GPi results in a loss of inhibitory drive to the
thalamus, giving rise to excessive motor activity which may be
represented clinically by the ballistic movements.

• Low firing frequency of the STN has been confirmed in a few cases,
using intraoperative recording.
• Long-term prognosis and outcome closely relate to the underlying
etiology.

• Movements often regress or become more choreic over several
months, but they can be quite exhausting or disabling when present,
and treatment is usually only indicated acutely and in patients whose
movements do not resolve spontaneously.

• Although the rarity of the condition has precluded controlled clinical
trials, there is ample evidence from case series and reports that
dopamine antagonists and dopamine depleters (VMAT2 inhibitors)
effectively decrease choreic movements.
• Beneficial results have also been obtained using gabapentin and
valproic acid.

MANAGEMENT OF CHOREA
• Chorea may cause physical disability, functional impairment, and
social isolation.
• It is important to understand the impact of the chorea on the
patient’s well-being and function to determine whether treatment is
warranted.
• In some conditions such as HD, it is often outsiders or family
members who notice the chorea more than the patient.

• The first step in managing chorea is to determine whether the impact
of the movements requires treatment at all.
• Chorea that is mild and does not interfere with daily function,
dexterity, or mobility does not necessarily need to be treated.

• It is important to be aware, however, that lack of awareness of
deficits (anosognosia) is a common feature of some
neurodegenerative diseases, including HD.
• As a result, the clinician and family should attempt to judge the
impact of the chorea in collaboration with the patient.

Management of Secondary Chorea
• When chorea results from an underlying disease, disease-specific
therapy is often the most effective approach to treatment.
• It is important not to miss the opportunity to treat conditions that are
reversible.
• Chorea that results from structural, metabolic, or infectious causes
can often be self-limited and may not require symptomatic treatment
outside of the acute setting.

• Therapies for specific causes of chorea include:
penicillin for Sydenham chorea
antimicrobials for CNS infections
immunotherapy for autoimmune conditions;
blood sugar control for hyperglycemi
management of abnormalities in sodium, calcium, or thyroid levels;

chelation for Wilson disease; and
phlebotomy for polycythemia
• For chorea due to paraneoplastic causes, immunotherapies may be
used, but treating the underlying cancer is critical.

• Chorea that is caused by levodopa often improves with reducing the
dose of levodopa and/or supplementing with other medications such
as amantadine.
• Of note, an extended-release form of amantadine has been approved
to manage levodopa-induced chorea.

• For tardive dyskinesia, vesicular monoamine transporter-2 (VMAT2)
inhibitors (often called dopamine depleters) are recommended, and
evidence is insufficient to support or refute withdrawing or switching
the offending/causative agent.

• Instead, the appropriateness of the offending agent should be
reviewed and assessed, and if necessary, dopamine-depleting agents
are recommended.
• Most genetic causes of chorea are treated symptomatically; however,
Wilson disease is an exception.

• Screening for Wilson disease early whenever suspicion exists is critical
because disease-modifying therapy with chelation and zinc can
reduce copper deposition, modify the disease course, and improve
symptoms.

• For NBIA disorders, no clear treatment guidelines have been established,
• although case reports of chelation therapies have been described in some of
these conditions.
• Paroxysmal kinesigenic dyskinesia and paroxysmal nonkinesigenic dyskinesia
may respond to antiseizure medications and dietary changes.
• For other genetic causes of chorea, including HD, management is primarily
symptomatic and supportive.

Pharmacologic Management of Chorea
• VMAT2 inhibitors deplete the release of dopamine presynaptically by
preventing packaging of monoamines into presynaptic storage vesicles.
• This results in fewer movements as less dopamine is released from
presynaptic terminals in the nigrostriatal pathway.
• Two VMAT2 inhibitors are approved by the US FDA for the management
of chorea related to HD: tetrabenazine and deutetrabenazine.

• The TETRA-HD (Efficacy and Safety of Tetrabenazine in Chorea) study
provided Class I evidence of the efficacy of tetrabenazine based on
improvement in motor chorea scores on the UHDRS.
• Potential side effects that may limit the use of tetrabenazine include
depression and suicidal ideation, sedation, and parkinsonism.
• Deutetrabenazine is also FDA approved for the management of HD
chorea.

• It is chemically identical to tetrabenazine, except that the metabolic
profile is altered by replacing key hydrogen atoms with deuterium.
• The incorporation of deuterium results in a longer half-life, less
frequent dosing, and more stable serum drug levels.

• The FIRST-HD (First Time Use of SD-809 in Huntington Disease) study
demonstrated significant improvement in UHDRS scores in patients
with HD compared to placebo.
• Deutetrabenazine was also studied for the management of tardive
dyskinesia, and the ARM-TD (Aim to Reduce Movements in Tardive
Dyskinesia) study demonstrated Class I evidence of improvement in
AIMS scores in this population compared to placebo.

• Deutetrabenazine is now approved for the management of HD chorea
and tardive dyskinesia, and has been used off label for the
management of other forms of chorea.
• It is thought to have less potential for side effects, such as mood
disorders and sedation, than tetrabenazine, but patients should still
be monitored for changes in mood, suicidal ideation, and
parkinsonism.

• Another VMAT2 inhibitor, valbenazine, is also FDA approved for the
management of tardive dyskinesia.
• Valbenazine has a once-daily dosing profile and was shown in the
KINECT-3 (A Phase 3 Study of NBI-98854 for the Treatment of Tardive
Dyskinesia) trial to effectively improve AIMS scores compared to
placebo in patients with tardive dyskinesia.
• It is currently being studied for other conditions, including HD chorea.

• Neuroleptics are frequently used off-label for the management of
chorea in various disorders, including HD.
• D2 -receptor blockade occurs with both typical and atypical
neuroleptics and results in inhibition of the indirect pathway, thereby
reducing movements.

• Despite having less disease-specific evidence for their use in chorea,
neuroleptics are often used as adjunctive treatments for behavioral
and psychiatric issues in HD and other degenerative choreas.
• They are sometimes also considered off-label for effects on weight
gain and sleep.

• Neuroleptics with greater D2 blockade, such as typical neuroleptics,
risperidone, and olanzapine, may be more effective in treating chorea
than neuroleptics such as quetiapine and clozapine, which have lower
D2 blockade.
• Neuroleptics should be used with caution because of the risk of
metabolic syndrome, somnolence, parkinsonism, and tardive
dyskinesia.

• Another medication that is sometimes used off-label in the
management of chorea is the NMDA receptor antagonist amantadine.
• Evidence for the benefit of amantadine has already been discussed in
the context of levodopa-induced dyskinesia, but evidence for use in
other forms of chorea, including HD and tardive dyskinesia, is limited.

• Antiseizure medications have multiple sites of action, including in the
basal ganglia, although they are rarely used in the neurodegenerative
choreas.
• These medications are used more often in pediatric patients and can
be useful in patients who also have seizures, such as those with
neuroacanthocytosis, juvenile HD, or DRPLA.

• When chorea is comorbid with dystonia, particularly when the onset
is focal, botulinum toxin injections may be considered.
• However, botulinum toxin is not approved specifically for the
management of chorea.

• Research on the use of cannabinoids for chorea is inconclusive.
• Cannabinoid receptors are present throughout the basal ganglia;
cannabinoid receptor type 1 (CB1) receptors, in particular, are
reduced as part of the degenerative process in HD.

• Although this suggests a rationale for manipulation of the
endocannabinoid system in the symptomatic management of
hyperkinetic movements, randomized controlled studies have thus far
shown inconsistent results.

Nonpharmacologic Management of Chorea
• Deep brain stimulation may be a treatment option for medication-
refractory hyperkinetic movement disorders.
• Deep brain stimulation has been studied in HD chorea and tardive
dyskinesia, but usage remains investigational.

• Targeting the globus pallidus internus has been shown to have
antichoreic effects, but the cognitive and neuropsychiatric features of
degenerative conditions such as HD make this a limited treatment
option in most cases.

• A multidisciplinary approach to the management of chorea is critical
to address the movements themselves as well as the comorbid
complications associated with many conditions that cause chorea,
such as HD.
• Addressing the psychiatric and cognitive aspects of
neurodegenerative diseases is as important as managing the motor
aspects.

• Individuals with neurodegenerative diseases can benefit from
working with speech, occupational, and physical therapists;
social workers
psychiatrists
neuropsychologists; and
genetic counselors to address the myriad of functional and social issues
associated with their disease

• Caloric demands are higher among individuals with chorea,
particularly in HD, and nutrition consultations may be helpful in
developing a healthy high-caloric diet.

• Trunk and limb chorea may lead to balance disorders and falls;
therefore, working with physical therapists on balance training and
core strengthening and implementing assistive devices may be useful.
• Multidisciplinary rehabilitation programs have been shown to
improve motor and balance deterioration in people with HD.

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