19. Chorea Curs Complet

5/20/2018 19. Chorea Curs Complet

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Chorea


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Chorea" is a borrowed Latin word that derives from theGreek khoreia,a choral dance. The basic Greek word for

dance (written with the Roman alphabet) is khoros.

The ad hoc Committee on Classification of the WorldFederation of Neurologyhas definedchorea as

"a state of excessive, spontaneous movements,irregularly timed, non-repetitive, randomly distributedand abrupt in character. These movements may vary inseverity from restlessness with mild intermittentexaggeration of gesture and expression, fidgeting

movements of the hands, unstable dance-like gait to acontinuous flow of disabling, violent movements


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Patients with chorea exhibit motor impersistence(ie, they cannotmaintain a sustained posture).

When attempting to grip an object, they alternately squeezeand release ("milkmaid's grip").When they attempt to protrude thetongue, the tongue often pops in and out ("harlequin's tongue").Patients often drop objects involuntarily. Also common are attemptsby patients to mask the chorea by voluntarily augmenting thechoreiform movements with semipurposeful movements.

Chorea involves both proximal and distal muscles. In most patients,normal tone is noted, but, in some instances, hypotoniais present.

In a busy movement disorder center, levodopa-induced chorea isthe most common movement disorder, followed by Huntingtondisease
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The term athetosiscomes from the Greek word athetos(notfixed).It is a slow form of chorea. Because of the slowness, themovements have a writhing (ie, squirming, twisting, or snakelike)appearance. Choreoathetosis is essentially an intermediate form.

Ballism or ballismusis considered a very severe form of chorea inwhich the movements have a violent, flinging quality.

In Greek, ballismosmeans "a jumping about or dancing."[2]Ballism has been defined as "continuous, violent, coordinated

involuntary activity involving the axial and proximal appendicularmusculature such that the limbs are flung about."

This movement disorder most often involves only one side ofthe body (ie, hemiballism or hemiballismus). Occasionally, bilateralmovements occur (ie, biballism or paraballism). Many patients withhemiballism have choreiform movements and vice versa, andhemiballism often evolves into hemichorea.


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Schematic diagram of the basal ganglia circuitry. Represented are the following: inhibitory (red arrows) and excitatory (green arrows)projections between the motor cortex, the putamen, the globus pallidus pars externa (GPe) and globus pallidus pars interna (GPi), thesubthalamic nucleus (STN), the substantia nigra pars reticulata (SNr) and substantia nigra pars compacta (SNc), and the ventrolateralthalamus (VL). D1 and D2 indicate the direct (regulated by dopamine D1 receptors) and indirect (regulated by dopamine D2 receptors)

pathways, respectively


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Pathophysiology

A simple model of basal ganglia function states that dopaminergicand GABAergic impulses from the substantia nigra and motorcortex, respectively, are funneled through the pallidum into themotor thalamus and motor cortex. These impulses are modulated inthe striatumvia two segregated, parallel, direct and indirect loops

through the medial pallidum and lateral pallidum/subthalamicnucleus. Subthalamic nucleus activity drives the medial pallidum toinhibit cortex-mediated impulses, thereby inducing parkinsonism.

Absent subthalamic nucleus inhibition enhances motor activity

through the motor thalamus, resulting in abnormal involuntarymovementssuch as dystonia, chorea, and tics. A classic example ofloss of subthalamic inhibitory driveis ballism


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History

Patients with chorea

may not initially be aware of the abnormal movements because they

may be subtle.can suppress the chorea temporarily and frequently camouflagesome of the movements by incorporating them into semipurposefulactivities (ie, parakinesia).

The inability to maintain voluntary contraction(ie, motorimpersistence), as is seen during manual grip (milkmaid grip) tests

or tongue protrusion, is a characteristic feature of chorea andresults in the dropping of objects and clumsiness.

Muscle stretch reflexes are often hung-up and pendular.

In severely affected patients, a peculiar dancelike gait may be noted.

Depending on the underlying cause of the chorea, other motorsymptomsinclude- dysarthria, dysphagia, postural instability, ataxia,dystonia, and myoclonus.


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Laboratory Studies Diagnosis of the primary choreatic conditions

history and clinical findings;

several laboratory studiesare useful, especially in distinguishing the secondary forms of chorea from theprimary forms.

Huntington disease: The only laboratory study presently available to confirm HD is genetictesting. It identifies a gene abnormality in the short arm of chromosome 4, characterizedby abnormal repetition of the trinucleotide CAG, the length of which determines the age ofonset (anticipation).

Wilson disease:A low serum ceruloplasmin level and serum copper values showingincreased urinary copper excretioncorroborate the diagnosis in most cases.

Liver functiontest results are usually abnormal.If the diagnosis is still uncertain, liver biopsycan help confirm the diagnosis.

Sydenham chorea: The chorea can lag behind the etiologic streptococcal infection by 1-6months, sometimes as long as 30 years; therefore, antistreptococcal antibodytiters mayno longer be elevated at presentation. Without documentation of an antecedentstreptococcal infection, the diagnosis of Sydenham chorea must be made by excludingother causes.

Neuroacanthocytosis: The diagnosis is confirmed by the presence of spiky erythrocytes(acanthocytes)in peripheral blood smears. The serum creatine kinase level may beelevated.

is based on


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Other laboratory studies useful in the differential diagnosis

of chorea include complement levels, antinuclear antibody titers,antiphospholipid antibody titers, amino acid levels in serum andurine, enzymatic studies from skin fibroblasts, thyrotropin levels,thyroxine values, and parathormone levels.


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Imaging Studies

MRI Patients with Huntington disease (HD) and chorea-acanthocytosis show decreased signalin theneostriatum, caudate, and putamen. No significantdifference has been observed between these

diseases. The decreased neostriatal signalcorresponds to increased iron deposition.

Generalized atrophy, as well as focal atrophy ofthe neostriatum, predominantly of the caudate, with

resulting enlargement of the frontal horns, follows theinitial findings of decreased neostriatal signal


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Medical Care

Only symptomatic treatment is available for patients with

chorea.Chorea may be a disabling symptom, leading to bruises,fractures, and falls, and may impair the ability of patients to feedthemselves.

The most widely used agents in the treatment of chorea are theneuroleptics. The basis of their mechanism of action is thought to

be related to blocking of dopamine receptors.Neuroleptics can be classified as typical and atypical.Typical neurolepticsinclude haloperidol and fluphenazine.

Atypical neurolepticsinclude risperidone, olanzapine, clozapine, andquetiapine.

Dopamine-depleting agents, such as reserpine and

tetrabenazine, represent another option in the treatment of chorea. GABAergic drugs, such as clonazepam, gabapentin, and valproate, can be used as adjunctive therapy.


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Coenzyme Q10 alone and in combination with minocycline have

been proposed as potential therapies

Intravenous immunoglobulin and plasmapheresis may shorten thecourse of the illness and decrease symptom severity in patients with

Sydenham chorea.


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Surgical Care

Deep brain stimulation is an emerging technique thatmay benefit patients, at least in certain cases.

Although deep brain stimulation is not yet used routinely

for chorea, as it is for PD, exciting progress has beenmade with this modality.

Cell transplantation is controversial and in early stages ofresearch. It has shown variable results for HD patientparticipants.


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Causes of Chorea

Inherited

Ataxia-telangiectasia Benign hereditary chorea Hallervorden-Spatz disease Hereditary spinocerebellar ataxias Huntington disease Inborn errors of metabolism

Glutaric acidemia, Propionic acidemia ,Homocystinuria Phenylketonuria,Sulfite oxidasedeficiency

Mitochondrial encephalomyopathies Neuroacanthocvtosis Paroxysmal disorders

Paroxysmal kinesiogenic choreoathetosis

Paroxysmal nonkinesiogenic choreoathetosis

Pyruvate carboxylase deficiency Wilson disease


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Drugs Antimetabolites

Anticholinergics

Anticonvulsants (eg, phenytoin, carbamazepine, phenobarbital) Antidopaminergic agents (eg, phenothiazines, haloperidol, metoclopramide) Antihistamines CNS stimulants (eg, amphetamines, methylphenidate, pemoline) Lithium

Dopamine agonists (eg, levodopa) Oral contraceptives

Endocrine

Hyperthyroidism

Chorea gravidarum Hypoparathyroidism, pseudohypoparathyroidism
http://emedicine.medscape.com/article/121865-overviewhttp://emedicine.medscape.com/article/1149725-overviewhttp://emedicine.medscape.com/article/1149725-overviewhttp://emedicine.medscape.com/article/121865-overview


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Immune/infectious

Behet disease Other infections - Pertussis, diphtheria, varicella Primary antiphospholipid antibody syndrome

Sydenham chorea Systemic lupus erythematosus Bacterial endocarditis Herpes simplex encephalitis HIV related Infectious mononucleosis

Lyme disease Mycoplasmal pneumonia Viral meningoencephalitis (eg, mumps, measles, varicella)

Vascular

Arteriovenous malformation

Basal ganglia infarction or hemorrhage

Vasculopathies/vasculitis: Churg-Strauss syndrome[1] ,moyamoya
http://emedicine.medscape.com/article/329099-overviewhttp://emedicine.medscape.com/article/1146456-overviewhttp://emedicine.medscape.com/article/896540-overviewhttp://emedicine.medscape.com/article/1165183-overviewhttp://emedicine.medscape.com/article/330178-overviewhttp://emedicine.medscape.com/article/330178-overviewhttp://emedicine.medscape.com/article/1165183-overviewhttp://emedicine.medscape.com/article/896540-overviewhttp://emedicine.medscape.com/article/1146456-overviewhttp://emedicine.medscape.com/article/329099-overview


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Metabolic Hypocalcemia

Hypoglycemia and hyperglycemia Hypomagnesemia Hyponatremia, hypernatremia, and central pontine myelinolysis Renal failureMiscellaneous Cerebral palsy

Head trauma Bronchopulmonary dysplasia (infantile chorea) Cardiopulmonary bypass - "Postpump chorea

Neoplastic Primary and metastatic brain tumors Primary CNS lymphomaToxins CO, Mg, organophosphate


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Pathophysiology and General Principles inTreatment of Chorea

Movement disorders (particularly chorea, athetosis, and dystonia)are thought to result from basal ganglia pathology.

Dopaminergic neurons within the substantia nigra project rostrallyto the neostriatum (caudate and putamen).

Chorea may be viewed as resulting from increased dopaminergicactivity in the projections from the substantia nigra to the striatum,resulting in decreased GABAergic projection from the striatum to theglobus pallidus.

Most of the drugs used in symptomatic treatment of chorea act

through attenuation of dopaminergic transmission orenhancement of GABA transmission. Anticonvulsant drugs may suppress chorea but also may induce

chorea, especially in patients with basal ganglia dysfunction.


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Rheumatic (Sydenham) Chorea

In 1684, Thomas Sydenham described the clinical syndrome thatnow bears his name. Originally termed St. Vitus' dance, it now isreferred to as rheumatic chorea. Stoll first proposed a relationshipbetween Sydenham chorea and rheumatic fever (RF) in 1780.

In 1889, Cheadle described the full rheumatic syndromeof carditis,

polyarthritis, chorea, subcutaneous nodules, and erythemamarginatum. Several decades later, epidemiologic and microbiologic studies

confirmed the etiological role of streptococcal infectionin RF.

More recently, Sydenham chorea (SC) has been linked to numerous

neuropsychiatric disorders, including obsessive compulsive disorder(OCD), attention deficit-hyperactivity disorder, depression andanxiety.


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Epidemiology

Sydenham chorea is the most common cause of acquired chorea in theyoung.During the latter part of the twentieth century the number ofreported cases of RF in the United States increased. This resurgenceappears to be associated with strains of group A beta hemolyticstreptococcal infection that are less likely to cause symptomatic pharyngitis.

In the United States, the incidence of RF is approximately 0.5-2 per

100,000 population per year.

Chorea is a major manifestation of acute RF and is the only evidence of RF in approximately 20% of cases.

In some outbreaks, chorea has been present in more than 30% of patients

with acute RF.

The female-to-male ratio is approximately 2:1, and most patients presentbetween 5-15 years of age.


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Clinical features and course

SC is a major manifestationof acute rheumatic fever.

According to the 1992 modification of the Jones criteria,chorea (or indolent carditis) alone is sufficient for diagnosis ofRF, provided other causes have been excluded.

SC typically presents with other manifestations of RF, but in20% of cases chorea may be the presenting or solemanifestation of RF.

The main features of SC are involuntary movements,hypotonia, and mild muscular weakness.

Chorea can be generalized or unilateral, predominantlyinvolving the face, hands, and arms. Movements are presentat rest, aggravated by stress, and usually cease during sleep.


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In about 20% of patients, only one side of the body may

seem to be affected (hemichorea); however, carefulexamination usually reveals some involvement of the oppositeside.

The choreic movements interfere with volitional movementsand result in a clumsy gait, dropping and spilling, andexplosive bursts of dysarthric speech.

Muscular weakness leads to inability to sustain a contraction(milkmaid's grip).

The pronator sign consists of hyperpronation of the hands,causing the palms to face outward when the arms are held overthe head. Another sign of weakness and hypotonia is the so-called choreic handwith the arms extended, the wrist will flex

and the metacarpophalangeal joints overextend.


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Some children may have such profound weakness that theyappear paralyzed. Not uncommonly, children are restricted tobed or are unable to attend school for the duration of theillness. Fortunately, paralytic chorea is uncommon.

Patients with SC may also have psychiatric symptomssuch asdepression, anxiety, personality changes, emotional lability,OCD, and attention deficit disorder (ADD).

Occasionally, these symptoms precede the onset of chorea


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On average, the disease resolves spontaneouslyin 3-6 months andrarely lasts longer than 1 year.

Mild chorea without functional disability may be found in a small

proportion of patients up to 10 years after the initial attack of SC.

About 20% of patients experience 2-10 recurrences, usually within 2years after the initial attack.


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Pathophysiology

Immunology: Evidence suggests that SC may result from the production ofimmunoglobin G antibodiesthat crossreact with antigens in the membrane of group Astreptococci and antigens in the neuronal cytoplasm of the caudate and subthalamic

nuclei, namely intracellular tubulinand extracellular lysoganglioside.Antineuronal antibodies have also been found in the cerebrospinal fluid (CSF) ofpatients with acute rheumatic chorea. Immunofluorescent staining has shown thatsera from approximately half of the children with SC have antibodies that react withneuronal cytoplasmic antigens in the caudate and subthalamic nuclei.

Serum antineuronal antibody titers have been found to decrease as the choreaimproves.

In children who suffer a relapse, the increase in symptom severity correlates with arise in these neuronal antibodies.


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Neuroimaging

MRI findings in SC are not consistent and may benormal.

Functional neuroimaging using fluorodeoxyglucose (FDG)positron emission tomography (PET) has demonstrated

reversible striatal hypermetaboli.


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Diagnosis

Diagnosis rests on a combination of clinical manifestations that candevelop in relation to group A streptococcal pharyngitis. These

include chorea, carditis, subcutaneous nodules, erythemamarginatum, and migratory polyarthritis. Because the incitinginfection is completely treatable, attention has been refocused on

prevention.


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Diagnosis

Diagnosis of SC may be difficult, because no single, establisheddiagnostic test is available.

SC usually develops in those aged 3-13 years and is believed to result froma preceding streptococcal infection.

The patient may have no history of rheumatic fever, and apreceding streptococcal infection cannot always be documented. Infectionscan be subclinical and often precede the development of neurologicsymptoms by age 1-6 months.

At least 25% of patients with SC fail to have serologic evidence ofprior infection.

Chorea may be the first and only manifestation of rheumatic fever.However, some patients may have subtle evidence of carditis byechocardiography despite a normal clinical examination and ECG. Chorea

alone is sufficient for diagnosis providing other causes of the condition havebeen excluded.


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Treatment

Treatment and prevention may involve multiple fields of discipline,including infectious diseases, cardiology, and neurology. For thisreason, several different classes of medications are used. These

include antibiotic, neuroleptic, and cardiac medications

(ethiologyc, pathogenic, symptomatic) A.The primary goal of treating an ARF attack is to eradicate streptococcalorganisms and bacterial antigensfrom the pharyngeal region.

Penicillinis the drug of choice in persons who are not at risk ofallergic reaction. A single parenteral injection of benzathine benzylpenicillincan ensure compliance.

Oral cephalosporins, rather than erythromycin, are recommended as

an alternative in patients who are allergic to penicillin. However, be

cautious of the 20% cross-reactivity of the cephalosporins with penicillin


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C

SC is usually self-limited, and treatment should be limited topatients with chorea severe enough to interfere with function.

Anticonvulsants(valproic acid and carbamazepine) have beenshown to be effective in diminishing choreic movements at doses

normally used for seizure control. In particular, valproate may bequite helpful in children with SC.Dopaminergic blockers(pimozide and haloperidol) are effective

and, when used in small doses, are usually well tolerated.Neurolepticssuch as haloperidol and pimozide remain an importanttreatment option, especially in older children

B. Steroidshave been used widely, but no controlled studies have been done


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y,to confirm steroid efficacy in chorea.Patients with carditis require prednisone. The goal is to decrease myocardialinflammation. May decrease inflammation by reversing increased capillarypermeability and suppressing PMN activity. After 2-3 wk, dosage may tapered,

reduced 25% each week. . Prednisone,

plasma exchange and intravenous immunoglobulin(IVIG) have beenshown to be effective. Case reports have suggested IVIG to be a safe,

effective option in disabling SC. Immunologic treatment can also be effective but is expensive and may be

associated with significant side effects.

The presence of antineuronal antibodies suggests that intravenousimmunoglobulin (IVIg) and plasma exchange may be effective.

More recent reports have shown IVIG to be an effective safe option.Because this treatment modality is quite expensive, it should be reservedfor protracted or debilitating cases.
http://reference.medscape.com/drug/prednisone-intensol-342747http://reference.medscape.com/drug/gammagard-s-d-carimune-nf-immune-globulin-iv-igiv-343138http://reference.medscape.com/drug/gammagard-s-d-carimune-nf-immune-globulin-iv-igiv-343138http://reference.medscape.com/drug/prednisone-intensol-342747


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Parents and school officials should be informed that emotionallability is characteristic of this organic condition.

Children with SC require prophylaxis against

streptococcal infections until 18 years of age.


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Chorea gravidarum

Background

Chorea gravidarum (CG) is the term given to chorea occurringduring pregnancy. This is not an etiologically or pathologicallydistinct morbid entity but a generic term for chorea of anycause starting during pregnancy.

Chorea gravidarum is regarded as a syndrome rather than aspecific disease entity.


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Incidence

Willson and Preece (1932) found that the overall incidence ofchorea gravidarum was approximately 1 case per 300 deliveries.

The condition is much more rare now.The decline is probably the result of a decline in rheumatic

fever (RF),which was a major cause of chorea gravidarum beforethe use of antibiotics for streptococcal pharyngitis.

In recent times, most cases of chorea appearing during pregnancyare caused by other diseases systemic lupus erythematosus[SLE], Huntington disease).

In general, about half the cases are idiopathic, with rheumatic feverand antiphospholipid syndrome (APLS) underlying most of theremainder.


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Patientprofile

Most patients with chorea gravidarum are young; theaverage age is 22 years.

Of initial attacks, 80% occur during first pregnancies,

and one half start during the first trimester.One thirdbegin in the second trimester.

Of afflicted women, 60% previously had chorea.Recurrences may occur in subsequent pregnancies,

particularly if antiphospholipid syndrome is the cause.


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PathophysiologySeveral pathogenetic mechanisms for chorea gravidarum have been offered, but none

have been proven. Willson and Preece noted that nearly 70%of their patients gave a previous

history of either rheumatic fever or chorea.Of patients who present with chorea and no apparent carditis,

20% may develop rheumatic heart disease after 20 years.Interestingly, 50% of patients with oral contraceptive-induced

chorea have a past history of chorea, which in 41% of cases is of rheumatic

origin.

The suggestion is that estrogens and progestational hormones maysensitize dopamine receptors (presumably at a striatal level) and inducechorea in individuals who are vulnerable to this complication by virtue ofpreexisting pathology in the basal ganglion.

Pathologic changes found at autopsy in chorea gravidarum includeperivascular degenerative changes in the caudate nucleus.


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TREATMENT

CG is not an indication for abortion or premature interruption ofpregnancy

Indicated for patients with disabling severe choreaReserpine = CI

Haloperidoleffective

Pimozide, valproate, carbamazepine

Discontinue the oral contraceptive pill

2/3 the choreea lasts until puerperium

Mortality12%

21% have recurrent chorea with subsequent pregnancies

Huntington disease (HD)


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Background

is an incurable, adult-onset, autosomal dominant inherited disorderassociated with

cell loss within a specific subset of neurons in the basalganglia and cortex.

HD is named after George Huntington, the physician who described it ashereditary chorea in 1872.

Characteristic features of HD includeinvoluntary movements, dementia, and behavioral changes.

Huntington disease (HD)


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Pathophysiology

The most striking neuropathology in HD occurs withinthe neostriatum, in which gross atrophy of the caudatenucleus and putamenis accompanied by selectiveneuronal loss and astrogliosis.

Marked neuronal loss also is seen in deep layers of the

cerebral cortex. Other regions, including the globuspallidus, thalamus, subthalamic nucleus, substantianigra, and cerebellum, show varying degrees of atrophydepending on the pathologic grade.

The extent of gross striatal pathology, neuronal loss, andgliosis provides a basis for grading the severity of HDpathology (grades 0-4)


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No gross striatal atrophy is observed in grades 0 and 1.

Grade 1 cases have neuropathologic changes that can bedetected microscopically but without gross atrophy.

In grade 2, striatal atrophy is present, but the caudate

nucleus remains convex.

In grade 3, striatal atrophy is more severe, and thecaudate nucleus is flat.

In grade 4, striatal atrophy is most severe, and themedial surface of the caudate nucleus is concave.


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is the expansion of a cysteine-adenosine-guanine (CAG)repeatencoding a polyglutamine tract in the N-terminus of the proteinproduct called huntingtin.

The function of huntingtin is not known. Normally, it is located inthe cytoplasm. The association of huntingtin with the cytoplasmicsurface of a variety of organelles, including transport vesicles,synaptic vesicles, microtubules, and mitochondria, raises thepossibility of the occurrence of normal cellular interactions that

might be relevant to neurodegeneration.

N-terminal fragments of mutant huntingtin accumulate and forminclusionsin the cell nucleus in the brains of patients with HD, aswell as in various animal and cell models of HD.

The presence of neuronal intranuclear inclusions (NIIs)initially ledto the view that they are toxic and, hence, pathogenic

The genetic basis of HD

E id i l


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Epidemiology

Frequency

United States

Estimates of the prevalence of HD in the United Statesrange from 4.1-8.4 per 100,000 people. Accurateestimates of the incidence of HD are not available.

International

The prevalence in most European countries ranges from1.63-9.95 per 100,000 people. The prevalence of HD inFinland and Japan is less than 1 per 100,000 people.


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Mortality/Morbidity

HD is a relentlessly progressive disorder, leading to

disability and death, usually from an intercurrent illness.

The mean age at death in all major series ranges from51-57 years, but the range may be broader. Duration of

illness varies considerably, with a mean of approximately19 years. Most patients survive for 10-25 years after theonset of illness.

In a large study, pneumonia and

cardiovasculardisease were the most common primarycauses of death.


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Juvenile HD(ie, onset of HD in patients younger than 20 years)

accounts for approximately 5-10% of all affected patients. Most patients with juvenile HD inherit the disease from their father,

whereas patients with onset of the disease after age 20 years aremore likely to have inherited the gene from their mother.Inheritance through the father can lead to earlier onset through

succeeding generations, a phenomenon termed anticipation. Thisis caused by greater instability of the HD allele duringspermatogenesis.

CAG repeat length correlates inversely with age of onset, and thecorrelation is stronger when the onset of symptoms occurs earlier.

The length of the CAG repeat is the most important factor indetermining age of onset of HD. Most studies show a mean age at onset ranging from 35-44 years.


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Huntington Disease Clinical Presentation

The clinical features of Huntington disease (HD) include amovement disorder, a cognitive disorder, and a behavioraldisorder.Patients may present with one or all disorders invarying degrees.

Chorea(derived from the Greek word meaning to dance) is

the most common movement disorderseen in HD.
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Initially, mild chorea may pass for fidgetiness. Severe choreamay appear as uncontrollable flailing of the extremities (ie,ballism), which interferes with function.

As the disease progresses, chorea coexists with and graduallyis replaced by dystonia and parkinsonian features, such asbradykinesia, rigidity, and postural instability, which areusually more disabling than the choreic syndrome per se.

In advanced disease, patients develop an akinetic-rigidsyndrome, with minimal or no chorea. Other late features arespasticity, clonus, and extensor plantar responses.

Dysarthria and dysphagiaare common. Abnormal eye movementsmay be seen early in the disease.

Other movement disorders, such as tics and myoclonus, may beseen in patients with HD.

Juvenile HD (Westphal variant),defined as having an age ofonset of younger than 20 years, is characterized byparkinsonian features, dystonia, long-tract signs, dementia,epilepsy, and mild or even absent chorea.


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Cognitive declineis characteristic of HD, but the rate ofprogression among individual patients can vary considerably.Dementia and the psychiatric features of HD are perhaps theearliest and most important indicators of functional impairment.

The dementiasyndrome associated with HD includes early onsetbehavioral changes, such as irritability, untidiness, and loss ofinterest. Slowing of cognition, impairment of intellectual function,and memory disturbances are seen later. This pattern correspondswell to the syndrome of subcortical dementia, and it has beensuggested to reflect dysfunction of frontal-subcortical neuronal

circuitry.

Early stages of HD are characterized by deficits in short-termmemory, followed by motor dysfunction and a variety of cognitivechanges in the intermediate stages of dementia.[6, 7] These deficitsinclude diminished verbal fluency, problems with attention,

executive function, visuospatial processing, and abstract reasoning.Language skills become affected in the final stages of the illness,resulting in a marked word-retrieval deficit.
http://emedicine.medscape.com/article/289706-overviewhttp://emedicine.medscape.com/article/289706-overview


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The behavioral disorderof HD is represented mostcommonly by affective illness.

Depressionis more prevalent, with a small percentage ofpatients experiencing episodic bouts of maniacharacteristic of bipolar disorder.

Patients with HD and persons at risk for HD may have anincreased rate of suicide.

Patients with HD also can develop psychosis, obsessive-compulsive symptoms, sexual and sleep disorders, andchanges in personality


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Tendon reflexes are variable in HD, ranging fromreduced in some patients to pathologically brisk with

clonus in other patients. The plantar response usually isflexor, but it may be extensor in advanced stages of theillness.

Other hyperkinesias, such as tics and myoclonus, maybe seen in HD.

Eye movement abnormalities can be seen early in thedisease.


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Imaging Studies

No single imaging technique is necessary or sufficient fordiagnosis of Huntington disease (HD).

Measurement of the bicaudate diameter(ie, the distancebetween the heads of the 2 caudate nuclei) by CT scanor MRI is a reliable marker of HD.


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Other Tests

Genetic testing (reported as the CAG repeatnumber for

each allele) is now commercially available.

Genetic testing may not be necessary in a patient with a typicalclinical picture and a genetically proven family history of HD.

In the absence of a family history of HD, patients with a suggestiveclinical presentation should undergo genetic testing to exclude orconfirm HD.

If the genetic test is negativefor HD, then testing forsystemic lupus erythematosus (SLE), antiphospholipidantibody syndrome, thyroid disease, neuroacanthocytosis,

DRPLA, Wilson disease, and other less common causes ofchorea may be reasonable, depending on the individualcase


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Medication Summary

Although no therapy is currently available to delay the onsetof symptoms or prevent the progression of the disease,symptomatic treatment of patients with Huntington disease(HD) may improve the quality of life and preventcomplications. Symptomatic treatmentfor HD can be divided

into drugs to treat the movement disorderand drugs to treatpsychiatric or behavioral problems.

Therapeutic options include dopamine-depleting agents (eg,reserpine, tetrabenazine) and dopamine-receptor antagonists(eg, neuroleptics).


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Medical Care

Depressionin patients with HD is treatable and should be recognizedpromptly. Selective serotonin reuptake inhibitors (SSRIs) should beconsidered as first-line therapy. Other antidepressants, including bupropion,venlafaxine, nefazodone, and tricyclic antidepressants, also can be used.Electroconvulsive therapy (ECT) can be used in patients with refractorydepression.

Antipsychotic medicationsmay be necessary in patients with hallucinations,delusions, or schizophrenia-like syndromes. Newer agents, such asquetiapine, clozapine, olanzapine, and risperidone, are preferred to olderagents because of the lower incidence of extrapyramidal side effects and thedecreased risk for tardive syndromes.

Irritabilitymay be treated with antidepressants, particularly the SSRIs;mood stabilizers, such as valproic acid or carbamazepine; and, if needed,atypical neuroleptics.

Other less frequent aspects of HD that may require pharmacologictreatment are mania, obsessive-compulsive disorder, anxiety, sexual

disorders, myoclonus, tics, dystonia, and epilepsy.


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Wilson Disease


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Background

Wilson disease is a rare autosomal recessiveinheriteddisorder of copper metabolism. The condition ischaracterized by excessive deposition of copperin the liver,brain, and other tissues.

The major physiologic aberration is excessive absorption of

copper from the small intestine and decreased excretion ofcopper by the liver.

The genetic defect, localized to arm 13q, has been shown toaffect the copper-transporting adenosine triphosphatase

(ATPase) gene (ATP7B) in the liver.


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Patients with Wilson disease more often initially present withhepatic manifestationswhen identified in the first decadeof

life as compared with more neuropsychiatricillness later,and the latter most commonly occurs during the thirddecade.

The diagnosis is established by no individual test but requires

the use of some combination of serum ceruloplasmin level,urinary copper excretion, presence of Kayser-Fleischer rings,and hepatic copper content when biopsy is required.

Etiology


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Etiology

The normal estimated total body copper content is 50-100 mg, and theaverage daily intake 2-5 mg, depending on an individuals intake of legumes,meats, shellfish, and chocolate.

Copper is an important component of several metabolic enzymes, includinglysyl oxidase, cytochrome c oxidase, superoxide dismutase, and dopaminebeta-hydroxylase.

Around 50-75% of intestinal copper is absorbed and then transported to thehepatocytes. This pathway is intact in Wilson disease. After copper reachesthe hepatocyte, it is incorporated into copper-containing enzymes and copper-

binding proteins (CBPs), including ceruloplasmin, a serum ferroxidase.Within the liver, the majority of in-infancy (< 6 mo) CBP granules

staining positive may be normal. After 6 months, positive staining of CBPs forcopper is almost exclusively found in association with liver diseases such asWilson disease, chronic biliary disorders (eg, primary biliary cirrhosis, primarysclerosing cholangitis), cirrhosis/extensive fibrosis, and primary liver tumors(most often fibrolamellar hepatocellular carcinoma).

Excess copper may be rendered nontoxic by forming complexes with apo-


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Excess copper may be rendered nontoxic by forming complexes with apo-metallothionein to produce copper-metallothionein, or it may be excreted intobile. Normal copper balance is maintained by regulation of excretion, rather thanabsorption, and the predominant route of copper excretion (approximately 95%)is hepatobiliary in nature.

In Wilson disease, the processes of incorporation of copper intoceruloplasmin and excretion of excess copper into bile are impaired. Thetransport of copper by the copper-transporting P-type ATPase is defective inWilson disease secondary to one of several mutations in theATP7Bgene. Bygenetic linkage studies, Bowcock and colleagues narrowed the assignment of the

Wilson disease locus to 13q14-q21.


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The excess copper resulting from Wilson disease promotes

free radical formation that results in oxidation of lipids andproteins. Ultrastructural abnormalities in the earliest stages of

hepatocellular injury, involving the endoplasmic reticulum,mitochondria, peroxisomes, and nuclei, have been identified.

Initially, the excess copper accumulates in the liver, leading todamage to hepatocytes. Eventually, as liver copper levelsincrease, it increases in the circulation and is deposited inother organs.


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Histologic findings

Histologic findings in the brain include the following:

Copper deposition in the basal ganglia[8] Opalski cells - Periodic acid-Schiffpositive altered glial

cells

Cavitary degeneration Gliosis Neuronal loss


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Epidemiology

In the United States, the carrier frequency is 1 per 90

individuals. The prevalence of Wilson disease is 1 per 30,000individuals. Worldwide, the incidence of Wilson disease is 10-30 million

cases, and the heterozygote carrier rate is 1 case per 100persons, with the genetic mutation frequency varying from

0.3-0.7%.

Age-related presentations

A German study of patients with Wilson disease illustratedthat patients presenting earliershow predominantly hepaticsymptoms, while those presenting latermore often presentwith neurological symptoms.


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The onset of neurologic symptomssecond / third decade

50% are symptomatic by age 15 years The initial event is a deposition of copper

in the liver.


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Wilson Disease Clinical Presentation

History

Consider hepatic Wilson diseasein the differential diagnosis of anyunexplained chronic liver disease, especially in individuals younger than40 years. The condition may also manifest as acute hepatitis.

Hepatic dysfunction is the presenting feature in more than half ofpatients.

The 3 major patterns of hepatic involvement are as follows: (1) chronic active hepatitis, (2) cirrhosis, (3) fulminant hepatic failure.The most common initial presentation is cirrhosis


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Hepatic dysfunctionis the presenting feature in more than half ofpatients. Although the condition may manifest as acute hepatitis,

the 3 major patterns of hepatic involvement are as follows: Chronic active hepatitis Cirrhosis (the most common initial presentation) Fulminant hepatic failure

Signs of fulminant hepatic failure include the following:

Ascites and prominent abdominal veins Spider nevi Palmar erythema Digital clubbing Hematemesis Jaundice

Neuropsychiatric features


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Neuropsychiatric features

Most patientswho present with neuropsychiatric manifestations have cirrhosis.

The most common presentingneurologic featureis asymmetric tremor, which isvariable in character and may be predominantly resting, postural, or kinetic.

Frequent earlysymptoms include the following: Difficulty speaking Excessive salivation Ataxia

Masklike facies Clumsiness with the hands Personality changesLate manifestations(now rare because of earlier diagnosis and treatment) include the

following: Dystonia Spasticity

Grand mal seizures Rigidity Flexion contractures

Neurologic signs


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Neurologic signs

Neurologic signs of Wilson disease include the following:

Parkinsonian symptoms- Rigidity, bradykinesia Dysarthria Tremor at rest or with action Dystonia, mainly of the face Dysdiadochokinesia Poor handwriting Incoordination Abnormal eye movements ( slow saccadic movement, limitation of upgaze)

Respiratory dyskinesia, which can present as an unusual cough[3] Polyneuropathy, which may be the initial manifestationand may bereversible with treatment[4]


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Psychiatric features(10-20% of patients) include the following:

Emotional lability

Impulsiveness Disinhibition Self-injurious behavior

Psychiatric abnormalities associated with Wilson disease has beendivided into the following 4 basic categories:

Behavioral Affective

Schizophrenic-like Cognitive


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Psychiatric signs

Psychiatric signs include the following: Hyperkinetic behavior Irritability or anger Emotional lability

Psychosis Mania Difficulty concentrating Abnormal behavior

Personality changes Depression Schizophrenia

Musculoskeletal manifestations


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Musculoskeletal manifestations

The arthropathyof Wilson disease is a degenerative process thatresembles premature osteoarthritis

Symptomatic joint disease usually arises late in the course of thedisease, frequently after age 20 years The arthropathy generally involves the spine and large appendicular

joints (eg, knees, wrists, hips) Osteochondritis dissecans, chondromalacia patellae, and

chondrocalcinosishave also been described

Hematologic and renal manifestations

Coombs-negative acute intravascular hemolysis (10-15%) Urolithiasis Hematuria


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Clinically, patients may resemble those with Fanconi syndrome,demonstrating defective renal acidification and excess renal lossesof amino acids, glucose, fructose, galactose, pentose, uric acid,phosphate, and calcium. The frequency of renal manifestations isvariable.

Urolithiasis, found in up to 16% of patients with Wilson disease,may be the result of hypercalciuria or poor acidification.

Hematuria and nephrocalcinosis are reported.

OPHTALMOLOGIC SYMTOMS


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Kayser-Fleischer rings

Formed by the deposition of copper in the Descemet membranein the limbus ofthe cornea

The color may range from greenish gold to brown Well-developed rings may be readily visible to the naked eye or with an

ophthalmoscope set at +40.When not visible to the unaided eye, the rings may beidentified using slit-lamp examinationor gonioscopy

Observed in up to 90% of individuals with symptomatic Wilson disease and almostinvariably present in those with neurologic manifestations

No longer considered pathognomonicof Wilson disease unless accompaniedby neurologic manifestations, as they may also be observed in patients with chronic

cholestatic disorders


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Ophthalmic findings

Sunflower cataractsare brilliantly multicolored and are visible only onslit-lamp examination.

They do not impair vision.

Other relatively uncommon ophthalmic findings include exotropicstrabismus, optic neuritis or pallor of the optic disc


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Additional manifestations

Skeletal abnormalities(eg, osteoporosis, osteomalacia, rickets,spontaneous fractures, polyarthritis)

Cardiac manifestations(eg, rhythm abnormalities, increased

autonomic tone) Skin pigmentation and a bluish discoloration at the base of the

fingernails (azure lunulae)

Hi l i fi di


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Histologic findings

Histologic findings in the brain include the following:

Copper deposition in the basal ganglia[8] Opalski cells - Periodic acid-Schiffpositive altered glial

cells

Cavitary degeneration Gliosis Neuronal loss

DIAGNOSIS


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G OS S

Approach Considerations

The presence of Kayser-Fleischer ringsand ceruloplasmin levelsof less than 20 mg/dLin a patient with neurologic signs orsymptomssuggest a diagnosis of Wilson disease.

If a patient is asymptomatic, exhibits isolated liver disease, andlacks corneal rings, the coexistence of a hepatic copperconcentration of more than 250 mg/g of dry weight and a lowserum ceruloplasmin level is sufficient to establish a diagnosis.Therefore, in the absence of Kayser-Fleischer rings orneurologic abnormalities, a liver biopsy for quantitative copper

determination is essential to establish the diagnosis of Wilsondisease.

Diagnosis


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Considerations in the workup of Wilson disease are as follows: Serum ceruloplasmin levels are less than 20 mg/dL(reference range, 20-40 mg/dL) in

approximately 90% of all patients with Wilson disease The urinary copper excretion rate is greater than 100 mcg/day(reference range, < 40

mcg/day) in most patients with symptomatic Wilson disease, but it may also be elevated inother cholestatic liver diseases In a patient with Kayser-Fleischer rings, a serum ceruloplasmin level < 0 mg/dL and 24-hoyr

urine copper excretion >40 mcg/day establish the diagnosis of Wilson disease Hepatic copper concentration (criterion standard) on a liver biopsy specimen is >250 mcg/g

of dry weighteven in asymptomatic patients; a normal result (15-55 mcg/g) effectivelyexcludes the diagnosis of untreated Wilson disease, but elevation may be found in otherchronic hepatic disorders

Radiolabeled copper testing directly assays hepatic copper metabolism Genetic testingis limited to screening of family members for an identified mutation detected

in the index patient Brain imagingshows characteristic findings; MRI appears to be more sensitive than CT in

detecting early lesions Abdominal imagingfindings are neither sensitive nor specific Resting ECGabnormalities include left ventricular or biventricular hypertrophy, early

repolarization, ST segment depression, T-wave inversion, and various arrhythmias Electron microscopic detection of copper-containing hepatocytic lysosomes is helpful in thediagnosis of the early stages of Wilson disease, in addition to the quantification of hepaticcopper by atomic absorption spectrophotometry

Genetic diagnosis


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g Linkage analysis has been used in family studies for presymptomatic

testing; however, the multiplicity of mutations (>200 mutations ofATP7Bhave been identified) that require screening in individualswithout affected family members is large, making such analysisimpractical. Therefore, the use of molecular testing is currently limitedto screening of family members for an identified mutation detected inthe index patient.

Abdominal imaging

Computed tomography (CT) scanning, magnetic resonance imaging(MRI), ultrasonography, and nuclear medicine studies of the liver havebeen uninformative, with findings neither specific nor sensitive forWilson disease.

Electrocardiography

Resting electrocardiographic abnormalities include left ventricular orbiventricular hypertrophy, early repolarization, ST segment depression,T-wave inversion, and various arrhythmias.


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Serum Ceruloplasmin

Serum ceruloplasmin levels are low in newborns and gradually risewithin the first 2 years of life. Approximately 90% of all patientswith Wilson disease have ceruloplasmin levels of less than 20 mg/dL(reference range, 20-40 mg/dL). (Ceruloplasmin is an acute phasereactant and may be increased in response to hepatic inflammation,pregnancy, estrogen use, or infection.)

Falsely low ceruloplasmin levels may be observed in any proteindeficiency state, including nephrotic syndrome, malabsorption,protein-losing enteropathy, and malnutrition. Ceruloplasmin levelsmay also be decreased in 10-20% of Wilson Disease geneheterozygotes, who do not develop Wilson disease and do not

require treatment.

Urinary Copper Excretion and Hepatic Copper


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U a y Coppe c e o a d epa c CoppeConcentration

Urinary copper excretion The urinary copper excretion rate is greater than 100 mcg/d

(reference range, < 40 mcg/d) in most patients withsymptomatic Wilson disease. The rate may also be elevated inother cholestatic liver diseases.

Hepatic copper concentration

This test is regarded as the criterion standard for diagnosis ofWilson disease. A liver biopsy with sufficient tissue reveals

levels of more than 250 mcg/g of dry weight even inasymptomatic patients.

B i MRI


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Brain MRI

MRI of the brain appears to be more sensitive than CT scanning in detectingearly lesions of Wilson disease.

MRI studies have identified focal abnormalities in the white matter, pons,and deep cerebellar nuclei. These lesions, measuring 3-15 mm in diameter,are typically bilateral, appearing with low signal intensity on T1-weightedimages and with high signal intensity on T2-weighted images, representingcell loss and gliosis. Other studies describe decreased signal intensity in theputamen and other parts of the basal ganglia, which may represent either

copper or iron ferritin deposition.

A characteristic "face of the giant panda"sign has been described, formedby high signal intensity in the tegmentum (except for the red nucleus),preserved signal intensity of the lateral portion of the pars reticulata of thesubstantia nigra, and hypointensity of the superior colliculus.


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PET Scanning

Positron emission tomography (PET) scanning revealsa significantly reduced regional cerebral metabolic rateof glucose consumptionin the cerebellum, striatum,and, to a lesser extent, in the cortex and thalamus.

PET scan analyses of patients with Wilson disease havealso demonstrated a marked reduction in the activity ofdopa-decarboxylase, indicative of impaired function ofthe nigrostriatal dopaminergic pathway.

Management


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Features of treatment of Wilson disease are as

follows: The mainstay of therapy is lifelong use ofchelating agents(eg, penicillamine, trientine)

Symptoms, particularly neurologic ones, may worsen with initiationof chelation

Surgical decompression or transjugularintrahepatic shunting (TIPS) is reserved forrecurrent or uncontrolled variceal bleedingunresponsive to standard conservative measures

Orthotopic liver transplantation is curative


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Other treatments for Wilson disease include the following:

Anticholinergics, baclofen, GABA antagonists, and levodopa to treatparkinsonism and dystonia

Antiepileptics to treat seizures Neuroleptics to treat psychiatric symptoms Protein restriction, lactulose, or both to treat hepatic

encephalopathy


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After the initiation of therapy with a chelating agent, thepatient needs to be aware of potential adverse effectsof the

agents with which he or she is being treated.For instance, some of the concerning adverseeffects are those commonly associated with penicillamine use.

In addition, a patient must also be aware of the potential to developworsening of some symptoms when chelation is started; in particular,patients with neurologic signs and symptoms can see worsening of thesewith chelation, and, in some instances, therapy needs to be reduced orstopped.

Laboratory tests in patients started on penicillamine should includehematology and biochemical monitoring, as well as urinalysis.


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With clinical progression, acute liver failure, or worseninghepatic function,the patient must be evaluated at a centerwith expertise in Wilson disease and the capability to performliver transplantation.

Orthotopic liver transplantation is curative treatment forWilson disease.


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Diet

Patients should generally avoid eating foods with a highcopper content, such as liver, chocolate, nuts, mushrooms,legumes, and shellfish (especially lobster). Drinking water

from atypical sources (eg, well water) should be analyzed forcopper content and replaced with purified water if thecopper content is greater than 0.2 parts per million.

Medication Summary


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Medication Summary

The mainstay of therapy for Wilson disease is the use of

chelating agentsandmedications that block copper absorption from the

gastrointestinal(GI) tract.

Zinc and penicillamineare lifelong medications for patients with Wilsondisease. Dosages vary with the severity of the disorder.

Another chelating agent is trientine, which may be more easily toleratedthan penicillamine.[1] Patients who do not respond to zinc therapy andwho have increased activities of liver enzymes should be identified sothat chelating agents may be added to the therapeutic regimen.

Class Summary

Ch l ti t bi d A i t t thi l bd t i i ti ti l


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Chelating agents bind excess copper. Ammonium tetrathiomolybdate is an investigationalchelating drug used at the University of Michigan as an initial treatment for patients whopresent with neurologic or psychiatric manifestations. This drugworks as a chelating agentand as an inhibitor of copper absorption from the GI tract.[17]

Penicillamine (Cuprimine, Depen)

Penicillamine forms soluble complexes with metals excreted in urine. It was the drug of choicebefore newer regimens were available. Because of extensive toxicities, alternative agents areused. It must be administered with pyridoxine 25 mg by mouth daily.

Trientine (Syprine)

Trientine is an effective oral chelator used to induce cupruresis. It is useful for patients whocannot tolerate penicillamine. It is indicated in Wilson disease if the initial presentation ishepatic. It should be administered with zinc

Zinc (Galzin)

Zinc is a cofactor for more than 70 types of enzymes. It is approved for patients initiallytreated with a chelating agent. It should be used for maintenance after initial chelationtherapy. Zinc acetate is the drug of choice in presymptomatic, pregnant, pediatricpopulations, and in some instance for maintenance in compliant patients who have undergonecopper chelation therapy
http://reference.medscape.com/drug/cuprimine-depen-penicillamine-343728http://reference.medscape.com/drug/cuprimine-depen-penicillamine-343728http://reference.medscape.com/drug/syprine-trientin-trientine-342888http://reference.medscape.com/drug/galzin-zinc-344449http://reference.medscape.com/drug/galzin-zinc-344449http://reference.medscape.com/drug/syprine-trientin-trientine-342888http://reference.medscape.com/drug/cuprimine-depen-penicillamine-343728http://reference.medscape.com/drug/cuprimine-depen-penicillamine-343728http://reference.medscape.com/drug/cuprimine-depen-penicillamine-343728


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Prognosis

Important clues for the diagnosis of Wilson disease that aclinician must recognize are a younger patient withhemolytic anemia, impaired hepatic synthetic function, andnormal alkaline phosphatase values.

Complications


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The major complicationsin patients with untreated Wilson disease are thoseassociated with acute liver failure, chronic hepatic dysfunction with eitherportal hypertension or hepatocellular carcinoma, and the sometimes-relentless course to cirrhosis, which is characterized by a progressivelassitude, fatigue, anorexia, jaundice, spider angiomas, splenomegaly, andascites. Bleeding from varices, hepatic encephalopathy, hepatorenal

syndrome, and coagulation abnormalities occur as liver failure ensues.Death occurs, generally at age 30 years, if emergent liver transplantation isnot performed.

Complications

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