Chorea

Chorea" is a borrowed Latin word that derives from the

Greek 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 World

Federation of Neurology has defined chorea as
"a state of excessive, spontaneous movements, irregularly timed, non-repetitive, randomly distributed and abrupt in character. These movements may vary in severity from restlessness with mild intermittent exaggeration of gesture and expression, fidgeting movements of the hands, unstable dance-like gait to a continuous flow of disabling, violent movements

 Patients with chorea exhibit motor impersistence (ie, they cannot

maintain a sustained posture). When attempting to grip an object, they alternately squeeze and release ("milkmaid's grip"). When they attempt to protrude the tongue, the tongue often pops in and out ("harlequin's tongue"). Patients often drop objects involuntarily. Also common are attempts by patients to mask the chorea by voluntarily augmenting the choreiform movements with semipurposeful movements.

Chorea involves both proximal and distal muscles. In most patients,

normal tone is noted, but, in some instances, hypotonia is present. In a busy movement disorder center, levodopa-induced chorea is the most common movement disorder, followed by Huntington disease

 The term athetosis comes from the Greek word athetos (not

fixed).It is a slow form of chorea. Because of the slowness, the movements have a writhing (ie, squirming, twisting, or snakelike) appearance. Choreoathetosis is essentially an intermediate form.

Ballism or ballismus is considered a very severe form of chorea in

which the movements have a violent, flinging quality. In Greek, ballismos means "a jumping about or dancing."[2] Ballism has been defined as "continuous, violent, coordinated involuntary activity involving the axial and proximal appendicular musculature such that the limbs are flung about." This movement disorder most often involves only one side of the body (ie, hemiballism or hemiballismus). Occasionally, bilateral movements occur (ie, biballism or paraballism). Many patients with hemiballism have choreiform movements and vice versa, and hemiballism often evolves into hemichorea.

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), the subthalamic nucleus (STN), the substantia nigra pars reticulata (SNr) and substantia nigra pars compacta (SNc), and the ventrolateral thalamus (VL). D1 and D2 indicate the direct (regulated by dopamine D1 receptors) and indirect (regulated by dopamine D2 receptors) pathways, respectively

Pathophysiology A simple model of basal ganglia function states that dopaminergic

and GABAergic impulses from the substantia nigra and motor cortex, respectively, are funneled through the pallidum into the motor thalamus and motor cortex. These impulses are modulated in the striatum via two segregated, parallel, direct and indirect loops through the medial pallidum and lateral pallidum/subthalamic nucleus. Subthalamic nucleus activity drives the medial pallidum to inhibit cortex-mediated impulses, thereby inducing parkinsonism.

Absent subthalamic nucleus inhibition enhances motor activity

through the motor thalamus, resulting in abnormal involuntary movements such as dystonia, chorea, and tics. A classic example of loss of subthalamic inhibitory drive is ballism

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 camouflage some of the movements by incorporating them into semipurposeful activities (ie, parakinesia). The inability to maintain voluntary contraction (ie, motor impersistence), as is seen during manual grip (milkmaid grip) tests or tongue protrusion, is a characteristic feature of chorea and results 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 motor symptoms include- dysarthria, dysphagia, postural instability, ataxia, dystonia, and myoclonus.

Laboratory Studies Diagnosis of the primary choreatic conditions

is based on
history and clinical findings; several laboratory studies are useful, especially in distinguishing the secondary forms of chorea from the primary forms.

Huntington disease: The only laboratory study presently available to confirm HD is genetic testing. It identifies a gene abnormality in the short arm of chromosome 4, characterized by abnormal repetition of the trinucleotide CAG, the length of which determines the age of onset (anticipation). Wilson disease: A low serum ceruloplasmin level and serum copper values showing increased urinary copper excretion corroborate the diagnosis in most cases. Liver function test results are usually abnormal. If the diagnosis is still uncertain, liver biopsy can help confirm the diagnosis. Sydenham chorea : The chorea can lag behind the etiologic streptococcal infection by 1-6 months, sometimes as long as 30 years; therefore, antistreptococcal antibody titers may no longer be elevated at presentation. Without documentation of an antecedent streptococcal infection, the diagnosis of Sydenham chorea must be made by excluding other causes. Neuroacanthocytosis: The diagnosis is confirmed by the presence of spiky erythrocytes (acanthocytes) in peripheral blood smears. The serum creatine kinase level may be elevated.

Other laboratory studies useful in the differential diagnosis

of chorea include complement levels, antinuclear antibody titers,

antiphospholipid antibody titers, amino acid levels in serum and urine, enzymatic studies from skin fibroblasts, thyrotropin levels, thyroxine values, and parathormone levels.

Imaging Studies

MRI
Patients with Huntington disease (HD) and choreaacanthocytosis show decreased signal in the neostriatum, caudate, and putamen. No significant difference has been observed between these diseases. The decreased neostriatal signal corresponds to increased iron deposition. Generalized atrophy, as well as focal atrophy of the neostriatum, predominantly of the caudate, with resulting enlargement of the frontal horns, follows the initial findings of decreased neostriatal signal

Medical Care

Only symptomatic treatment is available for patients with

Chorea may be a disabling symptom, leading to bruises, fractures, and falls, and may impair the ability of patients to feed themselves. The most widely used agents in the treatment of chorea are the neuroleptics. 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 neuroleptics include haloperidol and fluphenazine. Atypical neuroleptics include risperidone, olanzapine, clozapine, and quetiapine. 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.

chorea.

 Coenzyme Q10 alone and in combination with minocycline have

been proposed as potential therapies

Intravenous immunoglobulin and plasmapheresis may shorten the

Sydenham chorea.

course of the illness and decrease symptom severity in patients with

Surgical Care

Deep brain stimulation is an emerging technique that

may 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 been made with this modality. Cell transplantation is controversial and in early stages of research. It has shown variable results for HD patient participants.

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 oxidase deficiency Mitochondrial encephalomyopathies Neuroacanthocvtosis Paroxysmal disorders Paroxysmal kinesiogenic choreoathetosis Paroxysmal nonkinesiogenic choreoathetosis Pyruvate carboxylase deficiency Wilson disease

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

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

Metabolic Hypocalcemia Hypoglycemia and hyperglycemia Hypomagnesemia Hyponatremia, hypernatremia, and central pontine myelinolysis Renal failure
Miscellaneous Cerebral palsy Head trauma Bronchopulmonary dysplasia (infantile chorea) Cardiopulmonary bypass - "Postpump chorea Neoplastic Primary and metastatic brain tumors Primary CNS lymphoma
Toxins CO, Mg, organophosphate

Pathophysiology and General Principles in Treatment of Chorea Movement disorders (particularly chorea, athetosis, and dystonia)
are thought to result from basal ganglia pathology. to the neostriatum (caudate and putamen).

Dopaminergic neurons within the substantia nigra project rostrally Chorea may be viewed as resulting from increased dopaminergic

activity in the projections from the substantia nigra to the striatum, resulting in decreased GABAergic projection from the striatum to the globus pallidus. Most of the drugs used in symptomatic treatment of chorea act through attenuation of dopaminergic transmission or enhancement of GABA transmission. Anticonvulsant drugs may suppress chorea but also may induce chorea, especially in patients with basal ganglia dysfunction.

Rheumatic (Sydenham) Chorea In 1684, Thomas Sydenham described the clinical syndrome that
now bears his name. Originally termed St. Vitus' dance, it now is referred to as rheumatic chorea. Stoll first proposed a relationship between Sydenham chorea and rheumatic fever (RF) in 1780.

In 1889, Cheadle described the full rheumatic syndrome of carditis,

Several decades later, epidemiologic and microbiologic studies

confirmed the etiological role of streptococcal infection in RF.

polyarthritis, chorea, subcutaneous nodules, and erythema marginatum.

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

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

Epidemiology
Sydenham chorea is the most common cause of acquired chorea in the

young. During the latter part of the twentieth century the number of reported cases of RF in the United States increased. This resurgence appears to be associated with strains of group A beta hemolytic streptococcal infection that are less likely to cause symptomatic pharyngitis. 100,000 population per year.

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

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 present

between 5-15 years of age.

Clinical features and course

SC is a major manifestation of acute rheumatic fever. According to the 1992 modification of the Jones criteria,
chorea (or indolent carditis) alone is sufficient for diagnosis of RF, provided other causes have been excluded.
20% of cases chorea may be the presenting or sole manifestation of RF.

SC typically presents with other manifestations of RF, but in The main features of SC are involuntary movements,

hypotonia, and mild muscular weakness. Chorea can be generalized or unilateral, predominantly involving the face, hands, and arms. Movements are present at rest, aggravated by stress, and usually cease during sleep.

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

seem to be affected (hemichorea); however, careful examination usually reveals some involvement of the opposite side. The choreic movements interfere with volitional movements and result in a clumsy gait, dropping and spilling, and explosive 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 over the head. Another sign of weakness and hypotonia is the socalled choreic handwith the arms extended, the wrist will flex and the metacarpophalangeal joints overextend.

 Some children may have such profound weakness that they

appear paralyzed. Not uncommonly, children are restricted to bed or are unable to attend school for the duration of the illness. Fortunately, paralytic chorea is uncommon.

Patients with SC may also have psychiatric symptoms such as

depression, anxiety, personality changes, emotional lability, OCD, and attention deficit disorder (ADD).

Occasionally, these symptoms precede the onset of chorea

 On average, the disease resolves spontaneously in 3-6 months and

rarely 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 2

years after the initial attack.

Pathophysiology

Immunology: Evidence suggests that SC may result from the production of

immunoglobin G antibodies that crossreact with antigens in the membrane of group A streptococci and antigens in the neuronal cytoplasm of the caudate and subthalamic nuclei, namely intracellular tubulin and extracellular lysoganglioside. Antineuronal antibodies have also been found in the cerebrospinal fluid (CSF) of patients with acute rheumatic chorea. Immunofluorescent staining has shown that sera from approximately half of the children with SC have antibodies that react with neuronal cytoplasmic antigens in the caudate and subthalamic nuclei.

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

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

Neuroimaging
MRI findings in SC are not consistent and may be
normal.

Functional neuroimaging using fluorodeoxyglucose (FDG)

positron emission tomography (PET) has demonstrated reversible striatal hypermetaboli.

Diagnosis
Diagnosis rests on a combination of clinical manifestations that can
develop in relation to group A streptococcal pharyngitis. These include chorea, carditis, subcutaneous nodules, erythema marginatum, and migratory polyarthritis. Because the inciting infection is completely treatable, attention has been refocused on prevention.

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

SC usually develops in those aged 3-13 years and is believed to result from
a preceding streptococcal infection. The patient may have no history of rheumatic fever, and a preceding streptococcal infection cannot always be documented. Infections can be subclinical and often precede the development of neurologic symptoms by age 1-6 months.

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

Chorea may be the first and only manifestation of rheumatic fever.

However, some patients may have subtle evidence of carditis by echocardiography despite a normal clinical examination and ECG. Chorea alone is sufficient for diagnosis providing other causes of the condition have been excluded.

Treatment
Treatment and prevention may involve multiple fields of discipline,
including infectious diseases, cardiology, and neurology. For this reason, 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 streptococcal

organisms and bacterial antigens from the pharyngeal region. Penicillin is the drug of choice in persons who are not at risk of allergic reaction. A single parenteral injection of benzathine benzylpenicillin can 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

 C SC is usually self-limited, and treatment should be limited to

patients with chorea severe enough to interfere with function.

shown to be effective in diminishing choreic movements at doses normally used for seizure control. In particular, valproate may be quite helpful in children with SC. Dopaminergic blockers (pimozide and haloperidol) are effective and, when used in small doses, are usually well tolerated. Neuroleptics such as haloperidol and pimozide remain an important treatment option, especially in older children

Anticonvulsants (valproic acid and carbamazepine) have been

B. Steroids have been used widely, but no controlled studies have been done to confirm steroid efficacy in chorea. Patients with carditis require prednisone. The goal is to decrease myocardial inflammation. May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. After 2-3 wk, dosage may tapered, reduced 25% each week.

Prednisone,

plasma exchange and intravenous immunoglobulin (IVIG) have been shown 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. immunoglobulin (IVIg) and plasma exchange may be effective.

The presence of antineuronal antibodies suggests that intravenous

More recent reports have shown IVIG to be an effective safe option.

Because this treatment modality is quite expensive, it should be reserved for protracted or debilitating cases.

 Parents and school officials should be informed that emotional

lability is characteristic of this organic condition.

Children with SC require prophylaxis against streptococcal infections until 18 years of age.

Chorea gravidarum
Background

Chorea gravidarum (CG) is the term given to chorea occurring

during pregnancy. This is not an etiologically or pathologically distinct morbid entity but a generic term for chorea of any

cause starting during pregnancy.

Chorea gravidarum is regarded as a syndrome rather than a

specific disease entity.

Incidence
Willson and Preece (1932) found that the overall incidence of
chorea 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 before the use of antibiotics for streptococcal pharyngitis.

In recent times, most cases of chorea appearing during pregnancy

are caused by other diseases systemic lupus erythematosus [SLE], Huntington disease).
and antiphospholipid syndrome (APLS) underlying most of the remainder.

In general, about half the cases are idiopathic, with rheumatic fever

Patient profile

Most patients with chorea gravidarum are young; the

average age is 22 years.

Of initial attacks, 80% occur during first pregnancies,

and one half start during the first trimester.One third begin in the second trimester. Of afflicted women, 60% previously had chorea. Recurrences may occur in subsequent pregnancies,

particularly if antiphospholipid syndrome is the cause.

Pathophysiology
Several 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 may sensitize dopamine receptors (presumably at a striatal level) and induce chorea in individuals who are vulnerable to this complication by virtue of preexisting pathology in the basal ganglion.

Pathologic changes found at autopsy in chorea gravidarum include

perivascular degenerative changes in the caudate nucleus.

TREATMENT

CG is not an indication for abortion or premature interruption of

pregnancy Indicated for patients with disabling severe chorea Reserpine = CI Haloperidol effective Pimozide, valproate, carbamazepine Discontinue the oral contraceptive pill 2/3 the choreea lasts until puerperium Mortality 12% 21% have recurrent chorea with subsequent pregnancies

Huntington disease (HD)

Background

is an incurable, adult-onset, autosomal dominant inherited disorder associated with

HD is named after George Huntington, the physician who described it as

cell loss within a specific subset of neurons in the basal ganglia and cortex.
hereditary chorea in 1872.

Characteristic features of HD include

involuntary movements, dementia, and behavioral changes.

Pathophysiology

The most striking neuropathology in HD occurs within

the neostriatum, in which gross atrophy of the caudate nucleus and putamen is accompanied by selective neuronal loss and astrogliosis. Marked neuronal loss also is seen in deep layers of the cerebral cortex. Other regions, including the globus pallidus, thalamus, subthalamic nucleus, substantia nigra, and cerebellum, show varying degrees of atrophy depending on the pathologic grade.

The extent of gross striatal pathology, neuronal loss, and

gliosis provides a basis for grading the severity of HD pathology (grades 0-4)

 No gross striatal atrophy is observed in grades 0 and 1. Grade 1 cases have neuropathologic changes that can be
detected 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 the

caudate nucleus is flat.

In grade 4, striatal atrophy is most severe, and the

medial surface of the caudate nucleus is concave.

The genetic basis of HD

is the expansion of a cysteine-adenosine-guanine (CAG) repeat

encoding a polyglutamine tract in the N-terminus of the protein product called huntingtin. the cytoplasm. The association of huntingtin with the cytoplasmic surface of a variety of organelles, including transport vesicles, synaptic vesicles, microtubules, and mitochondria, raises the possibility of the occurrence of normal cellular interactions that might be relevant to neurodegeneration.

The function of huntingtin is not known. Normally, it is located in

N-terminal fragments of mutant huntingtin accumulate and form

well as in various animal and cell models of HD.

inclusions in the cell nucleus in the brains of patients with HD, as

The presence of neuronal intranuclear inclusions (NIIs) initially led

to the view that they are toxic and, hence, pathogenic

Epidemiology
Frequency United States

Estimates of the prevalence of HD in the United States

range from 4.1-8.4 per 100,000 people. Accurate estimates of the incidence of HD are not available.

International The prevalence in most European countries ranges from 1.63-9.95 per 100,000 people. The prevalence of HD in Finland and Japan is less than 1 per 100,000 people.

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 from

51-57 years, but the range may be broader. Duration of illness varies considerably, with a mean of approximately 19 years. Most patients survive for 10-25 years after the onset of illness. In a large study, pneumonia and cardiovascular disease were the most common primary

causes of death.

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 are more likely to have inherited the gene from their mother.

is caused by greater instability of the HD allele during spermatogenesis. CAG repeat length correlates inversely with age of onset, and the correlation is stronger when the onset of symptoms occurs earlier.

Inheritance through the father can lead to earlier onset through succeeding generations, a phenomenon termed anticipation. This

The length of the CAG repeat is the most important factor in

determining age of onset of HD. Most studies show a mean age at onset ranging from 35-44 years.

Huntington Disease Clinical Presentation

The clinical features of Huntington disease (HD) include a

movement disorder, a cognitive disorder, and a behavioral disorder. Patients may present with one or all disorders in varying degrees.

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

the most common movement disorder seen in HD.

 Initially, mild chorea may pass for fidgetiness. Severe chorea may appear as uncontrollable flailing of the extremities (ie, ballism), which interferes with function. As the disease progresses, chorea coexists with and gradually is replaced by dystonia and parkinsonian features, such as bradykinesia, rigidity, and postural instability, which are usually more disabling than the choreic syndrome per se. In advanced disease, patients develop an akinetic-rigid syndrome, with minimal or no chorea. Other late features are spasticity, clonus, and extensor plantar responses. Dysarthria and dysphagia are common. Abnormal eye movements may be seen early in the disease. Other movement disorders, such as tics and myoclonus, may be seen in patients with HD. Juvenile HD (Westphal variant), defined as having an age of

onset of younger than 20 years, is characterized by parkinsonian features, dystonia, long-tract signs, dementia, epilepsy, and mild or even absent chorea.

 Cognitive decline is characteristic of HD, but the rate of

progression among individual patients can vary considerably. Dementia and the psychiatric features of HD are perhaps the earliest and most important indicators of functional impairment. behavioral changes, such as irritability, untidiness, and loss of interest. Slowing of cognition, impairment of intellectual function, and memory disturbances are seen later. This pattern corresponds well to the syndrome of subcortical dementia, and it has been suggested to reflect dysfunction of frontal-subcortical neuronal circuitry.
memory, followed by motor dysfunction and a variety of cognitive changes in the intermediate stages of dementia.[6, 7] These deficits include 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.

The dementia syndrome associated with HD includes early onset

Early stages of HD are characterized by deficits in short-term

 The behavioral disorder of HD is represented most

commonly by affective illness.

Depression is more prevalent, with a small percentage of

patients experiencing episodic bouts of mania characteristic of bipolar disorder.

Patients with HD and persons at risk for HD may have an

increased rate of suicide.

Patients with HD also can develop psychosis, obsessivecompulsive symptoms, sexual and sleep disorders, and changes in personality

 Tendon reflexes are variable in HD, ranging from

reduced in some patients to pathologically brisk with clonus in other patients. The plantar response usually is flexor, but it may be extensor in advanced stages of the illness.

Other hyperkinesias, such as tics and myoclonus, may

be seen in HD.
disease.

Eye movement abnormalities can be seen early in the

Imaging Studies

No single imaging technique is necessary or sufficient for

diagnosis of Huntington disease (HD). Measurement of the bicaudate diameter (ie, the distance between the heads of the 2 caudate nuclei) by CT scan or MRI is a reliable marker of HD.

Other Tests

Genetic testing (reported as the CAG repeat number for

each allele) is now commercially available.
Genetic testing may not be necessary in a patient with a typical clinical picture and a genetically proven family history of HD. In the absence of a family history of HD, patients with a suggestive clinical presentation should undergo genetic testing to exclude or confirm HD.

If the genetic test is negative for HD, then testing for

systemic lupus erythematosus (SLE), antiphospholipid antibody syndrome, thyroid disease, neuroacanthocytosis, DRPLA, Wilson disease, and other less common causes of chorea may be reasonable, depending on the individual case

Medication Summary

Although no therapy is currently available to delay the onset

of symptoms or prevent the progression of the disease, symptomatic treatment of patients with Huntington disease (HD) may improve the quality of life and prevent complications. Symptomatic treatment for HD can be divided into drugs to treat the movement disorder and drugs to treat psychiatric or behavioral problems.

Therapeutic options include dopamine-depleting agents (eg,

reserpine, tetrabenazine) and dopamine-receptor antagonists (eg, neuroleptics).

Medical Care Depression in patients with HD is treatable and should be recognized

promptly. Selective serotonin reuptake inhibitors (SSRIs) should be considered 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 refractory depression.

Antipsychotic medications may be necessary in patients with hallucinations,

delusions, or schizophrenia-like syndromes. Newer agents, such as quetiapine, clozapine, olanzapine, and risperidone, are preferred to older agents because of the lower incidence of extrapyramidal side effects and the decreased risk for tardive syndromes.
mood stabilizers, such as valproic acid or carbamazepine; and, if needed, atypical neuroleptics. treatment are mania, obsessive-compulsive disorder, anxiety, sexual disorders, myoclonus, tics, dystonia, and epilepsy.

Irritability may be treated with antidepressants, particularly the SSRIs;

Other less frequent aspects of HD that may require pharmacologic

Wilson Disease

Background

Wilson disease is a rare autosomal recessive inherited

disorder of copper metabolism. The condition is characterized by excessive deposition of copper in the liver, brain, and other tissues. The major physiologic aberration is excessive absorption of copper from the small intestine and decreased excretion of copper by the liver. affect the copper-transporting adenosine triphosphatase (ATPase) gene (ATP7B) in the liver.

The genetic defect, localized to arm 13q, has been shown to

Patients with Wilson disease more often initially present with hepatic manifestations when identified in the first decade of life as compared with more neuropsychiatric illness later, and the latter most commonly occurs during the third decade. 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

The normal estimated total body copper content is 50-100 mg, and the

average 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, including lysyl oxidase, cytochrome c oxidase, superoxide dismutase, and dopamine beta-hydroxylase. hepatocytes. This pathway is intact in Wilson disease. After copper reaches the hepatocyte, it is incorporated into copper-containing enzymes and copperbinding 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 for copper is almost exclusively found in association with liver diseases such as Wilson disease, chronic biliary disorders (eg, primary biliary cirrhosis, primary sclerosing cholangitis), cirrhosis/extensive fibrosis, and primary liver tumors (most often fibrolamellar hepatocellular carcinoma).

Around 50-75% of intestinal copper is absorbed and then transported to the

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

metallothionein to produce copper-metallothionein, or it may be excreted into bile. Normal copper balance is maintained by regulation of excretion, rather than absorption, and the predominant route of copper excretion (approximately 95%) is hepatobiliary in nature.

In Wilson disease, the processes of incorporation of copper into

ceruloplasmin and excretion of excess copper into bile are impaired. The transport of copper by the copper-transporting P-type ATPase is defective in Wilson disease secondary to one of several mutations in the ATP7B gene. By genetic linkage studies, Bowcock and colleagues narrowed the assignment of the Wilson disease locus to 13q14-q21.

 The excess copper resulting from Wilson disease promotes

free radical formation that results in oxidation of lipids and proteins. 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 to damage to hepatocytes. Eventually, as liver copper levels increase, it increases in the circulation and is deposited in other organs.

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

Epidemiology

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

individuals. The prevalence of Wilson disease is 1 per 30,000 individuals. Worldwide, the incidence of Wilson disease is 10-30 million cases, and the heterozygote carrier rate is 1 case per 100 persons, with the genetic mutation frequency varying from 0.3-0.7%.

Age-related presentations

A German study of patients with Wilson disease illustrated

that patients presenting earlier show predominantly hepatic symptoms , while those presenting later more often present with neurological symptoms .

 The onset of neurologic symptoms

second / third decade 50% are symptomatic by age 15 years The initial event is a deposition of copper in the liver.

Wilson Disease Clinical Presentation

History

Consider hepatic Wilson disease in the differential diagnosis of any

unexplained chronic liver disease, especially in individuals younger than 40 years. The condition may also manifest as acute hepatitis. Hepatic dysfunction is the presenting feature in more than half of patients.

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

 Hepatic dysfunction is the presenting feature in more than half of Chronic active hepatitis Cirrhosis (the most common initial presentation) Fulminant hepatic failure
patients. Although the condition may manifest as acute hepatitis, the 3 major patterns of hepatic involvement are as follows:

Signs of fulminant hepatic failure include the following: Ascites and prominent abdominal veins Spider nevi Palmar erythema Digital clubbing Hematemesis Jaundice

Neuropsychiatric features
Most patients who present with neuropsychiatric manifestations have cirrhosis. The most common presenting neurologic feature is asymmetric tremor, which is
variable in character and may be predominantly resting, postural, or kinetic. Frequent early symptoms include the following: Difficulty speaking Excessive salivation Ataxia Masklike facies Clumsiness with the hands Personality changes Late manifestations (now rare because of earlier diagnosis and treatment) include the following: Dystonia Spasticity Grand mal seizures Rigidity Flexion contractures

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 manifestation and may be

reversible with treatment[4]

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

Emotional lability Impulsiveness Disinhibition Self-injurious behavior

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

Behavioral Affective Schizophrenic-like Cognitive

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

The arthropathy of Wilson disease is a degenerative process that

resembles premature osteoarthritis Symptomatic joint disease usually arises late in the course of the disease, frequently after age 20 years The arthropathy generally involves the spine and large appendicular joints (eg, knees, wrists, hips) Osteochondritis dissecans, chondromalacia patellae, and chondrocalcinosis have also been described

Hematologic and renal manifestations

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

 Clinically, patients may resemble those with Fanconi syndrome,

demonstrating defective renal acidification and excess renal losses of amino acids, glucose, fructose, galactose, pentose, uric acid, phosphate, and calcium. The frequency of renal manifestations is variable. 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 Kayser-Fleischer rings

Formed by the deposition of copper in the Descemet membrane in the limbus of

the 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 be identified using slit-lamp examination or gonioscopy Observed in up to 90% of individuals with symptomatic Wilson disease and almost invariably present in those with neurologic manifestations No longer considered pathognomonic of Wilson disease unless accompanied by neurologic manifestations, as they may also be observed in patients with chronic cholestatic disorders

Ophthalmic findings
Sunflower cataracts are brilliantly multicolored and are visible only on
slit-lamp examination. They do not impair vision.

Other relatively uncommon ophthalmic findings include exotropic

strabismus, optic neuritis or pallor of the optic disc

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)

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

Approach Considerations

The presence of Kayser-Fleischer rings and ceruloplasmin levels

of less than 20 mg/dL in a patient with neurologic signs or symptoms suggest a diagnosis of Wilson disease. If a patient is asymptomatic, exhibits isolated liver disease, and lacks corneal rings, the coexistence of a hepatic copper concentration of more than 250 mg/g of dry weight and a low serum ceruloplasmin level is sufficient to establish a diagnosis. Therefore, in the absence of Kayser-Fleischer rings or neurologic abnormalities, a liver biopsy for quantitative copper determination is essential to establish the diagnosis of Wilson disease.

Diagnosis

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 in other 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 weight even in asymptomatic patients; a normal result (15-55 mcg/g) effectively excludes the diagnosis of untreated Wilson disease, but elevation may be found in other chronic hepatic disorders Radiolabeled copper testing directly assays hepatic copper metabolism Genetic testing is limited to screening of family members for an identified mutation detected in the index patient Brain imaging shows characteristic findings; MRI appears to be more sensitive than CT in detecting early lesions Abdominal imaging findings are neither sensitive nor specific Resting ECG abnormalities 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 the diagnosis of the early stages of Wilson disease, in addition to the quantification of hepatic copper by atomic absorption spectrophotometry

Genetic diagnosis Linkage analysis has been used in family studies for presymptomatic testing; however, the multiplicity of mutations (>200 mutations of ATP7B have been identified) that require screening in individuals without affected family members is large, making such analysis impractical. Therefore, the use of molecular testing is currently limited to screening of family members for an identified mutation detected in the index patient. Abdominal imaging Computed tomography (CT) scanning, magnetic resonance imaging (MRI), ultrasonography, and nuclear medicine studies of the liver have been uninformative, with findings neither specific nor sensitive for Wilson disease. Electrocardiography Resting electrocardiographic abnormalities include left ventricular or biventricular hypertrophy, early repolarization, ST segment depression, T-wave inversion, and various arrhythmias.

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

Falsely low ceruloplasmin levels may be observed in any protein

deficiency state, including nephrotic syndrome, malabsorption, protein-losing enteropathy, and malnutrition. Ceruloplasmin levels may also be decreased in 10-20% of Wilson Disease gene heterozygotes, who do not develop Wilson disease and do not require treatment.

Urinary Copper Excretion and Hepatic Copper Concentration

Urinary copper excretion The urinary copper excretion rate is greater than 100 mcg/d (reference range, < 40 mcg/d) in most patients with symptomatic Wilson disease. The rate may also be elevated in other cholestatic liver diseases.

Hepatic copper concentration

This test is regarded as the criterion standard for diagnosis of

Wilson disease. A liver biopsy with sufficient tissue reveals levels of more than 250 mcg/g of dry weight even in asymptomatic patients.

Brain MRI

MRI of the brain appears to be more sensitive than CT scanning in detecting

early 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-weighted images and with high signal intensity on T2-weighted images, representing cell loss and gliosis. Other studies describe decreased signal intensity in the putamen 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, formed

by high signal intensity in the tegmentum (except for the red nucleus), preserved signal intensity of the lateral portion of the pars reticulata of the substantia nigra, and hypointensity of the superior colliculus.

PET Scanning

Positron emission tomography (PET) scanning reveals

a significantly reduced regional cerebral metabolic rate of glucose consumption in the cerebellum, striatum, and, to a lesser extent, in the cortex and thalamus.

PET scan analyses of patients with Wilson disease have

also demonstrated a marked reduction in the activity of dopa-decarboxylase, indicative of impaired function of the nigrostriatal dopaminergic pathway.

Management Features of treatment of Wilson disease are as follows: The mainstay of therapy is lifelong use of chelating agents (eg, penicillamine, trientine)

Symptoms, particularly neurologic ones, may worsen with initiation

Surgical decompression or transjugular

of chelation

Orthotopic liver transplantation is curative

intrahepatic shunting (TIPS) is reserved for recurrent or uncontrolled variceal bleeding unresponsive to standard conservative measures

Other treatments for Wilson disease include the following:

Anticholinergics, baclofen, GABA antagonists, and levodopa to treat

parkinsonism and dystonia Antiepileptics to treat seizures Neuroleptics to treat psychiatric symptoms Protein restriction, lactulose, or both to treat hepatic encephalopathy

 After the initiation of therapy with a chelating agent, the

patient needs to be aware of potential adverse effects of the agents with which he or she is being treated. For instance, some of the concerning adverse effects are those commonly associated with penicillamine use.

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

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

 With clinical progression, acute liver failure, or worsening

hepatic function, the patient must be evaluated at a center with expertise in Wilson disease and the capability to perform liver transplantation.

Orthotopic liver transplantation is curative treatment for

Wilson disease.

Diet

Patients should generally avoid eating foods with a high

copper content, such as liver, chocolate, nuts, mushrooms, legumes, and shellfish (especially lobster). Drinking water from atypical sources (eg, well water) should be analyzed for copper content and replaced with purified water if the copper content is greater than 0.2 parts per million.

Medication Summary

The mainstay of therapy for Wilson disease is the use of

chelating agents and medications that block copper absorption from the gastrointestinal (GI) tract.

Zinc and penicillamine are lifelong medications for patients with Wilson

disease. Dosages vary with the severity of the disorder. Another chelating agent is trientine, which may be more easily tolerated than penicillamine.[1] Patients who do not respond to zinc therapy and who have increased activities of liver enzymes should be identified so that chelating agents may be added to the therapeutic regimen.

Class Summary

Chelating agents bind excess copper. Ammonium tetrathiomolybdate is an investigational

chelating drug used at the University of Michigan as an initial treatment for patients who present with neurologic or psychiatric manifestations. This drug works as a chelating agent and 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 choice
before newer regimens were available. Because of extensive toxicities, alternative agents are used. 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 who
cannot tolerate penicillamine. It is indicated in Wilson disease if the initial presentation is hepatic. It should be administered with zinc

Zinc (Galzin)

Zinc is a cofactor for more than 70 types of enzymes. It is approved for patients initially

treated with a chelating agent. It should be used for maintenance after initial chelation therapy. Zinc acetate is the drug of choice in presymptomatic, pregnant, pediatric populations, and in some instance for maintenance in compliant patients who have undergone copper chelation therapy

Prognosis

Important clues for the diagnosis of Wilson disease that a

clinician must recognize are a younger patient with hemolytic anemia, impaired hepatic synthetic function, and normal alkaline phosphatase values.

Complications

The major complications in patients with untreated Wilson disease are those associated with acute liver failure, chronic hepatic dysfunction with either portal hypertension or hepatocellular carcinoma, and the sometimesrelentless course to cirrhosis, which is characterized by a progressive lassitude, fatigue, anorexia, jaundice, spider angiomas, splenomegaly, and ascites. 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 is not performed.