Chorea Gravidarum 

Updated: Aug 11, 2017
Author: Tarakad S Ramachandran, MBBS, MBA, MPH, FAAN, FACP, FAHA, FRCP, FRCPC, FRS, LRCP, MRCP, MRCS; Chief Editor: Selim R Benbadis, MD 

Overview

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 is an involuntary abnormal movement, characterized by abrupt, brief, nonrhythmic, nonrepetitive movement of any limb, often associated with nonpatterned facial grimaces.[1, 2, 3]

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

Incidence

Most of the more common and serious movement disorders rarely occur during reproductive years. Hence clinicians are not very familiar with chorea gravidarum. Willson and Preece (1932) found that the overall incidence of chorea gravidarum was approximately 1 case per 300 deliveries.[4] According to them, the first description of chorea with onset during pregnancy was made by Horstius in 1661. The condition is much more rare now. Zegart and Schwartz (1968) found that one patient had been encountered in the course of 139,000 deliveries in 3 major Philadelphia hospitals.[5] 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 (eg, systemic lupus erythematosus [SLE], Huntington disease). In general, about half the cases are idiopathic, with rheumatic fever and antiphospholipid syndrome (APLS) underlying most of the remainder.[6]

Maia et al (2012) describe that chorea gravidarum is a frequent complication of pregnancy in patients with previous history of Sydenham's chorea and an increased risk of miscarriage should be considered. They favor the notion that chorea gravidarum results from hormonal changes acting on previously dysfunctional basal ganglia.[7]

Patient profile

Most patients with chorea gravidarum are young; the average age is 22 years.[4] Almost all reported patients have been Caucasians, although this may be due to a bias in the older literature, in which the vast majority of reported cases are among European patients. Of initial attacks, 80% occur during first pregnancies, and one half start during the first trimester.[4] 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. A family history of transient chorea is not unusual.

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.[4] 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.

Pathology of rheumatic brain disease is of a nonspecific arteritis with endothelial swelling, perivascular lymphocytic infiltration, and petechial hemorrhages. Aschoff bodies are not present in the brain.[8, 9] These changes are evident to some extent throughout the cerebrum but are most prominent in the corpus striatum. Severe neuronal loss occurs in the caudate nucleus and putamen. The same pathologic changes have been reported for chorea gravidarum, but all those patients also had cardiac disease.[4] Brain tissue from patients with acute rheumatic fever with or without chorea has not been studied for the presence of antistreptococcal antibodies. Presumably, as the inflammation resolves, the chorea disappears and degenerative changes are left in small arterioles.

Several lines of evidence suggest that heightened dopamine activity occurs either by denervation hypersensitivity or by aberrant sprouting of dopamine terminals on the remaining striatal neurons. A possible relationship between chorea gravidarum and moyamoya disease has been reported in a 16-year-old pregnant patient.[10] The choreic movements may be caused by ischemia or enhanced dopaminergic sensitivity mediated by increased female hormones during pregnancy.

Koide et al reported that from 1994-2004, 8 patients were diagnosed with clinically definite opsoclonus-myoclonus syndrome (a movement disorder) at Tokyo Metropolitan Neurological Hospital. This rare disorder occurred during pregnancy in 25% of their cases and they raised the possibility of a susceptibility factor in pregnancy. The relationship between opsoclonus-myoclonus syndrome and pregnancy, like chorea gravidarum, remains unclear.[11]

 

Presentation

History

Emotional stress aggravates the movements of chorea gravidarum. During sleep, the movements disappear. The chorea may be unilateral hemichorea. The patient may attempt to disguise chorea by incorporating it into a mannerism or gesture. Choreic movements largely affect the extremities but vary greatly in complexity and temporal expression from one patient to another. The patient may be restless and fidgety and is often unaware of it and may not complain about it; hence, the clinician might be misled or totally miss the diagnosis.

Generally, the affected limb is hypotonic; joints are floppy, and knee jerks are pendular. Normally the arms dangle by the sides, but with chorea (ie, hypotonia), they flail about. Wrist and fingers assume the shape of a dinner fork with abduction of the thumb. At times, continuous involuntary movements may be impossible to sustain. Protruded tongue darts in and out uncontrollably. Varying hand strength is referred to as "milkmaid" grip. Choreic movements are rapid, purposeless, irregular, jerky movements that seem to randomly flow from one part of the body to another.

Obtain a thorough past history including a history of rheumatic fever and confidential inquiry about illicit drug use and any psychiatric treatment with neuroleptics or metoclopramide (ie, dopamine antagonists).

  • Relationship to rheumatic heart disease

    • Chorea gravidarum is linked strongly to rheumatic fever. At least 35% of patients have a definite history of acute rheumatic fever and Sydenham chorea; 4% of those with chorea gravidarum had acute rheumatic fever.[4]

    • Women with normal pregnancies before rheumatic fever developed chorea in subsequent pregnancies.[12, 13]

    • Carditis was found in 87% of fatal cases.[4]

    • Sydenham chorea can follow the onset rheumatic fever by as much as 7 months.[14] Both conditions are related to group A streptococcal infections. Isolated recurrences of chorea among a group of 60 children with a history of Sydenham chorea followed an episode of streptococcal pharyngitis by a week, 3 months, or even 6 months.[15] By the time chorea develops, antistreptolysin O (ASO) titers may have returned to normal. This does not imply that all cases of chorea gravidarum are related to an immediately preceding streptococcal infection; the fact that chorea recurs in the same woman with several pregnancies is statistically against this. Moreover, Jonas et al were able to document that a woman with chorea and a history of acute rheumatic fever had been free of streptococcal infection for 15 months prior to the presentation of chorea in the sixth month of pregnancy.[16]

  • Rheumatic brain disease: Sydenham chorea, some mental status changes, emotional lability to hysterical traits, psychotic delusions, and hallucinations can occur.[17] Seizures[18] and papilledema[19] can occur.

  • Rheumatic encephalopathy

    • Rheumatic encephalopathy is reflected in the EEG findings.[20]

    • EEG changes are not limited to patients with clinical manifestations of chorea. Slow waves (3-6 Hz) can occur continually or in intermittent rhythmic paroxysms. They may be generalized or predominantly over the frontal and central regions.

    • Changes may be unilateral in hemichorea.[21] Improvement in EEG pattern parallels recovery from rheumatic carditis and chorea, usually within 6 months.

Physical

Physical examination includes a careful general, systemic, and neurologic examination. Look especially for involuntary movements and mental status changes.

Causes

The most probable cause of chorea gravidarum is the reactivation by some mechanism of subclinical damage to basal ganglia resulting from previous rheumatic encephalopathy. Oral contraceptives and possibly other mechanisms may activate the same mechanism.

In 2004, Miranda et al reported of a case of chorea associated with the use of the oral contraceptives, in which antibasal ganglia antibodies have also been detected, suggesting an immunological basis to the pathogenesis of this disorder.[22] However, the presence of antibodies in serum does not necessarily infer pathogenicity; the antibodies could be produced as part of tissue damage.[23] To demonstrate that a disorder is autoimmune, 5 criteria must be fulfilled[24] . The criteria are (1) the presence of autoantibodies, (2) the presence of antibodies in target tissue, (3) the induction of disease in an animal model by passive transfer of the antibody, (4) the induction of disease in an animal model by autoantigen immunization, and (5) improvement of clinical symptoms after removal of the antibodies with plasma exchange.

 

DDx

Diagnostic Considerations

Briefly, genetic syndromes with chorea include Huntington disease; HDL1-3; inherited prion disease; spinocerebellar ataxias 1, 3, and 17; neuroacanthocytosis; dentatorubro-pallidoluysian atrophy (DRPLA); brain iron accumulation disorders; Wilson's disease; benign hereditary chorea; Friedreich ataxia; and mitochondrial disease. Acquired causes of chorea include vascular disease, postinfective autoimmune central nervous system disorders (PANDAS), drugs, systemic lupus erythematosus, antiphospholipid syndrome, thyrotoxicosis, AIDS, chorea gravidarum, and polycythaemia rubra vera.[25]

Primary differential diagnosis is as follows:

  • Familial paroxysmal choreoathetosis

  • Benign hereditary chorea

Secondary differential diagnosis is as follows:

Drugs/toxicity

  • Anticonvulsants (eg, phenytoin, carbamazepine, phenobarbital)

  • Antiparkinson agents

  • Neuroleptics (eg, chlorpromazine, haloperidol, pimozide)

  • Noradrenergic stimulants

  • Steroids

  • Estrogens

  • Lead toxicity

Infectious

  • AIDS

  • Meningovascular syphilis

  • Infectious mononucleosis

  • Lyme disease

  • Sydenham chorea

  • Viral encephalitis

  • Subacute sclerosing panencephalitis

  • Ramsay-Hunt syndrome (ie, progressive myoclonic ataxia)

Genetic

  • Heredodegenerative/degenerative disorders

  • Ataxia telangiectasia

  • Hallervorden-Spatz disease

  • Huntington disease (including Westphal variant)

  • Neuronal ceroid lipofuscinoses

  • Pelizaeus-Merzbacher disease

  • Wilson disease

  • Dentatorubral pallidoluysian atrophy

  • Cerebellar system degenerations

  • Pallidonigral degeneration

  • Multiple system atrophy

  • Olivopontocerebellar atrophy

  • Striatonigral degeneration

  • Progressive pallidal atrophy

  • Fahr disease

  • Paroxysmal dystonic choreoathetosis

  • Familial intention tremor and lipofuscinosis

  • Ataxia telangiectasia

  • Dystonia musculorum deformans

  • Dihydroxyphenylalanine-responsive dystonia

  • Spasmodic torticollis

  • Meige syndrome

  • Task-specific tremor (writer's or voice tremor)

  • Senile chorea

Inherited disorders of metabolism

  • Abetalipoproteinemia

  • Fahr disease

  • Glutaric aciduria

  • Lesch-Nyhan syndrome

  • Pyruvate decarboxylase deficiency

  • Sulfite oxidase deficiency

Metabolic/endocrine disorders

  • Encephalopathies (eg, hepatic, renal)

  • Hyperparathyroidism

  • Hyperthyroidism

  • Hypoglycemia

  • Hyponatremia

  • Hypernatremia

Miscellaneous

  • Systemic lupus erythematosus

  • Henoch-Schönlein purpura

  • Peripheral neuropathies (eg, Charcot-Marie-Tooth disease, Guillain-Barré syndrome)

  • Space-occupying lesions of the brain

  • Tic disorders

  • Transient tic disorder

  • Chronic motor or vocal tic disorder

  • Tourette syndrome

Vascular/trauma

  • Cardiac surgery

  • Cerebral hemorrhage

  • Transient cerebral ischemia

  • Vasculitis

  • Antiphospholipid antibody syndrome

Other systemic disorders

  • Lupus erythematosus

  • Polycythemia vera

  • Neuroacanthocytosis

  • Acquired hepatocerebral degeneration

Vale et al. (2013) consulted the case books available at the Queen Square Library, from 1878 to 1911, comprising 42 volumes, to analyze the case notes of 127 patients with chorea under the care of William Richard Gowers, his major contribution to the study of choreas.[26] Their results are as follows:

  • 97 patients (76.3%) were female and the age of presentation ranged from 4 to 60 years (mean 14.3)
  • 43 patients (33.8%) experienced recurrent attacks of chorea
  • 29 patients (22.8%) had a family history of chorea
  • Past history of rheumatic fever was observed in 46 patients (36.2%)
  • 54 patients (42.5%) had speech impairment while a similar number had a cardiac murmur
  • Generalized chorea occurred in 87.4% and hemichorea in 11.8%

Gowers diagnosed many different forms of chorea including Huntington's disease, paralytic, persistent, recurrent, tetanoid, functional, maniacal, hemichorea and chorea gravidarum.

Sydenham chorea

Sydenham chorea first was described by Thomas Sydenham in his Schedula Monitoria in 1686. He named this new disease "St. Vitus' dance" to differentiate it from "dancing mania," a practice seen in the religious ceremonies of the day by those who danced to exorcise prevalent epidemic illnesses.[27] Along with carditis and arthritis, Sydenham chorea is a diagnostic indicator of rheumatic fever.

Sydenham chorea is characterized by involuntary movements that tend to be generalized or unilateral, involving predominantly the extremities and the face. The movements occur at rest, may start gradually or abruptly, and are exacerbated by stress. Like other tremors of extrapyramidal origin, they disappear during sleep. Neurologic examination often reveals hypotonia, motor restlessness, and choreic movements in combination, resulting in incoordination, gait disturbances, and dysarthria. When weakness caused by hypotonia is severe, these patients have a special form of Sydenham chorea termed chorea paralytic or chorea mollis.[28] In addition, Sydenham chorea can present with psychiatric manifestations including depression, anxiety, personality changes, emotional lability, obsessive-compulsive disorder, tics, and attention deficit disorder. Behavior disturbances may include crying, irritability, and inattentiveness.

In the 1980s, an outbreak of group A streptococcal tonsillitis in Rhode Island was associated with a 10-fold increase in the incidence of motor tics (without chorea); the concept of poststreptococcal tics was born.[29] Subsequent identification of further patients led to the development of a new acronym: PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections).[30] In addition to tics, patients with PANDAS had a high incidence of psychiatric disorders, particularly obsessive-compulsive disorder. However, Dale et al have demonstrated that cohorts of Sydenham chorea are predominantly female, whereas poststreptococcal tic cohorts are predominantly male.[31]

Alvarenga et al, by comparing 51 heart disease patients with history of rheumatic fever and 46 heart disease patients with no rheumatic fever history, found a higher prevalence of obsessive-compulsive symptoms in the patients with rheumatic fever.[32] This suggests that rheumatic fever activity is not a necessary condition for the expression of neuropsychiatric symptoms.

In a significant subgroup of patients, Sydenham chorea recurrence might represent either a primary underlying abnormality that increases their susceptibility to chorea or a movement disorder that is the outcome of permanent subclinical damage to the basal ganglia following the initial Sydenham chorea episode. In other words, it might not be a true relapse of rheumatic fever.[33]

Huntington disease

Huntington disease is an autosomal dominant inherited progressive neurodegenerative disorder characterized by chorea, complete motor disability, and mental status changes culminating in dementia and mental status changes. The average age at onset is 35-45 years, but it can occur in individuals from childhood to those older than 80 years.

Huntington disease is relentlessly progressive and characterized by generalized chorea, which is a hallmark of the disorder. The chorea is mild initially, and affected persons appear fidgety or restless. The movements may be merged into intentional gestures and may seem to be semipurposeful or unusual mannerisms. The patient eventually develops a wide-based gait associated with lurching, dipping, and falling, often resembling a marionette. Myoclonus and seizures might occur. Ocular motility abnormalities might include difficulty in generating saccadic movements. Other movement disorders, including parkinsonism, dystonia, and tic, also may be present in patients with Huntington disease.

Other clinical features include personality and behavioral changes, progressive memory loss, lack of attention span and, most commonly, depression. Neuro-psychiatric abnormalities are present in almost all patients. Suicide accounts for about 7.5% of deaths. The average duration of the natural course of the disease before death is about 17 years. The autosomal dominant inheritance is fully penetrant and confers a 50% risk of passage to offspring of affected individuals. The gene for Huntington disease codes for a protein that has been designated huntingtin. The function of the gene product and its mechanism of pathogenesis are not yet known.

A genetic test result of greater than 39 CAG repeats in the Huntington disease gene is diagnostic. However, genetic counseling is recommended strongly before testing, particularly in at-risk patients who are asymptomatic.

Currently, no treatment is available to prevent progression of Huntington disease. Patients are given symptomatic treatment for the chorea. Although progressive intellectual impairment generally occurs, mental status problems in individuals with Huntington disease are difficult to treat; therapy with antidepressant, antipsychotic, and antianxiety agents may be tried. Nonpharmacologic interventions, including speech therapy, swallowing evaluation, physical therapy, adaptation strategies, and counseling, are also important. Social service intervention is often necessary.

Relationship to antiphospholipid antibody syndrome

Antiphospholipid syndrome (APS) is a disorder characterized by recurrent venous or arterial thrombosis, recurrent fetal loss, and thrombocytopenia associated with the presence of lupus anticoagulant, anticardiolipin antibody, or both. Anticardiolipin and antiphospholipid are essentially interchangeable terms. Depending on the assay used to detect them, they cross-react. Several subtypes that do not cross-react have been identified but are currently of little clinical significance.

Antiphospholipid antibodies (aPLs) include anticardiolipin antibodies (aCL), the lupus anticoagulant (LAC), antibodies to other phospholipids such as phosphatidylserine[34] and phosphatidylethanolamine, and antibodies to phospholipid-binding proteins.[35]

The presence of LAC is characterized by prolonged activated partial thromboplastin time (aPTT) that is not corrected by addition of normal plasma but is corrected by freeze-thawed platelets or phospholipids. aCL is measured by enzyme-linked immunosorbent assay (ELISA).

In select high-risk pregnant populations without SLE, aPLs have been linked with adverse pregnancy outcomes such as preeclampsia, intrauterine growth retardation (IUGR), fetal distress, chorea gravidarum[36] , and postpartum morbidity. However, the relationship between aPL and pregnancy complications in the general obstetric population is less clear. Some evidence indicates that the HELLP syndrome (ie, hemolysis, elevated liver enzymes, and low platelets) may be a manifestation of APS.[37, 38]

A case of chorea gravidarum and progressive cerebral infarction due to factor V Leiden homozygosity has been reported.[39] This was the first such case in the literature, and treatment with unfractionated intravenous heparin had produced a good clinical response.

A variety of microangiopathic antiphospholipid-associated syndromes like HELLP syndrome, thrombotic thrombocytopenic purpura, and thrombotic microangiopathic syndromes should be differentiated from the microvascular occlusions that are seen in the antiphospholipid syndrome. In these conditions, the antibodies might not be pathogenic, but, alternatively, generated by small vessel endothelial damage.[40]

Treatment consists of long-term anticoagulation with warfarin and antiplatelet drugs. During pregnancy, heparin may need to be substituted for warfarin. For acute exacerbations, steroids and immunosuppressive therapy have been used. No evidence supports prophylactic therapy as helpful in patients who have been and are asymptomatic.

Moyamoya disease

In 2000, Unno et al reported a case of chorea gravidarum associated with moyamoya disease. A 16-year-old girl developed acute left choreic movements during her fourth week of pregnancy. She has had transient ischemic attacks since she was 10 years old. During the eighth week of pregnancy, a brain MRI showed old ischemic lesions deep in the right frontal white matter. Her angiograph revealed a complete obstruction of the terminal portion of the right internal carotid artery with a developed moyamoya network. After her abortion, all involuntary movements completely subsided. The choreic movements might have been caused not only by ischemia but also by enhanced dopaminergic sensitivity mediated by elevations in female sex hormones due to pregnancy.[10]

In a 2007 report, Kim et al reported the association of chorea gravidarum with moyamoya disease.[41]

Differential Diagnoses

 

Workup

Laboratory Studies

See the list below:

  • Maintain a high index of suspicion and vigilance when making the diagnosis of chorea gravidarum and considering the differential diagnosis.

  • Acute rheumatic fever- Erythrocyte sedimentation rate (ESR), throat culture, C-reactive protein, and ASO titer

  • Wilson disease - Serum ceruloplasmin and urinary copper (24 h)

  • Systemic lupus erythematosus - ESR, antinuclear antibody, anticardiolipin antibodies, and lupus anticoagulant assays

  • Phenothiazine reaction history - Therapeutic trial of intravenous (IV) benztropine

  • Polycythemia - CBC, hemoglobin, and hematocrit

  • Hyperthyroidism - Thyroxine (T4), thyroid-stimulating hormone (TSH)

  • Hypoparathyroidism - Serum calcium and phosphate

  • Vascular disease

    • Hypercoagulability of pregnancy; investigations for hyperlipidemia, diabetes, valvular heart disease, hyperviscosity states, hemoglobinopathies, or congenital cerebrovascular disease (moyamoya)

    • In a young patient with cerebral infarction, in the absence of hypertension and atrial fibrillation, vasculitides and thrombophilic tendencies must be considered. Testing for thrombophilia with estimation of anticardiolipin antibody, antithrombin III levels, prothrombin gene, protein S, protein C resistance, and factor V Leiden should be considered.

  • Meningovascular syphilis - Venereal Disease Research Laboratory test (VDRL), fluorescent treponemal antibody absorption test (FTA-ABS)

  • Drugs - Serum levels of anticonvulsants, theophylline, lithium, and tricyclic antidepressants

  • Drug toxicity due to amphetamine and cocaine - Serum levels and urine screening

  • Lead toxicity - Serum lead level

  • Neuroacanthocytosis peripheral smear for acanthocytes

  • Adult-onset Tay-Sachs disease - Assay of serum lysosomal enzymes

  • Husby has described antineuronal antibodies using an immunofluorescent technique in 46% of patients with Sydenham chorea (n = 30) compared with 14% of patients with rheumatic fever (without chorea) (n = 50) and only 1.8-4% of control subjects (n = 203). He further demonstrated a potential correlation between antibody reactivity and the clinical status, with antibody disappearance on chorea remission.[42]

Imaging Studies

See the list below:

  • Hypoparathyroidism: CT scan may reveal bilateral basal ganglia calcificans.

  • MRI

    • Huntington disease (MRI of the brain to exclude caudate atrophy) and neuroacanthocytosis

    • Wilson disease - Striatal damage

    • Systemic lupus erythematosus, locular infarcts - Small arterial damage

    • Rare basal ganglia tumor

Other Tests

See the list below:

  • Obtain ECG whenever a suspicion of rheumatic fever exists to exclude carditis. EEG may show evidence of rheumatic encephalopathy.

  • Perform a slit-lamp examination to rule out Kayser-Fleischer rings that would indicate Wilson disease.

 

Treatment

Medical Care

Declining incidence of chorea gravidarum in modern times reflects, in part, the declining frequency of rheumatic fever. Naturally this results in a situation in which a greater proportion of chorea gravidarum is secondary to other diseases such as systemic lupus erythematosus or Huntington chorea. An increased risk of systemic lupus erythematosus exacerbation is present during pregnancy and especially during the first 2 months postpartum, when the risk is 7 times that of nonpregnant individuals. Although a majority of patients with systemic lupus erythematosus and chorea gravidarum or chorea have improved after starting steroid therapy, spontaneous remissions have occurred without change of steroid dose or with haloperidol therapy alone. Patients whose symptoms did not respond to steroids or haloperidol benefited from other drugs.

Ichikawa et al reported morphologic alterations of an acute or relatively acute nature in the corpus callosum in at least 11 of the cases they reviewed.[43] This suggests that the response to steroid therapy may depend on whether the primary vascular lesion involving the basal ganglion is of an acute or chronic nature.

Traditional therapy has consisted of rest or seclusion and careful feeding. Usually chorea gravidarum is manageable nonpharmacologically. In mild chorea, patients are generally unaware of the involuntary movements. In general, abnormal choreic movements are more distressing to the observers than to the patient. Early approaches to therapy included sedation and steroids. Phenothiazines have benefited some patients. Chorea gravidarum is not an indication for abortion or premature interruption of pregnancy.

  • Drug treatment is indicated for patients with disabling severe chorea, when chorea interferes with the patient's health in general, or when the fetus is in danger due to dehydration, malnutrition, disturbed sleep, or injury.

    • Reserpine is potentially toxic to the fetus and is relatively contraindicated during pregnancy.

    • In 1972, Axley described the therapeutic value of haloperidol, a butyrophenone, in rheumatic chorea.[44] In 1973, Shenker et al reported its effectiveness in Sydenham chorea.[45] Since then, haloperidol has been effective therapy for Sydenham chorea and moderate-to-severe chorea gravidarum.[46, 47] A potent dopamine antagonist, it usually is administered in doses of 2-6 mg/d, although for more severe cases initial doses of 20 mg/d or more may be required.

    • Limited studies have demonstrated that risk of birth defects attributable to haloperidol is acceptably low as judged from studies of infants born to women who took haloperidol for control of hyperemesis gravidarum[48, 49] , especially if given after the first trimester when embryonic organogenesis is complete. In any instance, discontinue haloperidol therapy as soon as possible to minimize the risk of tardive dyskinesia. Most common adverse reactions include extrapyramidal effects. Thus far, haloperidol has proven to be an effective, acceptably safe treatment for moderately severe to severe chorea gravidarum.

    • Low-dose chlorpromazine either alone (25-50 mg PO/IM tid/qid) or in combination with diazepam (5 mg tid) has proved to be effective in ameliorating chorea.

    • Shannon and Fenichel suggest that pimozide, another neuroleptic drug, may have fewer adverse effects than haloperidol. They suggest that it has virtually no effect on norepinephrine receptors, thus in low doses (2 mg bid) and during short-term treatment has a lower risk for the appearance of tardive dyskinesia while improving Sydenham chorea symptoms.[50]

    • More recently, valproic acid has been reported to be effective at suppressing choreic movements. This drug enhances the activity of GABA, an inhibitory neurotransmitter of the striatonigral and striatopallidal circuit, which is decreased markedly in brains of individuals with chorea. The use of sodium valproate in Sydenham chorea shows evidence of response within 10 days, with a dose of 15-20 mg/kg/d.

    • Carbamazepine also may have a positive effect in Sydenham chorea. Pallares and Hurtado reported a large improvement in the first week of treatment of one patient using 20 mg/kg/d.[51] They suggest that the cholinergic action of carbamazepine in the striatum increases the acetylcholine level, inducing a new equilibrium in the balance of the dopaminergic and cholinergic systems. In patients with Sydenham chorea, the dopaminergic system is hyperactive, and the cholinergic system is hypoactive. The stimulus by carbamazepine on the cholinergic system promotes a relative decrease in dopamine, similar to the action produced by neuroleptic drugs.

  • Treatment of chorea induced by estrogen is as follows:

    • In at least 2 dozen cases[52, 53] , most patients are young nulliparae who have taken oral contraceptives for less than 4 months, and recovery can occur within 2 days of stopping oral contraceptives. Approximately one half previously had Sydenham chorea, rheumatic fever, or chorea gravidarum.

    • Treatment consists of discontinuing the oral contraceptive pill. Use of dopamine antagonists is indicated only if needed. Whether subsequent pregnancies trigger chorea in these women has not been reported.

 

Medication

Medication Summary

The goals of pharmacotherapy are to reduce morbidity and prevent complications.

Antipsychotic agents

Class Summary

These agents are useful, perhaps owing to their sedating properties.

Haloperidol (Haldol, Haldol Decanoate, Halperon)

Antipsychotic and strong tranquilizer; butyrophenone used in treatment of acute psychosis, acute schizophrenia, manic phases, control of aggression, agitation, and disorganized and psychotic thinking. May be used to help treat false perceptions (eg, hallucinations, delusions), Gilles de la Tourette syndrome, and psychosis associated with dementia, depressions, or mania.

More likely to cause adverse effects such as tardive dyskinesia than most other antipsychotic drugs.

Risperidone (Risperdal)

Benzisoxazole derivative, novel antipsychotic drug. Well absorbed after PO administration, has high bioavailability, and exhibits dose proportionality in therapeutic dose range, although interindividual plasma concentrations vary considerably. Food does not affect extent of absorption, thus can be administered with or without meals.

Peak plasma concentrations of parent drug reached within 1-2 h after intake. Mainly metabolized via hydroxylation and oxidative N-dealkylation. Major metabolite is 9-hydroxy-risperidone, which has similar activity to parent drug; clinical effect brought about by active moiety, namely risperidone plus 9-hydroxy-risperidone.

Hydroxylation depends on debrisoquine 4-hydroxylase (ie, metabolism of risperidone is sensitive to debrisoquine hydroxylation-type genetic polymorphism). Consequently, concentrations of parent drug and active metabolite differ substantially in extensive and poor metabolizers. However, concentration of active moiety (risperidone plus 9-hydroxy-risperidone) did not differ substantially between extensive and poor metabolizers, and elimination half-lives were similar in all subjects (approximately 20-24 h).

Rapidly distributed. Volume of distribution 1-2 L/kg. Steady-state concentrations of risperidone and active moiety were reached within 1-2 d and 5-6 d, respectively. In plasma, bound to albumin and alpha1-acid glycoprotein. Plasma protein binding of risperidone is approximately 88% and that of metabolite 77%. One wk after administration, 70% of dose excreted in urine and 14% in feces. In urine, risperidone plus 9-hydroxy-risperidone represents 35-45% of dose. Remainder is inactive metabolites.

Evaluated at dose range of 1-16 mg/d PO and compared to both placebo and haloperidol, studies indicated that risperidone is an effective antipsychotic agent improving both positive and negative symptoms.

Pimozide (Orap)

Diphenylbutylpiperidine derivative with neuroleptic properties. Relatively nonsedating and can be administered in single daily dose.

Appears to have selective ability to block central dopaminergic receptors, although it affects norepinephrine turnover at higher doses. Extrapyramidal effects also are observed, but it appears to have fewer autonomic effects. Peak plasma level in humans occurs 3-8 h after administration, and plasma levels decrease slowly to approximately 50% of peak level at 48-72 h after dosing.

Used to suppress severe motor and phonic tics in patients with Tourette disorder whose symptoms have not responded satisfactorily to standard treatment (eg, haloperidol). Use also extended to management of manifestations of chronic schizophrenia in which main manifestations do not include excitement, agitation, or hyperactivity. Not indicated in treatment of patients with mania or acute schizophrenia.

Anticonvulsants

Class Summary

These agents have proven useful in the management of severe muscle spasms and provide sedation.

Chloral hydrate (Noctec, Aquachloral)

Hypnotic and anxiolytic. At normal doses, this sleep induction does not affect breathing, blood pressure, or reflexes. When used in combination with analgesics, can help manage pain after surgery. Used for sedation for procedures (eg, CT scan) or for agitation that is interfering with ventilation.

Onset of action is 10-15 min. Metabolized to an active metabolite, trichloroethanol, which is excreted by kidney after conjugation to glucuronide salt. Plasma life is 8-64 h in neonates (mean 37 h). Protein binding is approximately 40%.

Available as supp, syr, or cap; mix syr with one-half glass (4 oz) water or fruit juice to minimize GI upset; cap should be swallowed whole followed by full glass (8 oz) of water or fruit juice.

Phenobarbital (Barbita, Solfoton, Luminal)

Barbiturate mostly used as anticonvulsant. Usually used in treatment of grand mal and focal motor epilepsy. In addition, used prophylactically for febrile seizures in children. Exact mode and site of action of phenobarbital (and other barbiturates) in suppression of seizure activity unknown. Believed to work by reducing neuronal excitability and by increasing motor cortex threshold to electrical stimulation.

Use also extends to suppression of anxiety and apprehension.

Valproic acid (Depakote, Depakene)

Anticonvulsant whose activity may be related to increased brain concentrations of GABA. Peak serum levels occur approximately 1-4 h after single PO dose. Serum half-life typically 6-16 h. Primarily metabolized in liver to glucuronide conjugate. Elimination of valproic acid and its metabolites occur principally in urine, with minor amounts in feces and expired air.

Used as sole or adjunctive therapy in treatment of simple or complex absence seizures, including petit mal, and useful in primary generalized seizures with tonic-clonic manifestations. Also used for manic phase of depression and in migraine.

Carbamazepine (Tegretol)

Chemically similar to cyclic antidepressants. Also manifests antimanic, antineuralgic, antidiuretic, anticholinergic, antiarrhythmic, and antipsychotic effects. Anticonvulsant action not known but may involve depressing activity in nucleus ventralis anterior of thalamus, resulting in reduction of polysynaptic responses and blocking posttetanic potentiation. Due to potentially serious blood dyscrasias, undertake benefit-to-risk evaluation before drug instituted. Peak serum levels in 4-5 h. Half-life (serum) in 12-17 h with repeated doses. Therapeutic serum levels are 4-12 mcg/mL. Metabolized in liver to active metabolite (ie, epoxide derivative) with half-life of 5-8 h. Metabolites excreted through feces and urine.

Antiemetics

Class Summary

These agents are used to control symptomatic nausea and may have antipsychotic effects.

Chlorpromazine (Ormazine, Thorazine)

Blocks postsynaptic mesolimbic dopamine receptors, has anticholinergic effects, and depresses reticular activating system. Blocks alpha-adrenergic receptors and depresses release of hypophyseal and hypothalamic hormones.

Benzodiazepines

Class Summary

By binding to specific receptor sites, these agents appear to potentiate effects of GABA and facilitate inhibitory GABA neurotransmission and other inhibitory transmitters.

Diazepam (Valium)

Anxiolytic sedative drug useful in symptomatic relief of anxiety and tension states. Also has adjunctive value in relief of certain neurospastic conditions. Peak blood levels reached within 1-2 h after single PO dosing. Acute half-life is 6-8 h with slower decline thereafter, possibly due to tissue storage. However, after repeated doses, blood levels increase significantly over 24-48 h.

In humans, comparable blood levels were obtained in maternal and cord blood, indicating placental transfer of drug.

Symptomatic management of mild-to-moderate degrees of anxiety in conditions dominated by tension, excitation, agitation, fear, or aggressiveness, such as may occur in psychoneurosis, anxiety reactions due to stress conditions, and anxiety states with somatic expression.

In acute alcohol withdrawal, may be useful in symptomatic relief of acute agitation, tremor, and impending acute delirium tremens.

As adjunct for relief of skeletal muscle spasm due to reflex spasm to local pathology, such as inflammation of muscle and joints or secondary to trauma; spasticity caused by upper motor neuron disorders, such as cerebral palsy and paraplegia; athetosis and rare "stiff man syndrome."

While usual daily dosages meet needs of most patients, some may require higher doses. In first few days of administration, cumulative effect may occur; therefore, increase dosage only after stabilization is apparent.

 

Follow-up

Prognosis

General prognosis

Chorea gravidarum seldom persists indefinitely. Without treatment, the disease abates in 30% of patients before they give birth. In almost two thirds of patients, the chorea lasts until puerperium. Symptoms often dramatically disappear in the days after childbirth. In some patients, neurological sequelae may continue in the form of various degrees of incoordination, tremor, and clumsiness.

The absence of a control group (ie, women without chorea gravidarum in pregnancy) from Beresford and Graham's analysis of chorea gravidarum in pregnancy makes interpretation of the statistics difficult; they report that death occurred in 1.5% of pregnancies, fetal death in 3.3%, and premature labor in 6.6%.[54]

Death is now rare[43] ; the mortality rate of 12% reported by Willson and Preece[4] reflects death due to underlying rheumatic heart disease.

In the case of drug-induced chorea gravidarum, movements clear on drug withdrawal, and specific antidote therapy often is not needed. Individual susceptibility for adverse effects from these drugs may be due to preexisting basal ganglia abnormalities, such as prior Sydenham chorea or hypoxic encephalopathy.

In the case of contraceptive-induced chorea gravidarum, researchers know from animal experiments that female hormones enhance postsynaptic dopaminergic sensitivity. By binding to presynaptic dopaminergic transporter sites, cocaine blocks dopamine reuptake, thus potentiating dopaminergic transmission. It also may influence postsynaptic receptor sensitivity.

Fetal prognosis

Spontaneous abortion occurs at a normal rate[5] , and infants are healthy.

Willson and Preece mentioned two 19th century cases of neonatal chorea. One case involved a microcephalic child with athetoid cerebral palsy. The other case was said to involve transient chorea, but the movements were not described further.[4]

In view of the current rarity of chorea gravidarum, fetal mortality is difficult to assess; however, in Beresford and Graham's series, fetal loss was 6.6%, and only one half of this loss was directly attributable to chorea.[54] In chorea gravidarum, maternal mortality is reportedly less than 1%.

Future pregnancy

Of women with chorea gravidarum, 21% have recurrent chorea with subsequent pregnancies.[4]

Several cases have been described in which attacks occurred in 3, 4, and even 5 pregnancies.[55, 56]