Chorea Gravidarum

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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]

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).

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.

Laboratory Studies

See the list below:

Imaging Studies

See the list below:

Other Tests

See the list below:

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.

Medication Summary

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

Haloperidol (Haldol, Haldol Decanoate, Halperon)

Clinical Context:  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)

Clinical Context:  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)

Clinical Context:  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.

Class Summary

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

Chloral hydrate (Noctec, Aquachloral)

Clinical Context:  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)

Clinical Context:  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)

Clinical Context:  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)

Clinical Context:  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.

Class Summary

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

Chlorpromazine (Ormazine, Thorazine)

Clinical Context:  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.

Class Summary

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

Diazepam (Valium)

Clinical Context:  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.

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.

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]

Author

Tarakad S Ramachandran, MBBS, MBA, MPH, FAAN, FACP, FAHA, FRCP, FRCPC, FRS, LRCP, MRCP, MRCS, Professor Emeritus of Neurology and Psychiatry, Clinical Professor of Medicine, Clinical Professor of Family Medicine, Clinical Professor of Neurosurgery, State University of New York Upstate Medical University; Neuroscience Director, Department of Neurology, Crouse Irving Memorial Hospital

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Nestor Galvez-Jimenez, MD, MSc, MHA, The Pauline M Braathen Endowed Chair in Neurology, Chairman, Department of Neurology, Program Director, Movement Disorders, Department of Neurology, Division of Medicine, Cleveland Clinic Florida

Disclosure: Nothing to disclose.

Chief Editor

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, Tampa General Hospital, University of South Florida Morsani College of Medicine

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Ceribell, Eisai, Greenwich, Growhealthy, LivaNova, Neuropace, SK biopharmaceuticals, Sunovion<br/>Serve(d) as a speaker or a member of a speakers bureau for: Eisai, Greenwich, LivaNova, Sunovion<br/>Received research grant from: Cavion, LivaNova, Greenwich, Sunovion, SK biopharmaceuticals, Takeda, UCB.

Additional Contributors

Stephen T Gancher, MD, Adjunct Associate Professor, Department of Neurology, Oregon Health Sciences University

Disclosure: Nothing to disclose.

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