Chorea Gravidarum 

Updated: Jun 29, 2021
Author: Saher K Choudhary, MD; 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 entity but rather a generic term for chorea of any cause starting during pregnancy. Therefore, CG is regarded as a syndrome rather than a specific disease entity. 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]

Pathophysiology

Rheumatic fever is no longer a major cause of chorea gravidarum (CG) and the pathophysiology of CG in current times is unclear. Several pathogenetic mechanisms for CG have been proposed, but none have been proven.

In regard to rheumatic fever, the pathologic changes in the brain reported in CG are similar to those found in rheumatic cardiac disease. These changes include nonspecific arteritis with endothelial swelling, perivascular lymphocytic infiltration, and petechial hemorrhages.[4] Of note, Aschoff bodies, found in the rheumatic heart disease, are not found in the brain.[5, 6] These pathologic changes in the brain are most prominent in the corpus striatum and associated with severe neuronal loss. The corpus striatum is considered to be the largest structure present in the basal ganglia. Classically, the corpus striatum is divided in two parts: dorsal striatum (caudate nucleus and putamen) and ventral striatum (nucleus accumbens and olfactory tubercle). The corpus striatum preforms a variety of different functions from cognitive process and behavior reinforcement to motor functions. It is the dorsal striatum, however, which is most significant in motor activity and commonly involved in hyperkinetic and hypokinetic movement disorders. 

In CG patients with autoimmune pathology, postmortem studies show diffuse foci of small hemorrhages present throughout the brain. These hemorrhages are most evident in basal ganglia and caudate nucleus with associated widespread vasculitis.[7, 8] Presumably, as the inflammation resolves, the chorea disappears, and degenerative changes are left in small arterioles.

Another pathologic hypothesis is related to hormonal mediation, particularly estrogen, given there is an increase in chorea cases among young women on oral contraceptives. Nausuda et al reported that modification of postsynaptic dopamine receptors produces dopamine hypersensitivity in high estrogen states.[9] Lee et al suggested that estrogen augments the neuronal function by increasing the expression of active D5 receptors.[10] Estrogen acts as a dopamine agonist on the striatal D2 receptors in the medial part of corpus striatum. In normal estrogen states there does not appear to be any effect on the striatal dopamine receptor expression.[11, 12] Oral contraceptives may activate the same high estrogen state mechanism of CG leading to chorea and further supporting the role of estrogen in CG. In 1950, Beresford and Graham postulated that, “It may be that pregnancy lowers the resistance of a patient who is inherently susceptible to chorea.”[13] Therefore, it has been hypothesized that another cause of CG may be from the reactivation of previous subclinical damage to the basal ganglia during high estrogen states including pregnancy.

In 2004, Miranda et al reported of a case of chorea associated with the use of the oral contraceptives, in which anti-basal ganglia antibodies were detected, suggesting a possible immunological basis to the pathogenesis of this disorder.[14]  However, the presence of antibodies in serum does not necessarily infer pathogenicity; the antibodies could be produced as part of tissue damage.[15] To demonstrate that a disorder is autoimmune, 5 criteria must be fulfilled.[16]  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.

Epidemiology

Incidence

Movement disorders rarely occur during reproductive years, therefore, clinicians are not very familiar with chorea gravidarum (CG). Willson and Preece found that the overall incidence of CG was approximately 1 case per 300 deliveries. According to them, the first description of chorea with onset during pregnancy was made by Horstius in 1661. Rheumatic fever secondary to untreated streptococcal pharyngitis was a major cause of CG at the time of Willson and Preece’s publication. They noted that nearly 70% of their patients had a previous history of either rheumatic fever or chorea.[4]  Since the widespread use of antibiotics for streptococcal pharyngitis, CG has become very uncommon.

Calculating the current incidence of CG is not possible given the rarity of the syndrome and lack of more recent published studies. However, a study by Zegart and Schwartz found that one patient with CG had been encountered among 139,000 deliveries in 3 major Philadelphia hospitals.[17]  In general, about half the cases of CG are idiopathic, with rheumatic fever and antiphospholipid syndrome (APS) responsible for the reminder of cases.[18]

Demographics

Most patients with CG are young; the average age of onset is 22 years old.[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 patients of European descent.

Of afflicted women, 60% previously had chorea and a family history of transient chorea is not unusual. When occurring with first pregnancies, 50% of CG cases occur in the first trimester and 30% of cases occur in the second trimester. Recurrence of CG in subsequent pregnancies may occur, particularly when associated with antiphospholipid syndrome.[4]  

Prognosis

General prognosis

Chorea gravidarum (CG) seldom persists indefinitely. Without treatment, the disease abates in about one third of patients before child delivery. In almost two thirds of patients, the chorea lasts up to 6 weeks postpartum, also known as puerperium. Symptoms often dramatically improve and disappear in the days after childbirth. In some patients, however, neurological sequelae may continue in the form of various degrees of incoordination, tremor, and clumsiness.

Mortality in patients with CG is now rare[7]  but, again, difficult to calculate given the scarcity of data. Willson and Preece reported a mortality rate of 12%.[4]  However, this likely reflects death due to underlying rheumatic heart disease rather than CG. Beresford and Graham's 1950 analysis of CG reported that death occurred in 1.5% of pregnancies, fetal death in 3.3%, and premature labor in 6.6%,[13]  However, due to the absence of a control group it is impossible to interpret this data. Additionally, advances in maternal-fetal medicine since 1950 would also likely improve these statistics. 

In the case of drug-induced CG and contraceptive-induced chorea, movements typically resolve after cessation of the drug; and specific therapeutic interventions are not often needed. Individual susceptibility for adverse effects from these drugs may be due to preexisting basal ganglia abnormalities, such as prior vascular insults, Sydenham chorea, or hypoxic encephalopathy.

Fetal prognosis

In view of the paucity of CG, fetal mortality is difficult to assess. 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]  It is not clear that these cases were related to CG and no further data is available since their 1932 report.

There is no increased risk of spontaneous abortion in CG[17]  and children are generally born healthy and there are not reports on delivery complications.  There is no data to indicate significant fetal complications and the 1950 Beresford and Graham report is unclear as noted above.

Future pregnancy

It is unclear what the recurrence rate of CG is in modern times. Willson and Preece reported 21% of women with CG have recurrent chorea with subsequent pregnancies.[4]  Several cases have been described in which attacks occurred in the third, fourth, and even fifth pregnancy.[19, 20]

 

Presentation

History

Chorea gravidarum (CG) is a rare clinical entity often without an identifiable cause, but its early recognition is important to decrease the maternal and fetal morbidity and mortality. The diagnosis requires a detailed patient history and physical examination along with thorough laboratory evaluation.

The clinical presentation is variable as chorea can present in various forms including generalized, focal, multifocal or hemichorea. It can also be unilateral or bilateral and include upper extremities and/or lower extremities. There are many different forms of chorea including Huntington's disease, paralytic, persistent, recurrent, tetanoid, functional, maniacal, hemichorea, and chorea gravidarum.[21]

Patients may attempt to disguise chorea by incorporating movements into a mannerisms or gestures. Some patients may appear simply restless or fidgety. Some may be unaware of the abnormal movements and, thus, may not complain about chorea or abnormal movements. Additionally, stress may aggravate the movements of CG and the movements disappear during sleep. These factors may lead to misdiagnosis of the condition.

As the exact etiology of CG is not clear, getting a comprehensive history from the patient is important. A thorough past medical history including rheumatic fever, history of recent infection with group A beta-hemolytic streptococcus (GABHS), and family history of chorea also needs to be identified. A pre-pregnancy history of Sydenham’s chorea has an increased risk of development if CG.[4] Of note, there are published case reports from the early 1900s in which women with normal pregnancies before rheumatic fever developed chorea in subsequent pregnancies after having rheumatic fever.[22, 23]

Immune-mediated conditions, including antiphospholipid antibody syndrome (APS) and systemic lupus erythematosus (SLE) may also predispose patients to a higher risk of CG. Therefore, a history of dermatological and joint complaints, clotting abnormalities, and spontaneous abortions may point to these etiologies being the cause of CG.

History should also focus on reviewing prescribed medications, particularly dopamine agonists, as well as inquiring about substance abuse and illicit drug use. Prior use of oral contraceptives (OC) also helps in supporting the diagnosis of recurrence of CG. Fernando et al reported the first case linking estrogen containing oral contraceptives to chorea. Chorea may also reappear in CG patients who later take OCs or use topical estrogen.[24]

A detailed history should be obtained to rule out other diagnoses that may manifest as chorea during pregnancy such as thyrotoxicosis, Wilson’s disease, and Huntington’s disease. Though patients with these diseases may have chorea during pregnancy, they are etiologically distinct pathological process and not typically considered to be CG.   

Physical

Clinical manifestations of chorea gravidarum (CG) may include the following:

  • Involuntary muscle movements: Typically the dance-like movements of chorea, which are rapid, purposeless, irregular, jerky movements that seem to randomly flow from one part of the body to another. These movements worsen with stress or anxiety and completely disappear during sleep. Generally, the affected limb may be hypotonic; joints are floppy, and knee jerks are pendular.  Wrist and fingers assume the shape of a dinner fork with abduction of the thumb.  
  • Facial grimacing: Involuntary movements are often associated with non-patterned grimacing of the face due to incoordination of muscles.
  • Milkmaid’s grip: Due to varying hand strength, when the patient tries to shake someone’s hand they may grip and release the fingers over and over again. This action appears similar to milking a cow, thus is referred to as milkmaid’s grip.
  • Darting tongue sign: When the patient tries to protrude his tongue, it may slide in and out uncontrollably. [25]
  • Dysarthria: Chorea movements may involve facial muscle leading to dysarthria. However, it should be noted that dysarthria can be present in some cases even without facial chorea. [26]
  • Mental status changes: Some cases of CG may present with confusion and agitation.  This is more likely when the etiology of CG is related to autoimmune disease.  
  • Neuropsychiatric symptoms: Chorea movements can be preceded by neuropsychiatric symptoms like emotional lability, mild cognitive changes, and psychosis. [27] Other clinical manifestations include personality changes, depression, chronic cognitive deficits, hypnic hallucinations, delirium, and Tourette-like symptom. [28]

The cerebral manifestation of rheumatic fever has sometimes historically been referred to as rheumatic brain disease. This may present as Sydenham’s chorea associated with mental status changes, emotional lability to hysterical traits, psychotic delusions, hallucinations, seizures, and papilledema depending on the severity of illness.[29, 30, 31] Encephalopathy associated with rheumatic fever, historically referred to as rheumatic encephalopathy, may be reflected in the EEG findings of 3–6 Hz slow waves, particularly over the frontal and central regions.[32]

The diagnosis of CG relies on a complete physical examination in which the involuntary, non-rhythmic, abrupt movements of chorea are identified during pregnancy, particularly in the first trimester. Case reports have documented dystonia as a sole presentation in the first trimester with resolution after delivery as a form of CG. Authors hypothesized that transient dystonia in these patients has a similar pathophysiology of CG due to the hyperkinetic nature of dystonia.[33]

Though CG is not a life-threatening condition, hyperthermia, rhabdomyolysis, myoglobinuria, and death have been reported in severe cases.[7]

Causes

There is evidence that chorea gravidarum (CG) is a sequela of rheumatic fever and autoimmune diseases. Although CG is a rare entity today, the etiology is most probably autoimmune in nature in industrialized nations, whereas it is rheumatic in nature in developing nations.

Causes contributing to CG include:

  • Lupus anticoagulant
  • Anticardiolipin antibody
  • Systemic lupus erythematosius
  • Vascular malformation in the basal ganglia region
  • Cerebrovascular disease involving the basal ganglia region
  • Oral contraceptive pills
  • Illicit substance abuse

Causes of chorea in during pregnancy include:

  • Thyrotoxicosis
  • Wilson’s disease
  • Huntington’s disease
  • Neuroacanthocytosis
 

DDx

Diagnostic Considerations

Genetic syndromes with chorea include Huntington's disease, HDL1-3, inherited prion disease, and spinocerebellar ataxias 1, 3, and 17 as well as neuroacanthocytosis, dentatorubro-pallidoluysian atrophy (DRPLA), brain iron accumulation disorders, Wilson's disease, benign hereditary chorea, Friedreich ataxia, and mitochondrial disease. Symptoms of these syndromes, including chorea, may occur during pregnancy but are etiologically distinct from chorea gravidarum (CG). These genetic syndromes should be ruled out with a thorough history, complete physical exam, and appropriate laboratory testing during the evalution of CG.   

CG falls under the category of acquired causes of chorea. Other acquired causes of chorea include vascular disease, postinfectious autoimmune central nervous system disorders (PANDAS), drugs, systemic lupus erythematosus, antiphospholipid syndrome, thyrotoxicosis, AIDS, and polycythemia rubra vera.[34]

Table 1. Primary differential diagnosis (Open Table in a new window)

Primary differential diagnosis
  • Familial paroxysmal choreoathetosis

  • Benign hereditary chorea

 

Table 2. Secondary differential diagnosis (Open Table in a new window)

Secondary differential diagnosis  
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
  • Pantothenate kinase-associated neurodegeneration (PKAN) disease
  • Huntington disease (including Westphal variant)
  • Neuronal ceroid lipofuscinoses
  • Dentatorubral pallidoluysian atrophy
  • Pallidopontonigral degeneration
  • Primary Atrophy of the Pallidal System (progressive pallidal atrophy)
  • ​Fahr disease
  • Paroxysmal dystonic choreoathetosis
  • Familial intention tremor and lipofuscinosis
  • Dystonia musculorum deformans
  • Dopa-responsive dystonia
  • Spasmodic torticollis
  • Meige syndrome
  • Task-specific tremor (writer's or voice tremor)
Inherited disorders of metabolism
  • Abetalipoproteinemia

  • Glutaric aciduria

  • Lesch-Nyhan syndrome

  • Pyruvate decarboxylase deficiency

  • Sulfite oxidase deficiency

Metabolic/endocrine disorders
  • Encephalopathies (eg, hepatic, renal)

  • Hyperparathyroidism

  • Hyperthyroidism

  • Hypoglycemia

  • Hyponatremia

  • Hypernatremia

Vascular/trauma
  • Cardiac surgery

  • Cerebral hemorrhage

  • Transient cerebral ischemia

  • Vasculitis

  • Antiphospholipid antibody syndrome

Other systemic disorders
  • Lupus erythematosus

  • Polycythemia vera

  • Neuroacanthocytosis

  • Acquired hepatocerebral degeneration

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

Sydenham chorea

Syndenham chorea was first described by Thomas Sydenham in his Schedula Monitoria in 1686. He named this new disease "St. Vitus' dance" after a practice seen in the religious ceremonies of the day by those who danced to exorcise prevalent epidemic illnesses.[35] Along with carditis and arthritis, Sydenham chorea is a diagnostic indicator of rheumatic fever.

Sydenham chorea is also associated with group A streptococcal infections and can follow the rheumatic fever by as much as 7 months.[36] 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.[37] It was widely thought that CG was Sydenham chorea manifesting during pregnancy.[7] The fact that chorea recurs in the same woman with several pregnancies argues against CG being related to acute streptococcal infection. 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.[38]

However, the association between CG and Sydenham chorea may represent either a primary underlying abnormality that increases 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.[39] Maia et al describe that CG is a frequent complication of pregnancy in patients with previous history of Sydenham chorea and an increased risk of miscarriage should be considered. They favor the notion that CG results from hormonal changes acting on previously dysfunctional basal ganglia.[40]

Huntington disease

Huntington disease is an autosomal dominant inherited progressive neurodegenerative disorder characterized by chorea, motor disability, psychiatric symptoms, behavior changes, and cognitive decline culminating in dementia. Huntington disease is a progressive and fatal disorder  hallmarked by generalized chorea. It should also be noted that in the early course of Huntington disease, the chorea is mild and affected persons appear fidgety or restless. Though it can occur in individuals from childhood to those older than 80 years, the average age at onset is 35–45 years old. It is uncommon for Huntington’s chorea to begin during pregnancy, however, as maternal age continues to increase this should be considered when evaluating for CG. 

Definitive diagnosis of Huntington disease is through genetic testing. It can be confirmed by targeted mutation analysis showing a CAG trinucleotide expansion of > 37 repeats in the Huntingtin gene. However, genetic counseling is recommended strongly before testing, particularly in at-risk patients who are asymptomatic. For families with HD preimplantation, genetic testing is possible to select embryos without the HD genetic mutation.

Currently, no treatment is available to prevent progression of Huntington disease. Patients with HD are provided with a multidisciplinary care team who can address both physical and psychological needs of patients and families. Patients are given symptomatic treatment for the chorea and psychiatric symptoms are similarly managed as any other psychiatric condition. Nonpharmacologic interventions, including speech therapy, swallowing evaluation, physical therapy, adaptation strategies, and counseling, are also important; and social service intervention is often necessary. Investigational therapies such as gene silencing are currently underway.

Antiphospholipid antibody syndrome

Antiphospholipid syndrome (APS) is thought to be a significant cause of CG in industrialized nations. In these cases, most patients present with symptoms in the second or third trimester. CG can sometimes be the sole presentation with no history of any autoimmune disease, so a complete evaluation is indicated particularly if there is history of fetal loss. Symptoms may also include mental status changes with agitation and confusion.

APS is a disorder characterized by recurrent venous or arterial thrombosis, recurrent fetal loss, and thrombocytopenia.  Antiphospholipid antibodies (aPLs) include anticardiolipin antibodies (aCL), the lupus anticoagulant (LAC), antibodies to other phospholipids such as phosphatidylserine[41] and phosphatidylethanolamine, and antibodies to phospholipid-binding proteins.[42] Of note, the presence of LAC is characterized by prolonged activated partial thromboplastin time (aPTT), which is not corrected by addition of normal plasma but is corrected by freeze-thawed platelets or phospholipids. In patients with lupus, anticoagulant antithrombotic therapy may be indicated.

Imaging in APS may be normal or may show focal abnormalities in the basal ganglia. CSF studies may reveal elevated protein and mild pleocytosis or may be normal. Postmortem studies in these patients reveal diffuse foci of small hemorrhages mostly in the basal ganglia and caudate nucleus. Some studies also reported widespread vasculitis. A few patients develop rhabdomyolysis, seizures, hemiplegia, and coma with hyperthermia being a poor prognostic factor.

Recurrence of CG with subsequent pregnancies in patients with APS has been reported and in some cases the results were fatal. Cervera et al reported a case series of 50 patients with antiphospholipid antibodies. Among them, 6% developed CG and 12% developed chorea after starting estrogen-containing oral contraceptives. Notably 34% developed recurrent symptoms when challenged with high estrogen states.[43]

Similar to APS, factor V Leiden mutation can cause venous and arterial thrombosis. A case of CG and progressive cerebral infarction due to factor V Leiden homozygosity has been reported.[44]  This was the first such case in the literature, and treatment with unfractionated intravenous heparin had produced a good clinical response.

Systemic lupus erythematosus

As with APS, systemic lupus erythematosus (SLE) is thought to be a significant cause of CG in industrialized nations. In patients with CG, the diagnosis of SLE should always be considered and it should be noted that chorea itself can be seen with SLE and not just CG. Chorea in SLE can be followed by other symptoms, however, sometimes chorea is the sole manifestation of SLE. As chorea in SLE responds to immunosuppression with steroids, symptomatic treatment of chorea with secondary agents is often not warranted.[45] Due to decreased incidence of rheumatic fever, most cases of CG are caused by other diseases including SLE and other autoimmune disorders. Patients with these disorders present in the second and third trimester with chorea, confusion, and agitation.

Moyamoya disease

Moyamoya is a non-inflammatory, non-atherosclerotic progressive vasculo-occlusive disease involving the distal internal carotid arteries and circle of Willis. In 2000, Unno et al reported a case of CG with moyamoya disease. The case reported a 16-year-old girl who had history of transient ischemic attacks developed acute left choreic movements during her fourth week of pregnancy. On imaging, 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 right internal carotid artery with a developed moyamoya network. It is of note that these movements completely subsided after abortion. Therefore, the authors hypothesized that the choreic movements might be caused not only by ischemia but also by enhanced dopaminergic sensitivity mediated by elevations in female sex hormones due to pregnancy.[46]

The association of moyamoya disease and CG is further supported by additional published studies since the 2000 report. In a 2007 report, Kim et al reported the association of CG with moyamoya disease.[47]  In 2009, a case of CG associated with Moyamoya disease in consecutive pregnancy was reported further linking moyamoya disease as an etiological agent of CG.[48]

 

Workup

Laboratory Studies

When making the diagnosis of chorea gravidarum (CG), it is important to keep in mind the diagnositc considerations and to maintain a high index of suspicion and vigilance.

  • Acute rheumatic fever   – erythrocyte sedimentation rate (ESR), throat culture, C-reactive protein, and ASO titer as well as antineuronal antibodies

    See the list below:

    • Husby 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. [49]
  • Wilson disease – serum ceruloplasmin and urinary copper (24 h)
  • Autoimmune disease (APS, SLE, etc) – ESR, antinuclear antibody, anticardiolipin antibodies, and lupus anticoagulant assays. Coagulation times PT and aPTT.
  • Vascular disease   – routine stroke evaluation should include risk factor screenings

    See the list below:

    • Hypercoagulability of pregnancy; investigations for hyperlipidemia, diabetes, valvular heart disease, hyperviscosity states, hemoglobinopathies, or congenital cerebrovascular disease (moyamoya)
    • In young patients with cerebral infarction, in the absence of other clear etiological causes, vasculitides and thrombophilic tendencies must be considered. Hypercoagulable testing including checking for anticardiolipin antibody, antithrombin III levels, prothrombin gene, protein S and protein C resistance, and factor V Leiden should be considered.
  • Hyperthyroidism – thyroxine (T4), thyroid-stimulating hormone (TSH)
  • Hypoparathyroidism – serum calcium and phosphate
  • Wilson disease – serum ceruloplasmin and urinary copper (24 h), liver function tests and electrolytes.
  • Neuro-acanthocytosis  – peripheral smear for acanthocytes
  • Polycythemia – CBC, hemoglobin, and hematocrit.
  • 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
  • Toxicology screening – (serum and urine levels) for amphetamine and cocaine.
  • Lead toxicity – serum lead level
  • Phenothiazine reaction history – therapeutic trial of intravenous (IV) benztropine
  • Adult-onset Tay-Sachs disease – assay of serum lysosomal enzymes

Imaging Studies

Useful imaging tests for chorea gravidarum (CG) include:

  • Echocardiography: Acute rheumatic fever
  • CT scan: Hypoparathyroidism (may reveal bilateral basal ganglia calcifications)
  • MRI: Evaluate for structural changes or lesions
    • Huntington disease – caudate atrophy
    • Neuroacanthocytosis – basal ganglia atrophy
    • Wilson disease – striatal damage
    • Systemic lupus erythematosus – small arterial damage, locular infarcts
    • Rare basal ganglia tumor

Other Tests

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

Usually, chorea gravidarum (CG) is manageable non-pharmacologically and traditional therapy consists of rest or seclusion and careful feeding. In mild chorea, patients are generally unaware of the involuntary movements and may have no complaints. In general, abnormal choreic movements are more distressing to the observers than to the patient. The mainstay of pharmacologic treatment is neuroleptic drugs, such as haloperidol, and steroids.

As noted previously, the declining incidence of CG in modern times reflects, in part, the declining frequency of rheumatic fever. This results in a situation in which a greater proportion of CG is secondary to other diseases such as autoimmune disorders. SLE exacerbation risk is 7 times higher during pregnancy and the first 2 months postpartum compared to nonpregnant individuals. Although a majority of patients with SLE and CG or chorea improve after starting or increasing 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.[7] 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.

In regards to oral contraceptive pill-/estrogen-induced chorea, whether subsequent pregnancies trigger chorea in these women is not known. The mainstay of treatment consists of discontinuing the oral contraceptive pill and using a dopamine antagonist only if needed (ie, symptoms persist after discontinuing the oral contraceptive pill). In at least 2 dozen cases,[50, 9]  most patients with estrogen-induced chorea were noted to be young, nulliparous women who had taken oral contraceptives for less than 4 months. A majority of these patients recovered within 2 days of stopping oral contraceptives. Of note, approximately 50% of patients had a history of Sydenham chorea, rheumatic fever, or CG. 

Pharmacologic treatment

Drug treatment is indicated for patients with disabling severe chorea, when chorea interferes with the patient's health, 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.
  • Haloperidol, a potent dopamine antagonist, remains a first line agent with starting dose of 2–6 mg/day up to 20 mg/day in severe cases
    • In 1972, Axley described the therapeutic value of haloperidol in rheumatic chorea. [51]  In 1973, Shenker et al reported its effectiveness in Sydenham chorea. [52]  Since then, haloperidol has been effective therapy for Sydenham chorea and moderate-to-severe CG. [53, 54]    
  • Limited studies have demonstrated that risk of birth defects attributable to haloperidol is low as judged from studies of infants born to women who took haloperidol for control of hyperemesis gravidarum, [55, 56] especially if given after the first trimester when embryonic organogenesis is complete.
  • It is recommended that haloperidol therapy be discontinued 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, relatively safe treatment for moderate-to-severe CG.
  • Chlorpromazine (25–50 mg PO/IM TID/QID) either as monotherapy or in combination with diazepam (5 mg TID) has proved to be effective in ameliorating chorea.
  • Pimozide (2 mg BID), another neuroleptic drug may have fewer adverse effects than haloperidol
    • Shannon and Fenichel suggest that pimozide has virtually no effect on norepinephrine receptors, thus in low doses and during short-term treatment has a lower risk for the appearance of tardive dyskinesia while improving Sydenham chorea symptoms. [57]
  • Valproic acid has been more recently reported to be effective at suppressing choreic movements.
    • Valproic acid 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. [58]  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. [53, 54]    
 

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.