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 |
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Table 2. Secondary differential diagnosis (Open Table in a new window)
| Secondary differential diagnosis | |
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| Drugs/toxicity |
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| Infectious |
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| Genetic |
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| Inherited disorders of metabolism |
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| Metabolic/endocrine disorders |
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| Vascular/trauma |
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| Other systemic disorders |
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| Miscellaneous |
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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]
Tables
| Primary differential diagnosis |
|---|
|
| Secondary differential diagnosis | |
|---|---|
| Drugs/toxicity |
|
| Infectious |
|
| Genetic |
|
| Inherited disorders of metabolism |
|
| Metabolic/endocrine disorders |
|
| Vascular/trauma |
|
| Other systemic disorders |
|
| Miscellaneous |
|
