- Email: [email protected]
Chorea gravidarum
Handbook of Clinical Neurology, Vol. 100 (3rd series) Hyperkinetic Movement Disorders W.J. Weiner and E. Tolosa, Editors # 2011 Elsevier B.V. All rights reserved
Chapter 15
Chorea gravidarum BRADLEY J. ROBOTTOM * AND WILLIAM J. WEINER Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, USA
INTRODUCTION Published accounts of chorea gravidarum (CG), or chorea beginning in pregnancy, date to the 19th century (Barnes, 1869; McCann, 1891; Osler, 1894). It is important to realize that CG is not a disease but a syndrome that describes any chorea beginning during pregnancy. The etiology is varied and has changed markedly in the last century. In 1932, the largest series of CG was reviewed – 951 cases (Wilson and Preece, 1932). The authors described an uncommon but highly morbid condition in which there was a high likelihood of underlying rheumatic fever. Although the most common causes of CG have changed since this review, this work remains the largest account of CG and contains a wealth of information on a syndrome which is no longer commonly encountered.
EPIDEMIOLOGY Historically, CG was a relatively common occurrence, with an incidence of 1 per 2275 pregnancies (Wilson and Preece, 1932). The British Medical Association reported that 1.5% of all choreas were CG (Wilson and Preece, 1932; Cardoso, 2002). In the 1932 article, rheumatic heart disease was found in 86% of cases of CG, and it was concluded that this was the most common cause. CG was usually diagnosed in primiparous women and the prognosis was dire, with an 18–33% maternal and 50% fetal mortality rate (Birbeck, 2006). The widespread availability of penicillin decreased the incidence of rheumatic fever and CG dramatically. Thirty years after the Wilson and Preece review, the incidence of CG was 1 per 139 000 (Zegart and Schwarz, 1968). Because of the rarity of the syndrome, it is difficult to find modern estimates of incidence. In one movement disorders center with a particular interest in chorea, CG accounted for 3.6% of patients (Cardoso et al., 1999).
CLINICAL CHARACTERISTICS Chorea describes irregular, unpredictable, brief jerky movements that move from one body part to another. When chorea is composed of large-amplitude movements with wild flinging or throwing movements it is referred to as ballism (Weiner and Lang, 1989). CG may be unilateral or bilateral, and the movements disappear during sleep. Chorea often involves the face as well as the limbs. Even without clear facial involvement, dysarthria may be present (Birbeck, 2006). The affected limbs are usually hypotonic. Symptoms usually begin in the first or early second trimester (McCann, 1891; Wilson and Preece, 1932; Nyman et al., 1997). In most patients, chorea resolves by the third trimester or abates within hours of delivery (Lewis and Parsons, 1966; Palanivelu, 2007). One patient with CG developed fatal hyperthermia (Ichikawa et al., 1980). CG may recur in later pregnancies, even in idiopathic cases (Ghanem, 1995). Chorea may also reappear in women who later take oral contraceptives (OC) or use topical estrogen (Caviness and Muenter, 1991). In addition to chorea, patients may also experience psychiatric symptoms. Symptoms associated with CG include personality changes, depression, tourettism, severe hypnic hallucinations, delirium, and chronic cognitive deficits (Brockington, 2006). Interestingly, the last case of psychosis attributed to CG was published in 1950 (Brockington, 2006). This raises the question of whether the nature of CG has changed as a result of an etiological shift, or whether this is due to reporting bias, with newer cases of psychosis and chorea during pregnancy being attributed to a specific diagnosis rather than CG. Recently, two patients were described who presented with dystonia in the first trimester (Lim et al., 2006; Buccoliero et al., 2007). Both patients had cervical
*Correspondence to: Bradley J. Robottom, M.D., Department of Neurology, University of Maryland School of Medicine, 110 S. Paca Street, 3-S-128, Baltimore, MD, 21201, USA. Fax 410-328-0167, E-mail: [email protected]
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dystonia without an identifiable secondary cause. Each case resolved before delivery. Though neither of the patients developed chorea, this possible new entity, dystonia gravidarum, is hypothesized to have a similar pathophysiological basis.
ETIOLOGY Historically, rheumatic fever was the most common cause of CG, accounting for 86% of cases (Wilson and Preece, 1932). Patients with CG secondary to rheumatic fever usually have a history of rheumatic heart disease, recurrent tonsillitis, or Sydenham’s chorea rather than acute rheumatic fever (Wilson and Preece, 1932). Even when there are no signs of acute rheumatic fever, antistreptolysin antibody titers may be elevated (Birbeck, 2006). With widely available and effective treatment for streptococcal infections, rheumatic fever is no longer a common cause of CG. Currently, half of all cases of CG are idiopathic (Dike, 1997; Qasim, 2000) (Table 15.1). In industrialized nations, systemic lupus erythematosus (SLE) and the antiphospholipid antibody syndrome (APS) are the most common identifiable causes of CG (Johnson and Richardson, 1968; Donaldson and Espiner, 1971; Ichikawa et al., 1980; Lubbe and Walker, 1983; Lubbe et al., 1984; Palanivelu, 2007). APS may be primary or secondary to SLE. Other pregnancy-related complications attributed to APS and SLE include spontaneous abortion, deep venous thrombosis, preterm delivery, intrauterine growth retardation, and preeclampsia (Kutteh, 1996; Huong et al., 1997). Because CG may be the presenting sign of autoimmune disease, a high degree of suspicion is required when evaluating a patient with CG. Particular care should be taken to inquire about a history of fetal loss, as this may be a clue to the presence of APS or SLE (Birbeck, 2006). Chorea is the movement disorder most frequently Table 15.1 Causes of chorea gravidarum Antiphospholipid antibody syndrome Systemic lupus erythematosus Rheumatic fever (including history of Sydenham’s chorea) Vascular disease ● Arteriovenous malformation ● Cerebrovascular accident ● Central nervous system vasculitis Thyrotoxicosis Wilson’s disease Drug-induced Huntington’s disease Idiopathic
observed in SLE (Cervera et al., 1997). SLE can result in small foci of hemorrhage within the brain, particularly within the basal ganglia (Johnson and Richardson, 1968). This underlying structural damage may form the basis for CG when the etiology is SLE. In a series of 50 patients with chorea secondary to APS, Cervera et al. (1997) reported that 11 of 31 patients who had brain imaging (computed tomography or magnetic resonance imaging (MRI)) had evidence of infarcts. The majority of infarcts were in the basal ganglia, though infarcts were also found in subcortical white matter. In this series, 6% of patients had CG, 12% developed chorea after starting estrogen-based OC, and 34% had recurrent episodes of chorea. Other causes of CG are uncommon. CG is considered in the differential diagnosis of Huntington’s disease (HD) (Anderson, 2005), though the clinical course, family history, and additional features of HD make the diagnosis clear as time passes. Wilson’s disease may also be included in the differential diagnosis of CG (Smith and Evatt, 2004). Although Wilson’s disease eventually causes multiorgan dysfunction, it may present with isolated neuropsychiatric disease (Das and Ray, 2006). Thyrotoxicosis and neuroacanthocytosis may be considered (Qasim, 2000; Birbeck, 2006), though isolated chorea would be a rare presentation of either condition. Cerebrovascular disease unrelated to APS or SLE has also been reported to cause CG (Qasim, 2000), as has moyamoya disease (Unno et al., 2000). Chorea may also be induced by pharmaceuticals or illicit drugs, and one should consider this in the differential diagnosis (Palanivelu, 2007).
PATHOPHYSIOLOGY Although chorea occurs more often in pregnancy than in the general population and Sydenham’s chorea is more common in females than males after puberty (Wilson and Preece, 1932), the basis for these associations was not clear until after estrogen-containing OC were introduced. After the first case was reported linking estrogen-containing OC to chorea (Fernando, 1966), the groundwork was established to investigate the role of female sex hormones on basal ganglia function. In the following decade, 22 additional cases of OCinduced chorea were reported (Nausieda et al., 1979a). Patients generally developed chorea within weeks of starting estrogen-containing OC, and it was hypothesized that only women with pre-existing basal ganglia abnormalities would develop chorea (Nausieda et al., 1979a). Subsequent research suggested that high estrogen states lead to dopamine hypersensitivity through modification of postsynaptic dopamine receptors (Nausieda et al., 1979b). The action of estrogen on
CHOREA GRAVIDARUM dopamine receptors at the striatal level is thought to induce chorea in susceptible individuals (Barber et al., 1976). Estrogen-containing OC have also been reported to cause paraballismus (Driesen and Wolters, 1987), and pregnancy has reportedly worsened other movement disorders, including hemimasticatory spasms and dystonia (Loscher et al., 1995; Cersosimo et al., 2004). In addition to movement disorders, estrogen may have effects on behaviors mediated by the basal ganglia (Van Hartesveldt and Joyce, 1986). Animal studies suggest that estrogen increases the concentration of dopamine in the brain through a number of mechanisms, including increased activity of tyrosine hydroxylase, increased dopamine release, and inhibition of dopamine reuptake (Pasqualini et al., 1995; Disshon et al., 1998; Xiao and Becker, 1998). Estrogen acts at the presynaptic substantia nigra neurons as well as their postsynaptic targets within the striatum (Shulman, 2002). Acutely, estradiol increases dopamine synthesis and release (Morissette et al., 1990; Blanchet et al., 1999). Chronic administration of estradiol results in increased D2 dopamine receptor binding (Bazzett and Becker, 1994) and increased dopamine release (Morissette and Di Paolo, 1993), with estradiol also working as a dopamine agonist at striatal D2 receptors (Levesque and Di Paolo, 1993). D5 receptors are upregulated by estrogen (Lee et al., 1999), providing more support for the hypothesis that estrogen plays a key role in the appearance of movement disorders in altered estrogen states. It is thought that in CG a previously asymptomatic lesion is unmasked during a high-estrogen state (Birbeck, 2006). When estrogen levels fall in the second and third trimester, CG may resolve spontaneously.
EVALUATION Because CG is a syndrome, all patients with CG require a thorough work-up. The history and physical examination should be used to help guide the clinician to an appropriate evaluation. If there is a history suggestive of rheumatic fever or streptococcal infection, then antistreptolysin antibody titers and throat cultures should be considered. If a diagnosis of rheumatic fever is made, an echocardiogram is warranted to rule out cardiac involvement as carditis was found in 87% of fatal cases (Wilson and Preece, 1932). A history of fetal loss, rash (including livedo reticularis), arthralgias, or deep-vein thrombosis is suggestive of rheumatic disease (APS or SLE). Complete blood count, antiphospholipid antibodies, lupus anticoagulant, antinuclear antibody, and sedimentation rate abnormalities may point toward a diagnosis of APS or SLE. Serum thyroxine and thyroid-stimulating hormone are useful
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to screen for thyrotoxicosis. Urine or serum toxicology screens should be used to rule out illicit drug use. A brain MRI may reveal structural lesions. If the initial work-up is negative, Wilson’s disease, a very rare condition, should be considered. A careful ophthalmologic exam to look for Kayser–Fleischer rings, serum ceruloplasmin, and 24-hour urine copper levels can be obtained to screen for Wilson’s disease. Gene testing for HD may also be undertaken, but should only be performed after the implications of genetic testing have been discussed with the patient.
TREATMENT Treatment strategies for CG can be divided into two categories: symptomatic treatment for chorea and treatment targeted at the underlying disease. This discussion will focus on symptomatic therapy for chorea, as disease treatment is variable depending on the underlying diagnosis. Pharmacologic treatment is indicated for disabling chorea, but it is often not necessary for mild, nondisabling chorea. Treatment relies primarily on dopamine receptor antagonists and dopaminedepleting agents. Haloperidol has proven efficacy in treating CG (Patterson, 1979; Donaldson, 1982). Based on haloperidol’s safety profile in the treatment of hyperemesis gravidarum, there is a low risk of birth defects (Van Waes and van de Velde, 1969). The highest risk for birth defects occurs if the fetus is exposed during organogenesis, so waiting until the first trimester passes to treat is advisable. High-potency (typical) neuroleptics are thought to be safer for the fetus; however, data are limited on newer, low-potency (atypical) neuroleptics (Altshuler et al., 1996). Benzodiazepines may also be used to control chorea (Peiris et al., 1976), though an effective dose may prove too sedating. As with neuroleptics, it is advisable to wait until after the first trimester before initiating therapy as there is an increased risk of cleft lip or cleft palate due to benzodiazepine exposure in the first trimester. Although the overall risk for cleft palate is low (0.7%), this represents a 10-fold increase compared to the general population (Altshuler et al., 1996). Neurotransmitter depletors such as reserpine and tetrabenazine are probably effective for CG, but safety data in pregnancy are not available. Therefore their use is not recommended.
CONCLUSION If no etiology is discovered for CG, the prognosis is favorable, with chorea resolving in the third trimester or shortly after childbirth. Because almost half of cases have an identifiable etiology, all patients require a thorough diagnostic evaluation. If an etiology is identified, treatment of the underlying illness may lead to
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resolution of chorea. Historically, CG had a mortality of 12% (Wilson and Preece, 1932), presumably due to the high incidence of rheumatic fever and related heart disease. Shortly after the introduction of penicillin, mortality dropped to 1% (Beresford and Graham, 1950). CG is now a rare entity and with proper treatment many pregnancies proceed to term, with normal infant mortality rates (Zegart and Schwarz, 1968). CG is a syndrome in which more often than not an etiology can be identified. It is important to investigate all patients who develop chorea during pregnancy because the underlying disease processes often require very specific treatment. In the future it may be possible to identify many more specific causes of chorea during pregnancy, and fewer cases of idiopathic CG will remain. It is very unlikely that pregnancy itself will be the etiology for CG, and therefore this diagnosis may become obsolete. In the meantime, if a woman develops chorea during pregnancy and no etiology can be identified, then CG is the proper nomenclature.
REFERENCES Altshuler LL, Cohen LS, Szuba MP et al. (1996). Pharmacologic management of psychiatric illness in pregnancy: dilemmas and guidelines. Am J Psychiatry 153: 592–606. Anderson KE (2005). Huntington disease and related disorders. Psychiatr Clin North Am 28: 275–290. Barber PV, Arnold AG, Evans G (1976). Recurrent hormone dependent chorea: effects of oestrogens and progestogens. Clin Endocrinol 5: 291–293. Barnes R (1869). On chorea in pregnancy. Trans Obstet Soc London 10: 147–195. Bazzett TJ, Becker JB (1994). Sex differences in the rapid and acute effects of estrogen on striatal D2 receptor binding. Brain Res 637: 163–172. Beresford OD, Graham AM (1950). Chorea gravidarum. J Obstet Gynaecol Br Emp 57: 616–625. Birbeck GL (2006). Chorea gravidarum. In: PW Kaplan (Ed.), Neurologic Disease in Women. Demos Medical Publishing, New York, pp. 355–358. Blanchet PJ, Fang J, Hyland K et al. (1999). Short-term effects of high-dose 17[b] estradiol in postmenopausal PD patients: a crossover study. Neurology 53: 91–95. Brockington I (2006). Psychosis complicating chorea gravidarum. Arch Womens Ment Health 9: 113–114. Buccoliero R, Palmeri S, Malandrini A et al. (2007). A case of dystonia with onset during pregnancy. J Neurol Sci 260: 265–266. Cardoso F (2002). Chorea gravidarum. Arch Neurol 59: 868–870. Cardoso F, Vargas AP, Cunningham MCQ et al. (1999). Chorea gravidarum: new lessons from an old disease. Neurology 52: A121. Caviness JN, Muenter MD (1991). An unusual cause of recurrent chorea. Mov Disord 6: 355–357.
Cersosimo MG, Bertoti A, Roca CU et al. (2004). Botulinum toxin in a case of hemimasticatory spasm with severe worsening during pregnancy. Clin Neuropharmacol 27: 6–8. Cervera R, Asherson RA, Font J et al. (1997). Chorea in the antiphospholipid syndrome. Clinical, radiologic, and immunologic characteristics of 50 patients from our clinics and the recent literature. Medicine 76: 203–212. Das SK, Ray K (2006). Wilson’s disease: an update. Nat Clin Pract Neurol 2: 842–893. Dike GL (1997). Chorea gravidarum: a case report and review. Md Med J 46: 436–439. Disshon KA, Boja JW, Dluzen DE (1998). Inhibition of striatal dopamine transporter activity by 17 b-estradiol. Eur J Pharmacol 345: 207–211. Donaldson IM, Espiner EA (1971). Disseminated lupus eryhthematosus presenting as chorea gravidarum. Arch Neurol 25: 240–244. Donaldson JO (1982). Control of chorea gravidarum with haloperidol. Obstet Gynecol 59: 381–382. Driesen JJ, Wolters EC (1987). Oral contraceptive induced paraballism. Clin Neurol Neurosurg 89: 49–51. Fernando SJN (1966). An attack of chorea complicating oral contraceptive therapy. Practitioner 197: 210–211. Ghanem Q (1995). Recurrent chorea gravidarum in four pregnancies. Can J Neurol Sci 12: 136–138. Huong DL, Wechsler B, Vauthier-Brouzes D et al. (1997). Outcome of planned pregnancies in systemic lupus erythematosus: a prospective study on 62 pregnancies. Br J Rheumatol 36: 772–777. Ichikawa K, Kim RC, Givelber H et al. (1980). Chorea gravidarum. Report of a fatal case with neuropathological observations. Arch Neurol 37: 429–432. Johnson R, Richardson E (1968). The neurological manifestations of systemic lupus erythematosus. Medicine 47: 337–369. Kutteh WH (1996). Antiphospholipid antibody-associated recurrent pregnancy loss: treatment with heparin and low-dose aspirin is superior to low-dose aspirin alone. Am J Obstet Gynecol 174: 1584–1589. Lee D, Dong P, Copolov D et al. (1999). D5 dopamine receptors mediate estrogen-induced stimulation of hypothalamic atrial natriuretic factor neurons. Mol Endocrinol 13: 344–352. Levesque D, Di Paolo T (1993). Modulation by estradiol and progesterone of the GTP effect on striatal D-2 dopamine receptors. Biochem Pharmacol 45: 723–733. Lewis BV, Parsons M (1966). Chorea gravidarum. Lancet 1: 284–286. Lim EC, Seet RC, Wilder-Smith EPV et al. (2006). Dystonia gravidarum: a new entity? Mov Disord 21: 69–70. Loscher W, Blanke T, Richter A et al. (1995). Gonadal sex hormones and dystonia: experimental studies in genetically dystonic hamsters. Mov Disord 10: 92–102. Lubbe WF, Walker EB (1983). Chorea gravidarum associated with circulating lupus anticoagulant: successful outcome of pregnancy with prednisone and aspirin therapy. Case report. Br J Obstet Gynecol 90: 487–490.
CHOREA GRAVIDARUM Lubbe WF, Butler WS, Palmer SJ et al. (1984). Lupus anticoagulant in pregnancy. Br J Obstet Gynecol 91: 357–363. McCann FJ (1891). Chorea gravidarum. Trans Obstet Soc London 33 (413–444): 466–485. Morissette M, Di Paolo T (1993). Effect of chronic estradiol and progesterone treatment of ovariectomized rats on brain dopamine uptake sites. J Neurochem 60: 1876–1883. Morissette M, Biron D, Di Paolo T (1990). Effect of estradiol and progesterone on rat striatal dopamine uptake sites. Brain Res Bull 25: 419–422. Nausieda PA, Koller WC, Weiner WJ et al. (1979a). Chorea induced by oral contraceptives. Neurology 29: 1605–1609. Nausieda PA, Koller WC, Weiner WJ et al. (1979b). Modification of post-synaptic dopaminergic sensitivity by female sex hormones. Life Sci 25: 521–526. Nyman M, Durling U, Lundell A (1997). Chorea gravidarum. Acta Obstet Gynecol Scand 76: 885–886. Osler W (1894). On chorea and choreiform affections. P. Blakiston, Philadelphia, pp. 41–44. Palanivelu LM (2007). Chorea gravidarum. J Obstet Gynaecol 27: 310. Pasqualini C, Olivier V, Guibert B et al. (1995). Acute stimulatory effect of estradiol on striatal dopamine synthesis. J Neurochem 65: 1651–1657. Patterson JF (1979). Treatment of chorea gravidarum with haloperidol. South Med J 72: 1220–1221.
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Peiris JB, Boralessa H, Lionel ND (1976). Clonazepam in the treatment of choreiform activity. Med J Aust 1: 225–227. Qasim A (2000). An unusual case of chorea gravidarum. Postgrad Med J 76: 374–375. Shulman LM (2002). Is there a connection between estrogen and Parkinson’s disease? Parkinsonism Relat Disord 8: 289–295. Smith M, Evatt M (2004). Movement disorders in pregnancy. Neurol Clin 22: 783–798. Unno S, Iijima M, Osawa M et al. (2000). A case of chorea gravidarum with moyamoya disease. Rinsho Sinkeigaku 40: 378–382. Van Hartesveldt C, Joyce JN (1986). Effects of estrogen on the basal ganglia. Neurosci Biobehav Rev 10: 1–14. Van Waes A, Van de Velde E (1969). Safety evaluation of haloperidol in the treatment of hyperemesis gravidarum. J Clin Pharmacol 9: 224. Weiner WJ, Lang AE (1989). Movement Disorders: a Comprehensive Survey. Futura Publishing, New York. Wilson P, Preece AA (1932). Chorea gravidarum. Arch Intern Med 49: 471–533. Xiao L, Becker JB (1998). Effects of estrogen agonists on amphetamine-stimulated striatal dopamine release. Synapse 29: 379–391. Zegart KN, Schwarz RH (1968). Chorea gravidarum. Obstet Gynecol 32: 24–27.
Chapter 15
Chorea gravidarum BRADLEY J. ROBOTTOM * AND WILLIAM J. WEINER Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, USA
INTRODUCTION Published accounts of chorea gravidarum (CG), or chorea beginning in pregnancy, date to the 19th century (Barnes, 1869; McCann, 1891; Osler, 1894). It is important to realize that CG is not a disease but a syndrome that describes any chorea beginning during pregnancy. The etiology is varied and has changed markedly in the last century. In 1932, the largest series of CG was reviewed – 951 cases (Wilson and Preece, 1932). The authors described an uncommon but highly morbid condition in which there was a high likelihood of underlying rheumatic fever. Although the most common causes of CG have changed since this review, this work remains the largest account of CG and contains a wealth of information on a syndrome which is no longer commonly encountered.
EPIDEMIOLOGY Historically, CG was a relatively common occurrence, with an incidence of 1 per 2275 pregnancies (Wilson and Preece, 1932). The British Medical Association reported that 1.5% of all choreas were CG (Wilson and Preece, 1932; Cardoso, 2002). In the 1932 article, rheumatic heart disease was found in 86% of cases of CG, and it was concluded that this was the most common cause. CG was usually diagnosed in primiparous women and the prognosis was dire, with an 18–33% maternal and 50% fetal mortality rate (Birbeck, 2006). The widespread availability of penicillin decreased the incidence of rheumatic fever and CG dramatically. Thirty years after the Wilson and Preece review, the incidence of CG was 1 per 139 000 (Zegart and Schwarz, 1968). Because of the rarity of the syndrome, it is difficult to find modern estimates of incidence. In one movement disorders center with a particular interest in chorea, CG accounted for 3.6% of patients (Cardoso et al., 1999).
CLINICAL CHARACTERISTICS Chorea describes irregular, unpredictable, brief jerky movements that move from one body part to another. When chorea is composed of large-amplitude movements with wild flinging or throwing movements it is referred to as ballism (Weiner and Lang, 1989). CG may be unilateral or bilateral, and the movements disappear during sleep. Chorea often involves the face as well as the limbs. Even without clear facial involvement, dysarthria may be present (Birbeck, 2006). The affected limbs are usually hypotonic. Symptoms usually begin in the first or early second trimester (McCann, 1891; Wilson and Preece, 1932; Nyman et al., 1997). In most patients, chorea resolves by the third trimester or abates within hours of delivery (Lewis and Parsons, 1966; Palanivelu, 2007). One patient with CG developed fatal hyperthermia (Ichikawa et al., 1980). CG may recur in later pregnancies, even in idiopathic cases (Ghanem, 1995). Chorea may also reappear in women who later take oral contraceptives (OC) or use topical estrogen (Caviness and Muenter, 1991). In addition to chorea, patients may also experience psychiatric symptoms. Symptoms associated with CG include personality changes, depression, tourettism, severe hypnic hallucinations, delirium, and chronic cognitive deficits (Brockington, 2006). Interestingly, the last case of psychosis attributed to CG was published in 1950 (Brockington, 2006). This raises the question of whether the nature of CG has changed as a result of an etiological shift, or whether this is due to reporting bias, with newer cases of psychosis and chorea during pregnancy being attributed to a specific diagnosis rather than CG. Recently, two patients were described who presented with dystonia in the first trimester (Lim et al., 2006; Buccoliero et al., 2007). Both patients had cervical
*Correspondence to: Bradley J. Robottom, M.D., Department of Neurology, University of Maryland School of Medicine, 110 S. Paca Street, 3-S-128, Baltimore, MD, 21201, USA. Fax 410-328-0167, E-mail: [email protected]
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dystonia without an identifiable secondary cause. Each case resolved before delivery. Though neither of the patients developed chorea, this possible new entity, dystonia gravidarum, is hypothesized to have a similar pathophysiological basis.
ETIOLOGY Historically, rheumatic fever was the most common cause of CG, accounting for 86% of cases (Wilson and Preece, 1932). Patients with CG secondary to rheumatic fever usually have a history of rheumatic heart disease, recurrent tonsillitis, or Sydenham’s chorea rather than acute rheumatic fever (Wilson and Preece, 1932). Even when there are no signs of acute rheumatic fever, antistreptolysin antibody titers may be elevated (Birbeck, 2006). With widely available and effective treatment for streptococcal infections, rheumatic fever is no longer a common cause of CG. Currently, half of all cases of CG are idiopathic (Dike, 1997; Qasim, 2000) (Table 15.1). In industrialized nations, systemic lupus erythematosus (SLE) and the antiphospholipid antibody syndrome (APS) are the most common identifiable causes of CG (Johnson and Richardson, 1968; Donaldson and Espiner, 1971; Ichikawa et al., 1980; Lubbe and Walker, 1983; Lubbe et al., 1984; Palanivelu, 2007). APS may be primary or secondary to SLE. Other pregnancy-related complications attributed to APS and SLE include spontaneous abortion, deep venous thrombosis, preterm delivery, intrauterine growth retardation, and preeclampsia (Kutteh, 1996; Huong et al., 1997). Because CG may be the presenting sign of autoimmune disease, a high degree of suspicion is required when evaluating a patient with CG. Particular care should be taken to inquire about a history of fetal loss, as this may be a clue to the presence of APS or SLE (Birbeck, 2006). Chorea is the movement disorder most frequently Table 15.1 Causes of chorea gravidarum Antiphospholipid antibody syndrome Systemic lupus erythematosus Rheumatic fever (including history of Sydenham’s chorea) Vascular disease ● Arteriovenous malformation ● Cerebrovascular accident ● Central nervous system vasculitis Thyrotoxicosis Wilson’s disease Drug-induced Huntington’s disease Idiopathic
observed in SLE (Cervera et al., 1997). SLE can result in small foci of hemorrhage within the brain, particularly within the basal ganglia (Johnson and Richardson, 1968). This underlying structural damage may form the basis for CG when the etiology is SLE. In a series of 50 patients with chorea secondary to APS, Cervera et al. (1997) reported that 11 of 31 patients who had brain imaging (computed tomography or magnetic resonance imaging (MRI)) had evidence of infarcts. The majority of infarcts were in the basal ganglia, though infarcts were also found in subcortical white matter. In this series, 6% of patients had CG, 12% developed chorea after starting estrogen-based OC, and 34% had recurrent episodes of chorea. Other causes of CG are uncommon. CG is considered in the differential diagnosis of Huntington’s disease (HD) (Anderson, 2005), though the clinical course, family history, and additional features of HD make the diagnosis clear as time passes. Wilson’s disease may also be included in the differential diagnosis of CG (Smith and Evatt, 2004). Although Wilson’s disease eventually causes multiorgan dysfunction, it may present with isolated neuropsychiatric disease (Das and Ray, 2006). Thyrotoxicosis and neuroacanthocytosis may be considered (Qasim, 2000; Birbeck, 2006), though isolated chorea would be a rare presentation of either condition. Cerebrovascular disease unrelated to APS or SLE has also been reported to cause CG (Qasim, 2000), as has moyamoya disease (Unno et al., 2000). Chorea may also be induced by pharmaceuticals or illicit drugs, and one should consider this in the differential diagnosis (Palanivelu, 2007).
PATHOPHYSIOLOGY Although chorea occurs more often in pregnancy than in the general population and Sydenham’s chorea is more common in females than males after puberty (Wilson and Preece, 1932), the basis for these associations was not clear until after estrogen-containing OC were introduced. After the first case was reported linking estrogen-containing OC to chorea (Fernando, 1966), the groundwork was established to investigate the role of female sex hormones on basal ganglia function. In the following decade, 22 additional cases of OCinduced chorea were reported (Nausieda et al., 1979a). Patients generally developed chorea within weeks of starting estrogen-containing OC, and it was hypothesized that only women with pre-existing basal ganglia abnormalities would develop chorea (Nausieda et al., 1979a). Subsequent research suggested that high estrogen states lead to dopamine hypersensitivity through modification of postsynaptic dopamine receptors (Nausieda et al., 1979b). The action of estrogen on
CHOREA GRAVIDARUM dopamine receptors at the striatal level is thought to induce chorea in susceptible individuals (Barber et al., 1976). Estrogen-containing OC have also been reported to cause paraballismus (Driesen and Wolters, 1987), and pregnancy has reportedly worsened other movement disorders, including hemimasticatory spasms and dystonia (Loscher et al., 1995; Cersosimo et al., 2004). In addition to movement disorders, estrogen may have effects on behaviors mediated by the basal ganglia (Van Hartesveldt and Joyce, 1986). Animal studies suggest that estrogen increases the concentration of dopamine in the brain through a number of mechanisms, including increased activity of tyrosine hydroxylase, increased dopamine release, and inhibition of dopamine reuptake (Pasqualini et al., 1995; Disshon et al., 1998; Xiao and Becker, 1998). Estrogen acts at the presynaptic substantia nigra neurons as well as their postsynaptic targets within the striatum (Shulman, 2002). Acutely, estradiol increases dopamine synthesis and release (Morissette et al., 1990; Blanchet et al., 1999). Chronic administration of estradiol results in increased D2 dopamine receptor binding (Bazzett and Becker, 1994) and increased dopamine release (Morissette and Di Paolo, 1993), with estradiol also working as a dopamine agonist at striatal D2 receptors (Levesque and Di Paolo, 1993). D5 receptors are upregulated by estrogen (Lee et al., 1999), providing more support for the hypothesis that estrogen plays a key role in the appearance of movement disorders in altered estrogen states. It is thought that in CG a previously asymptomatic lesion is unmasked during a high-estrogen state (Birbeck, 2006). When estrogen levels fall in the second and third trimester, CG may resolve spontaneously.
EVALUATION Because CG is a syndrome, all patients with CG require a thorough work-up. The history and physical examination should be used to help guide the clinician to an appropriate evaluation. If there is a history suggestive of rheumatic fever or streptococcal infection, then antistreptolysin antibody titers and throat cultures should be considered. If a diagnosis of rheumatic fever is made, an echocardiogram is warranted to rule out cardiac involvement as carditis was found in 87% of fatal cases (Wilson and Preece, 1932). A history of fetal loss, rash (including livedo reticularis), arthralgias, or deep-vein thrombosis is suggestive of rheumatic disease (APS or SLE). Complete blood count, antiphospholipid antibodies, lupus anticoagulant, antinuclear antibody, and sedimentation rate abnormalities may point toward a diagnosis of APS or SLE. Serum thyroxine and thyroid-stimulating hormone are useful
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to screen for thyrotoxicosis. Urine or serum toxicology screens should be used to rule out illicit drug use. A brain MRI may reveal structural lesions. If the initial work-up is negative, Wilson’s disease, a very rare condition, should be considered. A careful ophthalmologic exam to look for Kayser–Fleischer rings, serum ceruloplasmin, and 24-hour urine copper levels can be obtained to screen for Wilson’s disease. Gene testing for HD may also be undertaken, but should only be performed after the implications of genetic testing have been discussed with the patient.
TREATMENT Treatment strategies for CG can be divided into two categories: symptomatic treatment for chorea and treatment targeted at the underlying disease. This discussion will focus on symptomatic therapy for chorea, as disease treatment is variable depending on the underlying diagnosis. Pharmacologic treatment is indicated for disabling chorea, but it is often not necessary for mild, nondisabling chorea. Treatment relies primarily on dopamine receptor antagonists and dopaminedepleting agents. Haloperidol has proven efficacy in treating CG (Patterson, 1979; Donaldson, 1982). Based on haloperidol’s safety profile in the treatment of hyperemesis gravidarum, there is a low risk of birth defects (Van Waes and van de Velde, 1969). The highest risk for birth defects occurs if the fetus is exposed during organogenesis, so waiting until the first trimester passes to treat is advisable. High-potency (typical) neuroleptics are thought to be safer for the fetus; however, data are limited on newer, low-potency (atypical) neuroleptics (Altshuler et al., 1996). Benzodiazepines may also be used to control chorea (Peiris et al., 1976), though an effective dose may prove too sedating. As with neuroleptics, it is advisable to wait until after the first trimester before initiating therapy as there is an increased risk of cleft lip or cleft palate due to benzodiazepine exposure in the first trimester. Although the overall risk for cleft palate is low (0.7%), this represents a 10-fold increase compared to the general population (Altshuler et al., 1996). Neurotransmitter depletors such as reserpine and tetrabenazine are probably effective for CG, but safety data in pregnancy are not available. Therefore their use is not recommended.
CONCLUSION If no etiology is discovered for CG, the prognosis is favorable, with chorea resolving in the third trimester or shortly after childbirth. Because almost half of cases have an identifiable etiology, all patients require a thorough diagnostic evaluation. If an etiology is identified, treatment of the underlying illness may lead to
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resolution of chorea. Historically, CG had a mortality of 12% (Wilson and Preece, 1932), presumably due to the high incidence of rheumatic fever and related heart disease. Shortly after the introduction of penicillin, mortality dropped to 1% (Beresford and Graham, 1950). CG is now a rare entity and with proper treatment many pregnancies proceed to term, with normal infant mortality rates (Zegart and Schwarz, 1968). CG is a syndrome in which more often than not an etiology can be identified. It is important to investigate all patients who develop chorea during pregnancy because the underlying disease processes often require very specific treatment. In the future it may be possible to identify many more specific causes of chorea during pregnancy, and fewer cases of idiopathic CG will remain. It is very unlikely that pregnancy itself will be the etiology for CG, and therefore this diagnosis may become obsolete. In the meantime, if a woman develops chorea during pregnancy and no etiology can be identified, then CG is the proper nomenclature.
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