Original Investigation | Neurology

Treatments and Outcomes Among Patients with Sydenham Chorea

A Meta-Analysis
Michael Eyre, MD; Terrence Thomas, MD; Emanuela Ferrarin, MSc; Sonia Khamis, MD; Sameer M. Zuberi, MD, PhD; Adrian Sie, MD; Tamsin Newlove-Delgado, MD, PhD;
Michael Morton, MD, PhD; Erika Molteni, MD, PhD; Russell C. Dale, MD, PhD; Ming Lim, MD, PhD; Margherita Nosadini, MD, PhD;
for the Sydenham’s Chorea Systematic Literature Review Working Group

Abstract Key Points

Question Which clinical and treatment
IMPORTANCE Sydenham chorea is the most common acquired chorea of childhood worldwide;
factors at onset of Sydenham chorea
however, treatment is limited by a lack of high-quality evidence.
are associated with chorea duration,
relapsing disease course, and
OBJECTIVES To evaluate historical changes in the clinical characteristics of Sydenham chorea and
functional outcome?
identify clinical and treatment factors at disease onset associated with chorea duration, relapsing
disease course, and functional outcome. Findings In this individual patient data
meta-analysis of 1479 patients, those
DATA SOURCES The systematic search for this meta-analysis was conducted in PubMed, Embase, receiving at least 1 month of
CINAHL, Cochrane Library, and LILACS databases and registers of clinical trials from inception to corticosteroids had a median chorea
November 1, 2022 (search terms: [Sydenham OR Sydenham’s OR rheumatic OR minor] AND chorea). duration of 1.2 months vs 2.8 months for
patients receiving none, a significant
STUDY SELECTION Published articles that included patients with a final diagnosis of Sydenham difference. Patients treated with
chorea (in selected languages). antibiotics, corticosteroids, or sodium
valproate had significantly reduced odds
DATA EXTRACTION AND SYNTHESIS This study followed the Preferred Reporting Items for of relapse.
Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Individual patient data on
Meaning These observational data
clinical characteristics, treatments, chorea duration, relapse, and final outcome were extracted. Data
support the use of corticosteroids,
from patients in the modern era (1945 through 2022) were entered into multivariable models and
antibiotics, and sodium valproate for
stratified by corticosteroid duration for survival analysis of chorea duration.
treatment of Sydenham chorea.

MAIN OUTCOMES AND MEASURES The planned study outcomes were chorea duration at onset,
monophasic course (absence of relapse after ⱖ24 months), and functional outcome (poor: modified + Supplemental content
Rankin Scale score 2-6 or persisting chorea, psychiatric, or behavioral symptoms at final follow-up Author affiliations and article information are
after ⱖ6 months; good: modified Rankin Scale score 0-1 and no chorea, psychiatric, or behavioral listed at the end of this article.

symptoms at final follow-up).

RESULTS In total, 1479 patients were included (from 307 articles), 1325 since 1945 (median [IQR]
age at onset, 10 [8-13] years; 875 of 1272 female [68.8%]). Immunotherapy was associated with
shorter chorea duration (hazard ratio for chorea resolution, 1.51 [95% CI, 1.05-2.19]; P = .03). The
median chorea duration in patients receiving 1 or more months of corticosteroids was 1.2 months
(95% CI, 1.2-2.0) vs 2.8 months (95% CI, 2.0-3.0) for patients receiving none (P = .004). Treatment
factors associated with monophasic disease course were antibiotics (odds ratio [OR] for relapse, 0.28
[95% CI, 0.09-0.85]; P = .02), corticosteroids (OR, 0.32 [95% CI, 0.15-0.67]; P = .003), and sodium
valproate (OR, 0.33 [95% CI, 0.15-0.71]; P = .004). Patients receiving at least 1 month of
corticosteroids had significantly lower odds of relapsing course (OR, 0.10 [95% CI, 0.04-0.25];
P < .001). No treatment factor was associated with good functional outcome.

(continued)

Open Access. This is an open access article distributed under the terms of the CC-BY License.

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 JAMA Network Open | Neurology Treatments and Outcomes Among Patients with Sydenham Chorea

Abstract (continued)

CONCLUSIONS AND RELEVANCE In this meta-analysis of treatments and outcomes in patients

with Sydenham chorea, immunotherapy, in particular corticosteroid treatment, was associated with
faster resolution of chorea. Antibiotics, corticosteroids and sodium valproate were associated with
a monophasic disease course. This synthesis of retrospective data should support the development
of evidence-based treatment guidelines for patients with Sydenham chorea.

JAMA Network Open. 2024;7(4):e246792. doi:10.1001/jamanetworkopen.2024.6792

Introduction
Sydenham chorea (SC) is an autoimmune neuropsychiatric disorder associated with prior group A
streptococcal (GAS) infection.1 It is 1 of the major manifestations of acute rheumatic fever (ARF) and
remains the most common acquired chorea of childhood worldwide, including some high-income
settings.2,3 In SC, chorea of the extremities, and, often, chorea of the face, tongue, and trunk are
usually accompanied by hypotonia and emotional or behavioral disturbances, most frequently
emotional lability.1 In a subgroup with severe disease, there is complete loss of tone and voluntary
movements (chorea paralytica).4,5 Most patients recover fully within 6 to 9 months, but symptoms
persist in up to 40% of patients, 1,6-8 and relapses occur in 16%-42%.9-12 Except for antibiotics, there
is limited consensus regarding treatment.1,13 Only 3 small randomized clinical trials (RCTs) assessing
immunotherapy for SC have been reported,14-16 and treatment strategies vary widely, with
corticosteroid use in recent cohorts ranging from 16% to 75%, and steroid regimens differing even
within centers.17-20 Herein we present a comprehensive evidence synthesis of published SC cases
with individual patient data (IPD), with the aims of describing the clinical features and management
of SC and of identifying associations between early clinical and treatment factors and disease course
and outcome.

Methods
Literature Search and Data Collection
For this meta-analysis, PubMed, Embase, CINAHL, Cochrane Library, and LILACS (Literatura Latino-
Americana e do Caribe em Ciências da Saúde) databases and registers of clinical trials were searched
from inception to November 1, 2022 (search terms: [Sydenham OR Sydenham’s OR rheumatic OR
minor] AND chorea). eFigure 1 and eTable 1 in Supplement 1 provide search and article selection
details. Cases from articles in selected languages (English, French, Spanish, Portuguese, and Italian)
with IPD were included if they included acute or subacute chorea onset and a final diagnosis of SC
according to the authors. If not provided, IPD was requested from the authors of articles published
since January 1, 2012, reporting at least 10 cases. Individual patient data on demographics,
preexisting conditions, symptoms, severity at the first SC episode, ARF manifestations, treatments,
and outcomes were collected using a standardized proforma (eMethods 1 in Supplement 1). This
study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA)
reporting guideline.

Study Outcomes
We evaluated 3 main outcomes: chorea duration at the first SC episode, relapsing disease course, and
final functional outcome. Relapsing disease course was defined as the occurrence of at least 1 relapse
(at any time); monophasic disease course was defined as no relapse after a minimum of 24 months’
follow-up. Poor functional outcome was defined as a modified Rankin Scale (mRS) score of 2 to 6 or
persisting chorea or psychiatric or behavioral symptoms at final follow-up 6 or more months after

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 JAMA Network Open | Neurology Treatments and Outcomes Among Patients with Sydenham Chorea

the last SC episode. Good functional outcome was defined as an mRS score of 0 to 1 and no chorea or
psychiatric or behavioral symptoms at final follow-up (at any time).

Statistical Analysis
For historical comparison, patients with disease onset (or if unknown, publication year) before 1945
(when penicillin first became commercially available and 1 year after the first ARF diagnostic criteria
were established21,22) were compared with patients from the modern era (1945 through 2022) using
the χ2 or Fisher exact test for nominal data, Mann-Whitney U test for continuous or ordinal data, and
Kaplan-Meier survival analysis with the log-rank test for chorea duration. To optimize data reliability
and relevance, only data since 1945 were included in subsequent analyses. Denominators for
descriptive data varied according to data availability. Symptomatic medications were grouped into
pharmacological classes, and differences in clinician-reported benefit were tested using pairwise χ2
tests with Bonferroni-corrected P values. Medication classes given to fewer than 10 patients were
not included. To assess the 3 main outcomes, 3 separate multivariable models were applied: a Cox
proportional hazards regression model for chorea duration at first episode (including symptomatic
medications and immunotherapy as time-varying features) and logistic regression models for
relapsing disease course and functional outcome. Missing values for 27 variables (eTable 2 in
Supplement 1) underwent hot-deck imputation prior to multivariable modeling (eMethods 2 in
Supplement 1).23,24 Sensitivity analyses were conducted for year of onset and missingness
(eMethods 3 in Supplement 1). In further univariate analyses of the nonimputed data, patients were
grouped according to corticosteroid treatment duration at the first episode (none, <1 month, or ⱖ1
month) to evaluate associations with chorea duration (Kaplan-Meier survival analysis) and relapsing
course (Fisher exact tests). Two-tailed P < .05 was regarded as significant. Analyses used Python,
version 3.10 (Python Software Foundation) with statsmodels, lifelines, and hail packages.

Results
Historical Trends
We identified 1479 patients with IPD (median [IQR] age at onset, 10 [8-13] years in 1354 patients; 985
of 1426 [69.1%] female and 441 of 1426 [30.9%] male) were identified from 307 articles25-331
(eFigure 1 in Supplement 1). Compared with 1325 patients identified in the modern era (1945 to
2022), 154 patients with onset before 1945 had more frequent fever (11 of 20 [55.0%] vs 66 of 458
[14.4%]) and worse severity (median [IQR] mRS, 4 [3-4] vs 3 [3-4]) during the first SC episode, longer
hospitalization (median, 40 [25-62] days vs 21 [10-35] days), more frequent arthritis or arthralgia (48
of 145 patients [33.1%] vs 275 of 1118 patients [24.6%]), shorter chorea duration at first episode
(median IQR, 2.0 [1.0-3.0] months vs 3.0 [1.2-6.0] months) and worse long-term outcome (5 of 13
patients [39%] vs 47 of 338 patients [13.9%] with poor functional outcome) (Figure 1 and eTable 3 in
Supplement 1).

Demographics and Background History

In total, 1325 patients from 50 countries had disease onset since 1945 (Table332; eTables 4-7 in
Supplement 1; Figure 2A and B). Median (IQR) age was 10 (8-13) years in 1202 patients, and 1265 of
1317 patients (96.1%) were younger than 18 years (Figure 2C). Of 1272 patients, 875 (68.8%) were
female and 397 (31.2%) were male. Of 1305 patients, 1111 (85.1%) were from populations considered
at low risk for ARF; 33 of 435 (7.6%) had a family history of ARF. Of 442 patients, 27 (6.1%) had a
history of other autoimmune or inflammatory diseases and 37 of 418 (8.9%) had preexisting
psychiatric, neurologic, or neurodevelopmental disorders.

Clinical Features of the First Episode of Sydenham Chorea

Preceding symptoms of infection were reported in 259 of 485 patients (53.4%). Initial presenting SC
symptoms were motor in 325 of 405 patients (80.2%), psychiatric or behavioral in 27 of 405 patients

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 JAMA Network Open | Neurology Treatments and Outcomes Among Patients with Sydenham Chorea

(6.7%) and both combined in 53 of 405 patients (13.1%). Chorea involved the limbs in 572 of 574
patients (99.7%), face in 234 of 309 patients (75.7%), and trunk in 136 of 287 patients (47.4%); 208
of 664 patients (31.3%) had hemichorea. Of 334 patients, 227 (70.1%) had impaired mobility, 177 of
264 patients (67.0%) had impaired object manipulation, 210 of 337 patients (62.3%) had impaired
speech, and 57 of 251 patients (22.7%) had impaired chewing or swallowing. Of 484 patients, 312
(64.5%) had psychiatric or behavioral symptoms, most frequently emotional lability, anxiety,
irritability, hyperactivity, and aggressive behavior (eFigure 2 in Supplement 1). Mental health

Figure 1. Historical Trends in Sydenham Chorea

A Immune treatments B Fever

100 100
Corticosteroids
IVIG
80 80
Plasma exchange
Patients, %

Patients, %
60 60

40 40

20 20

0 0

1880 1900 1920 1940 1960 1980 2000 2020 1880 1900 1920 1940 1960 1980 2000 2020
Year Year

C Chorea duration D Other treatments

5 100
Antibiotics
Median duration at first event, mo

Haloperidol
4 80
Sodium valproate
Patients, %

3 60

2 40

1 20

0 0

1880 1900 1920 1940 1960 1980 2000 2020 1880 1900 1920 1940 1960 1980 2000 2020
Year Year

E Relapse F Poor functional outcome

100 100

80 80
Patients, %

Patients, %

60 60

40 40

20 20

0 0

1880 1900 1920 1940 1960 1980 2000 2020 1880 1900 1920 1940 1960 1980 2000 2020
Year Year

Plotted points represent patients grouped into 10 epochs: 1883-1912, 1913-1942, and 10-year intervals thereafter. IVIG indicates intravenous immunoglobulin.

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 JAMA Network Open | Neurology Treatments and Outcomes Among Patients with Sydenham Chorea

Table. Clinical Characteristics, Treatments, and Outcomes in 1325 Patients with SC Since 1945

Characteristic, Treatment, or Outcome Patients, No./total No. (%)a

Demographics and background history
Age at onset, y (n = 1202)
Mean (SD) 10.9 (5.0)
Median (IQR) 10.3 (8.0-13.0)
Sex
Female 875/1272 (68.8)
Male 397/1272 (31.2)
Family history of ARF 33/435 (7.6)
Preexisting psychiatric, neurologic, or neurodevelopmental disorders 37/418 (8.9)
Current economic classification of country of residence
or health care provisionb
Income
High 598/1317 (45.4)
Upper-middle 638/1317 (48.4)
Lower-middle 79/1317 (6.0)
Low 2/1317 (0.2)
Low population ARF risk 1111/1305 (85.1)
Clinical features of the first SC episode (within first 3 mo after initial presentation)
Symptoms of infection preceding SC onset 259/485 (53.4)
Time between infection and SC onset, wk (n = 158/259)
Mean (SD) 9.9 (12.1)
Median (IQR) 8.0 (3.0-14.0)
Antibiotics given before onset of ARF/SC 43/347 (12.4)
Hemichorea 208/664 (31.3)
Limb 572/574 (99.7)
Face 234/309 (75.7)
Trunk involvement 136/287 (47.4)
Impaired mobility
Any 227/324 (70.1)
Severe: bedridden 38/324 (11.7)
Impaired speech
Any 210/337 (62.3)
Severe: unable to speak 11/337 (3.3)
Impaired object manipulation
Any 177/264 (67.0)
Severe: fully dependent for self-care and feeding 62/264 (23.5)
Impaired chewing or swallowing
Any 57/251 (22.7)
Severe: nasogastric tube or parenteral feeding 16/251 (6.4)
Hypotonia 151/246 (61.4)
Motor impersistence (milkmaid’s grip) 66/125 (52.8)
Abnormal tongue movements (darting tongue) 53/146 (36.3)
Muscle weakness 63/196 (32.1)
Any psychiatric or behavioral symptom 312/484 (64.5)
Emotional lability 139/415 (33.5)
Fever 66/458 (14.4)
Worst mRS score (n = 460)
Mean (SD) 3.2 (0.9)
Median (IQR) 3.0 (3.0-4.0)
Carditis or valvulitis 610/1151 (53.0)
Arthritis or arthralgia 275/1118 (24.6)
Erythema marginatum or subcutaneous nodules 31/836 (3.7)

(continued)

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Table. Clinical Characteristics, Treatments, and Outcomes in 1325 Patients with SC Since 1945 (continued)

Characteristic, Treatment, or Outcome Patients, No./total No. (%)a

Investigation findings at the first SC episode (within first 3 mo after initial presentation)
ASOT elevated 393/547 (71.8)
Anti-DNase B elevated 80/134 (59.7)
Throat culture positive for GAS 68/182 (37.4)
Elevated ESR 255/470 (54.3)
Elevated CRP 94/340 (27.6)
ECG findings
Prolonged PR interval 41/337 (12.2)
Any other abnormality 16/177 (9.0)
Abnormal brain structural MRI
Any 43/225 (19.1)
Basal ganglia abnormal (focal swelling or T2/FLAIR hyperintensity) 16/223 (7.2)
White matter abnormal (focal T2/FLAIR hyperintensity) 15/224 (6.7)
Abnormal EEG findings (slow/disorganized activity and/or epileptic activity)
Any 84/153 (54.9)
Focal or diffuse slow or disorganized activity 77/149 (51.7)
Epileptic activity (epileptic discharges or electrographic seizures) 7/147 (4.8)
Abnormal CSF findings
Any 8/32 (25.0)
Pleocytosis ≥5 cells/uL (nonbloody tap only) 4/31 (12.9)
Intrathecal oligoclonal bands (present in CSF unmatched in serum) 2/26 (7.7)
Treatment of the first SC episode
Antibiotics after onset of ARF/SC
Any 744/867 (86.1)
IM penicillin G benzathine 591/782 (75.6)
Oral penicillin 68/770 (8.8)
Oral amoxicillin 12/770 (1.6)
Any immunotherapy given at first SC episode 231/898 (25.7)
Steroids 208/898 (23.2)
Any 56/882 (6.3)
IV methylprednisolone 40/867 (4.6)
IM ACTH 16/867 (1.8)
Oral steroids
Any 167/881 (19.0)
Prednisone 111/848 (13.1)
Deflazacort or dexamethasone 4/845 (0.5)
Duration of IV and oral steroid treatment at first episode, wk (n = 136/208)
Mean (SD) 6.9 (8.8)
Median (IQR) 4.0 (2.4-8.0)
IVIG 21/898 (2.3)
Plasma exchange 12/898 (1.3)
Time between SC symptom onset and first IT, d (n = 135/231)
Mean (SD) 38.1 (86.5)
Median (IQR) 17.0 (10.0-30.0
Symptomatic pharmacological treatments given at first episode
Any 540/687 (78.6)
Haloperidol 241/663 (36.3)
Valproate 136/663 (20.5)
Phenobarbital 62/663 (9.4)
Total weeks of symptomatic treatments at first episode (n = 169/540)
Mean (SD) 18.9 (80.6)
Median (IQR) 8.0 (4.0-14.0)

(continued)

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 JAMA Network Open | Neurology Treatments and Outcomes Among Patients with Sydenham Chorea

Table. Clinical Characteristics, Treatments, and Outcomes in 1325 Patients with SC Since 1945 (continued)

Characteristic, Treatment, or Outcome Patients, No./total No. (%)a

Clinical course and final follow-up
Abbreviations: ACTH, Adrenocorticotropic hormone;
Full resolution of chorea after the first SC episode 529/622 (85.0)
ARF, acute rheumatic fever; ASOT, antistreptolysin O
Time from initial SC onset to initial full resolution of chorea, mo (n = 353/529)
titer; CRP, C-reactive protein; CSF, cerebrospinal fluid;
Median (IQR) 3.0 (1.2-6.0) ECG, electrocardiography; EEG,
Time from initial SC onset to final follow-up, mo (n = 720) electroencephalography; ESR, erythrocyte
Mean (SD) 36.6 (100.7) sedimentation rate; FLAIR, Fluid attenuated inversion
recovery; GAS, group A streptococcus; IM,
Median (IQR) 12.0 (5.0-24.3)
intramuscular; IT, immunotherapy; IV, intravenous;
Relapse of SC 263/766 (34.3)
IVIG, intravenous immunoglobulin; MRI, magnetic
Ongoing chorea at final follow-up 138/595 (23.2) resonance imaging; mRS, modified Rankin Scale; SC,
Any psychiatric or behavioral symptoms at final follow-up 28/472 (5.9) Sydenham chorea.
mRS score at final follow-up (n = 203)c a
Descriptive data are provided for patients with
Mean (SD) 0.3 (0.7) available information, hence the varying
Median (IQR) 0 denominators.
b
0 153 (75.4) Data retrieved from The World Bank on January
22, 2024.332
1 34 (16.7)
c
2 13 (6.4) Included only patients with mRS 0 to 1 at any time
and patients with mRS 2 or higher with 6 months or
3 3 (1.5)
longer follow-up from last SC event.

specialist assessment was reported in 57 of 324 patients (17.6%), specific assessment tools in 42 of
321 patients (13.1%), and assignment of a formal psychiatric diagnosis in 31 of 312 patients (9.9%). In
total, 452 of 498 patients (90.8%) were hospitalized. The median (IQR) mRS score at nadir was 3
(3-4) in 460 patients; 139 of 460 patients (30.2%) had severe disease (mRS 4-5), including 28 of 234
patients (12.0%) with mRS score of 5 and complete loss of self-care skills. Other major manifestations
of ARF included carditis or valvulitis in 610 of 1151 patients (53.0%), arthritis or arthralgia in 275 of
1118 patients (24.6%), and skin manifestations in 31 of 836 patients (3.7%).

Findings at the First Episode of Sydenham Chorea

Evidence of preceding streptococcal infection was reported in 559 of 655 patients (85.3%)2:
elevated antistreptolysin O titer in 393 of 547 patients (71.8%), elevated anti-DNase B titer in 80 of
134 patients (59.7%), and GAS present in the throat culture for 68 of 182 patients (37.4%). Of 470
patients, 255 (54.3%) had elevated erythrocyte sedimentation rate, and 94 of 340 patients (27.6%)
had elevated C-reactive protein (Table). Of 337 patients, 41 (12.2%) had a prolonged PR interval, and
16 of 177 patients (9.0%) had other electrocardiographic abnormalities. Of 225 patients, 43 (19.1%)
had findings on brain magnetic resonance imaging, including 16 of 223 (7.2%) showing abnormal
basal ganglia and 15 of 224 (6.7%) showing abnormal white matter. Of 153 patients, 84 (54.8%) had
abnormal findings on electroencephalograms: 77 of 149 (51.7%) with slow or disorganized
background activity and 7 of 147 (4.8%) with discharges or seizures. Of 32 patients, 8 (25.0%) had
abnormal findings in cerebral spinal fluid, including 4 of 31 (12.9%) with pleocytosis and 2 of 26
(7.7%) with intrathecal oligoclonal bands; 0 of 30 patients had elevated CSF protein.

Treatment of the First Episode of Sydenham Chorea

Antibiotics were used as treatment in 744 of 867 patients (86.1%), and immunotherapy in 231 of 898
patients (25.7%): 208 of 898 patients (23.2%) received corticosteroids, 21 of 898 patients (2.3%)
received intravenous immunoglobulin, and 12 of 898 patients (1.3%) received plasma exchange. Of
165 patients, 9 (5.5%) had adverse events associated with immunotherapy (eTable 5 in
Supplement 1). Of 687 patients, 540 (78.6%) received symptomatic pharmacological treatments,
including haloperidol for 241 of 663 patients (36.3%) and sodium valproate for 136 of 663 patients
(20.5%). Clinician-reported benefit was most frequent for sodium channel blockers (carbamazepine
in 18 patients, phenytoin in 2 patients; 18 of 20 patients [90.0%] with benefit) and antihistamines
(hydroxyzine in 13 patients, diphenhydramine in 3 patients; 13 of 16 patients [81.2%] with benefit)

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 JAMA Network Open | Neurology Treatments and Outcomes Among Patients with Sydenham Chorea

Figure 2. Patient Demographics and Clinician-Reported Response to Symptomatic Medications at the First Episode of Sydenham Chorea

A Country of residence or health care provision

Brazil
Turkey
Italy
US
UK
Thailand
Israel
New Zealand
France
India
Egypt
Kuwait
Tunisia
Germany
Australia
Chile
Spain
Canada
Netherlands
Switzerland

0 50 100 150 200 250 300 350

Patients, No.

B Year of disease onset C Age at onset

250 350

300
200
250
Patients, No.

Patients, No.

150 200

100 150

100
50
50

0 0
1940 1950 1960 1970 1980 1990 2000 2010 2020 0 4 8 12 16 20 24 28 32
Calendar year Age at disease onset, y

D Clinician-reported response to symptomatic medications

Sodium channel blockers

(20 patients from 13 articles) Impression of benefit
Antihistamines Benefit unclear
(16 patients from 5 articles)
Impression of no benefit
Second-generation antipsychotics
(17 patients from 7 articles)
Chlorpromazine and other phenothiazines
(51 patients from 27 articles)
Sodium valproate a
(133 patients from 56 articles)
Haloperidol b, c
(242 patients from 85 articles)
Phenobarbitone and other barbiturates b, d
(66 patients from 32 articles)
Benzodiazepines b, e
(41 patients from 27 articles)
0 20 40 60 80 100
Patients, %

a
Data are shown for the first episode of Sydenham chorea in 1325 patients with disease P = .001 vs sodium channel blockers.
onset since 1945. The top 20 countries of 50 total are shown. Data on year of onset were b
P < .001 vs sodium channel blockers.
available in 416 patients and inferred from year of publication in the remaining. Seven c
P = .04 vs antihistamines.
patients with disease onset after 32 years of age are not shown. Significance indicated for
d
comparisons of proportion with clinician-reported benefit in pairwise χ2 tests P = .01 vs antihistamines.
e
(Bonferroni-corrected). P < .001 vs antihistamines.

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 JAMA Network Open | Neurology Treatments and Outcomes Among Patients with Sydenham Chorea

(Figure 2D and eTable 6 in Supplement 1). Of 408 patients, 36 (8.8%) had adverse events associated
with symptomatic treatments, including 23 (5.6%) with severe adverse events (attributed to
haloperidol in 13 patients, chlorpromazine and other phenothiazines in 9 patients, and sodium
valproate in 1 patient) (eTable 7 in Supplement 1).

Descriptive Data on Disease Course and Functional Outcome

Median (IQR) duration of follow-up was 12 (5-37) months for 720 patients. There were no deaths.

Chorea Duration and Disease Course

Of 622 patients, 529 (85.0%) had full resolution of chorea at the first episode. The median (IQR)
chorea duration was 3.0 (1.2-6.0) months (Figure 3A). Including all patients with available data on
disease course, 263 of 766 patients (34.3%) experienced relapse; among them 171 of 240 (71.3%)
relapsed once, 47 of 240 (19.6%) relapsed twice, 15 of 240 (6.3%) relapsed 3 times, and 7 of 240
(2.9%) experienced relapse 4 or more times (maximum 8 times). Median (IQR) interval to first
relapse was 16.0 (8.3-48.0) months in 189 patients. Evidence of GAS infection was reported in 31 of
98 patients (31.6%) compared with 559 of 655 (85.3%) at the initial episode (P < .001).

Functional Outcome
Including all patients with available follow-up data, 138 of 595 patients (23.2%) had ongoing chorea
at final follow-up, 28 of 472 patients (5.9%) had ongoing psychiatric or behavioral symptoms, and 12
of 395 patients (3.0%) had ongoing cognitive or school performance problems. Among patients with
a final follow-up of 6 or more months after the last SC episode (or final mRS score of 0-1 at any time),
187 of 203 (92.1%) had an mRS score of 0 or 1 at final follow-up (median, 0; range, 0-3).

Clinical and Treatment Factors Associated With Disease Course and Outcome
Chorea Duration
We included 178 patients in the model for chorea duration at first episode (Figure 4A; eTable 8 in
Supplement 1). Immunotherapy was associated with shorter chorea duration (hazard ratio [HR] for
chorea resolution during treatment 1.51 [95% CI, 1.05-2.19]; P = .03). Carditis or valvulitis was
associated with longer chorea duration (HR, 0.72 [95% CI, 0.52-0.99]; P = .04). The median chorea
duration in 55 patients treated with 1 or more months of steroids was 1.2 months (95% CI, 1.2-2.0) vs
2.8 months (95% CI, 2.0-3.0) for 243 patients not treated with steroids (Tarone-Ware test P = .004;
log-rank test P = .02). The median chorea duration for 55 patients treated for less than 1 month with

Figure 3. Time to Chorea Resolution at the First Episode of Sydenham Chorea

A Whole cohort B Stratified by duration of corticosteroid treatment

100 100

No corticosteroids (n = 243)
80 80 Corticosteroids <1 mo (n = 55)
Patients with chorea, %

Patients with chorea, %

Corticosteroids ≥1 mo (n = 55)

60 60

40 40

20 20

0 0
0 3 6 9 12 15 18 0 3 6 9 12 15 18
Time from chorea onset, mo Time from chorea onset, mo
No. at risk No. at risk
Whole cohort 436 163 84 69 41 29 28 No steroids 243 87 43 34 18 14 13
Corticosteroids <1 mo 55 21 12 11 3 2 2
Corticosteroids ≥1 mo 55 10 7 6 6 3 3

Shading indicates 95% CIs.

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 JAMA Network Open | Neurology Treatments and Outcomes Among Patients with Sydenham Chorea

steroids was 2.5 months (95% CI, 1.5-5.0), not significantly different from the groups with 1 or more
months of treatment (P = .08) or no steroid treatment (P = .84) (Figure 3B).

Disease Course
We included 345 patients in the model for relapsing disease course (263 with relapse) (Figure 4B;
eTable 8 in Supplement 1). Factors associated with relapsing course were arthritis or arthralgia (odds
ratio [OR], 3.07 [95% CI, 1.15-8.17]; P = .02) and treatment with haloperidol at the first episode (OR,
2.02 [95% CI, 1.01-4.03]; P = .046). Factors associated with monophasic course were treatment with
antibiotics (OR, 0.28 [95% CI, 0.09-0.85]; P = .02), corticosteroids (OR, 0.32 [95% CI, 0.15-0.67];
P = .003), or sodium valproate (OR, 0.33 [95% CI, 0.15-0.71]; P = .004). Compared with the odds for
184 patients not treated with steroids, the odds of experiencing a relapsing course were significantly
lower (OR, 0.10 [95% CI, 0.04-0.25]; P < .001) among 33 patients treated for 1 or more months with
steroids and significantly lower (OR, 0.31 [95% CI, 0.10-0.97]; P = .03) among 17 patients treated for
less than 1 month with steroids. There was no significant difference in relapsing disease course
between the treatment groups of less than 1 month and 1 or more months (OR, 0.34 [95% CI, 0.08-
1.34]; P = .12).

Functional Outcome
We included 338 patients in the model for functional outcome (47 patients [13.9%] with poor
outcome) (Figure 4C; eTable 8 in Supplement 1). Factors associated with poor outcome were
treatment with plasma exchange (OR, 94.2 [95% CI, 12.51-709]; P < .001), history of other
autoimmune or inflammatory diseases (OR, 6.02 [95% CI, 1.31-27.57]; P = .02) and younger age (<5
years) at disease onset (OR, 4.23 [95% CI, 1.17-15.27]; P = .03). Carditis or valvulitis was associated
with good outcome (OR, 0.24 [95% CI, 0.10-0.56]; P = .001).

Figure 4. Independent Associations of Clinical and Treatment Factors With Disease Course and Outcome

A At first episode Association Association

with shorter with longer
Hazard ratio (95% CI) chorea duration chorea duration
Treatment with immunotherapy 1.51 (1.05-2.19)
Carditis or valvulitis 0.72 (0.52-0.99)

10 1 0.1 0.01
Hazard ratio (95% CI)

B Relapsing disease course Association Association

with monophasic with relapsing
Odds ratio (95% CI) course course
Treatment with antibiotics 0.28 (0.09-0.85)
Treatment with corticosteroids 0.32 (0.15-0.67)
Treatment with sodium valproate 0.33 (0.15-0.71)
Treatment with haloperidol 2.02 (1.01-4.03)
Arthritis or arthralgia 3.07 (1.15-8.17)

0.1 1 10 100
Odds ratio (95% CI)

C Multivariable models Association with Association with

good functional poor functional
Odds ratio (95% CI) outcome outcome
Carditis or valvulitis 0.24 (0.10-0.56)
Age at onset <5 y 4.23 (1.17-15.27)
Other autoimmune or inflammatory diseases 6.02 (1.31-27.57)
Treatment with plasma exchange 94.20 (12.51-709.19)
Data are shown for variables significant at P < .05 in
0.1 1 10 100 the Cox proportional hazards regression model (A) and
Odds ratio (95% CI) logistic regression models (B, C).

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Discussion
To our knowledge, this individual patient data meta-analysis is the most comprehensive evidence
synthesis to date for SC, including IPD from 1479 cases. We found that immunotherapy, in particular
with corticosteroids, was associated with faster resolution of chorea at the first episode, and that
antibiotics, corticosteroids, and sodium valproate were associated with lower rates of relapse, which
occurred in 34.3% of patients overall. We found that 86.1% of patients had a good final functional
outcome, but no treatment factors were identified in association with this.
Sydenham chorea was one of the earliest conditions recognized in neurology, and its distinctive
features, including the full rheumatic syndrome recognized since 1889,333 give us some confidence
that the disorder has been relatively consistently identified over time. We found that age at onset
(median 10 years) and female preponderance (2.2:1)12 have remained almost constant for more than
100 years, while the frequencies of fever, arthritis or arthralgia, and poor functional outcome have
reduced in the modern era (Figure 1). In the modern era, 12.0% of patients had complete loss of
upper and lower limb function (possibly consistent with chorea paralytica). Psychiatric or behavioral
symptoms were reported in 64.5% of patients, with formal psychiatric diagnoses (including
attention-deficit/hyperactivity disorder or obsessive-compulsive disorder) assigned in 9.9% of
patients. However, mental health specialist assessment was reported in only 17.6% of cases. In
cohorts undergoing standardized psychiatric evaluations, rates of attention-deficit/hyperactivity
disorder up to 31% and obsessive-compulsive disorder up to 24% have been reported.8,334
The median duration of chorea at the first episode was 3 months (Figure 3A), longer than
reported in the era before 1945 and rising to 4 months in recent decades (Figure 1), perhaps due to
increased recognition of subtle or fluctuating chorea. Immunotherapy was associated with shorter
chorea duration, with significantly higher HR for chorea resolution during treatment (Figure 4A).
Further analysis stratified by steroid treatment duration showed significantly shorter chorea duration
(median 1.2 months) for patients receiving steroids for 1 or more months (Figure 3B). Our finding of
benefit for steroids in hastening resolution of the acute SC episode is consistent with previous
observational studies,5,7,11,17,335-341 and the only placebo-controlled RCT to date, in which 22 children
receiving prednisone had a mean (SD) chorea duration of 1.8 (0.8) months vs 3.9 (2.8) months for
placebo.15 Although we were unable to evaluate intravenous immunoglobulin specifically due to
small numbers, this treatment has also been shown in an RCT to reduce the duration of symptomatic
treatment required.16 The only factor associated with longer chorea duration in the present study
was carditis or valvulitis, with a reduced HR for chorea resolution of 0.72. Carditis may indicate
greater inflammatory activity and more severe disease6; a recent report similarly identified arthritis
as a risk factor for longer chorea duration,17 although this finding was not replicated in the
present study.
Symptomatic medications were used in 78.6% of patients. We did not find any associations with
chorea duration; however, clinicians often reported benefit, most frequently for treatment with
sodium channel blockers, such as carbamazepine,342,343 antihistamines, and second-generation
antipsychotics (Figure 2D; eTable 6 in Supplement 1), none of which were associated with severe
adverse events in the present study (eTable 7 in Supplement 1). Haloperidol was less frequently
associated with benefit and more frequently associated with severe adverse events such as
hypertonia or parkinsonism. In 1 study, 23% of SC patients receiving haloperidol required treatment
change due to adverse effects344; SC has been hypothesized to be a risk factor for drug-induced
parkinsonism.345
Relapse was reported in 34.3% of patients overall, similar to previous studies.9-11 We found that
antibiotic treatment was associated with significantly reduced odds of relapsing course
(Figure 4B),346 and as we were unable to account for treatment adherence, the actual benefit may
exceed this value.7,9,12 Treatment with corticosteroids at the first episode was associated with 3.1-fold
reduced odds of relapsing course. Although this association has been suggested in previous studies,
it has not been previously observed with statistical significance.5,335,340 Additional analysis

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confirmed that even steroid courses for less than 1 month were associated with monophasic disease
course. Unexpectedly, treatment with sodium valproate was also associated with reduced odds of
relapsing course. Valproate is regarded as a safe and efficacious treatment for symptom relief in
SC342,344,347 but has not been previously associated with protection against relapse. Valproate is a
histone deacetylase inhibitor that can induce epigenetic modifications to immune cells; in an ex vivo
study of monocyte-derived macrophages from patients with systemic lupus erythematosus,
valproate upregulated anti-inflammatory macrophages and cytokines while downregulating
proinflammatory macrophages and tumor necrosis factor α.348 In animal models, valproate reduces
inflammation in the optic nerve and spinal cord.349,350 As epigenetic modifications can be long-
lasting, it is plausible that valproate could reduce relapse risk in SC; however, the proposed anti-
inflammatory mechanisms are speculative and require further study. Conversely, treatment with
haloperidol was associated with increased odds of relapsing course. It has been suggested that some
SC recurrences may reflect a persisting susceptibility to movement disorder rather than true relapses
of ARF,9,351 and indeed, in the present study, evidence of GAS infection was less frequent at
recurrence (31.6%) than at presentation (85.3%). One possibility is that some patients treated with
haloperidol had such a susceptibility due to baseline differences (eg, worse disease severity or lower-
resource health care settings), which we were unable to control for in our multivariable model.
Another possibility is that haloperidol may induce long-term basal ganglia changes (as observed in
first-episode psychosis352), which could confer future susceptibility to dyskinesia in some patients,
although this hypothesis remains to be adequately explored.
Poor functional outcome occurred in 13.9% of patients. There is a well-described group of
patients who develop chronic disease with persistent chorea or psychiatric symptoms1,6-8 despite no
evidence of immunological difference from patients in remission and no structural brain injury,
although abnormalities suggestive of neuronal loss in the basal ganglia have been reported from
magnetic resonance spectroscopy.353,354 We found that patients with poor outcome were more
likely to be younger than 5 years at onset, undergo plasma exchange, and have comorbid
autoimmune or inflammatory disorders; they were also less likely to have carditis or valvulitis
(Figure 4C). Plasma exchange is rarely used in SC and is mainly used as rescue therapy after failure of
other treatments.355 Hence, the association with poor outcome likely reflects a severity bias, which
our main severity measure (mRS score ⱖ4) may not capture. Other treatments were not significantly
associated with long-term outcome in the present study; however a previous RCT showed benefit
for intravenous immunoglobulin therapy in more subtle functional outcome measures.356 The
association of carditis with good functional outcome is contrary to previous studies of prolonged SC6
and remains to be explained; it could be that some patients in the poor outcome group had additional
or alternative neurological disorders that were not associated with carditis.

Limitations
The main limitations of this meta-analysis were the retrospective nature of the data, inclusion of
articles only in a subset of languages, underrepresentation of low and lower-middle income countries
(Table), and inclusion of case reports that were susceptible to diagnostic error (especially in older
cohorts, when, for example, N-methyl-d-aspartate receptor antibody testing was not available) and
reporting biases, such as reporting patients with worse disease, atypical features (eg, abnormal
findings on magnetic resonance imaging), or atypical treatment response. The data on clinician-
reported benefit from symptomatic medications may be especially subject to such biases, and the
medications evaluated as most beneficial in this analysis were given to relatively small numbers of
patients. Estimates of feature frequencies may be biased by underreporting of negative findings or
conversely by underreporting of more subtle positive findings (eg, individual psychiatric symptoms).
Adverse treatment effects were also likely underreported. Data collected were limited by
heterogeneous availability, hence hot-deck imputation was used to enable multivariable analysis.
Although this method generates clinically plausible values (by constraining imputation to values
already present in the database), it does not guarantee complete extinction of bias, as implicit

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 JAMA Network Open | Neurology Treatments and Outcomes Among Patients with Sydenham Chorea

assumptions are required in the choice of metric to match donors to recipients.23 As data were
missing not at random, sensitivity analyses were conducted for year of onset and missingness
(eMethods 3, eTables 9-17 in Supplement 1); however, the main findings for immunotherapy,
corticosteroids, and valproate were supported by sensitivity analyses on reduced data sets
(eTables 9-17 in Supplement 1). Functional outcome evaluation as good vs poor was a pragmatic
grouping of different outcome measures (mRS, persisting chorea, or psychiatric or behavioral
symptoms), necessary to enable analysis of heterogeneously reported data. We acknowledge that
this grouping may oversimplify important patient differences, and the predictor variables may not
capture all patient complexities, potentially explaining some associations between treatments and
adverse outcomes.

Conclusions
This meta-analysis found evidence to support the use of immunotherapy, in particular
corticosteroids, to reduce the duration of chorea at the first episode of SC and to support the use of
antibiotics, corticosteroids, and sodium valproate to reduce the risk of relapse, although the
mechanism of action for valproate is not fully understood and requires further investigation. Most
patients achieved a good final functional outcome; however, specific treatment factors associated
with this outcome remain unknown. This synthesis should help direct future research questions and
is forming the base for an ongoing international effort with Delphi methodology to provide
consensus-based recommendations for the management of SC.

ARTICLE INFORMATION
Accepted for Publication: February 17, 2024.
Published: April 16, 2024. doi:10.1001/jamanetworkopen.2024.6792
Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2024 Eyre M
et al. JAMA Network Open.
Corresponding Author: Michael Eyre, MD, Department of Biomedical Engineering, School of Biomedical
Engineering and Imaging Sciences, King’s College London, 3rd Floor, Lambeth Wing, St Thomas’ Hospital, London
SE1 7EH, United Kingdom ([Link]@[Link]).
Author Affiliations: School of Biomedical Engineering and Imaging Sciences, King’s College London, London,
United Kingdom (Eyre); Children’s Neurosciences, Evelina London Children’s Hospital at Guy’s and St Thomas’ NHS
Foundation Trust, London, United Kingdom (Eyre); Department of Paediatrics, Neurology Service, KK Women’s
and Children’s Hospital, Singapore (Thomas); Centro di Riferimento Oncologico di Aviano IRCCS, Aviano, Italy
(Ferrarin); Children’s Neurosciences, Evelina London Children’s Hospital at Guy’s and St Thomas’ NHS Foundation
Trust, London, United Kingdom (Khamis); Paediatric Neurosciences Research Group, Royal Hospital for Children,
Glasgow, United Kingdom (Zuberi); Institute of Health and Wellbeing, University of Glasgow, Glasgow, United
Kingdom (Zuberi, Sie, Morton); NHS Lanarkshire, Bothwell, United Kingdom (Sie); Children and Young People’s
Mental Health (ChYMe) Research Collaboration, University of Exeter Medical School, Exeter, United Kingdom
(Newlove-Delgado); School of Biomedical Engineering and Imaging Sciences, King’s College London, United
Kingdom (Molteni); Kids Neuroscience Centre, The Children’s Hospital at Westmead, Faculty of Medicine and
Health, University of Sydney, Westmead, Australia (Dale); Faculty of Life Sciences and Medicine, King’s College
London, United Kingdom (Lim); Children’s Neurosciences, Evelina London Children’s Hospital at Guy’s and St
Thomas’ NHS Foundation Trust, London, United Kingdom (Lim); Paediatric Neurology and Neurophysiology Unit,
Department of Women’s and Children’s Health, University Hospital of Padova, Padova, Italy (Nosadini);
Neuroimmunology Group, Paediatric Research Institute “Città della Speranza,” Padova, Italy (Nosadini).
Author Contributions: Drs Eyre and Nosadini had full access to all of the data in the study and take responsibility
for the integrity of the data and the accuracy of the data analysis. Drs Lim and Nosadini are considered
co–senior authors.
Concept and design: Eyre, Thomas, Zuberi, Sie, Newlove-Delgado, Morton, Dale, Lim, Nosadini.
Acquisition, analysis, or interpretation of data: Eyre, Thomas, Ferrarin, Khamis, Zuberi, Newlove-Delgado, Morton,
Molteni, Dale, Lim, Nosadini.

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 JAMA Network Open | Neurology Treatments and Outcomes Among Patients with Sydenham Chorea

Drafting of the manuscript: Eyre, Ferrarin, Zuberi, Morton, Dale, Lim, Nosadini.
Critical review of the manuscript for important intellectual content: All authors.
Statistical analysis: Eyre, Molteni.
Obtained funding: Lim.
Administrative, technical, or material support: Ferrarin, Khamis, Zuberi, Newlove-Delgado, Morton.
Supervision: Zuberi, Molteni, Dale, Lim, Nosadini.
Conflict of Interest Disclosures: Dr Ferrarin reported being a permanent collaborator of the Sydenham’s Chorea
Association. Dr Sie reported being the chair of the Sydenham’s Chorea Association. Dr Newlove-Delgado reported
receiving grants from the British Association for Childhood Disability, British Medical Association Helen H Lawson
Award, and Sydenham’s Chorea Association during the conduct of the study. Dr Morton reported being the
honorary president of the Sydenham’s Chorea Association. Dr Molteni reported receiving support from the
Medical Research Council Skills Development Fellowship Scheme. Dr Dale reported receiving support from
National Health and a Medical Research Council Investigator grant (Australia), and the Petre Foundation. Dr Lim
reported receiving personal fees from Octapharma, Roche, Novartis, Amgen; receiving grants from the Dancing
Eye Syndrome Society, Great Ormond Street Hospital Charity, Multiple Sclerosis Society UK, and the Sparks
Charity; receiving research support grants from the London Clinical Research Network and the Evelina Appeal,
National Institute of Health Research, Action Medical Research, Boston Children’s Hospital Research Fund, and the
GOSH charity outside the submitted work; and being the UK Clinical lead for the MR-MinMo study. No other
disclosures were reported.
Funding/Support: Dr Eyre was supported by Action Medical Research (GN2835) and the British Paediatric
Neurology Association. Dr Nosadini was supported by the University of Padova (DOR2323722).
Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection,
management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and
decision to submit the manuscript for publication.
Group Information: The members of the Sydenham’s Chorea Systematic Literature Review Working Group are
listed in Supplement 2.
Data Sharing Statement: See Supplement 3.
Additional Contributions: We thank the Sydenham’s Chorea Association ([Link]) for supporting
this project and offering to guarantee expenses in the project development phase. We thank Laura Ciolfi (Scientific
and Patient Library, Centro di Riferimento Oncologico di Aviano, IRCCS, Aviano, Italy) who gave support for the
bibliographic search, Andrea Parro (Scientific and Patient Library, Centro di Riferimento Oncologico di Aviano,
IRCCS, Aviano, Italy) who supported us in the retrieval of full texts, and Eva Wooding, MD, (University of Exeter
Medical School, Exeter, UK) and Alexander Simpson, MD, (Royal Hospital for Children & Young People, Edinburgh,
UK) who contributed to the working group formulating the scope of the systematic review. They were not
compensated beyond their usual salaries for the stated contributions.

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doi:10.1007/s11011-015-9681-1

SUPPLEMENT 1.
eMethods 1. Literature Search and Data Collection
eMethods 2. Statistical Analysis
eMethods 3. Sensitivity Analysis
eFigure 1. PRISMA Flow Diagram
eFigure 2. Symptom Frequencies Among Patients With Reported Psychiatric/Behavioural Symptoms
eTable 1. Literature Search and Record Selection: Databases Searched and Numbers of Records Retrieved,
Screened and Included

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 JAMA Network Open | Neurology Treatments and Outcomes Among Patients with Sydenham Chorea

eTable 2. Proportions of Missing (Imputed) Data in the Multivariable Models

eTable 3. Historical Comparison of Patients With Disease Onset Before and After 1945
eTable 4. Complete Descriptive Data in 1325 Patients with Sydenham’s Chorea Since 1945
eTable 5. Adverse Events Associated With Immunotherapy
eTable 6. Clinician-Reported Benefit From Symptomatic Medications
eTable 7. Adverse Events Associated With Symptomatic Medications
eTable 8. Multivariable Model Results
eTable 9. Data Missingness According to Year of Disease Onset
eTable 10. Nested Model for Chorea Duration at First Episode With Twentieth Century Cases Withheld
eTable 11. Nested Model for Relapsing Disease Course With Twentieth Century Cases Withheld
eTable 12. Nested Model for Poor Functional Outcome With Twentieth Century Cases Withheld
eTable 13. Outcome Distributions for Variables With High Missingness in the Chorea Duration at First Episode
Model
eTable 14. Outcome Distributions for Variables With High Missingness in the Relapsing Disease Course Model
eTable 15. Outcome Distributions for Variables With High Missingness in the Poor Functional Outcome Model
eTable 16. Nested Model for Chorea Duration at First Episode With Cases Missing Data in ⱖ1 Missing Not at
Random (MNAR) Variables Withheld
eTable 17. Nested Model for Poor Functional Outcome with Cases Missing Data in ⱖ1 Missing Not at Random
(MNAR) Variables Withheld

SUPPLEMENT 2.
Nonauthor Collaborators. Members of the Sydenham’s Chorea Systematic Literature Review Working Group

SUPPLEMENT 3.
Data Sharing Statement

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