What’s Known

Molecular mimicry causes genetically predisposed patients to experience acute rheumatic fever following group A Streptococcus infection. Sydenham’s chorea is an autoimmune neuropsychiatric disorder in children with inconsistent outcomes and complications.

What’s New

Cardiac involvement was significantly associated with sex in the context of Sydenham’s chorea, with boys showing more severe involvement than girls. In terms of chorea localization, a statistically significant relationship was found between the female sex and bilateral localization.

Introduction

Molecular mimicry can render genetically predisposed individuals susceptible to acute rheumatic fever (ARF) following group A Streptococcus infection. ¹ ARF is estimated to affect 8.51 per 100,000 children and adolescents worldwide. However, data regarding the incidence and prevalence of ARF among pediatric populations in Middle Eastern nations is sparse. ² Except for valvular abnormalities, ARF resolves without complications. Less frequently, chorea might be developed as a result of autoimmune involvement of the basal ganglia. ³ According to clinical and epidemiologic findings, group A Streptococcus infection was associated with Sydenham’s chorea (SC). These include a chronological link between recorded infections and chorea, as well as potential associations between chorea and rheumatic links, carditis, and arthritis, as well as a significant decrease in the incidence of SC after mass production and increased availability of antibiotics. ⁴

Antineuronal antibodies resulting from a Streptococcal infection may cross-react with epitopes on basal ganglia neurons to generate SC, an autoimmune neuropsychiatric disorder. Anti-basal antibodies induce kinase II enzymes, releasing dopamine and causing movement dysfunction. ⁵ SC is a hyperkinetic disorder associated with unpredictable and spasmodic movements of the muscles in the face and extremities, as well as hypotonia, which may have an emotional component. Chorea, hyperkinetic movement disorder, anxiety, mood disorders, attention deficit, or obsessive-compulsive disorder frequently co-occurs with neurologic and neuropsychiatric symptoms. SC can develop months after Streptococcal pharyngitis, making it difficult to establish a Streptococcal cause of the disease. ⁶

SC is the most frequent type of acquired chorea, which is usually a self-limited condition that may last between 2-7 months. ⁷ Investigations from several countries indicated that about one-third of all children with ARF might later develop SC. ⁸ A lab-based diagnosis of SC is usually confirmed by increased levels of erythrocyte sedimentation rate (ESR) or anti-streptolysin-O (ASO) and anti-DNAse B. However, electroencephalography (EEG) and neuroimaging might indicate normal findings. ⁵ Considering that SC can be associated with the Jones criteria for ARF, ⁹ it is recommended to perform a cardiac examination, as up to one-third of SC patients may develop cardiac complications. In early phases, 30-75% of individuals with chorea exhibit certain degrees of cardiac involvement. Asymptomatic valvular dysfunction, especially of the mitral valve, can only be detected by echocardiography. The normal course of chorea in patients with carditis is highly similar to those without cardiac involvement. However, female patients may experience prolonged illness. ¹⁰ In patients with ARF, whose clinical manifestations are limited to chorea, cardiac involvement might occur during recurrence. ¹¹

Despite the available evidence regarding a potential relationship between ARF and SC in children, it is not clear whether such associations might exist. Data in developing countries, including Iran, is particularly sparse. To address the existing information gap between ARF and SC, we attempted to assess the cardiac function and integrity in pediatric patients who were referred with symptoms of SC to an institutional tertiary hospital in northwestern Iran.

Patients and Methods

Study Design

This cross-sectional study was conducted on pediatric SC patients who were admitted to an institutional tertiary hospital in Tabriz (Iran) from 2009 to 2022. We reviewed the medical records of all patients aged less than 18 and were diagnosed with SC secondary to ARF. Patients who met the revised Jones criteria were considered definite cases and were followed up. The cardiac evaluations were performed at the end of 6-month and one-year time intervals. The Jones criteria, which are used to make a clinical diagnosis of ARF, include a series of major criteria, such as carditis, arthritis, chorea, erythema marginatum, subcutaneous nodules, and minor criteria such as polyarthralgia, fever≥38.5, ESR≥60 mm/hr, and/or CRP≥3 mg/dL. The presence of two major criteria or one major and two minor criteria is frequently considered to be sufficient for ARF diagnosis. The exclusion criteria included positive history of prior cardiac or neuropsychiatric complications (before contracting ARF), positive history of clinical visits by different pediatric neurologists and cardiologists during hospitalization or the follow-up period, and incomplete or missing medical records.

Based on observation of chorea symptoms, a pediatric neurologist made a clinical diagnosis of SC. When there was no evidence of carditis at the time of chorea presentation, the cases were classified as isolated chorea. The chorea was classified into four categories: 1) Mild: unaware of chorea, 2) Mild-to-moderate: aware of chorea, 3) Moderate-to-severe: disabled but able to walk, and 4) Severe: unable to walk. Two pediatric neurologists performed a complete physical and conventional clinical evaluation for chorea, including chorea localization, darting tongue, and milkmaid grip. A review of laboratory testing was conducted, which included ASO, C-reactive protein (CRP), ESR, thyroid, liver, and kidney functions, chest X-ray, and echocardiography. After an initial assessment, the patients were followed up for one year, with cardiologic examinations being performed after 6 and 12 months. The cardiac and neuropsychiatric follow-ups were performed by the initial pediatric cardiologist and neurologists.

In individuals with no prior history of either valvular insufficiency, carditis was diagnosed based on echocardiographic indicators of mitral regurgitation (MR), aortic regurgitation or insufficiency (AI), or both. In the absence of any other clinical indications that would have suggested carditis, two qualified pediatric cardiologists independently classified the patients based on Doppler echocardiographic evidence of valvular insufficiency. The following Doppler echocardiographic guidelines were used to identify pathological mitral insufficiency. Patients with no history of MR were screened for MR using both two-chamber (long axis) and four-chamber imaging. The following three criteria were used to distinguish mitral regurgitation from physiologic regurgitation: (I) Detection of mosaic color regurgitation jet at a minimum of two distinct sites or planes; (II) Regurgitating flow sample spanning the entire duration of systole by pulsed or continuous wave Doppler; and (III) Detection of pulsed or continuous waves exceeding the expected pressure gradient between the left ventricle and the left atrium. For echocardiographic examinations, an ultrasound imaging device (Sonos 1000, Hewlett-Packard, CA, USA) was utilized. The cardiac structures were characterized using 2.5, 3.5, and 5 MHz transducers. Following the standards of the American Society of Echocardiography, echocardiography (ECG) was performed with the leads placed in the standard precordial position. The apical five and parasternal long-axis views were utilized for aortic insufficiency, and only a high-velocity diastolic mosaic color jet in at least two planes was considered acceptable. Regurgitation close to the valve leaflets was seen as physiological.

All procedures performed in this study were in accordance with the ethical standards of the Ethics Committee of Tabriz University of Medical Sciences (code: IR.TBZMED.REC.1399.634), as well as the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. All patients’ parents or guardians were asked to provide written informed consent after receiving a detailed explanation of the protocol of the study.

Statistical Analysis

The SPSS software version 22.0 (IBM, NY, USA) was used to interpret the data using Chi square and Fisher’s exact tests. Besides, mean values, standard deviations, frequencies, and percentages were calculated. P<0.05 was considered statistically significant.

Results

ARF

Eighty-five ARF patients including 49 (57.6%) boys and 36 (42.4%) girls with a mean age of 9.7±2.7 were recruited in the present study. Primary echocardiography revealed cardiac involvement in 36 (42.4%) patients (table 1). Girls had a significantly higher prevalence of cardiac involvement than boys (47.2 vs. 38.8%, P=0.04).

Sydenham’s Chorea

Of the 85 patients with ARF, 18 (21%) were diagnosed with SC, and their medical records were subsequently reviewed. The majority of cases were girls (66.7% vs. 33.3%). The patients’ age ranged from 7 to 9.7 years. Of the 18 patients, 5 (27.7%) patients developed SC immediately after ARF, 10 (55.6%), with a female predominance, developed SC sub-acutely in less than a month, and the remaining 3 (16.7%) acquired SC symptoms well after a month (P=0.29). The frequency of Jones criteria among the patients is presented in table 2. Minor criteria were reported in all female patients and only two male cases, typically at age 8 (P=0.03).

Cardiac Findings

Of the 18 patients, 12 (83.3%) girls (P=0.01) and 6 (33.3%) boys (P=0.02) indicated cardiac involvement, while the others had isolated chorea. Details regarding the progression of cardiac involvement are summarized in table 3. The analysis revealed that cardiac involvement was significantly associated with sex (P=0.04).

Neurologic Findings

Chorea was mild in 5 (28%) patients, mild-to-moderate in 8 (44%), moderate-to-severe in 4 (23%), and severe in 1 (5%) patient. In addition, SC was found in 66.7% of girls and 50% of boys. Table 4 summarizes neuropsychiatric complications in SC patients within a year following diagnosis. Neither neuropsychiatric symptoms nor progress were found to be significantly associated with specific treatments and sex (P=0.06).

Treatment

The therapeutic intervention for the 18 SC patients included sodium valproate (7, 38.9%), risperidone (3, 16.7%), prednisolone (4, 22.2%), phenobarbital (2, 11.1%), and haloperidol (2, 11.1%). Every patient also received penicillin. However, no correlations were found between treatment and cardiac or neurologic progression (P=0.20).

Discussion

In this study, 85 children with a mean age of 9.7±2.7 who were suspected of having SC secondary to ARF were surveyed. On the first echocardiographic examination, mitral valve regurgitation (MR) was found in 42.4% of patients, with a predominance of female patients. 66.7% of the 18 patients (12 girls and 6 boys) with a diagnosis of SC had cardiac involvement, with a higher prevalence of MR in both sexes (P=0.04). The pattern of cardiac involvement indicated a significant intergroup difference. However, no such difference was noted during the one-year follow-up. Finally, a significant association was found between the female sex and the localization of SC.

In contrast to several previous studies, ^{12 - 14} the present study revealed that ARF was more frequent in boys, with a younger mean age. In addition, although all female patients met the revised Jones criteria, only two male patients did so, indicating that a diagnostic approach for boys might be more challenging. Considering that carditis is a common early symptom of ARF, affecting 80% of patients during the first two weeks, the role of echocardiography in ARF management has increased. ¹⁵ In the present study, 42% of cases had initial positive echocardiographic abnormalities, with the majority of them being girls. However, in a larger investigation, the prevalence was reported to be 81.0%, ¹⁶ which was almost two times higher. Carditis can range in severity from asymptomatic moderate MR to critically ill patients with dyspnea, palpitations, and heart failure. The findings showed that MR was the most frequent condition. Although it is detected as an isolated sign, MR is typically accompanied by AI. Although pericarditis was suggested to affect 4-11% of ARF patients, the present study found no signs of pericarditis in any of the patients. ¹⁷

Several studies reported a prevalence of 7.9%-32% for ARF-related SC. ^{18 - 20} However, the present study identified the condition in only 21% of the studied population. Some recent studies indicated a decline in the incidence to less than 5%. ²¹ The patient’s age in the present study was within the typical peak incidence of SC, which was between 8 and 9 years, with a female predominance. 61% of the studied patients had generalized chorea, and 39% had hemichorea, which was almost in line with the finding of the largest European study on SC. ¹⁶ However, according to a review article, hemichorea was expected in 20% of SC patients. ²²

Most of the patients in this study manifested the dart sign, the milkmaids sign, the pronator sign, writing difficulty, athetosis, and emotional instability. In the present study, 89% had neurological symptoms, of which 17% were present after one year. According to a nationwide study, 60% of patients experienced neurological symptoms, particularly dysarthria, and dysgraphia. Within 6 months from the onset of the symptoms, 93% of the patients achieved neurological remission, while 9% relapsed. ¹⁶

Carditis is a rather frequently occurring complication in SC. Hence, a clinical examination, electrocardiogram, and echocardiogram are strongly recommended to rule out potential cardiac tissue inflammation. Echocardiography facilitates the early detection of carditis, while negatively regulating the length of prophylactic antibiotic use, which may prevent serious rheumatic heart disease complications. Although a murmur strongly predicts carditis in patients with SC, the absence of a murmur does not rule it out. ^{2 , 15} According to the findings of the present study, 67% of SC patients presented valvular involvement, but none exhibited pericarditis, which was consistent with a previous study report that up to 80% of SC patients might develop carditis, particularly pericarditis. ²³ However, more extensive studies reported that 45-71% of patients might develop valvular issues, particularly MR. ²⁴ Given the evidence that cardiac involvement is not necessarily accompanied by neurological signs associated with frontostriatal motor circuit impairment, the underlying pathophysiological mechanisms of heart and brain dysfunction might be distinct. ¹¹

Despite the probability of spontaneous resolution of asymptomatic carditis, symptomatic rheumatic heart disease might still develop within 10 years from the onset of infection. ²⁵ In the present investigation, the persistence of echocardiographically diagnosed valvular regurgitation increased by about 16% during the 6-month and 12-month follow-up periods. The number of patients with valvular involvement (83%) was higher than the prevalence of 72.2% reported by a larger study with a follow-up period of two years. ²⁶ Clinically visible carditis was reported to increase the likelihood of recurrence and subsequent development of rheumatic heart disease in patients with an initial episode of ARF. The potential relapse or development of rheumatic heart disease in patients with SC, particularly those with echocardiographic indications of valve dysfunction, necessitates ongoing monitoring of these patients. ¹⁵

There is currently no agreement on the treatment of SC. In the past, symptom-specific treatments such as valproate, haloperidol, pimozide, tiapride, and carbamazepine were recommended for severe SC. Despite the scarcity of data, the use of immunoglobulins, plasmapheresis, and steroids was supported by the most compelling evidence among immunosuppressants in SC treatment. ^{16 , 22 , 27} In this study, the majority of the patients were given valproate. In the case of SC, the therapeutic approach is determined based on the clinical experience of the physician, medical preference, and the limited availability of scientific evidence. Although most patients might not have an active infection at the onset of chorea, treatment usually includes a 10-day course of oral penicillin or a single injectable dose of penicillin. ²⁸ The present therapeutic approach and those of the previous studies ¹⁶ had no difference in neurological outcomes.

The duration of SC, as indicated by previous investigations, is variable. A review of SC cases in a large cohort of ARF patients revealed that chorea in SC patients who were treated lasted 4.8 weeks, but it lasted 11.7 weeks in those who were not. Regional differences in chorea persistence might have resulted in contradictions, which could be attributed to genetic susceptibility and selection bias, among other factors. The prevalence of persistent SC is assumed to be higher in referral clinics for movement disorder studies than in the community or general pediatric clinics. ²²

Despite several statistically significant findings, it should be noted that the present study had some limitations. The most important of which was the limited number of participants and the short follow-up period. As a result, more investigations are required to provide a more comprehensive clinical image of the relationship between ARF and SC.

Conclusion

The patient’s age, sample size, and location, as well as genetic with race/ethnicity consideration, the severity of SC, and the relatively short period of follow-up might account for the stated discrepancies. Larger multicenter studies are required to fill in the data gap regarding the clinical course of SC, particularly neurologic and cardiac involvement, as well as the treatment and probable sequelae, to gain a better understanding of SC. Based on the findings of the present study, patients with SC might suffer from neurologic and cardiac issues within more than a year from the onset of infection. Therefore, practitioners are recommended to be mindful of early detection, detection and management of complications, as well as attempt to educate patients effectively, while not overlooking prospective cardiac and neurologic evaluation in later follow-ups.

Acknowledgment

The present article was financially supported by Tabriz University of Medical Sciences (Grant No. IR.TBZMED.REC.1399.634). Support from the Pediatric Health Research Center is gratefully acknowledged.

Authors’ Contribution

A.J.K: Study concept and design, drafting, and critical revision of the manuscript; V.K.: Data analysis and curation, drafting, and critical revision of the manuscript; MS: Acquisition and interpretation of data, drafting, and critical revision of the manuscript; SS: Study concept and design, drafting, and critical revision of the manuscript. All authors have read and approved the final manuscript and agree to be accountable for all aspects of the work, such that the questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Conflict of Interest:

None declared.

References

1. Auala T, Zavale BG, Mbakwem AC, Mocumbi AO. Acute Rheumatic Fever and Rheumatic Heart Disease: Highlighting the Role of Group A Streptococcus in the Global Burden of Cardiovascular Disease. Pathogens. 2022; 11Publisher Full Text | DOI | PubMed
2. Zimmerman M, Sable C. Acute Rheumatic Fever and Rheumatic Heart Disease. In: Echocardiography in Pediatric and Congenital Heart Disease: From Fetus to Adult. Wiley-Blackwell: New Jersey; 2021. DOI
3. Orsini A, Foiadelli T, Sica A, Santangelo A, Carli N, Bonuccelli A, et al. Psychopathological Impact in Patients with History of Rheumatic Fever with or without Sydenham’s Chorea: A Multicenter Prospective Study. Int J Environ Res Public Health. 2022; 19Publisher Full Text | DOI | PubMed
4. Vreeland A, Thienemann M, Cunningham M, Muscal E, Pittenger C, Frankovich J. Neuroinflammation in Obsessive-Compulsive Disorder: Sydenham Chorea, Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections, and Pediatric Acute Onset Neuropsychiatric Syndrome. Psychiatr Clin North Am. 2023; 46:69-88. DOI | PubMed
5. Chain JL, Alvarez K, Mascaro-Blanco A, Reim S, Bentley R, Hommer R, et al. Autoantibody Biomarkers for Basal Ganglia Encephalitis in Sydenham Chorea and Pediatric Autoimmune Neuropsychiatric Disorder Associated With Streptococcal Infections. Front Psychiatry. 2020; 11:564. Publisher Full Text | DOI | PubMed
6. Tanz RR, Heaberlin LE, Harvey E, Katsogridakis YL, Burns RR, Rippe J, et al. Performance of a Molecular Test for Group A Streptococcus Pharyngitis. J Pediatric Infect Dis Soc. 2023; 12:56-9. DOI | PubMed
7. Risavi BL, Iszkula E, Yost B. Sydenham’s Chorea. J Emerg Med. 2019; 56:e119-e21. DOI | PubMed
8. Hawkes MA, Ameriso SF. Neurologic complications of rheumatic fever. Handb Clin Neurol. 2021; 177:23-31. DOI | PubMed
9. 9. Guidelines for the diagnosis of rheumatic fever. Jones Criteria, 1992 update. Special Writing Group of the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the Young of the American Heart Association. JAMA. 1992; 268:2069-73. PubMed
10. Çiftlik SS. Rheumatic Heart Diseases. Chronic Disease Follow-Ups for Adults in Primary Care. Nova Science: New York; 2022.
11. Vasconcelos LPB, da Silva Bastos Vasconcelos MC, Di Flora F, de Oliveira FAP, Lima PD, Silva L, et al. Neurological and Psychiatric Disorders in Patients with Rheumatic Heart Disease: Unveiling what is Beyond Cardiac Manifestations. Glob Heart. 2022; 17:62. Publisher Full Text | DOI | PubMed
12. Fabi M, Calicchia M, Miniaci A, Balducci A, Tronconi E, Bonetti S, et al. Carditis in Acute Rheumatic Fever in a High-Income and Moderate-Risk Country. J Pediatr. 2019; 215:187-91. DOI | PubMed
13. Marino A, Cimaz R, Pelagatti MA, Tattesi G, Biondi A, Menni L, et al. Acute Rheumatic Fever: Where Do We Stand? An Epidemiological Study in Northern Italy. Front Med (Lausanne).. 2021; 8:621668. Publisher Full Text | DOI | PubMed
14. Corsenac P, Heenan RC, Roth A, Rouchon B, Guillot N, Hoy D. An epidemiological study to assess the true incidence and prevalence of rheumatic heart disease and acute rheumatic fever in New Caledonian school children. J Paediatr Child Health. 2016; 52:739-44. DOI | PubMed
15. Sujhithra A, Jayanthi S, Chokkalingam M, Danisvijay D, Vidhya R, Rajaratnam SA. Echocardiographic Parameters, Clinical Profile and Presence of Streptococcus pyogenes Virulent Genes in Pharyngitis and Rheumatic Fever. Journal of Pure & Applied Microbiology. 2022; 16:1028-38. DOI
16. Orsini A, Foiadelli T, Magistrali M, Carli N, Bagnasco I, Dassi P, et al. A nationwide study on Sydenham’s chorea: Clinical features, treatment and prognostic factors. Eur J Paediatr Neurol. 2022; 36:1-6. DOI | PubMed
17. Wang CR, Lee NY, Tsai HW, Yang CC, Lee CH. Acute rheumatic fever in adult patients. Medicine (Baltimore).. 2022; 101:e29833. Publisher Full Text | DOI | PubMed
18. Gurses D, Kocak G, Tutar E, Ozbarlas N, Turkish ARFsg. Incidence and clinical characteristics of acute rheumatic fever in Turkey: Results of a nationwide multicentre study. J Paediatr Child Health. 2021; 57:1949-54. DOI | PubMed
19. Boyarchuk O, Boytsanyuk S, Hariyan T. Acute rheumatic fever: clinical profile in children in western Ukraine. J Med Life. 2017; 10:122-6. Publisher Full Text | PubMed
20. Kocevar U, Toplak N, Kosmac B, Kopac L, Vesel S, Krajnc N, et al. Acute rheumatic fever outbreak in southern central European country. Eur J Pediatr. 2017; 176:23-9. DOI | PubMed
21. Joshi A, Shrestha RP, Shrestha PS, Dangol S, Shrestha NC, Poudyal P, et al. Sydenham’s Chorea as Presentation of Rheumatic Heart Disease. Kathmandu Univ Med J (KUMJ).. 2015; 13:271-3. DOI | PubMed
22. Vasconcelos LPB, Vasconcelos MC, Nunes MDCP, Teixeira AL. Sydenham’s chorea: an update on pathophysiology, clinical features and management. Expert Opinion on Orphan Drugs. 2019; 7:501-11. DOI
23. Rossi M, Wainsztein N, Merello M. Cardiac Involvement in Movement Disorders. Mov Disord Clin Pract. 2021; 8:651-68. Publisher Full Text | DOI | PubMed
24. Illan Ramos M, Sagastizabal Cardelus B, Garcia Ron A, Guillen Martin S, Berzosa Sanchez A, Ramos Amador JT. Chorea as the presenting feature of acute rheumatic fever in childhood; case reports from a low-prevalence European setting. BMC Infect Dis. 2021; 21:322. Publisher Full Text | DOI | PubMed
25. Guilherme L, Sampaio R, de Barros SF, Köhler K, Spina G, Tarasoutchi F, et al. Rheumatic fever and rheumatic heart disease. The Heart in Rheumatic, Autoimmune and Inflammatory Diseases. Elsevier: Amsterdam; 2017. DOI
26. Ekici F, Cetin, II, Cevik BS, Senkon OG, Alpan N, Degerliyurt A, et al. What is the outcome of rheumatic carditis in children with Sydenham’s chorea?. Turk J Pediatr. 2012; 54:159-67. PubMed
27. Favaretto E, Gortani G, Simonini G, Pastore S, Di Mascio A, Cimaz R, et al. Preliminary data on prednisone effectiveness in children with Sydenham chorea. Eur J Pediatr. 2020; 179:993-7. DOI | PubMed
28. Dean SL, Singer HS. Treatment of Sydenham’s Chorea: A Review of the Current Evidence. Tremor Other Hyperkinet Mov (N Y).. 2017; 7:456. Publisher Full Text | DOI | PubMed