DEVELOPMENTAL MEDICINE & CHILD NEUROLOGY
SYSTEMATIC REVIEW
Neuropsychiatric manifestations of Sydenham’s chorea: a systematic review MALLIKA PUNUKOLLU 1
| NADINE MUSHET 2 | MARISA LINNEY 3 | COLM HENNESSY 4 | MICHAEL MORTON 5
1 Institute of Health and Wellbeing, College of Medical, Veterinary and Life Sciences, Caledonia House, Royal Hospital for Sick Children, University of Glasgow, Yorkhill, Glasgow; 2 Liaison Psychiatry Team, Royal Hospital for Sick Children, Yorkhill, Glasgow; 3 Department of Child and Adolescent Psychiatry, Midpark Hospital, Dumfries; 4 National Child Inpatient Unit, Caledonia Ward, Royal Hospital for Sick Children, Yorkhill, Glasgow; 5 Liaison Psychiatry Team, Royal Hospital for Sick Children, Yorkhill, Glasgow, UK. Correspondence to Mallika Punukollu, Institute of Health and Wellbeing, College of Medical, Veterinary and Life Sciences, University of Glasgow, Caledonia House, Royal Hospital for Sick Children, Yorkhill, Glasgow G3 8SJ, UK. E-mail: [email protected] This article is commented on by Teixeira on pages 5–6 of this issue.
PUBLICATION DATA
Accepted for publication 19th March 2015. Published online 28th April 2015. ABBREVIATIONS
OCD PANDAS
Obsessive-compulsive disorder Paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections
AIM Sydenham’s chorea is a post-streptococcal, autoimmune, neuropsychiatric movement disorder. Sydenham’s chorea is a major criterion for diagnosis of acute rheumatic fever with the implication of potential long-term sequelae including cardiac complications. It is well established that there is psychiatric comorbidity in Sydenham’s chorea, but there are variations in the literature regarding the nature and prevalence of psychiatric diagnoses associated with Sydenham’s chorea. The aim of this review was to systematically evaluate the evidence for psychiatric symptoms presenting with Sydenham’s chorea. Knowledge of comorbid psychiatric symptomatology will support early diagnosis and treatment, leading to improved long-term outcomes for children with Sydenham’s chorea. METHOD The study used a systematic search strategy, using MEDLINE, MEDLINE in Process, EMBASE, and The Cochrane Library. Abstracts were screened to identify relevant papers which were then assessed further. Eligible papers were summarized. RESULTS A total of 1429 abstracts of relevant studies were found, and 49 papers reporting neuropsychiatric symptoms in Sydenham’s chorea were summarized. Obsessive-compulsive disorder was the most commonly studied, and hence reported, neuropsychiatric symptom in children with Sydenham’s chorea. The studies analysed used a variety of tools to identify affected children and used different methods for analysing results. Attention-deficit– hyperactivity disorder, affective disorders, tic disorders, executive function disturbances, and psychotic features were also reported as comorbidities. INTERPRETATION There is good evidence of neuropsychiatric comorbidities in Sydenham’s chorea. In countries with a high prevalence of rheumatic fever, the early recognition of salient cognitive and psychiatric symptoms may aid in the management of Sydenham’s chorea.
Sydenham’s chorea, also known as chorea minor, is a hyperkinetic movement disorder characterized by rapid and uncoordinated jerking movements, which mainly affect the face, hands, and feet. Sydenham’s chorea is a long-established condition, first described by Thomas Sydenham in 1686. An alternative eponym for Sydenham’s chorea, ‘Saint Vitus dance’, makes reference to St Vitus, martyred in 303AD, and the manic dancing that historically took place in front of his statue on his feast day. Sydenham’s chorea is temporally associated with group A b-haemolytic streptococcus infection, and this association is supported by laboratory studies.1 The diagnosis fulfils the Jones criteria for rheumatic fever.2 Streptococcal pharyngitis, caused by group A streptococcus, is a common bacterial infection in children and young adults. Most infections are uncomplicated and respond easily to appropriate antibiotics. Infections may be so minor – resolving 16 DOI: 10.1111/dmcn.12786
without intervention – that affected individuals do not seek medical attention. The causal relationship between group A streptococcus infection and Sydenham’s chorea is supported by clinical and epidemiologic observations.3 These include the observed temporal relationship between documented infections and the occurrence of chorea with other manifestations of rheumatic disease, carditis, and arthritis, as well as the reduction in the incidence of Sydenham’s chorea in the post-antibiotic era.3 The prevalence of rheumatic fever varies across the world;4 however, Sydenham’s chorea is the most common form of acquired chorea. This is supported by case series from Tunisia, Iran, Turkey, and Brazil,5–9 where Sydenham’s chorea occurs in approximately one-third of children suffering from rheumatic fever.9 The high prevalence of movement and emotional disorders in first-degree relatives of children with Sydenham’s chorea suggests that a genetic © 2015 Mac Keith Press
predisposition is important in disease development, in addition to environmental and neurochemical triggers.10,11 An autoimmune response, triggered by group A streptococcal infection, has been proposed as an aetiology for subgroups of children with other, more common and chronic neuropsychiatric diagnoses, including tic disorders, obsessive-compulsive disorder (OCD), and attentiondeficit–hyperactivity disorder (ADHD),11,12 but there are controversies regarding this issue. The occurrence of neuropsychiatric symptoms, including tics and OCD, after streptococcal infection has been described by Swedo et al.,13 who coined the acronym PANDAS (paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections). While there is agreement that autoimmune disorders may cause acute-onset neuropsychiatric disorders in children, other authors highlight a range of other aetiologies and question the emphasis on streptococcal infection. In a robust critique of PANDAS, Singer et al.14 argue for the use of a broader description of childhood-onset acute neuropsychiatric symptoms (CANS), covering a range of presentations with widely different diagnoses. Swedo et al.15 also propose the use of a broader description for such symptoms – paediatric acute-onset neuropsychiatric syndromes (PANS) – of which PANDAS and Sydenham’s chorea are included alongside acute neuropsychiatric conditions arising from other causes. Children with Sydenham’s chorea or PANDAS share an array of neuropsychiatric symptoms (as described by Swedo et al.15) but an important difference between these disorders is the clinically assessed presence of significant chorea at disease onset in Sydenham’s chorea. A diagnosis of Sydenham’s chorea means that the Jones criteria for rheumatic fever have been met2 and that a cardiac assessment should be carried out, as studies indicate that up to one-third of patients with Sydenham’s chorea may develop cardiac complications.16 To reduce the risk of rheumatic heart disease, long-term penicillin prophylaxis is required. Furthermore, in Sydenham’s chorea, the usual, established therapies for psychiatric disorders are recommended. The autoimmune and radiological changes associated with Sydenham’s chorea have been evaluated; however, no single laboratory test or imaging technique is diagnostic for Sydenham’s chorea.17 Sydenham’s chorea causes a high burden of distress to patients and their families. Patients suffer from unpredictable periods of abnormal movements and behaviour disorders, with missed school days and poor school performance causing a significant reduction in functionality.17 The delineation of the neuropsychiatric manifestations associated with Sydenham’s chorea is still emerging; case reports, population studies, and clinical reviews on these disorders have not been systematically analysed. This review examines the evidence concerning neuropsychiatric findings associated with Sydenham’s chorea. The review aims to increase awareness of the neuropsychiatric aspects of Sydenham’s chorea, as managing these effectively may reduce the burden of this illness.
• • • •
What this paper adds Psychiatric disorders are common in Sydenham’s chorea and should be diagnosed accordingly. Obsessive-compulsive disorder, mood disorders, anxiety, attention-deficit– hyperactivity disorder, and tic disorders are common comorbidities in patients with Sydenham’s chorea and there is evidence that psychotic disorders may be more likely in this group. There is limited but intriguing evidence of executive dysfunction in Sydenham’s chorea. There is currently insufficient evidence to determine the nature of the relationship between the psychiatric symptomatology and the motor manifestations of Sydenham’s chorea.
METHOD Literature search strategy The literature search was performed in accordance with the Preferred Reporting Items for Systematic Review and Metaanalyses guidelines (PRISMA; see Appendix S1, online supporting information). Articles from English and nonEnglish peer-reviewed literature, published between 1946 and 2014, were considered. Searches were performed using The Cochrane Library, NHS Scotland Knowledge Network, MEDLINE, MEDLINE in Process, EMBASE, Dynamed, and the TRIP Database (guidelines). Searches were carried out in June 2013 and again in April 2014, and were limited to ‘children’ or ‘human’ and the following expanded movement disorder vocabulary: ‘Sydenham’s chorea’ or ‘chorea minor’ or ‘rheumatic fever’ or ‘streptococcal infections in conjunction with cognitive and psychiatric’ (see Appendix S2, online supporting information, for full search strategy). One author (MP) conducted the literature search and reviewed all the abstracts, and four authors (MP, NM, ML, CH) assessed the eligibility of the studies by independently reviewing the selected abstracts. Studies were rated based on the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE)18 critical appraisal checklist. All authors were blinded to each other’s results. Interobserver agreement was 100%. The eligible literature was examined for any evidence of risk factors. Three authors (MP, NM, ML) assessed these factors to determine if a risk profile could be established to predict which children with Sydenham’s chorea might develop psychiatric complications. Inclusion and exclusion criteria The relevant publications identified described controlled clinical trials, guidelines, meta-analyses, practice guidelines, randomized controlled trials, systematic reviews, epidemiological studies, case–control studies, longitudinal cohorts, and family-based studies. This review was limited to publications related to Sydenham’s chorea, and those describing other forms of chorea were excluded. Articles were selected that (1) described Sydenham’s chorea, acute, chronic or in remission, with neuropsychiatric symptoms and (2) used some form of standard assessment or self-reporting of neuropsychiatric symptoms according to Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) or International Review
17
Classification of Diseases, 10th edition (ICD-10) criteria, and/or assessed neuropsychiatric complications using validated rating scales, or (3) assessed cognitive impairment with neuropsychological testing. Taking into account the low population prevalence of Sydenham’s chorea, case studies of individuals were also included. Articles were excluded if they did not contain any information regarding comorbidities between Sydenham’s chorea and neuropsychiatric symptoms.
RESULTS A total of 1429 abstracts were screened for any mention of the neuropsychiatric aspects of Sydenham’s chorea. Of these, 102 relevant clinical studies reporting cognitive and psychiatric symptoms of Sydenham’s chorea were found (see Appendix S3, online supporting information, for PRISMA flow chart). All 102 full-text publications were screened and assessed for eligibility, 49 of which were deemed eligible and therefore assessed further for quality; these 49 publications constituted the final sample used in this review. Information on study design, cohort setting, population demographics, and measures for the included studies is provided in Table I. Most studies (n=32) were retrospective case series that collected data from children’s records from 2 weeks to 34 years after the onset of chorea. Studies that assessed prechorea behaviour did so retrospectively by parental recall, often within the first 3 months of chorea onset. Behavioural outcomes for children with chorea were often compared with those of reference groups, which comprised either healthy children without chorea or children attending the hospital or clinic for other medical problems. Reference groups were matched with groups of children with chorea for age, sex, and (sometimes) sociodemographic characteristics. Comparisons with reference groups helped control for the typical developmental trajectory. Ten studies included statistical analyses of the association of Sydenham’s chorea with psychiatric symptoms (Table II). Studies without reference groups relied on population norms. Specific measures were used to assess psychiatric symptoms, such as the YaleBrown Obsessive Compulsive scale and the Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children – Epidemiological Version. A selection of the measures used are shown in Table II. Most commonly, parents or primary caregivers reported the information. Overall, the literature strongly suggests that children with Sydenham’s chorea are at a higher risk of adverse psychiatric outcomes than children without Sydenham’s chorea. Sydenham’s chorea has been linked to diagnoses of new-onset psychiatric disorders, including ADHD, mood disorders, anxiety disorders, and depressive disorders, shortly after Sydenham’s chorea diagnosis. Risk factors for behavioural outcome in Sydenham’s chorea Pre-chorea status In a retrospective case series, Ridel et al.19 found that ADHD and anxiety symptoms in children with Sydenham’s 18 Developmental Medicine & Child Neurology 2016, 58: 16–28
chorea were sometimes reported even before the appearance of chorea (4/14) and did not increase significantly during the acute phase (5/14), suggesting an underlying vulnerability.
Age at which chorea developed None of the studies reviewed showed any correlation between the age at onset of chorea and the subsequent manifestation or severity of psychiatric symptoms. Chorea severity/chronicity Moreira et al.20 looked at a number of psychiatric conditions, including ADHD, OCD, and anxiety disorders. Most psychiatric disorders were equally common in children with remitted Sydenham’s chorea and in those with persistent Sydenham’s chorea, suggesting that the risk of psychiatric comorbidities was elevated regardless of the motor outcome. However, depressive disorders were more commonly diagnosed in children with persistent Sydenham’s chorea (p=0.03). In addition, Maia et al.21 found that ADHD was more common in children with persistent Sydenham’s chorea (p=0.03) than in those with acute or remitted Sydenham’s chorea. In addition, Beato et al.22 showed similar levels of executive functioning impairments in individuals with persistent Sydenham’s chorea and in those with Sydenham’s chorea that had remitted. Sex Alvarenga et al.23 assessed obsessive-compulsive symptoms in individuals with heart disease with and without a history of rheumatic fever. Higher frequencies of obsessive-compulsive symptoms were found in males with a history of rheumatic fever than in the comparison male group without rheumatic fever (p=0.038). No differences were observed regarding obsessive-compulsive symptoms in females with a history rheumatic fever compared with females without rheumatic fever. Maia et al.21 reported that anxiety is more common in females with Sydenham’s chorea than in males (p=0.003). This finding is supported by Moreira et al.,20 who also found that females with Sydenham’s chorea exhibited more anxiety symptoms than males (p=0.03). In addition, all of the case studies included in this review – which typically depict unusual or extreme presentations of Sydenham’s chorea, such as those with associated psychosis – were of females. Asbahr et al.24 observed a trend for females with Sydenham’s chorea to report hoarding obsessions more frequently than males (Mann–Whitney U=720, p=0.053). Genetic factors Demiroren et al.5 found that consanguinity was present in 15.4% (10/65) of participants with Sydenham’s chorea; however, there was no comparison group and no other study has replicated this finding. Dale et al.10 found that 27.5% (11/40) of participants with Sydenham’s chorea had a family history of ICD-10 psychiatric disorders; however,
Table I: Papers which studied associations between Sydenham’s chorea and neuropsychiatric complications Reference
Year
Country
Numbers of individuals studied
Age groupa
Study type
Neuropsychiatric findings
Chapman et al.47
1958
USA
8 with SC
Child
Case series review
Matthews et al.28
1960
Australia
20 with SC
Child
Case review
Sacks et al.35
1962
USA
20 with SC, 20 with RF
Child
Case–control
Freeman et al.27
1965
USA
40 with SC, 30 comparisons
Adult
Retrospective case–control
Wilcox and Nasrallah41
1986
USA
N/A
Retrospective case–control
Wilcox and Nasrallah40
1988
USA
600 with psychotic conditions, 369 without 29 with SC, 29 comparisons
2 with schizophrenia, 3 with OCD traits, 2 with anxiety, 1 with depression Average intelligence of group, on WISC, less than general population average. Serious longstanding emotional difficulties in all children and serious maladjustment with respect to family relationships Less assertiveness on TAT, drawing of figures incomplete in chorea group i.e. no hands Personality Disorders in 26/ 40, Psychoneurosis in 7/40 (Phobic, OCD, Conversion, Anxiety). Seventy-five percent of individuals with SC had psychiatric disturbances; 25% of comparisons had psychiatric disturbance 12 with chorea in psychosis group; 0 in control group
Child
Prospective cohort study over 10y
Swedo et al.54
1989
USA
Child
Case–control
Prasher and Barrett55
1993
UK
23 with SC, 14 with RF without chorea 1 with SC
Child
Case study
Swedo et al.29
1993
USA
11 with SC
Child
Prospective case series
Casey et al.36,37
1994
USA
10 with SC; 10 comparisons
Child
Case–control
Swedo56
1994
USA
1 with SC
Child
Case study
Janner57
1995
USA
1 with SC
Child
Case study
Abbas et al.58 Black and Perlmutter34 Mercadante et al.59
1996 1997
India USA
20 with SC 1 with SC
17–19y olds Adult
Cross-sectional Case report
1997
Brazil
10 with SC
Child
Systematic
8.9 RR of developing schizophrenia in SC group compared with comparison group. The total number of psychiatric symptoms 10y after initial hospitalization was much greater in patients with a history of chorea than in a surgical comparison group (p
SYSTEMATIC REVIEW
Neuropsychiatric manifestations of Sydenham’s chorea: a systematic review MALLIKA PUNUKOLLU 1
| NADINE MUSHET 2 | MARISA LINNEY 3 | COLM HENNESSY 4 | MICHAEL MORTON 5
1 Institute of Health and Wellbeing, College of Medical, Veterinary and Life Sciences, Caledonia House, Royal Hospital for Sick Children, University of Glasgow, Yorkhill, Glasgow; 2 Liaison Psychiatry Team, Royal Hospital for Sick Children, Yorkhill, Glasgow; 3 Department of Child and Adolescent Psychiatry, Midpark Hospital, Dumfries; 4 National Child Inpatient Unit, Caledonia Ward, Royal Hospital for Sick Children, Yorkhill, Glasgow; 5 Liaison Psychiatry Team, Royal Hospital for Sick Children, Yorkhill, Glasgow, UK. Correspondence to Mallika Punukollu, Institute of Health and Wellbeing, College of Medical, Veterinary and Life Sciences, University of Glasgow, Caledonia House, Royal Hospital for Sick Children, Yorkhill, Glasgow G3 8SJ, UK. E-mail: [email protected] This article is commented on by Teixeira on pages 5–6 of this issue.
PUBLICATION DATA
Accepted for publication 19th March 2015. Published online 28th April 2015. ABBREVIATIONS
OCD PANDAS
Obsessive-compulsive disorder Paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections
AIM Sydenham’s chorea is a post-streptococcal, autoimmune, neuropsychiatric movement disorder. Sydenham’s chorea is a major criterion for diagnosis of acute rheumatic fever with the implication of potential long-term sequelae including cardiac complications. It is well established that there is psychiatric comorbidity in Sydenham’s chorea, but there are variations in the literature regarding the nature and prevalence of psychiatric diagnoses associated with Sydenham’s chorea. The aim of this review was to systematically evaluate the evidence for psychiatric symptoms presenting with Sydenham’s chorea. Knowledge of comorbid psychiatric symptomatology will support early diagnosis and treatment, leading to improved long-term outcomes for children with Sydenham’s chorea. METHOD The study used a systematic search strategy, using MEDLINE, MEDLINE in Process, EMBASE, and The Cochrane Library. Abstracts were screened to identify relevant papers which were then assessed further. Eligible papers were summarized. RESULTS A total of 1429 abstracts of relevant studies were found, and 49 papers reporting neuropsychiatric symptoms in Sydenham’s chorea were summarized. Obsessive-compulsive disorder was the most commonly studied, and hence reported, neuropsychiatric symptom in children with Sydenham’s chorea. The studies analysed used a variety of tools to identify affected children and used different methods for analysing results. Attention-deficit– hyperactivity disorder, affective disorders, tic disorders, executive function disturbances, and psychotic features were also reported as comorbidities. INTERPRETATION There is good evidence of neuropsychiatric comorbidities in Sydenham’s chorea. In countries with a high prevalence of rheumatic fever, the early recognition of salient cognitive and psychiatric symptoms may aid in the management of Sydenham’s chorea.
Sydenham’s chorea, also known as chorea minor, is a hyperkinetic movement disorder characterized by rapid and uncoordinated jerking movements, which mainly affect the face, hands, and feet. Sydenham’s chorea is a long-established condition, first described by Thomas Sydenham in 1686. An alternative eponym for Sydenham’s chorea, ‘Saint Vitus dance’, makes reference to St Vitus, martyred in 303AD, and the manic dancing that historically took place in front of his statue on his feast day. Sydenham’s chorea is temporally associated with group A b-haemolytic streptococcus infection, and this association is supported by laboratory studies.1 The diagnosis fulfils the Jones criteria for rheumatic fever.2 Streptococcal pharyngitis, caused by group A streptococcus, is a common bacterial infection in children and young adults. Most infections are uncomplicated and respond easily to appropriate antibiotics. Infections may be so minor – resolving 16 DOI: 10.1111/dmcn.12786
without intervention – that affected individuals do not seek medical attention. The causal relationship between group A streptococcus infection and Sydenham’s chorea is supported by clinical and epidemiologic observations.3 These include the observed temporal relationship between documented infections and the occurrence of chorea with other manifestations of rheumatic disease, carditis, and arthritis, as well as the reduction in the incidence of Sydenham’s chorea in the post-antibiotic era.3 The prevalence of rheumatic fever varies across the world;4 however, Sydenham’s chorea is the most common form of acquired chorea. This is supported by case series from Tunisia, Iran, Turkey, and Brazil,5–9 where Sydenham’s chorea occurs in approximately one-third of children suffering from rheumatic fever.9 The high prevalence of movement and emotional disorders in first-degree relatives of children with Sydenham’s chorea suggests that a genetic © 2015 Mac Keith Press
predisposition is important in disease development, in addition to environmental and neurochemical triggers.10,11 An autoimmune response, triggered by group A streptococcal infection, has been proposed as an aetiology for subgroups of children with other, more common and chronic neuropsychiatric diagnoses, including tic disorders, obsessive-compulsive disorder (OCD), and attentiondeficit–hyperactivity disorder (ADHD),11,12 but there are controversies regarding this issue. The occurrence of neuropsychiatric symptoms, including tics and OCD, after streptococcal infection has been described by Swedo et al.,13 who coined the acronym PANDAS (paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections). While there is agreement that autoimmune disorders may cause acute-onset neuropsychiatric disorders in children, other authors highlight a range of other aetiologies and question the emphasis on streptococcal infection. In a robust critique of PANDAS, Singer et al.14 argue for the use of a broader description of childhood-onset acute neuropsychiatric symptoms (CANS), covering a range of presentations with widely different diagnoses. Swedo et al.15 also propose the use of a broader description for such symptoms – paediatric acute-onset neuropsychiatric syndromes (PANS) – of which PANDAS and Sydenham’s chorea are included alongside acute neuropsychiatric conditions arising from other causes. Children with Sydenham’s chorea or PANDAS share an array of neuropsychiatric symptoms (as described by Swedo et al.15) but an important difference between these disorders is the clinically assessed presence of significant chorea at disease onset in Sydenham’s chorea. A diagnosis of Sydenham’s chorea means that the Jones criteria for rheumatic fever have been met2 and that a cardiac assessment should be carried out, as studies indicate that up to one-third of patients with Sydenham’s chorea may develop cardiac complications.16 To reduce the risk of rheumatic heart disease, long-term penicillin prophylaxis is required. Furthermore, in Sydenham’s chorea, the usual, established therapies for psychiatric disorders are recommended. The autoimmune and radiological changes associated with Sydenham’s chorea have been evaluated; however, no single laboratory test or imaging technique is diagnostic for Sydenham’s chorea.17 Sydenham’s chorea causes a high burden of distress to patients and their families. Patients suffer from unpredictable periods of abnormal movements and behaviour disorders, with missed school days and poor school performance causing a significant reduction in functionality.17 The delineation of the neuropsychiatric manifestations associated with Sydenham’s chorea is still emerging; case reports, population studies, and clinical reviews on these disorders have not been systematically analysed. This review examines the evidence concerning neuropsychiatric findings associated with Sydenham’s chorea. The review aims to increase awareness of the neuropsychiatric aspects of Sydenham’s chorea, as managing these effectively may reduce the burden of this illness.
• • • •
What this paper adds Psychiatric disorders are common in Sydenham’s chorea and should be diagnosed accordingly. Obsessive-compulsive disorder, mood disorders, anxiety, attention-deficit– hyperactivity disorder, and tic disorders are common comorbidities in patients with Sydenham’s chorea and there is evidence that psychotic disorders may be more likely in this group. There is limited but intriguing evidence of executive dysfunction in Sydenham’s chorea. There is currently insufficient evidence to determine the nature of the relationship between the psychiatric symptomatology and the motor manifestations of Sydenham’s chorea.
METHOD Literature search strategy The literature search was performed in accordance with the Preferred Reporting Items for Systematic Review and Metaanalyses guidelines (PRISMA; see Appendix S1, online supporting information). Articles from English and nonEnglish peer-reviewed literature, published between 1946 and 2014, were considered. Searches were performed using The Cochrane Library, NHS Scotland Knowledge Network, MEDLINE, MEDLINE in Process, EMBASE, Dynamed, and the TRIP Database (guidelines). Searches were carried out in June 2013 and again in April 2014, and were limited to ‘children’ or ‘human’ and the following expanded movement disorder vocabulary: ‘Sydenham’s chorea’ or ‘chorea minor’ or ‘rheumatic fever’ or ‘streptococcal infections in conjunction with cognitive and psychiatric’ (see Appendix S2, online supporting information, for full search strategy). One author (MP) conducted the literature search and reviewed all the abstracts, and four authors (MP, NM, ML, CH) assessed the eligibility of the studies by independently reviewing the selected abstracts. Studies were rated based on the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE)18 critical appraisal checklist. All authors were blinded to each other’s results. Interobserver agreement was 100%. The eligible literature was examined for any evidence of risk factors. Three authors (MP, NM, ML) assessed these factors to determine if a risk profile could be established to predict which children with Sydenham’s chorea might develop psychiatric complications. Inclusion and exclusion criteria The relevant publications identified described controlled clinical trials, guidelines, meta-analyses, practice guidelines, randomized controlled trials, systematic reviews, epidemiological studies, case–control studies, longitudinal cohorts, and family-based studies. This review was limited to publications related to Sydenham’s chorea, and those describing other forms of chorea were excluded. Articles were selected that (1) described Sydenham’s chorea, acute, chronic or in remission, with neuropsychiatric symptoms and (2) used some form of standard assessment or self-reporting of neuropsychiatric symptoms according to Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) or International Review
17
Classification of Diseases, 10th edition (ICD-10) criteria, and/or assessed neuropsychiatric complications using validated rating scales, or (3) assessed cognitive impairment with neuropsychological testing. Taking into account the low population prevalence of Sydenham’s chorea, case studies of individuals were also included. Articles were excluded if they did not contain any information regarding comorbidities between Sydenham’s chorea and neuropsychiatric symptoms.
RESULTS A total of 1429 abstracts were screened for any mention of the neuropsychiatric aspects of Sydenham’s chorea. Of these, 102 relevant clinical studies reporting cognitive and psychiatric symptoms of Sydenham’s chorea were found (see Appendix S3, online supporting information, for PRISMA flow chart). All 102 full-text publications were screened and assessed for eligibility, 49 of which were deemed eligible and therefore assessed further for quality; these 49 publications constituted the final sample used in this review. Information on study design, cohort setting, population demographics, and measures for the included studies is provided in Table I. Most studies (n=32) were retrospective case series that collected data from children’s records from 2 weeks to 34 years after the onset of chorea. Studies that assessed prechorea behaviour did so retrospectively by parental recall, often within the first 3 months of chorea onset. Behavioural outcomes for children with chorea were often compared with those of reference groups, which comprised either healthy children without chorea or children attending the hospital or clinic for other medical problems. Reference groups were matched with groups of children with chorea for age, sex, and (sometimes) sociodemographic characteristics. Comparisons with reference groups helped control for the typical developmental trajectory. Ten studies included statistical analyses of the association of Sydenham’s chorea with psychiatric symptoms (Table II). Studies without reference groups relied on population norms. Specific measures were used to assess psychiatric symptoms, such as the YaleBrown Obsessive Compulsive scale and the Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children – Epidemiological Version. A selection of the measures used are shown in Table II. Most commonly, parents or primary caregivers reported the information. Overall, the literature strongly suggests that children with Sydenham’s chorea are at a higher risk of adverse psychiatric outcomes than children without Sydenham’s chorea. Sydenham’s chorea has been linked to diagnoses of new-onset psychiatric disorders, including ADHD, mood disorders, anxiety disorders, and depressive disorders, shortly after Sydenham’s chorea diagnosis. Risk factors for behavioural outcome in Sydenham’s chorea Pre-chorea status In a retrospective case series, Ridel et al.19 found that ADHD and anxiety symptoms in children with Sydenham’s 18 Developmental Medicine & Child Neurology 2016, 58: 16–28
chorea were sometimes reported even before the appearance of chorea (4/14) and did not increase significantly during the acute phase (5/14), suggesting an underlying vulnerability.
Age at which chorea developed None of the studies reviewed showed any correlation between the age at onset of chorea and the subsequent manifestation or severity of psychiatric symptoms. Chorea severity/chronicity Moreira et al.20 looked at a number of psychiatric conditions, including ADHD, OCD, and anxiety disorders. Most psychiatric disorders were equally common in children with remitted Sydenham’s chorea and in those with persistent Sydenham’s chorea, suggesting that the risk of psychiatric comorbidities was elevated regardless of the motor outcome. However, depressive disorders were more commonly diagnosed in children with persistent Sydenham’s chorea (p=0.03). In addition, Maia et al.21 found that ADHD was more common in children with persistent Sydenham’s chorea (p=0.03) than in those with acute or remitted Sydenham’s chorea. In addition, Beato et al.22 showed similar levels of executive functioning impairments in individuals with persistent Sydenham’s chorea and in those with Sydenham’s chorea that had remitted. Sex Alvarenga et al.23 assessed obsessive-compulsive symptoms in individuals with heart disease with and without a history of rheumatic fever. Higher frequencies of obsessive-compulsive symptoms were found in males with a history of rheumatic fever than in the comparison male group without rheumatic fever (p=0.038). No differences were observed regarding obsessive-compulsive symptoms in females with a history rheumatic fever compared with females without rheumatic fever. Maia et al.21 reported that anxiety is more common in females with Sydenham’s chorea than in males (p=0.003). This finding is supported by Moreira et al.,20 who also found that females with Sydenham’s chorea exhibited more anxiety symptoms than males (p=0.03). In addition, all of the case studies included in this review – which typically depict unusual or extreme presentations of Sydenham’s chorea, such as those with associated psychosis – were of females. Asbahr et al.24 observed a trend for females with Sydenham’s chorea to report hoarding obsessions more frequently than males (Mann–Whitney U=720, p=0.053). Genetic factors Demiroren et al.5 found that consanguinity was present in 15.4% (10/65) of participants with Sydenham’s chorea; however, there was no comparison group and no other study has replicated this finding. Dale et al.10 found that 27.5% (11/40) of participants with Sydenham’s chorea had a family history of ICD-10 psychiatric disorders; however,
Table I: Papers which studied associations between Sydenham’s chorea and neuropsychiatric complications Reference
Year
Country
Numbers of individuals studied
Age groupa
Study type
Neuropsychiatric findings
Chapman et al.47
1958
USA
8 with SC
Child
Case series review
Matthews et al.28
1960
Australia
20 with SC
Child
Case review
Sacks et al.35
1962
USA
20 with SC, 20 with RF
Child
Case–control
Freeman et al.27
1965
USA
40 with SC, 30 comparisons
Adult
Retrospective case–control
Wilcox and Nasrallah41
1986
USA
N/A
Retrospective case–control
Wilcox and Nasrallah40
1988
USA
600 with psychotic conditions, 369 without 29 with SC, 29 comparisons
2 with schizophrenia, 3 with OCD traits, 2 with anxiety, 1 with depression Average intelligence of group, on WISC, less than general population average. Serious longstanding emotional difficulties in all children and serious maladjustment with respect to family relationships Less assertiveness on TAT, drawing of figures incomplete in chorea group i.e. no hands Personality Disorders in 26/ 40, Psychoneurosis in 7/40 (Phobic, OCD, Conversion, Anxiety). Seventy-five percent of individuals with SC had psychiatric disturbances; 25% of comparisons had psychiatric disturbance 12 with chorea in psychosis group; 0 in control group
Child
Prospective cohort study over 10y
Swedo et al.54
1989
USA
Child
Case–control
Prasher and Barrett55
1993
UK
23 with SC, 14 with RF without chorea 1 with SC
Child
Case study
Swedo et al.29
1993
USA
11 with SC
Child
Prospective case series
Casey et al.36,37
1994
USA
10 with SC; 10 comparisons
Child
Case–control
Swedo56
1994
USA
1 with SC
Child
Case study
Janner57
1995
USA
1 with SC
Child
Case study
Abbas et al.58 Black and Perlmutter34 Mercadante et al.59
1996 1997
India USA
20 with SC 1 with SC
17–19y olds Adult
Cross-sectional Case report
1997
Brazil
10 with SC
Child
Systematic
8.9 RR of developing schizophrenia in SC group compared with comparison group. The total number of psychiatric symptoms 10y after initial hospitalization was much greater in patients with a history of chorea than in a surgical comparison group (p
