Tuesday, November 23, 2021

A nationwide study on Sydenham's chorea: Clinical features, treatment and prognostic factors

 Alessandro Orsini, Thomas Foiadelli, Mariasole Magistrali, Niccolò Carli, Irene Bagnasco, Patrizia Dassi, Alberto Verrotti, Daniele Marcotulli, Carlotta Canavese, Francesco Nicita, Alessandro Capuano, Chiara Marra, Anna Fetta, Margherita Nosadini, Stefano Sartori, Amanda Papa, Maurizio Viri, Filippo Greco, Piero Pavone, Gabriele Simonini,  Sara Matricardi, Sabrina Siquilini, Francesca Marchese, Elisa De Grandis, Bernadette Marrè Brunenghi, Clara Malattia, Francesco Bassanese, Patrizia Bergonzini, Alice Bonuccelli, Rita Consolini, Gian Luigi Marseglia, Diego Peroni, Pasquale Striano, Duccio Cordelli, Salvatore Savasta. A nationwide study on Sydenham's chorea: Clinical features, treatment and prognostic factors. European Journal of Paediatric Neurology. November 06, 2021 DOI:https://doi.org/10.1016/j.ejpn.2021.11.002



SC is a post-streptococcal disease causing a typical movement and psychiatric disorder.


Evidence-based guidelines for SC are currently lacking.


Treatment heterogeneity was high in our national retrospective multicenter cohort.


Treatment with immunotherapy or symptomatic drugs did not differ in terms of outcome.


Use of symptomatic drugs was associated with a slight increased risk of relapse.



Sydenham's Chorea (SC) is a neuropsychiatric disorder and a major manifestation of acute rheumatic fever. The erroneous assumption that SC is a benign and self-limiting disease, has led to a lack of high-quality scientific evidence of the therapeutical and prognostic features of SC.

Study design

We retrospectively analyzed the medical records of patients <18-years old with SC in 17 Italian pediatric centers. Recorded data included clinical, instrumental and laboratory parameters. Prognostic risk factors including treatment regimens were assessed with univariate and multivariate sub-analysis.


We included 171 patients with SC. 66% had generalized chorea, and 34% hemichorea. 81% had carditis (subclinical in 65%). Additional neurological symptoms were reported in 60% of the patients, mainly dysarthria and dysgraphia. 51% had neuropsychiatric symptoms at onset, which persisted after 12 months in 10%. Among psychiatric manifestations, the most common was anxiety disorder/depression (77%). Neurological remission was reached by 93% of the patients at 6 months; 9% relapsed. Patients were treated as follows: 11% penicillin alone, 37% immunomodulatory therapy, 16% symptomatic drugs (i.e. anti-seizure medication, dopamine antagonists) and 37% both symptomatic and immunomodulatory treatment. Neurological outcome did not differ between groups. Patients receiving symptomatic drugs had a higher risk of relapse on multivariate analysis (p = 0.045).


Treatment of SC was largely heterogeneous. Based on our results, immunomodulatory therapy did not show higher efficacy at medium term, although it was associated to a slightly lower risk of relapse compared to symptomatic therapy. Longitudinal studies are needed to assess specific risk factors and best treatment options.

Courtesy of: https://www.mdlinx.com/journal-summary/a-nationwide-study-on-sydenhams-chorea-clinical-features-treatment-and-prognostic-factors/4R5CkzQlJfMqBaeDlD9fp1

Tuesday, November 16, 2021

COVID-19 and neuropsychiatric symptoms in teenagers

Investigators reported anti-SARS-CoV-2 autoantibodies in the cerebrospinal fluid of three teens who came to the emergency department with neuropsychiatric symptoms. The scientists believe that emergency department doctors should be open to the possibility that young people presenting for the first time with unexplained neuropsychiatric problems could have an autoantibody response to the COVID-19 infection, and should be evaluated accordingly. 

Scientists have identified anti-SARS-CoV-2 antibodies and anti-neuronal auto-antibodies in the cerebrospinal fluid (CSF) of two of three teenagers who presented to an emergency department with subacute neuropsychiatric problems, including paranoid delusions, suicidal ideation, anxiety, obsessive behavior, and cognitive slowing. 

While many teenagers present to the emergency department with neuropsychiatric symptoms, these three teens were the only ones who presented to the University of California, San Francisco (UCSF) with these symptoms in the setting of a recent COVID-19 infection and for whom a neurology consult was called. Two tested positive with direct detection tests, and one was seropositive (antibody testing) with a recent exposure. 

All three also had abnormal CSF with restricted oligoclonal bands, elevated protein, and/or an elevated immunoglobulin G (IgG) index. None of them met the criteria for multisystem inflammatory syndrome in children, which has been associated with some cases of COVID-19 in young patients. 

The findings, published online on October 25 in JAMA Neurology, suggest that the virus could be associated with central nervous system inflammation and leave some pediatric COVID-19 patients with new onset neuropsychiatric symptoms that do not respond to traditional psychiatric medications. 

One of the teenagers seemed to improve after immunotherapy, another had a modest response, while the third teens' symptoms improved after treatment with lorazepam and olanzapine without immunotherapy. 

The scientists believe that emergency department doctors should be open to the possibility that young people presenting for the first time with unexplained neuropsychiatric problems could have an auto-antibody response to the COVID-19 infection, and should be evaluated accordingly…

In the first case, UCSF pediatric resident Claire Johns, MD, had evaluated a teenager who presented with acute delusions and psychosis, and called on the neurology service to help assess the patient. The teenager had erratic and paranoid-like behavior, insomnia and social withdrawal. The teen had a history of marijuana use and unspecified anxiety and depression, was initially treated with psychiatric medications, but was discharged after 11 days. The teen was readmitted a day later with persistent delusions.

The teenager had tested positive for COVID-19 during the first hospitalization, although the teen had no respiratory symptoms. On readmission, a lumbar puncture showed elevated protein and elevated IgG index. An MRI of the brain showed non-specific T2/FLAIR white matter hyperintensities in the frontal lobes. The pediatric specialists ordered intravenous immunoglobulin (IVIg) and the teen quickly improved enough to be discharged from the hospital. The teen's blood and CSF were later sent for further analysis to Dr. Wilson and his colleagues who identified abnormal antibody production in the teen's CSF.

The second teen had a history of anxiety and motor tics and a “foggy brain,: according to the description in the paper. The teen's father had just been diagnosed with COVID-19, and a week later the teen developed fever and respiratory symptoms and improved without treatment. Over the next six weeks, the teen experienced a host of neuropsychiatric symptoms, including word-finding difficulty and problems concentrating, insomnia, mood swings, and it morphed into aggression and suicidal ideation. The teen was treated without success with psychiatric medications, and admitted to the hospital ten weeks after the neuropsychiatric symptoms began.

Back in the hospital, the patient tested positive for SARS-CoV2 antibodies. The teen's slowed thinking and memory problems improved after IV methylprednisolone, and was discharged on lithium and risperidone. Six days later, still in the throes of aggression and suicidal ideation, the teen was readmitted. Another lumbar puncture showed elevated CSF protein and IVIg was administered for three days. The patient was discharged with psychiatric medicines but six months later there was still lingering forgetfulness and attention problems. A third lumbar puncture at six months still showed elevated protein.

The third teenager was taken to the emergency department after four days of extremely erratic and odd repetitive behaviors, insomnia, and anorexia. There was no previous history of psychiatric symptoms. In the ED, a SARS-CoV-2 test came back positive. The teen had an elevated white blood cell count, creatine kinase, and C-reactive protein as well as ideomotor apraxia, a lack of motivation, disorganized behavior, and agitation. Psychiatric medications were administered for a few days and then stopped. The patient's symptoms improved during the weeklong hospitalization, and the teen was discharged without any psychiatric medications.“One important difference is that the teen who improved was treated soon after their symptoms started whereas the second patient's treatment was delayed by over two months,” said Dr. Johns. The third young person had mania and insomnia and tested positive for SARS-CoV2 but did not have evidence of auto-antibodies in the CSF…

“Merely identifying these autoantibodies and some of their antigens does not causally link them to these young peoples' symptoms,” added Dr. Bartley. “In some patients, the specific regions of the SARS-CoV-2 proteome targeted by the serum antibodies differed from the antigens in the CSF, suggesting that a compartmentalized immune response might be occurring in the CNS.”


Bartley CM, Johns C, Ngo TT, Dandekar R, Loudermilk RL, Alvarenga BD, Hawes IA, Zamecnik CR, Zorn KC, Alexander JR, Wapniarski AE, DeRisi JL, Francisco C, Nash KB, Wietstock SO, Pleasure SJ, Wilson MR. Anti-SARS-CoV-2 and Autoantibody Profiles in the Cerebrospinal Fluid of 3 Teenaged Patients With COVID-19 and Subacute Neuropsychiatric Symptoms. JAMA Neurol. 2021 Oct 25:e213821. doi: 10.1001/jamaneurol.2021.3821. Epub ahead of print. PMID: 34694339; PMCID: PMC8546622.


ImportanceNeuropsychiatric manifestations of COVID-19 have been reported in the pediatric population.

Objective: To determine whether anti-SARS-CoV-2 and autoreactive antibodies are present in the cerebrospinal fluid (CSF) of pediatric patients with COVID-19 and subacute neuropsychiatric dysfunction.

Design, setting, and participants: This case series includes 3 patients with recent SARS-CoV-2 infection as confirmed by reverse transcriptase-polymerase chain reaction or IgG serology with recent exposure history who were hospitalized at the University of California, San Francisco Benioff Children's Hospital and for whom a neurology consultation was requested over a 5-month period in 2020. During this period, 18 total children were hospitalized and tested positive for acute SARS-CoV-2 infection by reverse transcriptase-polymerase chain reaction or rapid antigen test.

Main outcomes and measures: Detection and characterization of CSF anti-SARS-CoV-2 IgG and antineural antibodies.

Results: Of 3 included teenaged patients, 2 patients had intrathecal anti-SARS-CoV-2 antibodies. CSF IgG from these 2 patients also indicated antineural autoantibodies on anatomic immunostaining. Autoantibodies targeting transcription factor 4 (TCF4) in 1 patient who appeared to have a robust response to immunotherapy were also validated.

Conclusions and relevance: Pediatric patients with COVID-19 and prominent subacute neuropsychiatric symptoms, ranging from severe anxiety to delusional psychosis, may have anti-SARS-CoV-2 and antineural antibodies in their CSF and may respond to immunotherapy.



Tuesday, November 9, 2021

Bainbridge-Ropers syndrome (ASXL3-related syndrome)

Inspired by a colleague's patient

Schirwani S, Albaba S, Carere DA, Guillen Sacoto MJ, Milan Zamora F, Si Y, Rabin R, Pappas J, Renaud DL, Hauser N, Reid E, Blanchet P, Foulds N, Dixit A, Fisher R, Armstrong R, Isidor B, Cogne B, Schrier Vergano S, Demirdas S, Dykzeul N, Cohen JS, Grand K, Morel D, Slavotinek A, Albassam HF, Naik S, Dean J, Ragge N, Cinzia C, Tedesco MG, Harrison RE, Bouman A, Palen E, Challman TD, Willemsen MH, Vogt J, Cunniff C, Bergstrom K, Walia JS, Bruel AL, Kini U, Alkuraya FS, Slegesky V, Meeks N, Girotto P, Johnson D; DDD Study, Newbury-Ecob R, Ockeloen CW, Prontera P, Lynch SA, Li D, Graham JM Jr, Balasubramanian M. Expanding the phenotype of ASXL3-related syndrome: A  description of 45 unpublished individuals with inherited and de novo pathogenic variants in ASXL3. Am J Med Genet A. 2021 Nov;185(11):3446-3458. doi: 10.1002/ajmg.a.62465. Epub 2021 Aug 26. PMID: 34436830.


The study aimed at widening the clinical and genetic spectrum of ASXL3-related syndrome, a neurodevelopmental disorder, caused by truncating variants in the ASXL3 gene. In this international collaborative study, we have undertaken a detailed clinical and molecular analysis of 45 previously unpublished individuals with ASXL3-related syndrome, as well as a review of all previously published individuals. We have reviewed the rather limited functional characterization of pathogenic variants in ASXL3 and discuss current understanding of the consequences of the different ASXL3 variants. In this comprehensive analysis of ASXL3-related syndrome, we define its natural history and clinical evolution occurring with age. We report familial ASXL3 pathogenic variants, characterize the phenotype in mildly affected individuals and discuss nonpenetrance. We also discuss the role of missense variants in ASXL3. We delineate a variable but consistent phenotype. The most characteristic features are neurodevelopmental delay with consistently limited speech, significant neuro-behavioral issues, hypotonia, and feeding difficulties. Distinctive features include downslanting palpebral fissures, hypertelorism, tubular nose with a prominent nasal bridge, and low-hanging columella. The presented data will inform clinical management of individuals with ASXL3-related syndrome and improve interpretation of new ASXL3 sequence variants.

Ikekwere JC, Osuagwu FC, LePlatte D, Ghaziuddin M. Comorbid Psychiatric Aspects of Bainbridge-Ropers Syndrome. Prim Care Companion CNS Disord. 2021 Jun 3;23(3):20m02783. doi: 10.4088/PCC.20m02783. PMID: 34086428.


Objective: Bainbridge-Ropers syndrome (BRPS) is a neurodevelopmental genetic disorder associated with mutations in the additional sex combs-like ASXL3 gene on chromosome 18q12.1. The objective of this study is to describe the comorbid psychiatric aspects of BRPS. 

Methods: A retrospective review was conducted of the electronic medical records of patients diagnosed with BRPS from 2013 to 2020 at an academic medical center. Results were deidentified and presented as frequencies and percentages. 

Results: Seven cases (5 White males and 2 White females) of BRPS were identified. The mean age at the time of referral was 12 years, while the mean age at diagnosis of BRPS was 7 years. Comorbid psychiatric symptoms and diagnoses associated with BRPS included global developmental delay: 6 (86%), sleep impairment: 5 (71%), autism spectrum disorder: 3 (43%), speech impairment: 2 (29%), disruptive behavior: 4 (57%), attention-deficit/hyperactivity disorder: 3 (43%), self-injurious behavior: 3 (43%), aggression: 4 (57%), and seizures: 3 (43%). All 7 patients (100%) had multiple DSM-5 diagnoses. 

Conclusions: These data highlight the need for awareness of the psychiatric comorbidity of BRPS. The findings also underscore the need for further research and emphasize the importance of multidisciplinary collaboration in the prompt assessment, diagnosis, and management of patients presenting with BRPS.

Cuddapah VA, Dubbs HA, Adang L, Kugler SL, McCormick EM, Zolkipli-Cunningham Z, Ortiz-González XR, McCormack S, Zackai E, Licht DJ, Falk MJ, Marsh ED. Understanding the phenotypic spectrum of ASXL-related disease: Ten cases and a review of the literature. Am J Med Genet A. 2021 Jun;185(6):1700-1711. doi: 10.1002/ajmg.a.62156. Epub 2021 Mar 10. PMID: 33751773.


Over the past decade, pathogenic variants in all members of the ASXL family of genes, ASXL1, ASXL2, and ASXL3, have been found to lead to clinically distinct but overlapping syndromes. Bohring-Opitz syndrome (BOPS) was first described as a clinical syndrome and later found to be associated with pathogenic variants in ASXL1. This syndrome is characterized by developmental delay, microcephaly, characteristic facies, hypotonia, and feeding difficulties. Subsequently, pathogenic variants in ASXL2 were found to lead to Shashi-Pena syndrome (SHAPNS) and in ASXL3 to lead to Bainbridge-Ropers syndrome (BRPS). While SHAPNS and BRPS share many core features with BOPS, there also seem to be emerging clear differences. Here, we present five cases of BOPS, one case of SHAPNS, and four cases of BRPS. By adding our cohort to the limited number of previously published patients, we review the overlapping features of ASXL-related diseases that bind them together, while focusing on the characteristics that make each neurodevelopmental syndrome unique. This will assist in diagnosis of these overlapping conditions and allow clinicians to more comprehensively counsel affected families.

Yu KP, Luk HM, Fung JLF, Chung BH, Lo IF. Further expanding the clinical phenotype in Bainbridge-Ropers syndrome and dissecting genotype-phenotype correlation in the ASXL3 mutational cluster regions. Eur J Med Genet. 2021 Jan;64(1):104107. doi: 10.1016/j.ejmg.2020.104107. Epub 2020 Nov 23. PMID: 33242595.


Bainbridge-Ropers syndrome (BRPS) [OMIM#615485] is a neurodevelopmental disorder, characterized by delayed psychomotor development with generalized hypotonia, intellectual disability with poor or absent speech, feeding difficulties, growth failure, specific craniofacial and minor skeletal features. It was firstly reported in 2013 by Bainbridge et al., who observed a group of individuals sharing overlapping features with Bohring-Opitz syndrome which were caused by pathogenic variant in ASXL1, who indeed carried truncating mutations in ASXL3. To date, 33 cases were described in the literature. BRPS is caused by loss-of-function mutations in ASXL3 which are mostly located in two mutational cluster regions (MCR). The exact molecular mechanism of these mutations resulting in the disease phenotype is still uncertain due to the observation of LOF mutations in healthy population. Here, we report four individuals with BRPS carrying de novo LOF mutations in ASXL3, comparing and summarizing the clinical phenotype of all BRPS reported so far. Furthermore, we try to dissect the genotype-phenotype correlation among the two well reported MCRs in all BRPS from the literature.