The risk of infections for multiple sclerosis and neuromyelitis optica spectrum disorder disease-modifying treatments: Eighth European Committee for Treatment and Research in Multiple Sclerosis Focused Workshop Review. April 2021.

Over the recent years, the treatment of multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) has evolved very rapidly and a large number of disease-modifying treatments (DMTs) are now available. However, most DMTs are associated with adverse events, the most frequent of which being infections. Consideration of all DMT-associated risks facilitates development of risk mitigation strategies. An international focused workshop with expert-led discussions was sponsored by the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and was held in April 2021 to review our current knowledge about the risk of infections associated with the use of DMTs for people with MS and NMOSD and corresponding risk mitigation strategies. The workshop addressed DMT-associated infections in specific populations, such as children and pregnant women with MS, or people with MS who have other comorbidities or live in regions with an exceptionally high infection burden. Finally, we reviewed the topic of DMT-associated infectious risks in the context of the current SARS-CoV-2 pandemic. Herein, we summarize available evidence and identify gaps in knowledge which justify further research.

6-month multidisciplinary follow-up and outcomes of patients with paediatric inflammatory multisystem syndrome (PIMS-TS) at a UK tertiary paediatric hospital: a retrospective cohort study.

BACKGROUND: Paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) is a new, rare, post-infectious complication of SARS-CoV-2 infection in children. We aimed to describe the 6-month outcomes of PIMS-TS. METHODS: This retrospective cohort study comprised children (aged <18 years) who fulfilled the UK Royal College of Paediatrics and Child Health (RCPCH) diagnostic criteria for PIMS-TS and were admitted to Great Ormond Street Hospital (London, UK) between April 4 and Sept 1, 2020. Patients were followed up by a multidisciplinary team of specialists at 6 weeks and 6 months after admission. Biochemical and functional outcomes were analysed. FINDINGS: 46 children were included in this study. The median age at presentation was 10·2 years (IQR 8·8-13·3), 30 (65%) patients were male and 16 (35%) were female, 37 (80%) were from minority ethnic groups, and eight (17%) had pre-existing comorbidities. All patients had elevated markers of systemic inflammation at baseline. None of the patients died. By 6 months, systemic inflammation was resolved in all but one patient. 38 (90%) of 42 patients who had positive SARS-CoV-2 IgG antibodies within 6 weeks of admission remained seropositive at 6 months. Echocardiograms were normal in 44 (96%) of 46 patients by 6 months, and gastrointestinal symptoms that were reported in 45 (98%) of 46 patients at onset were present in six (13%) of 46 patients at 6 months. Renal, haematological, and otolaryngological findings largely resolved by 6 months. Although minor abnormalities were identified on neurological examination in 24 (52%) of 46 patients at 6 weeks and in 18 (39%) of 46 at 6 months, we found minimal functional impairment at 6 months (median Expanded Disability Status Scale score 0 [IQR 0-1]). Median manual muscle test-8 scores improved from 53 (IQR 43-64) during hospital admission to 80 (IQR 68-80) at 6 months, but 18 (45%) of 40 patients showed 6-min walk test results below the third centile for their age or sex at 6 months. PedsQL responses revealed severe emotional difficulties at 6 months (seven [18%] of 38 by parental report and eight [22%] of 38 by self report). 45 (98%) of 46 patients were back in full-time education (virtually or face to face) by 6 months. INTERPRETATION: Despite initial severe illness, few organ-specific sequelae were observed at 6 months. Ongoing concerns requiring physical re-conditioning and mental health support remained, and physiotherapy assessments revealed persisting poor exercise tolerance. Longer-term follow-up will help define the extended natural history of PIMS-TS. FUNDING: None.

Neurological manifestations of SARS-CoV-2 infection in hospitalised children and adolescents in the UK: a prospective national cohort study.

BACKGROUND: The spectrum of neurological and psychiatric complications associated with paediatric SARS-CoV-2 infection is poorly understood. We aimed to analyse the range and prevalence of these complications in hospitalised children and adolescents. METHODS: We did a prospective national cohort study in the UK using an online network of secure rapid-response notification portals established by the CoroNerve study group. Paediatric neurologists were invited to notify any children and adolescents (age <18 years) admitted to hospital with neurological or psychiatric disorders in whom they considered SARS-CoV-2 infection to be relevant to the presentation. Patients were excluded if they did not have a neurological consultation or neurological investigations or both, or did not meet the definition for confirmed SARS-CoV-2 infection (a positive PCR of respiratory or spinal fluid samples, serology for anti-SARS-CoV-2 IgG, or both), or the Royal College of Paediatrics and Child Health criteria for paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS). Individuals were classified as having either a primary neurological disorder associated with COVID-19 (COVID-19 neurology group) or PIMS-TS with neurological features (PIMS-TS neurology group). The denominator of all hospitalised children and adolescents with COVID-19 was collated from National Health Service England data. FINDINGS: Between April 2, 2020, and Feb 1, 2021, 52 cases were identified; in England, there were 51 cases among 1334 children and adolescents hospitalised with COVID-19, giving an estimated prevalence of 3·8 (95% CI 2·9-5·0) cases per 100 paediatric patients. 22 (42%) patients were female and 30 (58%) were male; the median age was 9 years (range 1-17). 36 (69%) patients were Black or Asian, 16 (31%) were White. 27 (52%) of 52 patients were classified into the COVID-19 neurology group and 25 (48%) were classified into the PIMS-TS neurology group. In the COVID-19 neurology group, diagnoses included status epilepticus (n=7), encephalitis (n=5), Guillain-Barré syndrome (n=5), acute demyelinating syndrome (n=3), chorea (n=2), psychosis (n=2), isolated encephalopathy (n=2), and transient ischaemic attack (n=1). The PIMS-TS neurology group more often had multiple features, which included encephalopathy (n=22 [88%]), peripheral nervous system involvement (n=10 [40%]), behavioural change (n=9 [36%]), and hallucinations at presentation (n=6 [24%]). Recognised neuroimmune disorders were more common in the COVID-19 neurology group than in the PIMS-TS neurology group (13 [48%] of 27 patients vs 1 [<1%] of 25 patients, p=0·0003). Compared with the COVID-19 neurology group, more patients in the PIMS-TS neurology group were admitted to intensive care (20 [80%] of 25 patients vs six [22%] of 27 patients, p=0·0001) and received immunomodulatory treatment (22 [88%] patients vs 12 [44%] patients, p=0·045). 17 (33%) patients (10 [37%] in the COVID-19 neurology group and 7 [28%] in the PIMS-TS neurology group) were discharged with disability; one (2%) died (who had stroke, in the PIMS-TS neurology group). INTERPRETATION: This study identified key differences between those with a primary neurological disorder versus those with PIMS-TS. Compared with patients with a primary neurological disorder, more patients with PIMS-TS needed intensive care, but outcomes were similar overall. Further studies should investigate underlying mechanisms for neurological involvement in COVID-19 and the longer-term outcomes. FUNDING: UK Research and Innovation, Medical Research Council, Wellcome Trust, National Institute for Health Research.

Neurologic and Radiographic Findings Associated With COVID-19 Infection in Children.

Importance: Neurological manifestations have been reported in adults with coronavirus disease 2019 (COVID-19), which is caused by the highly pathogenic virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Objective: To report the neurological manifestations of children with COVID-19. Design, Setting, and Participants: In this case-series study, patients younger than 18 years who presented with SARS-CoV-2 infection and neurological symptoms to Great Ormond Street Hospital for Children (London, UK) between March 1, 2020, and May 8, 2020, were included after infection was confirmed by either a quantitative reverse transcription-polymerase chain reaction assay by nasopharyngeal swab or a positive test result for IgG antibodies against SARS-CoV-2 in serum. Main Outcomes and Measures: Clinical and paraclinical features were retrieved from electronic patient records. Results: Of the 27 children with COVID-19 pediatric multisystem inflammatory syndrome, 4 patients (14.8%) who were previously healthy had new-onset neurological symptoms. Symptoms included encephalopathy, headaches, brainstem and cerebellar signs, muscle weakness, and reduced reflexes. All 4 patients required intensive care unit admission for the treatment of COVID-19 pediatric multisystem inflammatory syndrome. Splenium signal changes were seen in all 4 patients on magnetic resonance imaging of the brain. In the 2 patients whose cerebrospinal fluid was tested, samples were acellular, with no evidence of infection on polymerase chain reaction or culture (including negative SARS-CoV-2 polymerase chain reaction results) and negative oligoclonal band test results. In all 3 patients who underwent electroencephalography, a mild excess of slow activity was found. Tests for N-methyl-d-aspartate receptor, myelin oligodendrocyte glycoprotein, and aquaporin-4 autoantibodies had negative results in all patients. In all 3 patients who underwent nerve conduction studies and electromyography, mild myopathic and neuropathic changes were seen. Neurological improvement was seen in all patients, with 2 making a complete recovery by the end of the study. Conclusions and Relevance: In this case-series study, children with COVID-19 presented with new neurological symptoms involving both the central and peripheral nervous systems and splenial changes on imaging, in the absence of respiratory symptoms. Additional research is needed to assess the association of neurological symptoms with immune-mediated changes among children with COVID-19.