Clinical characteristics of patients with myelin oligodendrocyte glycoprotein antibodies.

PURPOSE OF REVIEW: The clinical landscape associated to myelin oligodendrocyte glycoprotein antibodies (MOG-Ab) has undergone a remarkable transformation over the past two decades, primarily driven by advancements in antibody detection techniques that have enhanced both the specificity and sensitivity of assays, enabling the identification of novel clinical phenotypes. RECENT FINDINGS: Recent pivotal research publications, comprehensive reviews from established research groups, and most notably the first proposed international criteria for MOG-Ab associated disease (MOGAD) have substantially enriched our understanding of the clinical features associated with MOG-Ab. This review presents a comprehensive overview of the clinical characteristics of patients with MOG-Ab, systematically examining each core clinical syndrome defined by the proposed international MOGAD criteria. We incorporated recent insights and discussed potential challenges in applying these criteria across diverse clinical scenarios. SUMMARY: The proposed international MOGAD criteria provide a comprehensive, homogeneous, and specific framework for characterizing the clinical features of patients with MOG-Ab, encompassing both paediatric and adult populations. In the future, the widespread adoption of specific and reliable assays for MOG-Ab detection, complemented by the development of surrogate fluid and imaging markers, holds promise for better characterizing atypical presentations, only-cerebrospinal fluid positivity and the MOGAD "seronegative" situations.

Teriflunomide in pediatric patients with relapsing multiple sclerosis: Open-label extension of TERIKIDS.

BACKGROUND: The double-blind TERIKIDS study demonstrated the efficacy and safety of teriflunomide. OBJECTIVE: To evaluate the efficacy, safety, and tolerability of continuous teriflunomide treatment in the TERIKIDS open-label extension. METHODS: In the double-blind period, children with relapsing MS were randomized to placebo or teriflunomide (14 mg adult-equivalent dose) for ⩽ 96 weeks. Participants received teriflunomide for ⩽ 192 weeks post-randomization in the open-label extension. RESULTS: The mean age at screening was 14.6 years. For teriflunomide/teriflunomide versus placebo/teriflunomide, estimated clinical relapse risk was reduced by 38% (hazard ratio (HR) 0.62; 95% confidence interval (CI) 0.39-0.98; p = 0.11) and numbers of gadolinium-enhancing T1 and new/enlarging T2 lesions were reduced by 43% (relative risk (RR) 0.570; 95% CI 0.33-0.98; p = 0.043) and 49% (RR 0.511; 95% CI 0.34-0.76; p = 0.001), respectively, in the combined double-blind and open-label periods. There was a trend toward reduced risk of 24-week sustained disability progression for teriflunomide/teriflunomide versus placebo/teriflunomide (HR 0.47; 95% CI 0.23-0.96). During the open-label extension, incidences of safety-related discontinuations were 4.0% (teriflunomide/teriflunomide) and 13.5% (placebo/teriflunomide), including two children who developed pancreatitis in the teriflunomide/teriflunomide group. CONCLUSION: Teriflunomide reduced the long-term risk of focal inflammatory activity, with generally manageable tolerability and no new safety signals. Further evidence would strengthen clinical efficacy findings.ClinicalTrials.gov: NCT02201108.

The Response Study: A French registry on pregnancy in women with MS and related disorders and their children up to 6 years-Protocol, recruitment status, and baseline characteristics.

BACKGROUND: Counseling on pregnancy is still challenging, particularly regarding the use of disease-modifying treatments (DMTs). We are lacking long-term outcomes in children exposed to DMTs. OBJECTIVES: This study aimed to set up a French pregnancy registry for women with multiple sclerosis (MS) and related disorders nested within the Observatoire Français de la Sclérose en Plaques (OFSEP) cohort. METHODS: Prospective, observational, multicentric, epidemiological study in France. Neurological visits are organized according to routine practice. Data are collected on the OFSEP minimal datasheet. Auto-questionnaires on pregnancy are completed by patients at Months 5-6 and 8 during pregnancy, and Months 3, 6, and 12 postpartum. A specific survey on analgesia is completed by anesthesiologists. Pediatric data are collected from the child's health book, where visits on Day 8, Month 9, and 24 are mandatory. Parents complete neurodevelopmental questionnaires at Year 1, Years 2 and 6. RESULTS: The RESPONSE study started in August 2019. On 7 April 2023, 515 women were included. Baseline demographics are presented. CONCLUSIONS: RESPONSE will provide rich information on the global management of pregnancy in France and prospective data on children until the age of 6 years, exposed or not to a DMT, including data on neurodevelopment that can be compared to the general population. STUDY FUNDING: EDMUS and ARSEP Foundation, Biogen, Roche.

Control of disease activity with large extended-interval dosing of rituximab/ocrelizumab in highly active pediatric multiple sclerosis.

Recent studies in adults suggested that extended-interval dosing of rituximab/ocrelizumab (RTX/OCR) larger than 12 months was safe and could improve safety. This was an observational cohort study of very active pediatric-onset multiple sclerosis (PoMS) (median (range) age, 16 (12-17) years) treated with RTX/OCR with 6 month standard-interval dosing (n = 9) or early extended-interval dosing (n = 12, median (range) interval 18 months (12-25)). Within a median (range) follow-up of 31 (12-63) months after RTX/OCR onset, one patient (standard-interval) experienced relapse and no patient showed disability worsening or new T2-weighted lesions. This study suggests that the effectiveness of RTX/OCR is maintained with a median extended-interval dosing of 18 months in patients with very active PoMS.

Early and Aggressive Treatment May Modify Anti-Hu Associated Encephalitis Prognosis.

Anti-Hu encephalitis is a paraneoplastic syndrome in adults. In children, rare cases of anti-Hu encephalitis were reported mostly without underlying tumors and clinical outcome are usually severe. Here, we describe a 4-year-old girl who developed cerebellar syndrome with abnormal behavior. The brain magnetic resonance imaging showed several T2/fluid-attenuated inversion recovery bilateral brain lesions and autoimmune assessment showed positive anti-Hu antibodies. Computed tomography scan revealed ganglioneuroblastoma which was surgically removed 3 months after onset. Aggressive immunotherapy including dexamethasone, rituximab, and intravenous immunoglobulins were used and a marked neurological improvement soon after 9 months of onset was observed with the child being able to go back to school. The short delay between diagnosis and start of aggressive immunotherapy demonstrate the paramount importance of early diagnosis and early specific therapy after onset of symptoms.

Long-term outcome of paediatric anti-N-methyl-D-aspartate receptor encephalitis.

AIM: To study long-term clinical and cognitive outcomes of patients with anti-N-methyl-d-aspartate receptor encephalitis (NMDAR-E), an acute autoimmune neurological disease with severe acute presentations. METHOD: In this French multicentre retrospective observational cohort study, patients no older than 18 years with a follow-up of at least 2 years were included. Data from clinical and cognitive assessments were collected. RESULTS: Eighty-one patients were included (57 females, 24 males; median age 10 years 7 months [range 1-18 years], median follow-up 40 months [range 25-53 months]). At last follow-up, 35 patients (45%) had cognitive impairment, 48 (70%) had academic difficulties, and 65 (92%) needed rehabilitation. Seventy-one patients (88%) had a modified Rankin Scale score of no more than 2. A higher number of symptoms at diagnosis was associated with cognitive impairment (p = 0.01), while an abnormal electroencephalogram at diagnosis increased the risk of academic difficulties (p = 0.03). INTERPRETATION: Although most children with NMDAR-E seemed to recover from motor disabilities, more than 45% had cognitive and academic difficulties. The initial severity of symptoms seems to have an impact on cognition and academic performances. WHAT THIS PAPER ADDS: Forty-five per cent of patients had cognitive impairment at ≥2 years diagnosis of anti-N-methyl-d-aspartate receptor encephalitis (NMDAR-E). Seventy per cent of patients had academic difficulties at ≥2 years diagnosis of NMDAR-E. Ninety-two per cent of patients needed rehabilitative care at ≥2 years diagnosis of NMDAR-E. A high number of symptoms at diagnosis were associated with cognitive impairment.

Clinical Features and Risk of Relapse in Children and Adults with Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease.

OBJECTIVE: The main objective was to compare clinical features, disease course, and myelin oligodendrocyte glycoprotein (MOG) antibody (Ab) dynamics between children and adults with MOG-Ab-associated disease (MOGAD). METHODS: This retrospective multicentric, national study included 98 children and 268 adults with MOGAD between January 2014 and September 2019. Cox regression model for recurrent time-to-event data and Kaplan-Meier curves for time to antibody negativity were performed for the objectives. RESULTS: Isolated optic neuritis was the most frequent clinical presentation in both children (40.8%) and adults (55.9%, p = 0.013), and acute disseminated encephalomyelitis syndrome was more frequent in children (36.7% vs 5.6%, p < 0.001). Compared to adults, children displayed better recovery (Expanded Disability Status Scale ≥ 3.0 at last follow-up reached only by 10 of 97 [10.3%] vs 66/247 [26.7%], p < 0.001). In the multivariate analysis, adults were at higher risk of relapse than children (hazard ratio = 1.41, 95% confidence interval [CI] = 1.12-1.78, p = 0.003). At 2 years, 64.2% (95% CI = 40.9-86.5) of nonrelapsing children became MOG-Ab negative compared to 14.1% (95% CI = 4.7-38.3) of relapsing children (log-rank p < 0.001), with no differences observed in adults (log-rank p = 0.280). INTERPRETATION: MOGAD patients differ in the clinical presentation at onset, showing an age-related shift in the clinical features across age groups. Compared to children, adults have a higher risk of relapse and worse functional recovery. Finally, children with monophasic disease become MOG-Ab negative earlier than relapsing children, but this is not true in adults. Considering these differences, management and treatment guidelines should be considered independently in children and adults. ANN NEUROL 2021;89:30-41.

Efficacy and safety of ofatumumab in recently diagnosed, treatment-naive patients with multiple sclerosis: Results from ASCLEPIOS I and II.

BACKGROUND: In the phase III ASCLEPIOS I and II trials, participants with relapsing multiple sclerosis receiving ofatumumab had significantly better clinical and magnetic resonance imaging (MRI) outcomes than those receiving teriflunomide. OBJECTIVES: To assess the efficacy and safety of ofatumumab versus teriflunomide in recently diagnosed, treatment-naive (RDTN) participants from ASCLEPIOS. METHODS: Participants were randomized to receive ofatumumab (20 mg subcutaneously every 4 weeks) or teriflunomide (14 mg orally once daily) for up to 30 months. Endpoints analysed post hoc in the protocol-defined RDTN population included annualized relapse rate (ARR), confirmed disability worsening (CDW), progression independent of relapse activity (PIRA) and adverse events. RESULTS: Data were analysed from 615 RDTN participants (ofatumumab: n = 314; teriflunomide: n = 301). Compared with teriflunomide, ofatumumab reduced ARR by 50% (rate ratio (95% confidence interval (CI)): 0.50 (0.33, 0.74); p < 0.001), and delayed 6-month CDW by 46% (hazard ratio (HR; 95% CI): 0.54 (0.30, 0.98); p = 0.044) and 6-month PIRA by 56% (HR: 0.44 (0.20, 1.00); p = 0.049). Safety findings were manageable and consistent with those of the overall ASCLEPIOS population. CONCLUSION: The favourable benefit-risk profile of ofatumumab versus teriflunomide supports its consideration as a first-line therapy in RDTN patients.ASCLEPIOS I and II are registered at ClinicalTrials.gov (NCT02792218 and NCT02792231).

Recombinant myelin oligodendrocyte glycoprotein quality modifies evolution of experimental autoimmune encephalitis in macaques.

Experimental autoimmune encephalitis (EAE) is a well-recognized model for the study of human acquired demyelinating diseases (ADD), a group of inflammatory disorders of the central nervous system (CNS) characterized by inflammation, myelin loss, and neurological impairment of variable severity. In rodents, EAE is typically induced by active immunization with a combination of myelin-derived antigen and a strong adjuvant as complete Freund's adjuvant (CFA), containing components of the mycobacterial wall, while myelin antigen alone or associated with other bacterial components, as lipopolysaccharides (LPS), often fails to induce EAE. In contrast to this, EAE can be efficiently induced in non-human primates by immunization with the recombinant human myelin oligodendrocyte glycoprotein (rhMOG), produced in Escherichia coli (E. coli), purified and formulated with incomplete Freund's adjuvant (IFA), which lacks bacterial elements. Here, we provide evidence indicating how trace amounts of bacterial contaminants within rhMOG may influence the course and severity of EAE in the cynomolgus macaque immunized with rhMOG/IFA. The residual amount of E. coli contaminants, as detected with mass spectrometry within rhMOG protein stocks, were found to significantly modulate the severity of clinical, radiological, and histologic hallmarks of EAE in macaques. Indeed, animals receiving the purest rhMOG showed milder disease severity, increased numbers of remissions, and reduced brain damage. Histologically, these animals presented a wider diversity of lesion types, including changes in normal-appearing white matter and prephagocytic lesions. Non-human primates EAE model with milder histologic lesions reflect more accurately ADD and permits to study of the pathogenesis of disease initiation and progression.

Temporal profile of lymphocyte counts and relationship with infections with fingolimod therapy in paediatric patients with multiple sclerosis: Results from the PARADIGMS study.

BACKGROUND: Reduction in absolute lymphocyte count (ALC) is expected with fingolimod treatment. OBJECTIVE: To evaluate the effect of fingolimod 0.5 mg versus intramuscular interferon ß-1a (30 µg) on ALC and its relationship with infections in paediatric-onset multiple sclerosis (POMS) up to 4 years. METHODS: We assessed ALC at baseline, monthly till 3 months, and every 3 months (core phase) and with variable periodicity (extension phase) of Phase 3 PARADIGMS study (N = 215). Incidence rates (IRs) of infection-related adverse events (infAEs)/100 patient-years were analysed by on-study nadir ALC. RESULTS: With fingolimod, ALC rapidly reduced to 29.9%-34.4% of baseline values within 2 weeks and remained stable thereafter; no relevant changes observed with interferon. IRs of infAEs were 67.6 with fingolimod and 61.8 with interferon; IR ratios with respect to interferon, overall: 1.09, by nadir ALC 0.2-0.4 × 109/L: 1.13 and >0.4 × 109/L: 0.91. Three patients had a single episode of ALC <0.2 × 109/L (core phase). No opportunistic infections were observed and infection risk did not increase during the extension phase. CONCLUSION: In paediatric patients, the overall incidence of infections was comparable between fingolimod and interferon. No association was observed between nadir ALC and infections in POMS, although sample size may have been too small to rule an association.

Charcot-Marie-Tooth disease misdiagnosed as chronic inflammatory demyelinating polyradiculoneuropathy: An international multicentric retrospective study.

BACKGROUND AND PURPOSE: Charcot-Marie-Tooth (CMT) disease, an untreatable hereditary polyneuropathy, may mimic chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), a treatable neuropathy. METHODS: In this retrospective study, we analyzed the characteristics of CMT patients misdiagnosed as CIDP at 16 university hospitals in three countries, compared these patients with a reference group of CIDP patients, and estimated the cost of misdiagnosis. RESULTS: Among 1104 CIDP cases, we identified 35 CMT patients misdiagnosed as CIDP (3.2%). All were initially diagnosed with definite or probable CIDP (European Federation of Neurological Societies/Peripheral Nerve Society criteria), and mutations in PMP22, MPZ, and 10 other CMT genes were found in 34%, 31%, and 35% of cases, respectively. In comparison with a reference group of 35 CIDP patients, CMT patients were younger (median age at disease onset = 39 vs. 56 years) and more frequently had motor weakness at disease onset (80% vs. 29%), hearing loss (14% vs. 0%), normal brachial plexus imaging (70% vs. 40%), lower cerebrospinal fluid protein content (median = 0.5 vs. 0.8 g/L), and lower treatment response (20% vs. 69%). Treatment cost in these 35 misdiagnosed patients was estimated at 4.6 million euros (M€), whereas the cost of CMT genetic analysis in 1104 patients was estimated at 2.7 M€. CONCLUSIONS: In this study, 35 of 1104 (3.2%) patients initially diagnosed with CIDP had CMT. Importantly, the cost of treating these 35 misdiagnosed patients was significantly higher than the cost of performing CMT genetic analysis in 1104 patients (4.6 M€ vs. 2.7 M€), suggesting that CMT genetic investigations should be more widely used before diagnosing CIDP.

Progressive Leukodystrophy-Like Demyelinating Syndromes with MOG-Antibodies in Children: A Rare Under-Recognized Phenotype.

Acquired demyelinating syndromes (ADS) are frequently associated with myelin oligodendrocytes glycoprotein (MOG) antibodies in children. Clinical phenotypes are heterogeneous and may delay the diagnosis, especially when they relapse and are atypical, mimicking diseases such as multiple sclerosis or neuromyelitis optica spectrum disorders . Here, we describe two children: one with a progressive cognitive and behavioral deterioration with seizures after only one relapse and the other with similar clinical impairments associated with multiple relapses. Brain magnetic resonance imaging revealed a subsequent progressive leukodystrophy-like lesion with diffuse bilateral white matter injuries in both patients. Cerebrospinal fluid analysis showed pleiocytosis, increased level of proteins with no oligoclonal bands. Metabolic and inflammatory blood markers were all negative. Brain biopsy was performed in the second child and nonspecific inflammatory lesions with no argument for histiocytosis or tumor were observed. Clinical and radiological stabilization were obtained after active immunotherapy. Retrospective analysis of anti-MOG antibodies in these two children was positive at the earlier stage of the disease and turned negative after treatment and during follow-up. Leukodystrophy-like ADS with anti-MOG-antibodies may display distinct progressive phenotype and have a severe neurological prognosis. Early diagnosis and appropriate treatment may improve outcome in these children.

Consistent control of disease activity with fingolimod versus IFN ß-1a in paediatric-onset multiple sclerosis: further insights from PARADIGMS.

BACKGROUND: In PARADIGMS, a double-blind phase III trial in 215 paediatric patients with multiple sclerosis (MS) (10 to <18 years), fingolimod administered for up to 2 years significantly reduced the annualised relapse rate (ARR) and rate of new/newly enlarged T2 (n/neT2) lesions compared with interferon (IFN) ß-1a. OBJECTIVES: To investigate (1) differences between treatment groups across subpopulations (treatment-naïve, younger/prepubertal patients); (2) disability progression. METHODS: ARRs at 10, 11 and 12 years were estimated based on predefined modelling extrapolations. Changes in Expanded Disability Status Scale (EDSS), and in 3 month (3M) and 6 month (6M) confirmed disability progression (CDP) were evaluated post hoc. RESULTS: In the treatment-naïve subpopulation, fingolimod reduced ARR and n/neT2 lesions by 85.8% and 53.4%, respectively versus INF ß-1a (both p<0.001), compared with 81.9% and 52.6% in the overall population. Model-based ARR reductions in younger patients (≤12 years) were 91.9%-94.6%. Twice as many IFN ß-1a-treated than fingolimod-treated patients had worse EDSS scores at study end (20.6% vs 10.5%, p=0.043). Risk reductions in 3M-CDP and 6M-CDP were 77.2% (p=0.007) and 80.2% (p=0.040), respectively. CONCLUSIONS: Fingolimod in paediatric MS was associated with consistent control of disease activity versus IFN ß-1a (including treatment-naïve and younger patients) and resulted in less disability progression for up to 2 years. TRIAL REGISTRATION NUMBER: NCT01892722.

Fatigue, depression, and quality of life in children with multiple sclerosis: a comparative study with other demyelinating diseases.

AIM: To evaluate fatigue, depression, and quality of life (QoL) of children with multiple sclerosis and compare to other acute demyelinating syndromes (ADS). METHOD: Children followed in the National Referral Centre of rare inflammatory brain and spinal diseases were included in this study. The Expanded Disability Status Scale, the fatigue severity scale, the Multiscore Depression Inventory for Children, and the Pediatric Quality of Life Inventory were used for evaluation. RESULTS: Thirty-seven children (23 females, 14 males) were included in this study. Multiple sclerosis was diagnosed in 26 children and ADS in 11 children. Although not significant, severe fatigue was less frequently reported by patients with multiple sclerosis than children with ADS (44% vs 63%, p=0.2). Depression was reported more often in the multiple sclerosis group compared to the ADS group (24% vs 18%, p=0.6). Concerning the QoL in patients with multiple sclerosis, both parents and children reported poor emotional and school functioning. Physical and social functioning were rated as being good in both groups, and was significantly higher in the children's group (p=0.007). INTERPRETATION: This study highlights the importance of fatigue and depression in children with ADS and particularly in paediatric onset multiple sclerosis. Moreover, difficulties in school and emotional functioning were the main concerns for parents and children in the multiple sclerosis group which need to be taken in account during their care and treatment proposal. WHAT THIS PAPER ADDS: Invisible signs such as fatigue and depression affect all forms of acute demyelinating syndromes (ADS) in children. Depression seems to be higher in children with multiple sclerosis than with other forms of ADS. Fatigue seems to be lower in children with multiple sclerosis than with other forms of ADS. Children with multiple sclerosis and their parents are most concerned with emotional and academic functioning.

FATIGA, DEPRESIÓN Y CALIDAD DE VIDA EN NIÑOS CON ESCLEROSIS MÚLTIPLE: UN ESTUDIO COMPARATIVO CON OTRAS ENFERMEDADES DESMIELINIZANTES: OBJETIVO: evaluar fatiga, depresión y calidad de vida (CDV) de niños con esclerosis múltiple y comparar con otros síndromes desmielinizantes agudos (SDA). METODO: Se incluyeron en el estudio los niños seguidos en el centro de referencia de enfermedades espinales y cerebrales inflamatorias raras. Se usaron para la evaluación la Escala de Estado de Discapacidad Expandida, la escala de severidad de fatiga, el inventario de puntaje múltiple de depresión para niños, y el inventario de calidad de vida pediátrico. RESULTADOS: Se incluyeron en este estudio 37 niños (23 niñas, 14 niños). Se diagnosticó esclerosis múltiple en 26 niños y SDA en 11 niños. Aunque no fue significativo, la fatiga se reportó en menor frecuencia en pacientes con esclerosis múltiple que en niños con SDA (44% vs 63%, p=0,2). Se reporto con más frecuencia depresión en el grupo de esclerosis múltiple en comparación con el grupo de SDA (24% vs 18%, p=0,6). En lo que concierne a la calidad de vida en pacientes con esclerosis múltiple, tanto los padres como los niños reportaron funciones emocionales y escolares disminuidas. Las funciones físicas y sociales fueron puntuadas como buenas en ambos grupos, y fue significativamente más alta en el grupo de los niños. (p=0,007). INTERPRETACION: este estudio resalta la importancia de la fatiga y la depresión en niños con SDA y particularmente con el inicio infantil de esclerosis múltiple. Además, las dificultades en la escuela y el funcionamiento emocional fueron las principales preocupaciones de los padres y los niños en el grupo de esclerosis múltiple que deben tenerse en cuenta durante el planeamiento de atención de la salud y tratamiento.

FADIGA, DEPRESSÃO E QUALIDADE DE VIDA EM CRIANÇAS COM ESCLEROSE MÚLTIPLA: UM ESTUDO COMPARATIVO COM OUTRAS DOENÇAS DESMIELINIZANTES: OBJETIVO: Avaliar fadiga, depressão e qualidade de vida (QV) de crianças com esclerose múltipla, e comparar com outras síndromes desmielinizantes agudas (SDA). MÉTODO: Crianças acompanhadas em um centro de referência nacional de doenças inflamatórias cerebrais e espinhais raras foram incluídas no estudo. A Escala Expandidade de Estado da Deficiência, a escala de severidade da fadiga, o Inventário multiescore de depressão para crianças, e o Inventário Pediátrico de Qualidade de Vida foram usados na avaliação. RESULTADOS: Trinta e sete crianças (23 do sexo feminino, 14 do sexo masculino) foram incluídas neste estudo. A esclerose múltipla foi diagnosticada em 26 crianças e SDA em 11 crianças. Embora não significativa, a fadiga severa foi menos frequentemente reportada por pacientes com esclerose múltipla do que em crianças com SDA (44% vs 63%, p=0,2). A depressão foi reportada mais frequentemente no grupo com esclerose múltipla comparado ao grupo com SDA. (24% vs 18%, p=0,6). Com relação à QV em pacientes com esclerose múltipla, pais e crianças reportaram pobre funcionamento emocional e escolar. O funcionamento físico e social foram pontuados como bons em ambos os grupos, sendo significativamente maior no grupo de crianças (p=0,007). INTERPRETAÇÃO: Este estudo destaca a importância da fadiga e depressão em crianças com SDA e particularmente nos casos de esclerose múltipla de início pediátrico. Além disso, dificuldades no funcionamento escolar e emocional foram as principais preocupações dos pais e crianças no grupo com esclerose múltipla, o que deve ser levado em conta durante a proposta de cuidado e tratamento.

Long-term outcome of vein of Galen malformation.

AIM: To describe the long-term outcomes of children by the time they reached school age with vein of Galen aneurysmal malformation (VGAM). METHOD: This was a retrospective observational study on a consecutive cohort of patients with VGAM. We included patients with at least one Francophone parent, aged between 6 and 11 years at the time of long-term evaluation. The neurological outcome was assessed with the King's Outcome Scale for Childhood Injury score and eight neurological and behavioural items from the Rivermead Postconcussion Symptoms questionnaire. RESULTS: All 52 patients (17 females, 32 males [data missing for n=3]) with at least one Francophone parent (5 fetuses and 47 children) were included. At the long-term evaluation time-point, 33 patients were alive and 19 patients had died. Risk of postnatal death was associated with severe neonatal cardiac failure (p=0.007) or isosystemic or suprasystemic pulmonary hypertension (p=0.014). Among survivors, 19 had a good outcome with normal schooling and 14 had a poor outcome. Moreover, among the good outcome patients, a large proportion had neurodevelopmental alterations. INTERPRETATION: Long-term outcome of patients with VGAM appears to be less favourable than outcome described at the short- and medium-term, even in the absence of encephalomalacia at birth. Even patients with good outcome often have neuropsychological disorders that may have repercussions on learning and requiring appropriate rehabilitation or medical management. WHAT THIS PAPER ADDS: Long-term outcome appears to be less favourable than described at short- and medium-term follow-up. Even patients with good outcome at these time-points often have minor neuropsychological disorders.

Risk factors for academic difficulties in children with myelin oligodendrocyte glycoprotein antibody-associated acute demyelinating syndromes.

AIM: To describe cognitive abilities through the evaluation of academic difficulties in children with acute demyelinating syndromes (ADS) and myelin oligodendrocyte glycoprotein (MOG) antibodies. METHOD: This was an observational, retrospective study of a French paediatric cohort that included children aged 18 years and younger. Clinical, biological, and imaging data were collected and academic outcome was measured. RESULTS: Seventy-six children were included in the study with a mean (SD) follow-up of 4 years 7 months (6y 4mo). Median age at disease onset was 9 years 1 months (interquartile range=4y 7mo-13y 11mo; 36 females, 40 males). Thirty-six children relapsed and 20 had academic difficulties at the last follow-up. Academic difficulties, as well as deep grey matter and putaminal lesions (p=0.047 and p=0.006 respectively), were significantly more prevalent in children aged 10 years and younger (p=0.02). Using univariate binary regression analysis, we found that age at disease onset of 10 years and younger (odds ratio [OR] 3.72 [95% confidence interval {CI} 1.19-11.64]; p=0.024), acute disseminated encephalomyelitis at disease onset (OR 52.5 [95% CI 5.97-461.4]; p<0.001), and deep grey matter lesions (OR 17.33 [95% CI 3.87-77.72]; p<0.001) were associated with academic difficulties. INTERPRETATION: MOG antibody-associated ADS have distinct clinical and radiological patterns that are age-dependent. Indirect cognitive evaluation through academic difficulties was prevalent in younger children and is associated with specific clinical and magnetic resonance imaging factors that need to be considered earlier on when assessing this patient population.

Anti-MOG autoantibodies pathogenicity in children and macaques demyelinating diseases.

BACKGROUND: Autoantibodies against myelin oligodendrocyte glycoprotein (anti-MOG-Abs) occur in a majority of children with acquired demyelinating syndromes (ADS) and physiopathology is still under investigation. As cynomolgus macaques immunized with rhMOG, all develop an experimental autoimmune encephalomyelitis (EAE), we assessed relatedness between anti-MOG-Abs associated diseases in both species. METHODS: The study includes 27 children followed for ADS and nine macaques with rhMOG-induced EAE. MRI lesions, cytokines in blood, and CSF at onset of ADS or EAE, as well as histopathological features of brain lesions were compared. RESULTS: Twelve children with anti-MOG-Abs ADS (ADS MOG+) and nine macaques with EAE, presented increased IL-6 and G-CSF in the CSF, whereas no such signature was found in 15 ADS MOG-. Furthermore, IgG and C1q were associated to myelin and phagocytic cells in brains with EAE (n = 8) and in biopsies of ADS MOG+ (n = 2) but not ADS MOG- children (n = 1). Macaque brains also revealed prephagocytic lesions with IgG and C1q depositions but no leukocyte infiltration. CONCLUSIONS: Children with ADS MOG+ and macaques with EAE induced with rhMOG, present a similar cytokine signature in the CSF and a comparable aspect of brain lesions indicating analogous pathophysiological processes. In EAE, prephagocytic lesions points at IgG as an initial effector of myelin attack. These results support the pertinence of modeling ADS MOG+ in non-human primates to apprehend the natural development of anti-MOG-associated disease, find markers of evolution, and above all explore the efficacy of targeted therapies to test primate-restricted molecules.

Early-onset stroke with moyamoya-like syndrome and extraneurological signs: a first reported paediatric series.

BACKGROUND: Moyamoya syndrome is characterised by an occlusion of the carotid terminations with the development of collateral vessels. Our objective is to describe a series of infants presenting early-onset moyamoya-like syndrome, which may constitute a distinct entity. METHODS: From a cohort of children with rare cerebral vascular pathologies, we studied eight infants (28 days-1 year) with early-onset moyamoya-like syndrome demonstrated by angiography. We retrospectively analysed the patterns on MRI and MRA, as well as all other available data. RESULTS: Median age at diagnosis was 7 months (IQR: 6-8) with arterial ischaemic stroke in the middle cerebral artery territory. All of the children experienced severe stroke recurrence within a median time of 11 months (IQR: 10-12), and all showed extraneurological symptoms. The anterior cerebral circulation was involved in all cases and the posterior circulation was involved in six. Two children died and all of the other children suffered permanent neurological deficits. CONCLUSIONS: The presence of extraneurological signs in cases of early-onset moyamoya syndrome is suggestive of a newly described systemic vasculopathy with predominantly cerebrovascular expression. Given its rapid progression marked by severe recurrent strokes and poor clinical outcome, early diagnosis could help in the decision to institute aggressive therapy.

Extracranial vertebral artery dissection in children: natural history and management.

INTRODUCTION: The objective of this study is to describe clinical and imaging presentation and outcome in extracranial vertebral artery dissection. METHODS: Single-centre retrospective study over a 14-year period included 20 consecutive patients under the age of 16 years with extracranial vertebral artery dissection. The diagnosis was based on vascular imaging performed at the acute phase and clinical symptoms. RESULTS: A male predominance was observed (sex ratio 9/1). The first symptoms consisted of headache (45%), neck pain (15%), nausea (30%) and vertigo (30%). Clinical signs leading to admission to hospital were hemiparesis (60%), visual disorders with oculomotor disorders (20%) or visual field defects (20%) and cerebellar syndrome (35%). Eight patients (40%) reported repeated transient episodes of neurological deficits, prior to the diagnosis. The segment most commonly affected was V2-V3 (50%), followed by V3 (15%) and V2 (15%), V3-V4 (10%) and proximal V4 (10%). All patients but one presented cerebral infarction. Eleven patients received first-line treatment with low molecular weight heparin (LMWH), and nine patients received aspirin. Three patients experienced a recurrence of symptoms, one under vitamin K antagonist (VKA) and 2 under aspirin. All three were switched to LMWH with success. Fifty-eight percent of the dissected arteries were occluded at long-term follow-up, although 73% of them were patent at the acute phase. CONCLUSION: Initial imaging must include posterior fossa vessels and the craniocervical region with V2-V3 segments. Conventional angiography may be indicated in the absence of a definitive diagnosis on noninvasive imaging. Healing of the dissected vertebral artery predominantly resulted in occlusion, which does not constitute a pejorative factor but indicates good quality healing.