Cerebral dural arteriovenous fistulas in patients with PTEN-related hamartoma tumor syndrome.

Central nervous system (CNS) dural arteriovenous fistulas (DAVF) have been reported in PTEN-related hamartoma tumor syndrome (PHTS). However, PHTS-associated DAVF remain an underexplored field of the PHTS clinical landscape. Here, we studied cases with a PTEN pathogenic variant identified between 2007 and 2020 in our laboratory (n = 58), and for whom brain imaging was available. Two patients had DAVF (2/58, 3.4%), both presenting at advanced stages: a 34-year-old man with a left lateral sinus DAVF at immediate risk of hemorrhage, and a 21-year-old woman with acute intracranial hypertension due to a torcular DAVF. Interestingly, not all patients had 3D TOF/MRA, the optimal sequences to detect DAVF. Early diagnosis of DAVF can be lifesaving, and is easier to treat compared to developed, proliferative, or complex lesions. As a result, one should consider brain MRI with 3D TOF/MRA in PHTS patients at genetic diagnosis, with subsequent surveillance on a case-by-case basis.

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.

KCNT1-related epilepsies and epileptic encephalopathies: phenotypic and mutational spectrum.

Variants in KCNT1, encoding a sodium-gated potassium channel (subfamily T member 1), have been associated with a spectrum of epilepsies and neurodevelopmental disorders. These range from familial autosomal dominant or sporadic sleep-related hypermotor epilepsy to epilepsy of infancy with migrating focal seizures (EIMFS) and include developmental and epileptic encephalopathies. This study aims to provide a comprehensive overview of the phenotypic and genotypic spectrum of KCNT1 mutation-related epileptic disorders in 248 individuals, including 66 previously unpublished and 182 published cases, the largest cohort reported so far. Four phenotypic groups emerged from our analysis: (i) EIMFS (152 individuals, 33 previously unpublished); (ii) developmental and epileptic encephalopathies other than EIMFS (non-EIMFS developmental and epileptic encephalopathies) (37 individuals, 17 unpublished); (iii) autosomal dominant or sporadic sleep-related hypermotor epilepsy (53 patients, 14 unpublished); and (iv) other phenotypes (six individuals, two unpublished). In our cohort of 66 new cases, the most common phenotypic features were: (i) in EIMFS, heterogeneity of seizure types, including epileptic spasms, epilepsy improvement over time, no epilepsy-related deaths; (ii) in non-EIMFS developmental and epileptic encephalopathies, possible onset with West syndrome, occurrence of atypical absences, possible evolution to developmental and epileptic encephalopathies with sleep-related hypermotor epilepsy features; one case of sudden unexplained death in epilepsy; (iii) in autosomal dominant or sporadic sleep-related hypermotor epilepsy, we observed a high prevalence of drug-resistance, although seizure frequency improved with age in some individuals, appearance of cognitive regression after seizure onset in all patients, no reported severe psychiatric disorders, although behavioural/psychiatric comorbidities were reported in ∼50% of the patients, sudden unexplained death in epilepsy in one individual; and (iv) other phenotypes in individuals with mutation of KCNT1 included temporal lobe epilepsy, and epilepsy with tonic-clonic seizures and cognitive regression. Genotypic analysis of the whole cohort of 248 individuals showed only missense mutations and one inframe deletion in KCNT1. Although the KCNT1 mutations in affected individuals were seen to be distributed among the different domains of the KCNT1 protein, genotype-phenotype considerations showed many of the autosomal dominant or sporadic sleep-related hypermotor epilepsy-associated mutations to be clustered around the RCK2 domain in the C terminus, distal to the NADP domain. Mutations associated with EIMFS/non-EIMFS developmental and epileptic encephalopathies did not show a particular pattern of distribution in the KCNT1 protein. Recurrent KCNT1 mutations were seen to be associated with both severe and less severe phenotypes. Our study further defines and broadens the phenotypic and genotypic spectrums of KCNT1-related epileptic conditions and emphasizes the increasingly important role of this gene in the pathogenesis of early onset developmental and epileptic encephalopathies as well as of focal epilepsies, namely autosomal dominant or sporadic sleep-related hypermotor epilepsy.

Adaptive behavior and psychiatric comorbidities in KCNB1 encephalopathy.

AIM: KCNB1 encephalopathy encompasses a broad phenotypic spectrum associating intellectual disability, behavioral disturbances, and epilepsies of various severity. Using standardized parental questionnaires, we aimed to capture the heterogeneity of the adaptive and behavioral features in a series of patients with KCNB1 pathogenic variants. METHODS: We included 25 patients with a KCNB1 encephalopathy, aged from 3.2 to 34.1 years (median = 10 years). Adaptive functioning was assessed in all patients using the French version of the Vineland Adaptive Behavior Scales, Second Edition (VABS-II) questionnaire. We screened global behavior with the Childhood Behavioral Check-List (CBCL, Achenbach) and autism spectrum disorder (ASD) with the Social Communication Questionnaire (SCQ). We used a cluster analysis to identify subgroups of adaptive profiles. RESULTS: VABS-II questionnaire showed pathological adaptive behavior in all participants with a severity of adaptive deficiency ranging from mild in 8/20 to severe in 7/20. Eight out of 16 were at risk of Attention Problems at the CBCL and 13/18 were at risk of autism spectrum disorder (ASD). The adaptive behavior composite score significantly decreased with age (Spearman's Rho=-0.72, p<0.001) but not the equivalent ages, suggesting stagnation and slowing but no regression over time. The clustering analysis identified two subgroups of patients, one showing more severe adaptive behavior. The severity of the epilepsy phenotype predicted the severity of the behavioral profile with a sensitivity of 70% and a specificity of 90.9%. CONCLUSION: This study confirms the deleterious consequences of early-onset epilepsy in addition to the impact of the gene dysfunction in patients with KCNB1 encephalopathy. ASD and attention disorders are frequent. Parental questionnaires should be considered as useful tools for early screening and care adaptation.

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.

Real-life use of videos in pediatric epilepsy consultations.

Paroxysmal events are usually not directly observed by physicians. The diagnosis remains challenging and relies mostly on the description of witnesses. The effectiveness of videos for seizure diagnosis has been validated by several studies, but their place in clinical practice is not yet clear. The aim of our study was to evaluate the real-life use of videos by child neurologists. We conducted a three-month prospective study in which child neurologists were asked to use a short questionnaire to evaluate all videos that were watched in their clinical practice for an initial diagnosis or during follow-up. A click-off meeting during the French pediatric neurology meeting allowed to recruit participants. A total of 165 questionnaires were completed by 15 physicians over the study period. The physicians were child neurologists working in secondary and tertiary/university hospitals, consulting children with epilepsy. Based on the evaluation of child neurologists, 51% of the videos consisted of epileptic seizures; 40%, nonepileptic paroxysmal events; and 9%, psychogenic nonepileptic seizures. Most of the videos were made on parental initiative. The use of video has modified the first diagnosis hypothesis in 35% of cases. The physicians' feelings regarding the interest of the video used during the diagnostic phase were similar to those of the video used during follow-up. It appears that videos have become a part of the epilepsy clinic and are helpful for diagnosis as well as during follow-up. Unfortunately, one of the limitations of this study is the absence of private practitioner.

Management and Outcomes of Neonatal Arteriovenous Brain Malformations with Cardiac Failure: A 17 Years' Experience in a Tertiary Referral Center.

OBJECTIVES: To assess the management and outcomes of neonatal arteriovenous brain malformations (mostly vein of Galen malformations) complicated by cardiac failure in the era of prenatal diagnosis and endovascular treatment in a tertiary referral center. STUDY DESIGN: This observational study included 77 living newborn infants with arteriovenous brain malformations with cardiac failure, admitted to our referral center from 2001 to 2017. All infants underwent cardiovascular evaluation including echocardiogram and brain magnetic resonance imaging. Long-term survivors had standard neurocognitive assessments. RESULTS: Infants were admitted to the neonatal intensive care unit at a median of 5 days of age (including 18 inborn patients since 2009). Sixty transarterial shunt embolizations were performed in 46 patients during their first month (at a median age of 7.5 days) or postponed beyond the first month in another 10 long-term survivors. Embolization was not performed in 21 infants, including 19 nonsurvivors with severe brain injury, uncontrolled cardiac failure, or multiple organ failure. Cardiac failure requiring vasopressor infusion occurred in 48 patients (64%) during the hospitalization. Infants who survived the first month underwent a median of 3 embolization sessions. Among the 51 survivors, 21 had a good outcome and 19 had a poor outcome at follow-up (median age, 5.3 years); 11 children were lost to follow-up. CONCLUSIONS: In the era of multidisciplinary prenatal diagnosis, using a standardized care protocol, 47% of liveborn infants with an arteriovenous shunt malformation with cardiac failure experienced a favorable outcome.

Three novel patients with epileptic encephalopathy due to biallelic mutations in the PLCB1 gene.

Biallelic mutations in the PLCB1 gene, encoding for a phospholipase C beta isoform strongly expressed in the brain, have been reported to cause infantile epileptic encephalopathy in only four children to date. We report here three additional patients to delineate the phenotypic and genotypic characteristics of the disease. Our three patients were one sporadic case with an intragenic homozygous deletion and two cousins with the homozygous p.(Arg222*) nonsense variant in PLCB1. These patients had severe to profound intellectual disability, epileptic spasms at age 3-5 months concomitant with developmental arrest or regression, other seizure types and drug-resistant epilepsy. With this report, we expand the clinical, radiologic and electroencephalographic knowledge about the extremely rare PLCB1-related encephalopathy. Since the first report in 2010, the overall number of reported patients with our additional patients is currently limited to seven. All seven patients had epileptic encephalopathy, mainly infantile spasms and 6/7 had profound intellectual disability, with one only being able to walk. Truncal hypotonia was the most frequent neurological sign, sometimes associated with pyramidal and/or extrapyramidal hypertonia of limbs. Microcephaly was inconstant. In conclusion, the phenotypical spectrum of PLCB1-related encephalopathy is relatively narrow, comprises infantile spasms and severe to profound intellectual disability, and does not seem to define a recognizable clinical entity.

Developmental and epilepsy spectrum of KCNB1 encephalopathy with long-term outcome.

OBJECTIVE: We aimed to delineate the phenotypic spectrum and long-term outcome of individuals with KCNB1 encephalopathy. METHODS: We collected genetic, clinical, electroencephalographic, and imaging data of individuals with KCNB1 pathogenic variants recruited through an international collaboration, with the support of the family association "KCNB1 France." Patients were classified as having developmental and epileptic encephalopathy (DEE) or developmental encephalopathy (DE). In addition, we reviewed published cases and provided the long-term outcome in patients older than 12 years from our series and from literature. RESULTS: Our series included 36 patients (21 males, median age = 10 years, range = 1.6 months-34 years). Twenty patients (56%) had DEE with infantile onset seizures (seizure onset = 10 months, range = 10 days-3.5 years), whereas 16 (33%) had DE with late onset epilepsy in 10 (seizure onset = 5 years, range = 18 months-25 years) and without epilepsy in six. Cognitive impairment was more severe in individuals with DEE compared to those with DE. Analysis of 73 individuals with KCNB1 pathogenic variants (36 from our series and 37 published individuals in nine reports) showed developmental delay in all with severe to profound intellectual disability in 67% (n = 41/61) and autistic features in 56% (n = 32/57). Long-term outcome in 22 individuals older than 12 years (14 in our series and eight published individuals) showed poor cognitive, psychiatric, and behavioral outcome. Epilepsy course was variable. Missense variants were associated with more frequent and more severe epilepsy compared to truncating variants. SIGNIFICANCE: Our study describes the phenotypic spectrum of KCNB1 encephalopathy, which varies from severe DEE to DE with or without epilepsy. Although cognitive impairment is worse in patients with DEE, long-term outcome is poor for most and missense variants are associated with more severe epilepsy outcome. Further understanding of disease mechanisms should facilitate the development of targeted therapies, much needed to improve the neurodevelopmental prognosis.

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.

Loss of function mutations in EPHB4 are responsible for vein of Galen aneurysmal malformation.

See Meschia (doi:10.1093/brain/awy066) for a scientific commentary on this article.Vein of Galen aneurysmal malformation is a congenital anomaly of the cerebral vasculature representing 30% of all paediatric vascular malformations. We conducted whole exome sequencing in 19 unrelated patients presenting this malformation and subsequently screened candidate genes in a cohort of 32 additional patients using either targeted exome or Sanger sequencing. In a cohort of 51 patients, we found five affected individuals with heterozygous mutations in EPHB4 including de novo frameshift (p.His191Alafs*32) or inherited deleterious splice or missense mutations predicted to be pathogenic by in silico tools. Knockdown of ephb4 in zebrafish embryos leads to specific anomalies of dorsal cranial vessels including the dorsal longitudinal vein, which is the orthologue of the median prosencephalic vein and the embryonic precursor of the vein of Galen. This model allowed us to investigate EPHB4 loss-of-function mutations in this disease by the ability to rescue the brain vascular defect in knockdown zebrafish co-injected with wild-type, but not truncated EPHB4, mimicking the p.His191Alafs mutation. Our data showed that in both species, loss of function mutations of EPHB4 result in specific and similar brain vascular development anomalies. Recently, EPHB4 germline mutations have been reported in non-immune hydrops fetalis and in cutaneous capillary malformation-arteriovenous malformation. Here, we show that EPHB4 mutations are also responsible for vein of Galen aneurysmal malformation, indicating that heterozygous germline mutations of EPHB4 result in a large clinical spectrum. The identification of EPHB4 pathogenic mutations in patients presenting capillary malformation or vein of Galen aneurysmal malformation should lead to careful follow-up of pregnancy of carriers for early detection of anomaly of the cerebral vasculature in order to propose optimal neonatal care. Endovascular embolization indeed greatly improved the prognosis of patients.

Autosomal recessive primary microcephaly due to ASPM mutations: An update.

Autosomal recessive microcephaly or microcephaly primary hereditary (MCPH) is a genetically heterogeneous neurodevelopmental disorder characterized by a reduction in brain volume, indirectly measured by an occipitofrontal circumference (OFC) 2 standard deviations or more below the age- and sex-matched mean (-2SD) at birth and -3SD after 6 months, and leading to intellectual disability of variable severity. The abnormal spindle-like microcephaly gene (ASPM), the human ortholog of the Drosophila melanogaster "abnormal spindle" gene (asp), encodes ASPM, a protein localized at the centrosome of apical neuroprogenitor cells and involved in spindle pole positioning during neurogenesis. Loss-of-function mutations in ASPM cause MCPH5, which affects the majority of all MCPH patients worldwide. Here, we report 47 unpublished patients from 39 families carrying 28 new ASPM mutations, and conduct an exhaustive review of the molecular, clinical, neuroradiological, and neuropsychological features of the 282 families previously reported (with 161 distinct ASPM mutations). Furthermore, we show that ASPM-related microcephaly is not systematically associated with intellectual deficiency and discuss the association between the structural brain defects (strong reduction in cortical volume and surface area) that modify the cortical map of these patients and their cognitive abilities.

Treatments of paediatric multiple sclerosis: Efficacy and tolerance in a longitudinal follow-up study.

AIM: To compare the efficacy and safety of newer and/or second-line disease-modifying treatments (DMTs) with interferon beta-1a. METHOD: This observational retrospective study included patients younger than 18 years old in the French KIDBIOSEP cohort who had a diagnosis of relapsing multiple sclerosis between 2008 and 2019 and received at least one DMT. Primary outcome was the annualized relapse rate (ARR). Secondary outcomes were the risk of new T2 or gadolinium-enhanced lesions on brain MRI. RESULTS: Among 78 patients enrolled, 50 were exposed to interferon and 76 to newer DMTs. Mean ARR went from 1.65 during pre-treatment period to 0.45 with interferon (p < 0.001). Newer DMTs reduced ARR compared to interferon: fingolimod 0.27 (p = 0.013), teriflunomide 0.25 (p = 0.225), dimethyl-fumarate 0.14 (p = 0.045), natalizumab 0.03 (p = 0.007). Risk of new lesions on MRI was reduced with interferon compared to pre-treatment period; it decreased even more with newer DMTs for T2 lesions. Regarding risk of new gadolinium-enhanced lesions, the added value of new treatments compared to interferon was less obvious, except for natalizumab (p = 0.031). CONCLUSION: In this real-world setting, newer DMTs showed better efficacy than interferon beta-1a on ARR and risk of new T2 lesions, with a good safety profile. Natalizumab tend to emerge as the most effective treatment.

Recurrent mutations in the CDKL5 gene: genotype-phenotype relationships.

Mutations in the cyclin-dependent kinase-like 5 gene (CDKL5) have been described in epileptic encephalopathies in females with infantile spasms with features that overlap with Rett syndrome. With more than 80 reported patients, the phenotype of CDKL5-related encephalopathy is well-defined. The main features consist of seizures starting before 6 months of age, severe intellectual disability with absent speech and hand stereotypies and deceleration of head growth, which resembles Rett syndrome. However, some clinical discrepancies suggested the influence of genetics and/or environmental factors. No genotype-phenotype correlation has been defined and thus there is a need to examine individual mutations. In this study, we analyzed eight recurrent CDKL5 mutations to test whether the clinical phenotype of patients with the same mutation is similar and whether patients with specific CDKL5 mutations have a milder phenotype than those with other CDKL5 mutations. Patients bearing missense mutations in the ATP binding site such as the p.Ala40Val mutation typically walked unaided, had normocephaly, better hand use ability, and less frequent refractory epilepsy when compared to girls with other CDKL5 mutations. In contrast, patients with mutations in the kinase domain (such as p.Arg59X, p.Arg134X, p.Arg178Trp/Pro/Gln, or c.145 + 2T > C) and frameshift mutations in the C-terminal region (such as c.2635_2636delCT) had a more severe phenotype with infantile spasms, refractory epileptic encephalopathy, absolute microcephaly, and inability to walk. It is important for clinicians to have this information when such patients are diagnosed.

Mutations and deletions in PCDH19 account for various familial or isolated epilepsies in females.

Mutations in PCDH19, encoding protocadherin 19 on chromosome X, cause familial epilepsy and mental retardation limited to females or Dravet-like syndrome. Heterozygous females are affected while hemizygous males are spared, this unusual mode of inheritance being probably due to a mechanism called cellular interference. To extend the mutational and clinical spectra associated with PCDH19, we screened 150 unrelated patients (113 females) with febrile and afebrile seizures for mutations or rearrangements in the gene. Fifteen novel point mutations were identified in 15 female patients (6 sporadic and 9 familial cases). In addition, qPCR revealed two whole gene deletions and one partial deletion in 3 sporadic female patients. Clinical features were highly variable but included almost constantly a high sensitivity to fever and clusters of brief seizures. Interestingly, cognitive functions were normal in several family members of 2 families: the familial condition in family 1 was suggestive of Generalized Epilepsy with Febrile Seizures Plus (GEFS+) whereas all three affected females had partial cryptogenic epilepsy. These results show that mutations in PCDH19 are a relatively frequent cause of epilepsy in females and should be considered even in absence of family history and/or mental retardation.