International consensus definitions for infection-triggered encephalopathy syndromes.

AIM: To develop standardized diagnostic criteria for 'infection-triggered encephalopathy syndrome (ITES)' and five specific clinical syndromes of ITES. METHOD: The draft definitions were based on existing criteria, standardized, and discussed by a panel of international experts using nominal group technique over 18 months to achieve consensus. All criteria use the same format: (1) presence of infection/fever; (2) clinical features including encephalopathy; (3) neuroradiological features on magnetic resonance imaging; (4) exclusion of other causes. RESULTS: We first highlighted differences between ITES and infectious and autoimmune encephalitis, which is the most important differential diagnosis. Consensus was achieved to define five specific ITESs: acute encephalopathy with biphasic seizures and late reduced diffusion; acute necrotizing encephalopathy; mild encephalopathy with a reversible splenial lesion; acute fulminant cerebral oedema; and acute shock with encephalopathy and multiorgan failure. Two further conditions that are currently classified as epilepsy syndromes but have similar features to ITES, namely febrile infection-related epilepsy syndrome and hemiconvulsion-hemiplegia-epilepsy syndrome, are also discussed. INTERPRETATION: The consensus definition is expected to improve awareness of this disease concept, provide diagnostic framework, and facilitate future international research and clinical trials.

Cerebral venous thrombosis and deep medullary vein thrombosis: Padua experience over the last two decades.

BACKGROUND: Cerebral venous thrombosis (CVT) is a cerebrovascular disorder that accounts for 20% of perinatal strokes. CVT incidence ranges from 0.67 to 1.12 per 100,000 newborns, while the incidence of "deep medullary vein thrombosis" (DMVT), a subtype of CVT, cannot be accurately estimated. This study aims to analyze the case history of CVT in the neonatal period, with a specific focus on DMVT. MATERIALS AND METHODS: Newborns diagnosed with CVT, with or without DMVT, between January 2002 and April 2023, were collected using the Italian Registry of Infantile Thrombosis (RITI). Cerebral MRIs were reviewed by an expert neuroradiologist following a standardized protocol. RESULTS: Forty-two newborns with CVT were identified, of which 27/42 (64%) had CVT, and the remaining 15/42 (36%) had DMVT (isolated DMVT in 9/15). Symptom onset occurred in the first week of life (median 8 days, IQR 4-14) with a male prevalence of 59%. The most common risk factors for CVT were complicated delivery (38%), prematurity (40%), congenital heart diseases (48%), and infections (40%). Seizures were the predominant presenting symptom in 52% of all cases. Hemorrhagic infarction was higher in cases with isolated DMVT (77%) compared to patients with CVT without DMVT (p = 0.013). Antithrombotic treatment was initiated in 36% of patients. Neurological impairment was observed in 48% of cases at discharge, while 18 out of 31 infants (58%) presented one or more neurological deficits at long term follow up.     Conclusion: DMVT occurs in over a third of neonates with CVT. Multicentric studies are essential to establish standardized protocols for therapy, neuroimaging, and follow-up in these patients.

The maturation of aperiodic EEG activity across development reveals a progressive differentiation of wakefulness from sleep.

During development, the brain undergoes radical structural and functional changes following a posterior-to-anterior gradient, associated with profound changes of cortical electrical activity during both wakefulness and sleep. However, a systematic assessment of the developmental effects on aperiodic EEG activity maturation across vigilance states is lacking, particularly regarding its topographical aspects. Here, in a population of 160 healthy infants, children and teenagers (from 2 to 17 years, 10 subjects for each year), we investigated the development of aperiodic EEG activity in wakefulness and sleep. Specifically, we parameterized the shape of the aperiodic background of the EEG Power Spectral Density (PSD) by means of the spectral exponent and offset; the exponent reflects the rate of exponential decay of power over increasing frequencies and the offset reflects an estimate of the y-intercept of the PSD. We found that sleep and development caused the EEG-PSD to rotate over opposite directions: during wakefulness the PSD showed a flatter decay and reduced offset over development, while during sleep it showed a steeper decay and a higher offset as sleep becomes deeper. During deep sleep (N2, N3) only the spectral offset decreased over age, indexing a broad-band voltage reduction. As a result, the difference between values in deep sleep and those in both light sleep (N1) and wakefulness increased with age, suggesting a progressive differentiation of wakefulness from sleep EEG activity, most prominent over the frontal regions, the latest to complete maturation. Notably, the broad-band spectral exponent values during deep sleep stages were entirely separated from wakefulness values, consistently across developmental ages and in line with previous findings in adults. Concerning topographical development, the location showing the steepest PSD decay and largest offset shifted from posterior to anterior regions with age. This shift, particularly evident during deep sleep, paralleled the migration of sleep slow wave activity and was consistent with neuroanatomical and cognitive development. Overall, aperiodic EEG activity distinguishes wakefulness from sleep regardless of age; while, during development, it reveals a postero-anterior topographical maturation and a progressive differentiation of wakefulness from sleep. Our study could help to interpret changes due to pathological conditions and may elucidate the neurophysiological processes underlying the development of wakefulness and sleep.

Prognostic relevance of quantitative and longitudinal MOG antibody testing in patients with MOGAD: a multicentre retrospective study.

BACKGROUND: IgG antibodies against myelin oligodendrocyte glycoprotein (MOG-IgG) define a subset of associated disorders (myelin oligodendrocyte glycoprotein associated disorders (MOGAD)) that can have a relapsing course. However, information on relapse predictors is scarce. The utility of retesting MOG-IgG over time and measuring their titres is uncertain. We aimed to evaluate the clinical relevance of longitudinal MOG-IgG titre measurement to predict relapses in patients with MOGAD. METHODS: In this retrospective multicentre Italian cohort study, we recruited patients with MOGAD and available longitudinal samples (at least one >3 months after disease onset) and tested them with a live cell-based assay with endpoint titration (1:160 cut-off). Samples were classified as 'attack' (within 30 days since a disease attack (n=59, 17%)) and 'remission' (≥31 days after attack (n=295, 83%)). RESULTS: We included 102 patients with MOGAD (57% adult and 43% paediatric) with a total of 354 samples (83% from remission and 17% from attack). Median titres were higher during attacks (1:1280 vs 1:640, p=0.001). Median onset titres did not correlate with attack-related disability, age or relapses. Remission titres were higher in relapsing patients (p=0.02). When considering the first remission sample available for each patient, titres >1:2560 were predictors of relapsing course in survival (log rank, p<0.001) and multivariate analysis (p<0.001, HR: 10.9, 95% CI 3.4 to 35.2). MOG-IgG seroconversion to negative was associated with a 95% relapse incidence rate reduction (incidence rate ratio: 0.05, p<0.001). CONCLUSIONS: Persistent MOG-IgG positivity and high remission titres are associated with an increased relapse risk. Longitudinal MOG-IgG titres could be useful to stratify patients to be treated with long term immunosuppression.

Gain of function SCN1A disease-causing variants: Expanding the phenotypic spectrum and functional studies guiding the choice of effective antiseizure medication.

OBJECTIVE: This study was undertaken to refine the spectrum of SCN1A epileptic disorders other than Dravet syndrome (DS) and genetic epilepsy with febrile seizures plus (GEFS+) and optimize antiseizure management by correlating phenotype-genotype relationship and functional consequences of SCN1A variants in a cohort of patients. METHODS: Sixteen probands carrying SCN1A pathogenic variants were ascertained via a national collaborative network. We also performed a literature review including individuals with SCN1A variants causing non-DS and non-GEFS+ phenotypes and compared the features of the two cohorts. Whole cell patch clamp experiments were performed for three representative SCN1A pathogenic variants. RESULTS: Nine of the 16 probands (56%) had de novo pathogenic variants causing developmental and epileptic encephalopathy (DEE) with seizure onset at a median age of 2 months and severe intellectual disability. Seven of the 16 probands (54%), five with inherited and two with de novo variants, manifested focal epilepsies with mild or no intellectual disability. Sodium channel blockers never worsened seizures, and 50% of patients experienced long periods of seizure freedom. We found 13 SCN1A missense variants; eight of them were novel and never reported. Functional studies of three representative variants showed a gain of channel function. The literature review led to the identification of 44 individuals with SCN1A variants and non-DS, non-GEFS+ phenotypes. The comparison with our cohort highlighted that DEE phenotypes are a common feature. SIGNIFICANCE: The boundaries of SCN1A disorders are wide and still expanding. In our cohort, >50% of patients manifested focal epilepsies, which are thus a frequent feature of SCN1A pathogenic variants beyond DS and GEFS+. SCN1A testing should therefore be included in the diagnostic workup of pediatric, familial and nonfamilial, focal epilepsies. Alternatively, non-DS/non-GEFS+ phenotypes might be associated with gain of channel function, and sodium channel blockers could control seizures by counteracting excessive channel function. Functional analysis evaluating the consequences of pathogenic SCN1A variants is thus relevant to tailor the appropriate antiseizure medication.

Autoimmune Encephalitis with Autoantibodies to NMDAR1 following Herpes Encephalitis in Children and Adolescents.

Herpes simplex virus (HSV) type 1 is a frequent pathogen causing infectious encephalitis (HSVE). Early treatment with intravenous acyclovir has led to a significant decrease in mortality. However, especially in children, deterioration during or after HSVE may occur without any evidence of HSV reactivation or improvement following repeated antiviral therapy. Here, we report 15 patients (age range 3 months to 15 years) who suffered from autoimmune encephalitis with autoantibodies to NMDAR1 following Herpes encephalitis, presenting with movement abnormalities (young children) or neuropsychiatric symptoms (older children) as major complaints, respectively. The diagnosis was based on positive cerebrospinal fluid (CSF) and/or serum anti-NMDAR-antibodies with two children showing only positive CSF antibody findings. The time lag between first symptoms and diagnosis of autoimmune encephalitis was significantly longer than between first symptoms and diagnosis of HSVE (p <0.01). All patients improved during immunosuppressive treatment, during which plasmapheresis or rituximab treatments were applied in 11 patients, irrespective of their age. Despite immunotherapy, no patients relapsed with HSVE. Early diagnosis and treatment of autoimmune encephalitis after HSVE may be associated with a better outcome so that high clinical awareness and routine testing for anti-NMDAR-antibodies after HSVE seems advisable. If autoimmune encephalitis is suspected, antibody testing should also be performed on CSF if negative in serum.

Epileptic phenotypes in autoimmune encephalitis: from acute symptomatic seizures to autoimmune-associated epilepsy.

OBJECTIVE: To describe the clinical and paraclinical findings, treatment options and long-term outcomes in autoimmune encephalitis (AE), with a close look to epilepsy. METHODS: In this retrospective observational cohort study, we enrolled patients with new-onset seizures in the context of AE. We compared clinical and paraclinical findings in patients with and without evidence of antibodies. RESULTS: Overall, 263 patients (138 females; median age 55 years, range 4-86) were followed up for a median time of 30 months (range 12-120). Antineuronal antibodies were detected in 63.50%.Antibody-positive patients had multiple seizure types (p=0.01) and prevalent involvement of temporal regions (p=0.02). A higher prevalence of episodes of SE was found in the antibody-negative group (p<0.001).Immunotherapy was prescribed in 88.60%, and effective in 61.80%. Independent predictors of favourable outcome of the AE were early immunotherapy (p<0.001) and the detection of antineuronal surface antibodies (p=0.01).Autoimmune-associated epilepsy was the long-term sequela in 43.73%, associated with cognitive and psychiatric disturbances in 81.73%. Independent predictors of developing epilepsy were difficult to treat seizures at onset (p=0.04), a high number of antiseizure medications (p<0.001), persisting interictal epileptiform discharges at follow-up (p<0.001) and poor response to immunotherapy during the acute phase (p<0.001). CONCLUSIONS: The recognition of seizures secondary to AE represents a rare chance for aetiology-driven seizures management. Early recognition and treatment at the pathogenic level may reduce the risk of long-term irreversible sequelae. However, the severity of seizures at onset is the major risk factor for the development of chronic epilepsy.This study provides class IV evidence for management recommendations.

Altered EEG markers of synaptic plasticity in a human model of NMDA receptor deficiency: Anti-NMDA receptor encephalitis.

Plasticity of synaptic strength and density is a vital mechanism enabling memory consolidation, learning, and neurodevelopment. It is strongly dependent on the intact function of N-Methyl-d-Aspartate Receptors (NMDAR). The importance of NMDAR is further evident as their dysfunction is involved in many diseases such as schizophrenia, Alzheimer's disease, neurodevelopmental disorders, and epilepsies. Synaptic plasticity is thought to be reflected by changes of sleep slow wave slopes across the night, namely higher slopes after wakefulness at the beginning of sleep than after a night of sleep. Hence, a functional NMDAR deficiency should theoretically lead to altered overnight changes of slow wave slopes. Here we investigated whether pediatric patients with anti-NMDAR encephalitis, being a very rare but unique human model of NMDAR deficiency due to autoantibodies against receptor subunits, indeed show alterations in this sleep EEG marker for synaptic plasticity. We retrospectively analyzed 12 whole-night EEGs of 9 patients (age 4.3-20.8 years, 7 females) and compared them to a control group of 45 healthy individuals with the same age distribution. Slow wave slopes were calculated for the first and last hour of Non-Rapid Eye Movement (NREM) sleep (factor 'hour') for patients and controls (factor 'group'). There was a significant interaction between 'hour' and 'group' (p = 0.013), with patients showing a smaller overnight decrease of slow wave slopes than controls. Moreover, we found smaller slopes during the first hour in patients (p = 0.022), whereas there was no group difference during the last hour of NREM sleep (p = 0.980). Importantly, the distribution of sleep stages was not different between the groups, and in our main analyses of patients without severe disturbance of sleep architecture, neither was the incidence of slow waves. These possible confounders could therefore not account for the differences in the slow wave slope values, which we also saw in the analysis of the whole sample of EEGs. These results suggest that quantitative EEG analysis of slow wave characteristics may reveal impaired synaptic plasticity in patients with anti-NMDAR encephalitis, a human model of functional NMDAR deficiency. Thus, in the future, the changes of sleep slow wave slopes may contribute to the development of electrophysiological biomarkers of functional NMDAR deficiency and synaptic plasticity in general.

Maternal autoimmunity and inflammation are associated with childhood tics and obsessive-compulsive disorder: Transcriptomic data show common enriched innate immune pathways.

Although genetic variation is a major risk factor of neurodevelopmental disorders, environmental factors during pregnancy and early life are also important in disease expression. Animal models demonstrate that maternal inflammation causes fetal neuroinflammation and neurodevelopmental deficits, and brain transcriptomics of neurodevelopmental disorders in humans show upregulated differentially expressed genes are enriched in immune pathways. We prospectively recruited 200 sequentially referred children with tic disorders/obsessive-compulsive disorder (OCD), 100 autoimmune neurological controls, and 100 age-matched healthy controls. A structured interview captured the maternal and family history of autoimmune disease and other pro-inflammatory states. Maternal blood and published Tourette brain transcriptomes were analysed for overlapping enriched pathways. Mothers of children with tics/OCD had a higher rate of autoimmune disease compared with mothers of children with autoimmune neurological conditions (p = 0.054), and mothers of healthy controls (p = 0.0004). Autoimmunity was similarly elevated in first- and second-degree maternal relatives of children with tics/OCD (p < 0.0001 and p = 0.014 respectively). Other pro-inflammatory states were also more common in mothers of children with tics/OCD than controls (p < 0.0001). Upregulated differentially expressed genes in maternal autoimmune disease and Tourette brain transcriptomes were commonly enriched in innate immune processes. Pro-inflammatory states, including autoimmune disease, are more common in the mothers and families of children with tics/OCD. Exploratory transcriptome analysis indicates innate immune signalling may link maternal inflammation and childhood tics/OCD. Targeting inflammation may represent preventative strategies in pregnancy and treatment opportunities for children with neurodevelopmental disorders.

Rituximab in patients with pediatric multiple sclerosis and other demyelinating disorders of the CNS: Practical considerations.

Anti-CD20 therapies have established efficacy in the treatment of immune-mediated neurological and non-neurological diseases. Rituximab, one of the first B-cell-directed therapies, is relatively inexpensive compared to newer anti-CD20 molecules, is available in many countries, and has been used off-label in pediatric patients with neuroimmune conditions. The objective of this paper is to describe the experience with rituximab in pediatric multiple sclerosis and other inflammatory immune-mediated disorders of the central nervous system (CNS), and to define a protocol for its use in clinical practice, in particular addressing doses, interval of administration, duration of treatment, and tests to perform at baseline and during follow-up.

Cardiac Myxoma as a Rare Cause of Pediatric Arterial Ischemic Stroke: Case Report and Literature Review.

BACKGROUND: Cardiac disorders are the second leading cause of pediatric arterial ischemic stroke (AIS). Limited literature is available on pediatric AIS caused by cardiac myxoma, a rare tumor in childhood. METHODS: We describe a new case of pediatric AIS due to a previously unknown atrial myxoma and we conduct a literature review on children with AIS due to cardiac myxoma. RESULTS: We identified 41 published pediatric cases of AIS and cardiac myxoma, including ours (56% males, median age at AIS was 11 years [range: 3-18]). AIS presentation was most frequently with hemiparesis/hemiplegia (89%). Multiple brain ischemic lesions were detected in 69% of patients, and arteriopathy in 91%. Seven patients underwent mechanical thrombectomy. At AIS presentation, 73% of children had one or more of the following clinical symptoms/signs suggesting a possible underlying cardiac myxoma: Carney's complex, cardiac auscultation abnormalities, extraneurological symptoms/signs, such as skin signs (12, 38, and 65%, respectively). Cardiac myxoma was diagnosed within 72 hours in 68% of cases. Death occurred in 11%, and 40% had persistent neurological deficits. CONCLUSION: Neurological presentation of AIS due to cardiac myxoma is similar to that of AIS with other etiologies, although clues suggesting a possible underlying cardiac myxoma can be detected in most cases. A timely diagnosis of cardiac myxoma in patients with AIS may favor prompt identification of candidates for endovascular therapy. Therefore, we suggest that in otherwise-healthy children presenting with AIS, transthoracic echocardiography should be performed early after stroke presentation.

Possible clinical role of MOG antibody testing in children presenting with acute neurological symptoms.

The differential diagnosis between acquired inflammatory demyelinating syndromes of the central nervous system (CNS), such as multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD) and acute disseminated encephalomyelitis (ADEM) can be very challenging at onset. Apart from cerebrospinal fluid oligoclonal bands and anti-aquaporin-4 antibodies (AQP4-Ab), definite diagnostic biomarkers are lacking. Anti-myelin oligodendrocyte glycoprotein antibodies (MOG-Abs) have been increasingly described in children with AQP4-seronegative NMOSD, ADEM and other inflammatory demyelinating CND syndromes; despite partial overlaps with AQP4-Ab disease, a novel "MOG-Ab-disorder" phenotype has been suggested. In this study, we tested the presence of MOG-Ab and AQP4-Ab in 57 children at first onset of acute neurological symptoms; three clinical subgroups were identified: 12 patients had acquired inflammatory demyelinating CNS syndromes, 11 had other autoimmune/immune-mediated disorders of the central and peripheral nervous system and 34 had non-immune-mediated CNS disorders. MOG-Abs were found positive only in a subset of cases in the subgroup with acquired inflammatory demyelinating CNS syndromes (in 2/12 patients, both with non-MS phenotype) and in none of the patients with other autoimmune and immune-mediated disorders of the central and peripheral nervous system or with non-immune-mediated disorders of the CNS.Data from the literature review support clinical and analytical observations.

Long-term effect of subthalamic and pallidal deep brain stimulation for status dystonicus in children with methylmalonic acidemia and GNAO1 mutation.

Status dystonicus (SD) is a rare and potentially life-threatening condition requiring intensive care management. Deep brain stimulation (DBS) has emerged as an effective treatment for SD refractory to medical management, but its application in this field is still limited. Here, we report the long-term outcome of four pediatric patients treated with DBS at the University Hospital of Padua, Italy, for SD refractory to medications. In addition, we present the results of a systematic literature review aimed at identifying published cases of SD treated with DBS, with focus on motor outcome. In our cohort, two children were affected by methylmalonic acidemia and suffered acute basal ganglia lesions, while the other two carried a pathogenic mutation in GNAO1 gene. DBS target was subthalamic nucleus (STN) in one case and globus pallidus internus (GPi) in three. All patients experienced SD resolution within 8-19 days after surgery. Mean post-operative follow-up was 5 years. We identified in the literature 53 additional SD cases treated with DBS (median age at DBS implantation: 12 years) with reported positive outcome in 51 and resolution of SD in a mean of 17 days after surgery. Our findings indicate that DBS is an effective treatment for SD refractory to medications, even in patients with acute basal ganglia lesions; STN can be an appropriate target when GPi is damaged. Moreover, data from long-term follow-up show that SD recurrences can be significantly reduced in frequency or abolished after DBS implantation.

Mycophenolate mofetil in paediatric autoimmune or immune-mediated diseases of the central nervous system: clinical experience and recommendations.

AIM: To gather data on mycophenolate mofetil (MMF) in paediatric autoimmune/immune-mediated central nervous system (CNS) conditions, focusing on safety and factors that may affect MMF efficacy. METHOD: Retrospective, multicentre study based on four paediatric neurology centres. RESULTS: Forty-four children were included (30 females, 14 males): 19 had proven/suspected autoimmune encephalitis, 14 had inflammatory demyelinating CNS diseases, and 11 had other autoimmune/immune-mediated CNS conditions. Before MMF, all received first-line immune therapies, and 17 had second-line rituximab and/or cyclophosphamide. MMF was started at a median of 9.5 months from disease onset (range 1-127mo) (median age 9y 4mo, range 1y 5mo-16y 5mo), and was used for median 18 months (range 0.3-73mo). On MMF, 31 patients were relapse-free, whereas eight relapsed (excluding patients with chronic-progressive course). Relapses on MMF were associated with medication weaning/cessation, or with suboptimal MMF dosage/duration. Adverse events of MMF occurred in eight patients: six moderate (gastrointestinal, movement disorder, dermatological) and two severe (infectious). INTERPRETATION: MMF use in paediatric neuroimmunology is heterogeneous, although relatively safe. We have identified factors that may affect MMF efficacy and provide recommendations on MMF usage. WHAT THIS PAPER ADDS: Mycophenolate mofetil (MMF) use was heterogeneous with relatively common adverse events, although mostly not severe. MMF treatment reduced median annualized relapse rate, although 20% of patients relapsed on MMF. A high relapse rate pre-MMF and late MMF start were associated with higher probability of relapsing on MMF. Most relapses were associated with suboptimal MMF dosage, short MMF duration, or concurrent medication weaning/discontinuation.

MICOFENOLATO DE MOFETILO EN ENFERMEDADES PEDIÁTRICAS AUTOINMUNES O INMUNO-MEDIADAS DEL SISTEMA NERVIOSO CENTRAL: EXPERIENCIA CLÍNICA Y RECOMENDACIONES: OBJETIVO: Recolectar información sobre el uso de Micofenolato de mofetilo (MMF) en enfermedades pediátricas del sistema nervioso central (SNC) autoinmunes o inmuno-mediadas, focalizando en la seguridad y otros factores que pudieran afectar la eficacia del MMF. MÈTODO: Estudio retrospectivo, multicéntrico, con base en cuatro centros de neurología infantil. RESULTADOS: Se incluyeron 44 niños (30 sexo femenino, 14 masculino): 19 de ellos tuvieron encefalitis autoimmune confirmada / sospechada, 14 tuvieron enfermedades inflamatorias desmielinizantes del SNC y 11 tuvieron otras condiciones autoinmunes o inmuno-mediadas del SNC. Previo al MMF todos recibieron terapias inmunológicas de primera línea, y 17 recibieron como segunda línea rituximab y / o ciclofosfamida. MMF fue iniciada a una mediana de 9.5 meses desde el comienzo de la enfermedad (rango 1-127 meses) (edad mediana 9 años y 4 meses, rango 1 año y 5 meses a 16 años y 5 meses), y fue utilizada por un tiempo mediana de 18 meses (rango 0.3 a 73 meses). Bajo MMF, 31 pacientes estuvieron libres de recidivas, mientras que 8 recidivaron (excluyendo aquellos con un curso crónico-progresivo). Las recaídas bajo el MMF estuvieron asociadas a suspensión/cese, o dosis de MMF o duración de tratamiento subóptimos. En ocho pacientes se observaron reacciones adversas al MMF: seis moderados (gastrointestinales, trastornos de movimiento o dermatológicos) y dos severos (infecciones). INTERPRETACIÓN: El uso de MMF en neuroinmunología pediátrica es heterogéneo, aunque relativamente seguro. Identificamos factores que pueden afectar la eficacia del MMF y proponemos recomendaciones sobre su uso.

MICOFENOLATO MOFETIL EM DOENÇAS PEDIÁTRICAS AUTO-IMUNES OU IMUNO-MEDIADAS DO SISTEMA NERVOSO CENTRAL: EXPERIÊNCIA CLÍNICA E RECOMENDAÇÕES: OBJETIVO: Reunir dados do micofenolato mofetil (MMF) em condições pediátricas auto-imunes ou imuno-mediadas do sistema nervoso central (SNC), com foco na segurança e nos fatores que podem afetar a eficácia do MMF. MÉTODO: Estudo restrospectivo multicêntrico baseado em quatro centros de neurologia pediátrica. RESULTADOS: Quarenta e quatro crianças foram incluídas (30 do sexo feminino, 14 do sexo masculino): 19 tiveram encefalite auto-imune comprovada/suspeita, 14 tiveram doenças inflamatórias desmielinizantes do SNC, e 11 tiveram outras condições auto-imunes ou imuno-mediadas do SNC. Antes do MMF, todas receberam imuno-terapias de primeira linha, e 17 tiveram rituximab e/ou ciclofosfamida de segunda linha. O MMF foi iniciado em uma mediana de 9.5 meses após o início da doença (variação de 1-127 meses) (idade mediana 9a 4m, variação 1a 5m a 16a 5m), e foi utilizado por uma mediana de 18 meses (variação 0.3-73m). Com MMF, 31 pacientes ficaram livres de recidivas, enquanto oito tiveram recidivas (excluídos os pacientes com curso crônico-progressivo). As recidivas com MMF forma associadas com desmame/descontinuidade da medicação, ou com dosagem/duração do MMF sub-ótimas. Efeitos adversos do MMF ocorreram em oito pacientes: seis moderados (gastrointestinal, desordem motora, dermatológico) e dois severos (infeccioso). INTERPRETAÇÃO: O uso de MMF em neuroimunologia pediátrica é heterogêneo, embora relativamente seguro. Identificamos fatores que podem afetar a eficácia do MMF e fornecemos recomendações sobre o uso de MMF.

Tuberous sclerosis-associated neuropsychiatric disorders: a paediatric cohort study.

AIM: We aimed to study tuberous sclerosis-associated neuropsychiatric disorders (TAND) in children and adolescents with tuberous sclerosis complex (TSC). METHOD: Retrospective and prospective cohort study conducted at a Paediatric Neurology Unit of an Italian Tertiary Care Hospital. Clinical and neuroimaging data were reviewed. Scores for neurological and epilepsy outcomes (Extended Glasgow Outcome Scale, Paediatric Version and Early Childhood Epilepsy Severity Scale modified), semi-structured interviews (authorized Italian version of the TAND checklist and Vineland Adaptive Behavior Scales) and questionnaires (Child Behavior Checklist [CBCL]) were applied at last follow-up. RESULTS: Thirty-two patients with TSC (age range 1-19y) were enrolled. Eighty-eight per cent had at least one TAND and 47% had intellectual disability. The TAND checklist showed internalizing problems in 25.8% of cases (vs 41.9% by CBCL), and externalizing problems in 41.9% (vs 9.7% by CBCL). TAND prevailed in patients with de novo mutation of TSC2, high tuber load, and severe neurological and epilepsy outcomes. INTERPRETATION: In our cohort, 78% of patients had more than four TAND behavioural problems; nevertheless, they did not show a constant and specific neuropsychiatric profile. Clinical, neurophysiological, and neuroradiological features were associated with several TAND. The TAND checklist appeared more effective than the CBCL, particularly in detecting externalizing problems. WHAT THIS PAPER ADDS: The Tuberous sclerosis-associated neuropsychiatric disorders (TAND) checklist is an effective tool for TAND screening. The TAND checklist helps define psychopathological and neuropsychiatric aspects in paediatric patients with Tuberous sclerosis complex (TSC). TAND were found in 88% of patients with TSC, whilst 78% had more than four TAND. TAND distribution depends on different clinical and neuroradiological features.

First-ever convulsive seizures in children presenting to the emergency department: risk factors for seizure recurrence and diagnosis of epilepsy.

AIM: Aetiologies of first-ever convulsive seizures may be diverse, not all leading to recurrence or epilepsy diagnosis. We aimed to describe the epidemiology of first-ever convulsive seizures in children, investigating risk factors for recurrence and epilepsy diagnosis. METHOD: This was a retrospective study of children presenting with a first-ever convulsive seizure to a tertiary-care paediatric emergency department (PED) in Italy, in a 12-month period (2011-2012). RESULTS: One hundred and eight children (57 males, 51 females) presented to the PED for a first-ever convulsive seizure; 90.7% were 6 months to 6 years old (median age 1y 10mo, mean 2y 7mo, range 0mo-14y 4mo). Seizure duration was less than 5 minutes in 76.8%. Seizures were 'unprovoked' in 19.4% and 'provoked' in 80.6%. At 4-year follow-up, 37.9% of patients experienced recurrence and 13.6% received a diagnosis of epilepsy. Factors significantly associated with recurrence were the 'unprovoked' nature of the first seizure, multiple seizures in the first 24 hours, positive family history of febrile seizures or epilepsy, and pre-existing neurological conditions/problems. Factors significantly associated with a diagnosis of epilepsy were the 'unprovoked' nature of the first seizure, age older than 6 years, pre-existing neurological conditions/problems, and focal onset of first seizure. INTERPRETATION: Children presenting to the PED with first-ever convulsive seizures represent a heterogeneous group. The identification of prognostic factors for recurrence and epilepsy diagnosis may help provide tailored counselling and follow-up. WHAT THIS PAPER ADDS: Seizures were 'unprovoked' in 19.4% and 'provoked' in 80.6% of children presenting to the emergency department. At 4-year follow-up, 37.9% relapsed, and 13.6% received a diagnosis of epilepsy. 'Unprovoked' first seizure, family history of febrile seizures, and pre-existing neurological conditions were associated with recurrence. 'Unprovoked' first seizure, age younger than 6 years, and pre-existing neurological conditions were associated with epilepsy diagnosis.

Relapse risk factors in anti-N-methyl-D-aspartate receptor encephalitis.

AIM: To identify factors that may predict and affect the risk of relapse in anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. METHOD: This was a retrospective study of an Italian cohort of patients with paediatric (≤18y) onset anti-NMDAR encephalitis. RESULTS: Of the 62 children included (39 females; median age at onset 9y 10mo, range 1y 2mo-18y; onset between 2005 and 2018), 21 per cent relapsed (median two total events per relapsing patient, range 2-4). Time to first relapse was median 31.5 months (range 7-89mo). Severity at first relapse was lower than onset (median modified Rankin Scale [mRS] 3, range 2-4, vs median mRS 5, range 3-5; admission to intensive care unit: 0/10 vs 3/10). At the survival analysis, the risk of relapsing was significantly lower in patients who received three or more different immune therapies at first disease event (hazard ratio 0.208, 95% confidence interval 0.046-0.941; p=0.042). Neurological outcome at follow-up did not differ significantly between patients with relapsing and monophasic disease (mRS 0-1 in 39/49 vs 12/13; p=0.431), although follow-up duration was significantly longer in relapsing (median 84mo, range 14-137mo) than in monophasic patients (median 32mo, range 4-108mo; p=0.002). INTERPRETATION: Relapses may occur in about one-fifth of children with anti-NMDAR encephalitis, are generally milder than at onset, and may span over a long period, although they do not seem to be associated with severity in the acute phase or with outcome at follow-up. Aggressive immune therapy at onset may reduce risk of relapse. WHAT THIS PAPER ADDS: Relapses of anti-N-methyl-D-aspartate receptor encephalitis may span over a long period. Relapses were not associated with severity in the acute phase or outcome at follow-up. Aggressive immune therapy at onset appears to decrease risk of relapse.

Cerebellar lesions as potential predictors of neurobehavioural phenotype in tuberous sclerosis complex.

AIM: To improve the genetic, clinical, and neuroradiological characterization of cerebellar involvement in tuberous sclerosis complex (TSC) and determine whether cerebellar lesions could be a reliable biomarker of neurological impairment. METHOD: This retrospective cohort study, held at two tertiary paediatric university centres, was conducted on patients with a confirmed diagnosis of TSC who underwent brain magnetic resonance imaging between October 2009 and May 2016. The study population consisted of 112 patients with TSC (median age 10y; range 5mo-38y; 61 females, 51 males). RESULTS: The results from multivariable statistical analysis indicated that cerebellar involvement (34 out of 112 patients, none carrying a TSC1 mutation) was the most powerful predictor of supratentorial cortical tuber load; however, cerebellar involvement was not the best predictor of clinical phenotype when supratentorial tuber load and TSC2 mutations were taken into consideration. The association between cerebellar lesions and a more severe clinical and neuroradiological phenotype was statistically significant and may be due to its strong association with TSC2 mutations and higher cortical tuber load. INTERPRETATION: Cerebellar involvement is not the best predictor of neurobehavioural outcome, including TSC-related autism, after adjusting for TSC2 and the number of cortical tubers. Its role in the TSC clinical phenotype needs to be investigated further. WHAT THIS PAPER ADDS: Cerebellar involvement is a powerful predictor of supratentorial cortical involvement and a potential biomarker of disease severity. Cerebellar lesions significantly correlate with a more severe clinical and neuroradiological phenotype. Cerebellar involvement is not the best predictor of neurobehavioural outcome.

Management of antibody-mediated autoimmune encephalitis in adults and children: literature review and consensus-based practical recommendations.

Autoimmune encephalitis associated with antibodies against neuronal surface targets (NSAE) are rare but still underrecognized conditions that affect adult and pediatric patients. Clinical guidelines have recently been published with the aim of providing diagnostic clues regardless of antibody status. These syndromes are potentially treatable but the choice of treatment and its timing, as well as differential diagnoses, long-term management, and clinical and paraclinical follow-up, remain major challenges. In the absence of evidence-based guidelines, management of these conditions is commonly based on single-center expertise.Taking into account different published expert recommendations in addition to the multicenter experience of the Italian Working Group on Autoimmune Encephalitis, both widely accepted and critical aspects of diagnosis, management and particularly of immunotherapy for NSAE have been reviewed and are discussed.Finally, we provide consensus-based practical advice for managing hospitalization and follow-up of patients with NSAE.

Rhinencephalon changes in tuberous sclerosis complex.

PURPOSE: Despite complex olfactory bulb embryogenesis, its development abnormalities in tuberous sclerosis complex (TSC) have been poorly investigated. METHODS: Brain MRIs of 110 TSC patients (mean age 11.5 years; age range 0.5-38 years; 52 female; 26 TSC1, 68 TSC2, 8 without mutation identified in TSC1 or TSC2, 8 not tested) were retrospectively evaluated. Signal and morphological abnormalities consistent with olfactory bulb hypo/aplasia or with olfactory bulb hamartomas were recorded. Cortical tuber number was visually assessed and a neurological severity score was obtained. Patients with and without rhinencephalon abnormalities were compared using appropriate parametric and non-parametric tests. RESULTS: Eight of110 (7.2%) TSC patients presented rhinencephalon MRI changes encompassing olfactory bulb bilateral aplasia (2/110), bilateral hypoplasia (2/110), unilateral hypoplasia (1/110), unilateral hamartoma (2/110), and bilateral hamartomas (1/110); olfactory bulb hypo/aplasia always displayed ipsilateral olfactory sulcus hypoplasia, while no TSC patient harboring rhinencephalon hamartomas had concomitant forebrain sulcation abnormalities. None of the patients showed overt olfactory deficits or hypogonadism, though young age and poor compliance hampered a proper evaluation in most cases. TSC patients with rhinencephalon changes had more cortical tubers (47 ± 29.1 vs 26.2 ± 19.6; p = 0.006) but did not differ for clinical severity (p = 0.45) compared to the other patients of the sample. CONCLUSIONS: Olfactory bulb and/or forebrain changes are not rare among TSC subjects. Future studies investigating clinical consequences in older subjects (anosmia, gonadic development etc.) will define whether rhinencephalon changes are simply an imaging feature among the constellation of TSC-related brain changes or a feature to be searched for possible implications in the management of TSC subjects.