Anticoagulation helps shrink giant venous lakes and arteriovenous fistulas in dural sinus malformation.

BACKGROUND: Dural sinus malformations (DSMs) associated with high flow arteriovenous shunts are a challenging disease in babies that can lead to severe neurological damage or death. We report our treatment strategy in seven consecutive DSMs. METHODS: We performed a retrospective analysis of seven consecutive patients from four centres, treated with transarterial embolization and anticoagulants. RESULTS: Mean clinical and imaging follow-up was 2.8 years (IQR1-3 1.8-5.3). At baseline, the median size of the dilated venous pouch (giant lake) was 35 mm (IQR1-3 24-41) that decreased to a normal or near normal venous collector diameter of median size 11.5 mm (IQR1-3 8.5-13.8). This was achieved after a median of two embolization sessions targeted on dural feeders (IQR1-3 1.5-2.5), leaving associated pial feeders untreated. There were no cerebral hemorrhagic complications during the anticoagulation treatment. Median percentage of shunt remaining after embolization was 30% (IQR1-3 12-30), which spontaneously decreased with anticoagulation and even after discontinuation of anticoagulation, in parallel with the reduction in diameter of the dilated sinus, up to healing (or near healing). At the last clinical assessment, the modified Rankin Scale score was 0 in four patients, 1 in one patient, and 3 in two patients. CONCLUSIONS: Anticoagulants may help to potentiate transarterial embolization in DSMs in babies by decreasing venous dilatation and reducing the remaining arteriovenous shunt, particularly the pial feeders. We did not observe recurrence of arteriovenous shunts after treatment, especially during anticoagulation treatment. Further studies are needed to support our findings.

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.

Effect of Dimethyl Fumarate vs Interferon ß-1a in Patients With Pediatric-Onset Multiple Sclerosis: The CONNECT Randomized Clinical Trial.

Importance: With few approved multiple sclerosis therapies in the pediatric population, there is a need for further approved treatment options. Limited data exist for dimethyl fumarate (DMF) treatment in pediatric-onset multiple sclerosis (POMS). Objective: To compare the efficacy, safety, and tolerability of DMF vs intramuscular interferon ß-1a (IFNß-1a) in POMS. Design, Setting, and Participants: The CONNECT study was an active-controlled, open-label, rater-blinded 96-week randomized clinical trial in patients with POMS aged 10 to less than 18 years treated between August 2014 and November 2020. Data were analyzed from January through October 2021. Interventions: Patients were randomized to DMF or IFNß-1a. Main Outcomes and Measures: The primary end point was the proportion of patients free of new or newly enlarging (N or NE) T2 hyperintense lesions at week 96 among trial completers. Secondary end points included number of N or NE T2 lesions, proportion of patients free of relapse, annualized relapse rate (ARR), and safety. The estimated proportion of participants who were relapse free up to week 96 was calculated based on the Kaplan-Meier method. Adjusted ARR was obtained from a negative binomial regression adjusted for baseline relapse rate, baseline Expanded Disability Status Scale (EDSS) score, and age group. Results: Among 150 patients with POMS in the intention-to-treat (ITT) population (median [range] age, 15 [10-17] years; 101 [67.3%] female patients), 78 individuals received DMF and 72 individuals received IFNß-1a. At week 96, the proportion of patients with no N or NE T2 hyperintense lesions among 103 trial completers was 16.1% (95% CI, 8.0%-27.7%) for DMF vs 4.9% (95% CI, 0.6%-16.5%) for IFNß-1a, and in a sensitivity analysis among the ITT population, the proportions were 10 patients receiving DMF (12.8%) vs 2 patients receiving IFNß-1a (2.8%). The estimated proportion of patients who remained relapse free at week 96 was 66.2% for DMF vs 52.3% for IFNß-1a. Adjusted ARR (95% CI) at week 96 was 0.24 (95% CI, 0.15-0.39) for DMF vs 0.53 (95% CI, 0.33-0.84) for IFNß-1a; the rate ratio for DMF vs IFNß-1a was 0.46 (95% CI, 0.26-0.80; P = .006). The number of treatment-emergent adverse events (TEAEs; 74 patients [94.9%] vs 69 patients [95.8%]), serious TEAEs (18 patients [23.1%] vs 21 patients [29.2%]), and treatment discontinuations due to TEAEs (5 patients [6.4%] vs 8 patients [11.1%]) was similar for DMF vs IFNß-1a. Conclusions and Relevance: This study found that more pediatric patients with POMS treated with DMF were free of new or newly enlarging T2 lesions and that the adjusted ARR was lower among these patients compared with those treated with interferon ß-1a. DMF was well tolerated. Trial Registration: ClinicalTrials.gov Identifier: NCT02283853.

Diagnosis and Management of Opsoclonus-Myoclonus-Ataxia Syndrome in Children: An International Perspective.

BACKGROUND AND OBJECTIVES: Opsoclonus-myoclonus-ataxia syndrome (OMAS) is a rare disorder of the nervous system that classically presents with a combination of characteristic eye movement disorder and myoclonus, in addition to ataxia, irritability, and sleep disturbance. There is good evidence that OMAS is an immune-mediated condition that may be paraneoplastic in the context of neuroblastoma. This syndrome may be associated with long-term cognitive impairment, yet it remains unclear how this is influenced by disease course and treatment. Treatment is largely predicated on immune suppression, but there is limited evidence to indicate an optimal regimen. METHODS: Following an international multiprofessional workshop in 2004, a body of clinicians and scientists comprising the International OMS Study group continued to meet biennially in a joint professionals and family workshop focusing on pediatric OMAS. Seventeen years after publication of the first report, a writing group was convened to provide a clinical update on the definitions and clinical presentation of OMAS, biomarkers and the role of investigations in a child presenting with OMAS, treatment and management strategies including identification and support of long-term sequelae. RESULTS: The clinical criteria for diagnosis were reviewed, with a proposed approach to laboratory and radiologic investigation of a child presenting with possible OMAS. The evidence for an upfront vs escalating treatment regimen was reviewed, and a treatment algorithm proposed to recognize both these approaches. Importantly, recommendations on monitoring of immunotherapy response and longer-term follow-up based on an expert consensus are provided. DISCUSSION: OMAS is a rare neurologic condition that can be associated with poor cognitive outcomes. This report proposes an approach to investigation and treatment of children presenting with OMAS, based on expert international opinion recognizing the limited data available.

Glial Fibrillary Acidic Protein Autoimmunity: A French Cohort Study.

BACKGROUND AND OBJECTIVES: To report the clinical, biological, and imaging features and clinical course of a French cohort of patients with glial fibrillary acidic protein (GFAP) autoantibodies. METHODS: We retrospectively included all patients who tested positive for GFAP antibodies in the CSF by immunohistochemistry and confirmed by cell-based assay using cells expressing human GFAPα since 2017 from 2 French referral centers. RESULTS: We identified 46 patients with GFAP antibodies. Median age at onset was 43 years, and 65% were men. Infectious prodromal symptoms were found in 82%. Other autoimmune diseases were found in 22% of patients, and coexisting neural autoantibodies in 11%. Tumors were present in 24%, and T-cell dysfunction in 23%. The most frequent presentation was subacute meningoencephalitis (85%), with cerebellar dysfunction in 57% of cases. Other clinical presentations included myelitis (30%) and visual (35%) and peripheral nervous system involvement (24%). MRI showed perivascular radial enhancement in 32%, periventricular T2 hyperintensity in 41%, brainstem involvement in 31%, leptomeningeal enhancement in 26%, and reversible splenial lesions in 4 cases. A total of 33 of 40 patients had a monophasic course, associated with a good outcome at last follow-up (Rankin Score ≤2: 89%), despite a severe clinical presentation. Adult and pediatric features are similar. Thirty-two patients were treated with immunotherapy. A total of 11/22 patients showed negative conversion of GFAP antibodies. DISCUSSION: GFAP autoimmunity is mainly associated with acute/subacute meningoencephalomyelitis with prodromal symptoms, for which tumors and T-cell dysfunction are frequent triggers. The majority of patients followed a monophasic course with a good outcome.

Clinical Trials for Gene Therapy in Lysosomal Diseases With CNS Involvement.

There are over 70 known lysosomal storage disorders (LSDs), most caused by mutations in genes encoding lysosomal hydrolases. Central nervous system involvement is a hallmark of the majority of LSDs and, if present, generally determines the prognosis of the disease. Nonetheless, brain disease is currently poorly targeted by available therapies, including systemic enzyme replacement therapy, mostly (but not only) due to the presence of the blood-brain barrier that restricts the access of orally or parenterally administered large molecules into the brain. Thus, one of the greatest and most exciting challenges over coming years will be to succeed in developing effective therapies for the treatment of central nervous system manifestations in LSDs. Over recent years, gene therapy (GT) has emerged as a promising therapeutic strategy for a variety of inherited neurodegenerative diseases. In LSDs, the ability of genetically corrected cells to cross-correct adjacent lysosomal enzyme-deficient cells in the brain after gene transfer might enhance the diffusion of the recombinant enzyme, making this group of diseases a strong candidate for such an approach. Both in vivo (using the administration of recombinant adeno-associated viral vectors) and ex vivo (auto-transplantation of lentiviral vector-modified hematopoietic stem cells-HSCs) strategies are feasible. Promising results have been obtained in an ever-increasing number of preclinical studies in rodents and large animal models of LSDs, and these give great hope of GT successfully correcting neurological defects, once translated to clinical practice. We are now at the stage of treating patients, and various clinical trials are underway, to assess the safety and efficacy of in vivo and ex vivo GT in several neuropathic LSDs. In this review, we summarize different approaches being developed and review the current clinical trials related to neuropathic LSDs, their results (if any), and their limitations. We will also discuss the pitfalls and the remaining challenges.

Use and Safety of Immunotherapeutic Management of N-Methyl-d-Aspartate Receptor Antibody Encephalitis: A Meta-analysis.

Importance: Overall, immunotherapy has been shown to improve outcomes and reduce relapses in individuals with N-methyl-d-aspartate receptor (NMDAR) antibody encephalitis (NMDARE); however, the superiority of specific treatments and combinations remains unclear. Objective: To map the use and safety of immunotherapies in individuals with NMDARE, identify early predictors of poor functional outcome and relapse, evaluate changes in immunotherapy use and disease outcome over the 14 years since first reports of NMDARE, and assess the Anti-NMDAR Encephalitis One-Year Functional Status (NEOS) score. Data Sources: Systematic search in PubMed from inception to January 1, 2019. Study Selection: Published articles including patients with NMDARE with positive NMDAR antibodies and available individual immunotherapy data. Data Extraction and Synthesis: Individual patient data on immunotherapies, clinical characteristics at presentation, disease course, and final functional outcome (modified Rankin Scale [mRS] score) were entered into multivariable logistic regression models. Main Outcomes and Measures: The planned study outcomes were functional outcome at 12 months from disease onset (good, mRS score of 0 to 2; poor, mRS score greater than 2) and monophasic course (absence of relapse at 24 months or later from onset). Results: Data from 1550 patients from 652 articles were evaluated. Of these, 1105 of 1508 (73.3%) were female and 707 of 1526 (46.3%) were 18 years or younger at disease onset. Factors at first event that were significantly associated with good functional outcome included adolescent age and first-line treatment with therapeutic apheresis, corticosteroids plus intravenous immunoglobulin (IVIG), or corticosteroids plus IVIG plus therapeutic apheresis. Factors significantly associated with poor functional outcome were age younger than 2 years or age of 65 years or older at onset, intensive care unit admission, extreme delta brush pattern on electroencephalography, lack of immunotherapy within the first 30 days of onset, and maintenance IVIG use for 6 months or more. Factors significantly associated with nonrelapsing disease were rituximab use or maintenance IVIG use for 6 months or more. Adolescent age at onset was significantly associated with relapsing disease. Rituximab use increased from 13.5% (52 of 384; 2007 to 2013) to 28.3% (311 of 1100; 2013 to 2019) (P < .001), concurrent with a falling relapse rate over the same period (22% [12 of 55] in 2008 and earlier; 10.9% [35 of 322] in 2017 and later; P = .006). Modified NEOS score (including 4 of 5 original NEOS items) was associated with probability of poor functional status at 1 year (20.1% [40 of 199] for a score of 0 to 1 points; 43.8% [77 of 176] for a score of 3 to 4 points; P = .05). Conclusions and Relevance: Factors influencing functional outcomes and relapse are different and need to be considered independently in development of evidence-based optimal management guidelines of patients with NMDARE.

Neurological involvement in secondary hemophagocytic lymphohistiocytosis in children.

OBJECTIVES: To describe neurological characteristics and CNS involvement on MRI in secondary hemophagocytic lymphohistiocytosis (sHLH) and differentiate it from primary hemophagocytic lymphohistiocytosis (pHLH) and acute disseminated encephalomyelitis (ADEM). METHODS: Nine children with sHLH who had neurological symptoms were retrospectively included. Characteristics of brain MRI were compared to those of 15 children with pHLH and neurological involvement and 44 children with ADEM. RESULTS: Three children (33%) presented with isolated neurological symptoms. Neurological signs occurred within one month following Epstein-Barr virus primary infection or systemic juvenile arthritis exacerbation in 8 patients (89%). Eight children (89%) had MRI lesions. sHLH MRI lesions were distinct of those of pHLH by morphology and signal with more frequent hyposignal intensities on T1-weighted sequences (p = 0.01) and well-defined and less fuzzy lesions (p = 0.03). All patients survived and one patient presented severe motor and cognitive disability. CONCLUSION: Neurological symptoms of sHLH are non-specific and their outcome is favorable in most of the children. MRI at onset may help to differentiate this condition from pHLH.

Intracerebral Gene Therapy in Four Children with Sanfilippo B Syndrome: 5.5-Year Follow-Up Results.

We report the safety (primary endpoint) and efficacy (secondary endpoint) of a novel intracerebral gene therapy at 5.5 years of follow-up in children with Sanfilippo B. An uncontrolled, phase 1/2 clinical trial was performed in four patients aged 20, 26, 30, and 53 months. Treatment consisted of 16 intracerebral and cerebellar deposits of a recombinant adeno-associated viral vector encoding human α-N-acetylglucosaminidase (rAAV2/5-hNAGLU) plus immunosuppression. An intermediate report at 30 months was previously published. Thirty treatment-emergent adverse events were reported between 30 and 66 months after surgery, including three classified as severe with no serious drug reactions. At 5.5 years, NAGLU activity was persistently detected in the lumbar cerebrospinal fluid (18% of unaffected control level). Circulating T cells reacting against NAGLU peptides were present, indicating a lack of acquired tolerance. Patients 2, 3, and 4 showed progressive brain atrophy and neurocognitive evolution that did not differ from untreated Sanfilippo A/B children. Patient 1, enrolled at 20 months of age, had a milder disease with normal brain imaging and a significantly better cognitive outcome than the three other patients and untreated patients, although not equivalent to normal children. After 5.5 years, the primary endpoint of this study was achieved with a good safety profile of the proposed treatment. We have also observed sustained enzyme production in the brain and absence of immunological tolerance. Cognitive benefit was not confirmed in the three oldest patients. Milder disease in the youngest patient supports further investigations of adeno-associated vector-mediated intracerebral gene therapy in Sanfilippo B.

International Consensus Recommendations for the Treatment of Pediatric NMDAR Antibody Encephalitis.

OBJECTIVE: To create an international consensus treatment recommendation for pediatric NMDA receptor antibody encephalitis (NMDARE). METHODS: After selection of a panel of 27 experts with representation from all continents, a 2-step Delphi method was adopted to develop consensus on relevant treatment regimens and statements, along with key definitions in pediatric NMDARE (disease severity, failure to improve, and relapse). Finally, an online face-to-face meeting was held to reach consensus (defined as ≥75% agreement). RESULTS: Corticosteroids are recommended in all children with NMDARE (pulsed IV preferred), with additional IV immunoglobulin or plasma exchange in severe patients. Prolonged first-line immunotherapy can be offered for up to 3-12 months (oral corticosteroids or monthly IV corticosteroids/immunoglobulin), dependent on disease severity. Second-line treatments are recommended for cases refractory to first-line therapies (rituximab preferred over cyclophosphamide) and should be considered about 2 weeks after first-line initiation. Further immunotherapies for refractory disease 1-3 months after second-line initiation include another second-line treatment (such as cyclophosphamide) and escalation to tocilizumab. Maintenance immune suppression beyond 6 months (such as rituximab redosing or mycophenolate mofetil) is generally not required, except for patients with a more severe course or prolonged impairments and hospitalization. For patients with relapsing disease, second-line and prolonged maintenance therapy should be considered. The treatment of NMDARE following herpes simplex encephalitis should be similar to idiopathic NMDARE. Broad guidance is provided for the total treatment duration (first line, second line, and maintenance), which is dictated by the severity and clinical course (i.e., median 3, 9 and 18 months in the best, average, and worst responders, respectively). Recommendations on the timing of oncologic searches are provided. CONCLUSION: These international consensus recommendations for the management of pediatric NMDARE aim to standardize the treatment and provide practical guidance for clinicians, rather than absolute rules. A similar recommendation could be applicable to adult patients.

Cell-Mediated Immunity to NAGLU Transgene Following Intracerebral Gene Therapy in Children With Mucopolysaccharidosis Type IIIB Syndrome.

Mucopolysaccharidosis type IIIB syndrome (Sanfilippo disease) is a rare autosomic recessif disorder caused by mutations in the α-N-acetylglucosaminidase (NAGLU) gene coding for a lysosomal enzyme, leading to neurodegeneration and progressive deterioration of cognitive abilities in affected children. To supply the missing enzyme, several recent human gene therapy trials relied on the deposit of adeno-associated virus (AAV) vectors directly into the brain. We reported safety and efficacy of an intracerebral therapy in a phase 1/2 clinical trial (https://clinicaltrials.gov/ct2/show/NCT03300453), with a recombinant AAV serotype 2/5 (rAAV2/5) coding human NAGLU in four children with MPS IIIB syndrome receiving immunosuppression. It was reported that AAV-mediated gene therapies might elicit a strong host immune response resulting in decreased transgene expression. To address this issue, we performed a comprehensive analysis of cellular immunity and cytokine patterns generated against the therapeutic enzyme in the four treated children over 5.5 years of follow-up. We report the emergence of memory and polyfunctional CD4+ and CD8+ T lymphocytes sensitized to the transgene soon after the start of therapy, and appearing in peripheral blood in waves throughout the follow-up. However, this response had no apparent impact on CNS transgene expression, which remained stable 66 months after surgery, possibly a consequence of the long-term immunosuppressive treatment. We also report that gene therapy did not trigger neuroinflammation, evaluated through the expression of cytokines and chemokines in patients' CSF. Milder disease progression in the youngest patient was found associated with low level and less differentiated circulating NAGLU-specific T cells, together with the lack of proinflammatory cytokines in the CSF. Findings in this study support a systematic and comprehensive immunomonitoring approach for understanding the impact immune reactions might have on treatment safety and efficacy of gene therapies.

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.

Imaging in Pediatric Multiple Sclerosis : An Iconographic Review.

Pediatric-onset multiple sclerosis (POMS) is defined by a first multiple sclerosis (MS) attack occurring before 18 years old and is diagnosed by demonstration of dissemination in time (DIT) and space (DIS). Although guidelines evolved over the years, they always recognized the importance of magnetic resonance imaging (MRI) for diagnosis. The 2017 McDonald criteria are increasingly used and have been validated in several cohorts. The use of MRI is the most important tool for the early diagnosis, monitoring, and assessment of treatment response of MS and standard protocols include precontrast and postcontrast T1, T2, fluid attenuation inversion recovery (FLAIR) and diffusion sequences. A distinctive MS lesion compromises white matter and it is well-demarcated and confluent, showing demyelination, inflammation, gliosis, and relative axonal preservation. Considering the growing recognition of pediatric MS as a differential diagnosis for children presenting with a clinical central nervous system event, we present a POMS lesions guide (periventricular, juxtacortical, infratentorial, spinal cord, cortical, tumefactive, black hole, contrast-enhanced). Owing to its rareness, POMS is a diagnosis by exclusion and MRI plays a fundamental role in distinguishing POMS from other demyelinating and non-demyelinating conditions. Three main groups of disorders can mimic POMS: inflammatory, metabolic and tumoral; however, imaging patterns earlier described lower the possibilities of alternative diagnoses and strongly suggest POMS when likely.

Mild Encephalitis/Encephalopathy with reversible splenial lesion syndrome: An unusual presentation of anti-GFAP astrocytopathy.

Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy is a rare recently defined antibody-mediated encephalitis. Meningo-encephalomyelitis presentation is frequent with lymphocytic pleiocytosis in the cerebro-spinal fluid and brain MRI classically demonstrates in 50% of cases, a linear perivascular enhancement extending radially from the ventricles. Here, we describe 2 cases of pediatric autoimmune GFAP astrocytopathy with limbic encephalitis presentation and peculiar MRI characteristics: one with normal MRI and the second suggestive of Mild Encephalitis/Encephalopathy with reversible splenial lesion syndrome (MERS). These two cases illustrate that anti-GFAP antibodies should be sought in children presenting limbic encephalitis with a normal and/or MERS suggestive MRI, as treatment strategies may differ.

Intradermal vaccination prevents anti-MOG autoimmune encephalomyelitis in macaques.

BACKGROUND: Autoimmune demyelinating diseases (ADD) are a major cause of neurological disability due to autoreactive cellular and humoral immune responses against brain antigens. A cure for chronic ADD could be obtained by appropriate immunomodulation. METHODS: We implemented a preclinical scheme to foster immune tolerance to myelin oligodendrocyte glycoprotein (MOG), in a cynomolgus-macaque model of experimental autoimmune encephalomyelitis (EAE), in which administration of recombinant human MOG (rhMOG) elicits brain inflammation mediated by MOG-autoreactive CD4+ lymphocytes and anti-MOG IgG. For immunotherapy, we used a recombinant antibody (Ab) directed against the dendritic cell-asialoglycoprotein receptor (DC-ASGPR) fused either to MOG or a control antigen PSA (prostate-specific antigen). FINDINGS: rhMOG and the anti-DC-ASGPR-MOG were respectively detected in CD1a+ DCs or CD163+ cells in the skin of macaques. Intradermal administration of anti-DC-ASGPR-MOG, but not control anti-DC-ASGPR-PSA, was protective against EAE. The treatment prevented the CD4+ T cell activation and proinflammatory cytokine production observed in controls. Moreover, the administration of anti-DC-ASGPR-MOG induced MOG-specific CD4+CD25+FOXP3+CD39+ regulatory lymphocytes and favoured an upsurge in systemic TGFß and IL-8 upon rhMOG re-administration in vivo. INTERPRETATION: We show that the delivery of an anti-DC-ASGPR-MOG allows antigen-specific adaptive immune modulation to prevent the breach of immune tolerance to MOG. Our findings pave the way for therapeutic vaccines for long-lasting remission to grave encephalomyelitis with identified autoantigens, such as ADD associated with anti-MOG autoantibodies. FUND: Work supported by the French ANR (ANR-11-INBS-0008 and ANR-10-EQPX-02-01), NIH (NIH 1 R01 AI 105066), the Baylor Scott and White Healthcare System funding and Roche Research Collaborative grants.

Relapsing encephalopathy with cerebellar ataxia are caused by variants involving p.Arg756 in ATP1A3.

Mutations in ATP1A3 lead to different phenotypes having in common acute neurological decompensation episodes triggered by a specific circumstance and followed by sequelae. Alongside Alternating Hemiplegia of Childhood (AHC), Rapid-onset Dystonia Parkinsonism (RDP) and Cerebellar ataxia, Areflexia, Pes cavus, Optic atrophy, Sensorineural hearing loss syndrome (CAPOS), a new Relapsing Encephalopathy with Cerebellar Ataxia (RECA) phenotype was published in 2015. We describe herein eight new pediatric cases. Most of them had no specific history when the first neurological decompensation episode occurred, before the age of 5 years, triggered by fever with severe paralytic hypotonia followed by ataxia with or without abnormal movements. Neurological sequelae with ataxia as the predominant symptom were present after the first episode in three cases and after at least one subsequent relapse in five cases. Five of the eight cases had a familial involvement with one of the two parents affected. The phenotype-genotype correlation is unequivocal with the causal substitution always located at position 756. The pathophysiology of the dysfunctions of the mutated ATPase pump, triggered by fever is unknown. Severe recurrent neurological decompensation episodes triggered by fever, without any metabolic cause, should lead to the sequencing of ATP1A3.

Acute transverse myelitis following an opsoclonus-myoclonus syndrome: An unusual presentation.

Opso-myoclonus syndrome (OMS) is a very rare and severe condition. Ataxia, opsoclonus, myoclonus and/or behavioral and sleeping disturbances define that autoimmune disorder syndrome which is paraneoplastic or triggered by an infection. Here, we report a 3 year-old immunocompetent boy who developed an atypical OMS which was later complicated by an acute transverse myelitis. Screening for neuroblastoma was negative and extensive infectious screening revealed an active HHV-6 infection confirmed by blood and cerebrospinal fluid PCR. A parainfectious disease was suggested and immunosuppressive treatment was initiated. After 2 years of follow-up, the patient has a left leg paresia needing a splint and is otherwise normal. Transverse myelitis can be associated with parainfectious OMS and earlier immunosuppressive treatment in these cases may be useful especially in young and immunocompetent children.

MOG antibody-related disorders: common features and uncommon presentations.

Myelin oligodendrocyte glycoprotein antibodies (MOG-Ab) have been reported in acute demyelinating encephalomyelitis (ADEM), optic neuritis (ON), and neuromyelitis optica spectrum disorders (NMOSD) in adults and pediatrics. We aimed to delineate the common features of MOG-Ab-related disorders in children and adults, and report uncommon presentations. Twenty-seven consecutive pediatric and adult patients testing positive for MOG-Ab, with a minimum follow-up of 6 months, were included. Comprehensive epidemiological, clinical, radiological, and laboratory data were retrospectively analyzed. Additionally, we compared radiological features between ADEM MOG-Ab-positive patients, and a group of ADEM MOG-Ab-negative ones, recruited during the same period. Among the whole cohort, 13 (48.1%) were pediatric, and 14 (51.9%) were female. MOG-Ab-related disorders comprised eight ADEM, eight ON, five isolated myelitis, four with NMOSD and two patients with multiple sclerosis, at last follow-up. After a median follow-up of 17.8 months, 11 (40.7%) patients presented a relapse. The most frequent clinical phenotype at onset was encephalopathy in pediatrics (53.9%) and myelitis in adults (50%) (p = 0.013). There were no other differences between both groups. When comparing ADEM MOG-Ab positive and negative patients, bilateral thalamic lesions were more often found in the positive group (p = 0.010). Unusual presentations were identified in three patients: patchy spinal cord gadolinium-enhancing lesions, an associated teratoma, and one presented with status epilepticus. MOG-Ab-related disorders shared common clinical and prognostic features, but encompass a spectrum wider than recently reported.