Heterozygous NOTCH1 Variants Cause CNS Immune Activation and Microangiopathy.

NOTCH1 belongs to the NOTCH family of proteins that regulate cell fate and inflammatory responses. Somatic and germline NOTCH1 variants have been implicated in cancer, Adams-Oliver syndrome, and cardiovascular defects. We describe 7 unrelated patients grouped by the presence of leukoencephalopathy with calcifications and heterozygous de novo gain-of-function variants in NOTCH1. Immunologic profiling showed upregulated CSF IP-10, a cytokine secreted downstream of NOTCH1 signaling. Autopsy revealed extensive leukoencephalopathy and microangiopathy with vascular calcifications. This evidence implicates that heterozygous gain-of-function variants in NOTCH1 lead to a chronic central nervous system (CNS) inflammatory response resulting in a calcifying microangiopathy with leukoencephalopathy. ANN NEUROL 2022;92:895-901.

Development and preliminary validation of the Sleep Screening for Children and Adolescents with Complex Chronic Conditions (SCAC).

Children and adolescents with complex chronic conditions, including those with life-threatening or life-limiting conditions, are a heterogeneous population. Many individuals exhibit sleep abnormalities that are measurable by proxy questionnaires. No suitable instrument to assess the wide range of different complex chronic conditions is currently available. The aim of the present study was to develop a screening tool-the Sleep Screening for Children and Adolescents with Complex Chronic Conditions-to effectively obtain sleep behaviour information in this population. Following a mixed-method design, potential items for the Sleep Screening for Children and Adolescents with Complex Chronic Conditions questionnaire were defined through literature research and expert meetings. In a pre-test with N = 60 family and professional caregivers, the items' relevance and comprehensibility as well as the instrument's overall design were assessed. For the main test, N = 315 participants were recruited in three tertiary paediatric hospitals. A principal components analysis detected the questionnaire's scales. Item analysis focused on mean values, range, difficulty and discriminatory power. Convergent validation of the Sleep Screening for Children and Adolescents with Complex Chronic Conditions was assessed via correlations between scale items. Most patients had neurological or neuromuscular diseases. Four scales ("Falling and staying asleep", "Sleep-associated respiration and arousal", "Daytime sleepiness" and "Sleep-associated movements") emerged. The item analysis showed satisfactory discriminative power. In the preliminary validation, all scales correlated positively with a child's care level and with various sleep circumstances items. Three scales additionally correlated with the number of complex chronic condition diagnoses. This newly developed questionnaire can provide clinicians with first indications of possible sleep problems in a growing paediatric population.

Neurofibromatosis type 1: A comparison of the 1997 NIH and the 2021 revised diagnostic criteria in 75 children and adolescents.

PURPOSE: Examining a cohort of patients suspicious of neurofibromatosis type 1 (NF1) we compared the revised diagnostic criteria with the previous National Institutes of Health (NIH) diagnostic criteria. We asked whether the refinement improved distinguishing between NF1, Legius syndrome, and constitutional mismatch repair deficiency (CMMRD). METHODS: A database search in the hospital information system of the University Children's Hospital Augsburg between 2017 and 2020 ascertained patients with International Classification of Diseases-10 code Q85.0; their clinical phenotype was evaluated by retrospective chart review. RESULTS: A total of 75 patients were identified (median age 11.0 years [range 1.1-22.6 years]; 35 female). At first suspicion of NF1, 44 patients met the NIH criteria and 56 met the revised diagnostic criteria. In total, 12 patients were diagnosed with NF1 after performing molecular genetic testing. In 31 patients, only pigmentary findings were present, whereas nonpigmentary NF1 manifestations presented with time in 9 patients. In 1 patient a heterozygous variant of uncertain significance was identified in SPRED1. Requirements for CMMRD testing were fulfilled in another patient. A total of 3 patients presented with segmental clinical findings. Three additional patients did not meet the NIH criteria, 1 of them presented with 1 additional feature of CMMRD without fulfilling requirements for testing. CONCLUSION: In our pediatric cohort, the revised diagnostic criteria discovered more patients with proven NF1 than the NIH criteria.

The need for tumor surveillance of children and adolescents with cancer predisposition syndromes: a retrospective cohort study in a tertiary-care children's hospital.

Expert recommendations for the management of tumor surveillance in children with a variety of cancer predisposition syndromes (CPS) are available. We aimed (1) at identifying and characterizing children who are affected by a CPS and (2) at comparing current practice and consensus recommendations of the American Association for Cancer Research workshop in 2016. We performed a database search in the hospital information system of the University Children's Hospital for CPS in children, adolescents, and young adults and complemented this by review of electronic patients' charts. Between January 1, 2017, and December 3, 2019, 272 patients with 41 different CPS entities were identified in 20 departments (144 [52.9%] male, 128 [47.1%] female, median age 9.1 years, range, 0.4-27.8). Three (1.1%) patients died of non-malignancy-associated complications of the CPS; 49 (18.0%) patients were diagnosed with malignancy and received regular follow-up. For 209 (95.0%) of the remaining 220 patients, surveillance recommendations were available: 30/220 (13.6%) patients received CPS consultations according to existing consensus recommendations, 22/220 (10.0%) institutional surveillance approaches were not complying with recommendations, 84/220 (38.2%) patients were seen for other reasons, and 84/220 (38.2%) were not routinely cared for. Adherence to recommendations differed extensively among CPS entities. CONCLUSION: The spectrum of CPS patients at our tertiary-care children's hospital is manifold. For most patients, awareness of cancer risk has to be enhanced and current practice needs to be adapted to consensus recommendations. Offering specialized CPS consultations and establishing education programs for patients, relatives, and physicians may increase adherence to recommendations. WHAT IS KNOWN: • A wide spectrum of rare syndromes manifesting in childhood is associated with an increased cancer risk. • For many of these syndromes, expert recommendations for management and tumor surveillance are available, although based on limited evidence. WHAT IS NEW: • Evaluating current practice, our data attest significant shortcomings in tumor surveillance of children and adolescents with CPS even in a tertiary-care children's hospital. • We clearly advocate a systematic and consistent integration of tumor surveillance into daily practice.

Clinical and Magnetic Resonance Imaging Outcome Predictors in Pediatric Anti-N-Methyl-D-Aspartate Receptor Encephalitis.

OBJECTIVE: To evaluate disease symptoms, and clinical and magnetic resonance imaging (MRI) findings and to perform longitudinal volumetric MRI analyses in a European multicenter cohort of pediatric anti-N-methyl-D-aspartate receptor encephalitis (NMDARE) patients. METHODS: We studied 38 children with NMDARE (median age = 12.9 years, range =1-18) and a total of 82 MRI scans for volumetric MRI analyses compared to matched healthy controls. Mixed-effect models and brain volume z scores were applied to estimate longitudinal brain volume development. Ordinal logistic regression and ordinal mixed models were used to predict disease outcome and severity. RESULTS: Initial MRI scans showed abnormal findings in 15 of 38 (39.5%) patients, mostly white matter T2/fluid-attenuated inversion recovery hyperintensities. Volumetric MRI analyses revealed reductions of whole brain and gray matter as well as hippocampal and basal ganglia volumes in NMDARE children. Longitudinal mixed-effect models and z score transformation showed failure of age-expected brain growth in patients. Importantly, patients with abnormal MRI findings at onset were more likely to have poor outcome (Pediatric Cerebral Performance Category score > 1, incidence rate ratio = 3.50, 95% confidence interval [CI] = 1.31-9.31, p = 0.012) compared to patients with normal MRI. Ordinal logistic regression models corrected for time from onset confirmed abnormal MRI at onset (odds ratio [OR] = 9.90, 95% CI = 2.51-17.28, p = 0.009), a presentation with sensorimotor deficits (OR = 13.71, 95% CI = 2.68-24.73, p = 0.015), and a treatment delay > 4 weeks (OR = 5.15, 95% CI = 0.47-9.82, p = 0.031) as independent predictors of poor clinical outcome. INTERPRETATION: Children with NMDARE exhibit significant brain volume loss and failure of age-expected brain growth. Abnormal MRI findings, a clinical presentation with sensorimotor deficits, and a treatment delay > 4 weeks are associated with worse clinical outcome. These characteristics represent promising prognostic biomarkers in pediatric NMDARE. ANN NEUROL 2020 ANN NEUROL 2020;88:148-159.

Cerebrospinal fluid findings in patients with myelin oligodendrocyte glycoprotein (MOG) antibodies. Part 2: Results from 108 lumbar punctures in 80 pediatric patients.

BACKGROUND: New-generation, cell-based assays have demonstrated a robust association of serum autoantibodies to full-length human myelin oligodendrocyte glycoprotein (MOG-IgG) with (mostly recurrent) optic neuritis, myelitis, and brainstem encephalitis, as well as with neuromyelitis optica (NMO)-like or acute-disseminated encephalomyelitis (ADEM)-like presentations. However, only limited data are yet available on cerebrospinal fluid (CSF) findings in MOG-IgG-associated encephalomyelitis (MOG-EM; also termed MOG antibody-associated disease, MOGAD). OBJECTIVE: To describe systematically the CSF profile in children with MOG-EM. MATERIAL AND METHODS: Cytological and biochemical findings (including white cell counts [WCC] and differentiation; frequency and patterns of oligoclonal bands; IgG/IgM/IgA and albumin concentrations and CSF/serum ratios; intrathecal IgG/IgM/IgA fractions; locally produced IgG/IgM/IgA concentrations; immunoglobulin class patterns; IgG/IgA/IgM reibergrams; Link index; measles/rubella/zoster [MRZ] reaction; other anti-viral and anti-bacterial antibody indices; CSF total protein; CSF L-lactate) from 108 lumbar punctures in 80 pediatric patients of mainly Caucasian descent with MOG-EM were analyzed retrospectively. RESULTS: Most strikingly, CSF-restricted oligoclonal IgG bands, a hallmark of multiple sclerosis (MS), were absent in 89% of samples (N = 96), and the MRZ reaction, the most specific laboratory marker of MS known so far, in 100% (N = 29). If present at all, intrathecal IgG synthesis was low, often transient and mostly restricted to acute attacks. Intrathecal IgM synthesis was present in 21% and exclusively detectable during acute attacks. CSF WCC were elevated in 54% of samples (median 40 cells/µl; range 6-256; mostly lymphocytes and monocytes; > 100/µl in 11%). Neutrophils were present in 71% of samples; eosinophils, activated lymphocytes, and plasma cells were seen only rarely (all < 7%). Blood-CSF barrier dysfunction (as indicated by an elevated albumin CSF/serum ratio) was present in 46% of all samples (N = 79) and at least once in 48% of all patients (N = 67) tested. CSF alterations were significantly more frequent and/or more pronounced in patients with acute spinal cord or brain disease than in patients with acute ON and varied strongly depending on attack severity. CSF L-lactate levels correlated significantly with the spinal cord lesions load (measured in vertebral segments) in patients with acute myelitis (p = 0.0099). An analysis of pooled data from the pediatric and the adult cohort showed a significant relationship of QAlb (p < 0.0005), CST TP (p < 0.0001), and CSF L-lactate (p < 0.0003) during acute attacks with age. CONCLUSION: MOG-IgG-associated EM in children is characterized by CSF features that are distinct from those in MS. With regard to most parameters, no marked differences between the pediatric cohort and the adult cohort analyzed in Part 1 were noted. Our findings are important for the differential diagnosis of pediatric MS and MOG-EM and add to the understanding of the immunopathogenesis of this newly described autoimmune disease.

Childhood multiple sclerosis is associated with reduced brain volumes at first clinical presentation and brain growth failure.

BACKGROUND: Paediatric multiple sclerosis (pedMS) patients at a single site were shown to have reduced brain volumes and failure of age-expected brain growth compared to healthy controls. However, the precise time of onset of brain volume loss remains unclear. OBJECTIVE: To longitudinally study brain volumes in a multi-centre European cohort at first presentation and after 2 years. METHODS: Brain volumes of high-resolution magnetic resonance imaging (MRI) data from 37 pedMS patients at first presentation prior to steroid therapy and at 2-year follow-up ( n = 21) were compared to matched longitudinal MRI data from the NIH Paediatric MRI Data Repository. RESULTS: Patients showed significantly reduced whole brain, grey and white matter and increased ventricular volumes at initial presentation and at follow-up compared to controls. Over 2 years, patients exhibited significant reduction of whole brain and white matter volumes, accompanied by increased ventricular volume. Brain volume loss at follow-up correlated with a higher number of infratentorial lesions, relapses and an increased Expanded Disability Status Scale (EDSS) score. CONCLUSIONS: In pedMS patients, brain volume loss is present already at first clinical presentation and accelerated over 2 years. Increased disease activity is associated with more severe brain volume loss. MRI brain volume change might serve as an outcome parameter in future prospective pedMS studies.

FOXG1 syndrome: genotype-phenotype association in 83 patients with FOXG1 variants.

PurposeThe study aimed at widening the clinical and genetic spectrum and assessing genotype-phenotype associations in FOXG1 syndrome due to FOXG1 variants.MethodsWe compiled 30 new and 53 reported patients with a heterozygous pathogenic or likely pathogenic variant in FOXG1. We grouped patients according to type and location of the variant. Statistical analysis of molecular and clinical data was performed using Fisher's exact test and a nonparametric multivariate test.ResultsAmong the 30 new patients, we identified 19 novel FOXG1 variants. Among the total group of 83 patients, there were 54 variants: 20 frameshift (37%), 17 missense (31%), 15 nonsense (28%), and 2 in-frame variants (4%). Frameshift and nonsense variants are distributed over all FOXG1 protein domains; missense variants cluster within the conserved forkhead domain. We found a higher phenotypic variability than previously described. Genotype-phenotype association revealed significant differences in psychomotor development and neurological features between FOXG1 genotype groups. More severe phenotypes were associated with truncating FOXG1 variants in the N-terminal domain and the forkhead domain (except conserved site 1) and milder phenotypes with missense variants in the forkhead conserved site 1.ConclusionsThese data may serve for improved interpretation of new FOXG1 sequence variants and well-founded genetic counseling.

Oligoclonal bands predict multiple sclerosis in children with optic neuritis.

We retrospectively evaluated predictors of conversion to multiple sclerosis (MS) in 357 children with isolated optic neuritis (ON) as a first demyelinating event who had a median follow-up of 4.0 years. Multiple Cox proportional-hazards regressions revealed abnormal cranial magnet resonance imaging (cMRI; hazard ratio [HR] = 5.94, 95% confidence interval [CI] = 3.39-10.39, p < 0.001), presence of cerebrospinal fluid immunoglobulin G oligoclonal bands (OCB; HR = 3.69, 95% CI = 2.32-5.86, p < 0.001), and age (HR = 1.08 per year of age, 95% CI = 1.02-1.13, p = 0.003) as independent predictors of conversion, whereas sex and laterality (unilateral vs bilateral) had no influence. Combined cMRI and OCB positivity indicated a 26.84-fold higher HR for developing MS compared to double negativity (95% CI = 12.26-58.74, p < 0.001). Accordingly, cerebrospinal fluid analysis may supplement cMRI to determine the risk of MS in children with isolated ON.

Antibodies to MOG and AQP4 in children with neuromyelitis optica and limited forms of the disease.

OBJECTIVE: To determine the frequency and clinical-radiological associations of antibodies to myelin oligodendrocyte glycoprotein (MOG) and aquaporin-4 (AQP4) in children presenting with neuromyelitis optica (NMO) and limited forms. METHODS: Children with a first event of NMO, recurrent (RON), bilateral ON (BON), longitudinally extensive transverse myelitis (LETM) or brainstem syndrome (BS) with a clinical follow-up of more than 12 months were enrolled. Serum samples were tested for MOG- and AQP4-antibodies using live cell-based assays. RESULTS: 45 children with NMO (n=12), LETM (n=14), BON (n=6), RON (n=12) and BS (n=1) were included. 25/45 (56%) children had MOG-antibodies at initial presentation (7 NMO, 4 BON, 8 ON, 6 LETM). 5/45 (11%) children showed AQP4-antibodies (3 NMO, 1 LETM, 1 BS) and 15/45 (33%) were seronegative for both antibodies (2 NMO, 2 BON, 4 RON, 7 LETM). No differences were found in the age at presentation, sex ratio, frequency of oligoclonal bands or median EDSS at last follow-up between the three groups. Children with MOG-antibodies more frequently (1) had a monophasic course (p=0.018) after one year, (2) presented with simultaneous ON and LETM (p=0.004) and (3) were less likely to receive immunosuppressive therapies (p=0.0002). MRI in MOG-antibody positive patients (4) less frequently demonstrated periependymal lesions (p=0.001), (5) more often were unspecific (p=0.004) and (6) resolved more frequently (p=0.016). CONCLUSIONS: 67% of all children presenting with NMO or limited forms tested positive for MOG- or AQP4-antibodies. MOG-antibody positivity was associated with distinct features. We therefore recommend to measure both antibodies in children with demyelinating syndromes.

Cerebellar Bottom-of-Fissure Dysplasia-a Novel Cerebellar Gray Matter Neuroimaging Pattern.

We report on seven patients with a novel neuroimaging finding that involves exclusively the cerebellar gray matter at the bottom of several fissures of both hemispheres but spares the vermis. The abnormal fissures were predominantly located in the lower and lateral parts of the cerebellar hemispheres. The affected cerebellar cortex was hypointense on T1-weighted and hyperintense on T2-weighted and fluid attenuation inversion recovery sequences. In some patients, the involved cerebellar gray matter was mildly thickened and the affected fissures slightly widened. In three of seven patients, the neuroimaging findings were unchanged on follow-up studies up to 6 years. The seven patients had various indications for the brain magnetic resonance imaging studies, and none of them had cerebellar dysfunction. Based on the similarity of the neuroimaging pattern with the cerebral "bottom-of-sulcus dysplasia," we coined the term "cerebellar bottom-of-fissure dysplasia" to refer to this novel neuroimaging finding. The neuroimaging characteristic as well as the unchanged findings on follow-up favors a stable "developmental" (malformative) nature. The lack of cerebellar dysfunction in the affected patients suggests that cerebellar bottom-of-fissure dysplasia represents most likely an incidental finding that does not require specific diagnostic investigation but allows a reassuring attitude.

Clinical pattern, mutations and in vitro residual activity in 33 patients with severe 5, 10 methylenetetrahydrofolate reductase (MTHFR) deficiency.

BACKGROUND: Severe methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare inborn defect disturbing the remethylation of homocysteine to methionine (<200 reported cases). This retrospective study evaluates clinical, biochemical genetic and in vitro enzymatic data in a cohort of 33 patients. METHODS: Clinical, biochemical and treatment data was obtained from physicians by using a questionnaire. MTHFR activity was measured in primary fibroblasts; genomic DNA was extracted from cultured fibroblasts. RESULTS: Thirty-three patients (mean age at follow-up 11.4 years; four deceased; median age at first presentation 5 weeks; 17 females) were included. Patients with very low (<1.5%) mean control values of enzyme activity (n = 14) presented earlier and with a pattern of feeding problems, encephalopathy, muscular hypotonia, neurocognitive impairment, apnoea, hydrocephalus, microcephaly and epilepsy. Patients with higher (>1.7-34.8%) residual enzyme activity had mainly psychiatric symptoms, mental retardation, myelopathy, ataxia and spasticity. Treatment with various combinations of betaine, methionine, folate and cobalamin improved the biochemical and clinical phenotype. During the disease course, patients with very low enzyme activity showed a progression of feeding problems, neurological symptoms, mental retardation, and psychiatric disease while in patients with higher residual enzyme activity, myelopathy, ataxia and spasticity increased. All other symptoms remained stable or improved in both groups upon treatment as did brain imaging in some cases. No clear genotype-phenotype correlation was obvious. DISCUSSION: MTHFR deficiency is a severe disease primarily affecting the central nervous system. Age at presentation and clinical pattern are correlated with residual enzyme activity. Treatment alleviates biochemical abnormalities and clinical symptoms partially.

Measuring teacher identity of physicians - a validation study of a questionnaire instrument.

BACKGROUND: Teacher identity is defined as a continuum of a person's self-conviction ('Identity is something I have') and a context-dependent action ('Identity is something I do in a context') (Lankveld et al. 2021). It has been identified a relevant contributor to physicians' teaching commitment. In this study, we further improve the currently only existing questionnaire instrument (37 items) measuring physicians' teacher identity. METHODS: Survey data on 147 clinicians at a German university hospital were (1) analyzed by confirmatory factor analysis (CFA). We tested (a) the model fits of the originally suggested scales and (b) potential for improvement of model fits by item reduction. As this could not reveal satisfactory fits for all scales, we (2) applied a principal axis factoring as an exploratory approach. Last, we combined findings from (1) and (2) with a theoretical item content discussion and suggest (3) reassembled scales which were again checked using CFA. FINDINGS: (1a) Two scales from the original instrument were successfully confirmed. (1b) Some scales benefited from item reduction. (2) The exploratory analysis identified three factors that explained at least 5% variance. (3) By integrating confirmatory and exploratory findings with a content analysis of the items, we propose a partially rearranged questionnaire instrument, comprising seven scales: (1) Feeling intrinsic satisfaction from teaching; (2) Feeling responsibility to teach; (3) Exchange of teaching experience; (4) Identification and enjoyment of the teaching role; (5) Development of teaching; (6) Teaching self-concept of ability; (7) Desired rewards for teaching. Four items were kept as single items. CONCLUSION: We suggest that when assessing teacher identity in physicians, all items should be constructed to allow for responses, even from physicians who are presently not actively involved in teaching. The scales benefited from categorizing items based on the continuum of teacher identity as outlined by van Lankveld et al. (2021).

Primary Headache Is Related to Reduced Health-Related Quality of Life in Children with Epilepsy.

Headache is a frequent comorbidity in patients with epilepsy. Data are sparse regarding the distribution of headache types in children with epilepsy (CWE). We aimed to assess the prevalence of primary headache types and their influence on health-related quality of life (QoL) in CWE. CWE filled out a validated headache questionnaire to assess migraine (MIG), tension-type headache (TTH), trigeminal-autonomic cephalalgia (TAC), or, if the criteria were not fulfilled, non-classifiable headache (NCH). QoL was measured using both patient and parent versions of a validated questionnaire. Of 119 CWE (59 female; 11.5 ± 3.1 y), headache was found in 46 (38.7%). Sixteen (34.8%) patients showed MIG, 9 (19.6%) patients TTH, and 21 (45.7%) patients described NCH. More girls reported headache (χ2 = 5.4, p = 0.02) when compared to boys. Overall, QoL was reduced in patients with headache from both the patients' and parents' points of view (70.8% [39.6; 87.5] vs. 77.0% [46.9; 95.8], p = 0.002; 71,9% [33.3; 87.5] vs. 78,1% [54.2; 95.8], p = 0.003). Headache is common among CWE with MIG as the most prevalent primary headache type and higher rates in female patients. Importantly, patients and their parents perceive a reduced overall QoL when suffering from headache.

Blood parameters in pediatric myelin oligodendrocyte glycoprotein antibody-associated disorders.

BACKGROUND AND OBJECTIVES: Patients with myelin oligodendrocyte glycoprotein antibody-associated disorders (MOGAD) clinically present e.g. with acute disseminated encephalomyelitis (ADEM), optic neuritis (ON), transverse myelitis (TM) or aquaporin-4-IgG (AQP4-IgG) negative neuromyelitis optica spectrum disorders (NMOSD)-like phenotypes. We aimed to analyze and compare blood parameters in children with MOGAD, AQP4-IgG-positive NMOSD (hence NMOSD), multiple sclerosis (MS) and healthy controls (HC). METHODS: We evaluated differences in complete blood counts (CBC), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR) and C-reactive protein (CRP) between these four groups and within the groups between clinical attack, acute treatment and remission. RESULTS: Our cohort consisted of 174 children and adolescents with a total of 550 timepoints: 66 patients had MOGAD (202 timepoints), 11 NMOSD (76 timepoints), 58 MS (219 timepoints) and 39 were HC (53 timepoints). At clinical attack, leukocyte counts were elevated in MOGAD compared to remission (p < 0.001) and compared to all other groups (p < 0.001). NLR was high in MOGAD and NMOSD, and PLR was high in NMOSD, however, after correction for multiple testing these findings did not remain significant. While glucocorticoids caused an increase of leukocyte counts and NLR in NMOSD and MS, these values remained stable during acute treatment in MOGAD. In remission, NLR normalized in MOGAD, while it stayed high in NMOSD. PLR increased in NMOSD and was significantly higher compared to all other groups. DISCUSSION: Some blood parameters, mainly leukocyte and differential counts, might help clinicians to evaluate disease activity, differentiate relapses from pseudo-relapses and even distinguish between different disease entities.

Comparative study of virus and lymphocyte distribution with clinical data suggests early high dose immunosuppression as potential key factor for the therapy of patients with BoDV-1 infection.

ABSTRACTBorna disease virus 1 (BoDV-1) was just recently shown to cause predominantly fatal encephalitis in humans. Despite its rarity, bornavirus encephalitis (BVE) can be considered a model disease for encephalitic infections caused by neurotropic viruses and understanding its pathomechanism is of utmost relevance. Aim of this study was to compare the extent and distribution pattern of cerebral inflammation with the clinical course of disease, and individual therapeutic procedures. For this, autoptic brain material from seven patients with fatal BVE was included in this study. Tissue was stained immunohistochemically for pan-lymphocytic marker CD45, the nucleoprotein of BoDV-1, as well as glial marker GFAP and microglial marker Iba1. Sections were digitalized and counted for CD45-positive and BoDV-1-positive cells. For GFAP and Iba1, a semiquantitative score was determined. Furthermore, detailed information about the individual clinical course and therapy were retrieved and summarized in a standardized way. Analysis of the distribution of lymphocytes shows interindividual patterns. In contrast, when looking at the BoDV-1-positive glial cells and neurons, a massive viral involvement in the brain stem was noticeable. Three of the seven patients received early high-dose steroids, which led to a significantly lower lymphocytic infiltration of the central nervous tissue and a longer survival compared to the patients who were treated with steroids later in the course of disease. This study highlights the potential importance of early high-dose immunosuppressive therapy in BVE. Our findings hint at a promising treatment option which should be corroborated in future observational or prospective therapy studies.ABBREVIATIONS: BoDV-1: Borna disease virus 1; BVE: bornavirus encephalitis; Cb: cerebellum; CNS: central nervous system; FL: frontal lobe; GFAP: glial fibrillary acid protein; Hc: hippocampus; Iba1: ionized calcium-binding adapter molecule 1; Iba1act: general activation of microglial cells; Iba1nod: formation of microglial nodules; IL: insula; Me: mesencephalon; Mo: medulla oblongata; OL: occipital lobe; pASS: per average of 10 screenshots; patearly: patients treated with early high dose steroid shot; patlate: patients treated with late or none high dose steroid shot; Po: pons; So: stria olfactoria; Str: striatum.

Clinical Effectiveness of Newborn Screening for Spinal Muscular Atrophy: A Nonrandomized Controlled Trial.

Importance: There is increasing evidence that early diagnosis and treatment are key for outcomes in infants with spinal muscular atrophy (SMA), and newborn screening programs have been implemented to detect the disease before onset of symptoms. However, data from controlled studies that reliably confirm the benefits of newborn screening are lacking. Objective: To compare data obtained on patients with SMA diagnosed through newborn screening and those diagnosed after clinical symptom onset. Design, Setting, and Participants: This nonrandomized controlled trial used data from the SMARTCARE registry to evaluate all children born between January 2018 and September 2021 with genetically confirmed SMA and up to 3 SMN2 copies. The registry includes data from 70 participating centers in Germany, Austria, and Switzerland. Data analysis was performed in February 2023 so that all patients had a minimal follow-up of 18 months. Exposure: Patients born in 2 federal states in Germany underwent screening in a newborn screening pilot project. All other patients were diagnosed after clinical symptom onset. All patients received standard care within the same health care system. Main Outcomes: The primary end point was the achievement of motor milestones. Results: A total of 234 children (123 [52.6%] female) were identified who met inclusion criteria and were included in the analysis: 44 (18.8%) in the newborn screening cohort and 190 children (81.2%) in the clinical symptom onset cohort. The mean (SD) age at start of treatment with 1 of the approved disease-modifying drugs was 1.3 (2.2) months in the newborn screening cohort and 10.7 (9.1) months in the clinical symptom onset cohort. In the newborn screening cohort, 40 of 44 children (90.9%) gained the ability to sit independently vs 141 of 190 (74.2%) in the clinical symptom onset cohort. For independent ambulation, the ratio was 28 of 40 (63.6%) vs 28 of 190 (14.7%). Conclusions and Relevance: This nonrandomized controlled trial demonstrated effectiveness of newborn screening for infants with SMA in the real-world setting. Functional outcomes and thus the response to treatment were significantly better in the newborn screening cohort compared to the unscreened clinical symptom onset group. Trial Registration: German Clinical Trials Register: DRKS00012699.

5qSMA: standardised retrospective natural history assessment in 268 patients with four copies of SMN2.

Newborn screening for 5qSMA offers the potential for early, ideally pre-symptomatic, therapeutic intervention. However, limited data exist on the outcomes of individuals with 4 copies of SMN2, and there is no consensus within the SMA treatment community regarding early treatment initiation in this subgroup. To provide evidence-based insights into disease progression, we performed a retrospective analysis of 268 patients with 4 copies of SMN2 from the SMArtCARE registry in Germany, Austria and Switzerland. Inclusion criteria required comprehensive baseline data and diagnosis outside of newborn screening. Only data prior to initiation of disease-modifying treatment were included. The median age at disease onset was 3.0 years, with a mean of 6.4 years. Significantly, 55% of patients experienced symptoms before the age of 36 months. 3% never learned to sit unaided, a further 13% never gained the ability to walk independently and 33% of ambulatory patients lost this ability during the course of the disease. 43% developed scoliosis, 6.3% required non-invasive ventilation and 1.1% required tube feeding. In conclusion, our study, in line with previous observations, highlights the substantial phenotypic heterogeneity in SMA. Importantly, this study provides novel insights: the median age of disease onset in patients with 4 SMN2 copies typically occurs before school age, and in half of the patients even before the age of three years. These findings support a proactive approach, particularly early treatment initiation, in this subset of SMA patients diagnosed pre-symptomatically. However, it is important to recognize that the register will not include asymptomatic individuals.

Long-term efficacy and safety of nusinersen in adults with 5q spinal muscular atrophy: a prospective European multinational observational study.

Background: Evidence for the efficacy of nusinersen in adults with 5q-associated spinal muscular atrophy (SMA) has been demonstrated up to a period of 16 months in relatively large cohorts but whereas patients reach a plateau over time is still to be demonstrated. We investigated the efficacy and safety of nusinersen in adults with SMA over 38 months, the longest time period to date in a large cohort of patients from multiple clinical sites. Methods: Our prospective, observational study included adult patients with SMA from Germany, Switzerland, and Austria (July 2017 to May 2022). All participants had genetically-confirmed, 5q-associated SMA and were treated with nusinersen according to the label. The total Hammersmith Functional Motor Scale Expanded (HFMSE) and Revised Upper Limb Module (RULM) scores, and 6-min walk test (6 MWT; metres), were recorded at baseline and 14, 26, and 38 months after treatment initiation, and pre and post values were compared. Adverse events were also recorded. Findings: Overall, 389 patients were screened for eligibility and 237 were included. There were significant increases in all outcome measures compared with baseline, including mean HFMSE scores at 14 months (mean difference 1.72 [95% CI 1.19-2.25]), 26 months (1.20 [95% CI 0.48-1.91]), and 38 months (1.52 [95% CI 0.74-2.30]); mean RULM scores at 14 months (mean difference 0.75 [95% CI 0.43-1.07]), 26 months (mean difference 0.65 [95% CI 0.27-1.03]), and 38 months (mean difference 0.72 [95% CI 0.25-1.18]), and 6 MWT at 14 months (mean difference 30.86 m [95% CI 18.34-43.38]), 26 months (mean difference 29.26 m [95% CI 14.87-43.65]), and 38 months (mean difference 32.20 m [95% CI 10.32-54.09]). No new safety signals were identified. Interpretation: Our prospective, observational, long-term (38 months) data provides further real-world evidence for the continuous efficacy and safety of nusinersen in a large proportion of adult patients with SMA. Funding: Financial support for the registry from Biogen, Novartis and Roche.

Comprehensive neurological evaluation of a cohort of patients with neurofibromatosis type 1 from a single institution.

Neurofibromatosis type 1 (NF1) is a phenotypically heterogenous multisystem cancer predisposition syndrome manifesting in childhood and adolescents. Central nervous system (CNS) manifestations include structural, neurodevelopmental, and neoplastic disease. We aimed to (1) characterize the spectrum of CNS manifestations of NF1 in a paediatric population, (2) explore radiological features in the CNS by image analyses, and (3) correlate genotype with phenotypic expression for those with a genetic diagnosis. We performed a database search in the hospital information system covering the period between January 2017 and December 2020. We evaluated the phenotype by retrospective chart review and imaging analysis. 59 patients were diagnosed with NF1 [median age 10.6 years (range, 1.1-22.6); 31 female] at last follow-up, pathogenic NF1 variants were identified in 26/29. 49/59 patients presented with neurological manifestations including 28 with structural and neurodevelopmental findings, 16 with neurodevelopmental, and 5 with structural findings only. Focal areas of signal intensity (FASI) were identified in 29/39, cerebrovascular anomalies in 4/39. Neurodevelopmental delay was reported in 27/59 patients, learning difficulties in 19/59. Optic pathway gliomas (OPG) were diagnosed in 18/59 patients, 13/59 had low-grade gliomas outside the visual pathways. 12 patients received chemotherapy. Beside the established NF1 microdeletion, neither genotype nor FASI were associated with the neurological phenotype. NF1 was associated with a spectrum of CNS manifestations in at least 83.0% of patients. Regular neuropsychological assessment complementing frequent clinical and ophthalmologic testing for OPG is necessary in the care of each child with NF1.