BACKGROUND:Acquired demyelinating syndromes (ADS) include rare diagnoses of acute disseminated encephalomyelitis (ADEM), clinically isolated syndrome (CIS), multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). Their characteristics in the Czech children are currently unknown. OBJECTIVES:To identify the epidemiology, diagnosis, care management, and outcomes of Czech children with ADS. METHODS:Data from a two-year prospective national multicenter study were analyzed. The incidence was calculated for the Czech population (< 18 years of age) per 100,000 per year sourcing data from the Czech Statistical Office. RESULTS:Our study covered 84.1% of the population and included 81 patients. The overall incidence of pediatric ADS was 2.24/100,000 (95% confidence interval [CI] 1.76-2.79). In particular, POMS, CIS, ADEM, and NMOSD had an incidence of 1.19 (0.85-1.62); 0.7 (0.35-1.33); 0.32 (0.16-0.57); and 0.03 (0.0007-0.16), respectively. Myelin oligodendrocyte glycoprotein (MOG) antibodies were present in 19.8% of all patients. Age was associated with diagnoses, MOG antibodies and preceding infections. After the first ADS episode, 6.3% of the children remained severely affected. CONCLUSION:This first comprehensive analysis of pediatric ADS in the Czech Republic provided unique data on ADS incidence, identified a significant proportion of POMS, and highlighted challenges in diagnosis and care.

Intracellular trafficking involves an intricate machinery of motor complexes, including the dynein complex, to shuttle cargo for autophagolysosomal degradation. Deficiency in dynein axonemal chains, as well as cytoplasmic light and intermediate chains, have been linked with ciliary dyskinesia and skeletal dysplasia. The cytoplasmic dynein 1 heavy chain protein (DYNC1H1) serves as a core complex for retrograde trafficking in neuronal axons. Dominant pathogenic variants in DYNC1H1 have been previously implicated in peripheral neuromuscular disorders (NMD) and neurodevelopmental disorders (NDD). As heavy-chain dynein is ubiquitously expressed, the apparent selectivity of heavy chain dyneinopathy for motor neuronal phenotypes remains currently unaccounted for. Here, we aimed to evaluate the full DYNC1H1-related clinical, molecular and imaging spectrum, including multisystem features and novel phenotypes presenting throughout life. We identified 47 cases from 43 families with pathogenic heterozygous variants in DYNC1H1 (aged 0-59 years) and collected phenotypic data via a comprehensive standardized survey and clinical follow-up appointments. Most patients presented with divergent and previously unrecognized neurological and multisystem features, leading to significant delays in genetic testing and establishing the correct diagnosis. Neurological phenotypes include novel autonomic features, previously rarely described behavioral disorders, movement disorders and periventricular lesions. Sensory neuropathy was identified in nine patients (median age of onset 10.6 years), of which five were only diagnosed after the second decade of life, and three had a progressive age-dependent sensory neuropathy. Novel multisystem features included primary immunodeficiency, bilateral sensorineural hearing loss, organ anomalies and skeletal manifestations, resembling the phenotypic spectrum of other dyneinopathies. We also identified an age-dependent biphasic disease course with developmental regression in the first decade and, following a period of stability, neurodegenerative progression after the second decade of life. Of note, we observed several cases in whom neurodegeneration appeared to be prompted by intercurrent systemic infections with double-stranded DNA viruses (Herpesviridae) or single-stranded RNA viruses (Ross River fever, SARS-CoV-2). Moreover, the disease course appeared to be exacerbated by viral infections regardless of age and/or severity of neurodevelopmental disorder manifestations, indicating a role of dynein in anti-viral immunity and neuronal health. In summary, our findings expand the clinical, imaging and molecular spectrum of pathogenic DYNC1H1 variants beyond motor neuropathy disorders and suggest a life-long continuum and age-related progression due to deficient intracellular trafficking. This study will facilitate early diagnosis and improve counselling and health surveillance of affected patients.

Background We recently described magnetic resonance imaging (MRI) features of children with transverse myelitis (TM) at first event with important and unique differences depending on the underlying disease entity. Objective To study the resolution of lesions over time in children with TM due to MOG-antibody associated disorders (MOGAD), multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD) or double seronegative TM. Patients and methods In this prospective study, 78 children from 29 different medical centres with TM as part of MOGAD (n = 34), MS (n = 20), NMOSD (n = 5) and in double seronegative children (n = 19) were included. A grading system consisting of 4 grades (grade 0 = complete resolution; grade 3 = no resolution at all) was used to compare the degree of lesion resolution over time in the different disease entities. Time to lesion resolution was evaluated by Kaplan-Meier statistics and log-rank test. Results Significant differences of the interval between first MRI until resolution of lesions were observed between the four disease entities. The most rapid and complete resolution was seen in MOGAD, followed by double seronegative, MS and NMOSD. Median periods until total resolution (grade 0) were 191 days (MOGAD), 750 days (double seronegative), 1117 days (MS), while none of the patients with NMOSD reached a complete resolution during the observation period. The better prognosis of MOGAD compared to MS was independent of sex, age, oligoclonal bands and cell count in the multivariate Cox analysis (P < 0.001). Conclusion Children with TM and antibodies to MOG show a faster resolution of radiological lesions compared to children with MS and NMOSD.

A two-year-old girl with an unremarkable family history was transferred to our tertiary care centre showcasing a severe dyselectrolytemia and a suspicion of tubulopathy. She was born to healthy nonconsanguienous parents at 35 weeks of gestation from dizygotic twins with birth weight of 2,550 g, polyhydramnios was not reported. One week prior to her admission to our department, she exhibited symptoms of acute upper respiratory tract infection and was admitted to the local hospital. Her physical examination showed mild dehydration, general muscle weakness, significantly reduced spontaneous physical activity and feeding difficulties initially attributed to an electrolyte imbalance. Laboratory examination revealed severe hypokalemia (2.1 mmol/L), hypernatremia (154.9 mmol/L), hypochloremia (91.0 mmol/L) and metabolic alkalosis (pH 7.6, bicarbonate 31.0 mmol/L). Both plasmatic renin and aldosterone were high: 643.5 ng/L and 5.9 nmol/L, respectively.

Objective: The pathophysiological processes leading to epileptogenesis and pharmacoresistance in epilepsy have been the subject of extensive preclinical and clinical research. The main impact on clinical practice is the development of new targeted therapies for epilepsy. We studied the importance of neuroinflammation in the development of epileptogenesis and pharmacoresistance in childhood epilepsy patients.Methods: A cross-sectional study conducted at two epilepsy centers in the Czech Republic compared 22 phar-macoresistant patients and 4 pharmacodependent patients to 9 controls. We analyzed the ProcartaPlexTM 9-Plex immunoassay panel consisting of interleukin (IL)-6, IL-8, IL-10, IL-18, CXCL10/IP-10, monocyte chemoattractant protein 1 (CCL2/MCP-1), B lymphocyte chemoattractant (BLC), tumor necrosis factor-alpha (TNF-& alpha;), and che-mokine (C-X3-X motif) ligand 1 (fractalkine/CXC3CL1) to determine their alterations in cerebrospinal fluid (CSF) and blood plasma, concurrently.Results: The analysis of 21 paired CSF and plasma samples in pharmacoresistant patients compared to controls revealed a significant elevation of CCL2/MCP-1 in CSF (p < 0.000512) and plasma (p < 0.00.017). Higher levels of fractalkine/CXC3CL1 were revealed in the plasma of pharmacoresistant patients than in controls (p < 0.0704), and we determined an upward trend in CSF IL-8 levels (p < 0.08). No significant differences in CSF and plasma levels were detected between pharmacodependent patients and controls.Conclusion: Elevated CCL2/MCP-1 in CSF and plasma, elevated levels of fractalkine/CXC3CL1 in CSF, and a trend toward elevated IL-8 in the CSF of patients with pharmacoresistant epilepsy indicate these cytokines as potential biomarkers of epileptogenesis and pharmacoresistance. CCL2/MCP-1was detected in blood plasma; this assess-ment may be easily achieved in clinical practice without the invasiveness of a spinal tap. However, due to the complexity of neuroinflammation in epilepsy, further studies are warranted to confirm our findings.

Our study presents a novel germline c.1715G>T (p.G572V) mutation in the gene encoding Toll-like receptor 8 (TLR8) causing an autoimmune and autoinflammatory disorder in a family with monozygotic male twins, who suffer from severe autoimmune hemolytic anemia worsening with infections, and autoinflammation presenting as fevers, enteritis, arthritis, and CNS vasculitis. The pathogenicity of the mutation was confirmed by in vitro assays on transfected cell lines and primary cells. The p.G572V mutation causes impaired stability of the TLR8 protein, cross-reactivity to TLR7 ligands and reduced ability of TLR8 to attenuate TLR7 signaling. This imbalance toward TLR7-dependent signaling leads to increased pro-inflammatory responses, such as nuclear factor-κB (NF-κB) activation and production of pro-inflammatory cytokines IL-1β, IL-6, and TNFα. This unique TLR8 mutation with partial TLR8 protein loss and hyperinflammatory phenotype mediated by TLR7 ligands represents a novel inborn error of immunity with childhood-onset and a good response to TLR7 inhibition.

This review focused on vaccination in children with movement disorders, including cerebral palsy and the movement disorders triggered by vaccination in children with and without neurological disabilities. The following clinical questions were addressed: 1) Can children with movement disorders be vaccinated? 2) Can vaccination trigger movement disorders in children without neurological disabilities? 3) Can vaccination trigger movement disorders in children with neurological disabilities? and 4) Is there any consensus of care concerning vaccination in children with movement disorders? Following the PRISMA reporting guidelines, 1096 records were identified and 34 relevant papers were included. No evidence that vaccinations are contraindicated for children with movement disorders was noticed. Several reports of neurological adverse events, including movement disorders in children without neurological disabilities after various types of vaccination, were found. The reporting rates were low, the causality was controversial, and patient outcomes were mostly favourable. There was limited (if any) evidence in our search that any vaccination leads to any movement disorder exacerbation. Finally, no generally accepted consensus or standards of care concerning vaccination in patients with movement disorders were found. In summary, we found few precautions for vaccination in this group of patients and concluded that general best practice guidelines for immunization should be followed. In addition, influenza and pneumococcal vaccines are recommended because they can reduce morbidity and mortality in individuals severely affected by movement restrictions.

Fetal intracranial hemorrhage represents a rare event with an estimated prevalence of 1:10 000 pregnancies. We report a patient diagnosed prenatally with intracranial hemorrhage and ventriculomegaly carrying a novel, previously unreported, likely pathogenic variant in COL4A1. At the gestational age of 27 weeks, dilation of lateral ventricles was detected during a routine prenatal ultrasound scan, confirmed by prenatal MRI at 30 + 3 weeks of gestation. Prenatal examinations included amniocentesis with conventional G-band karyotyping and arrayCGH, and maternal testing for TORCH and parvovirus B19 infections. Virtual gene panel based on whole-exome sequencing data was performed postnatally. At the age of 2.5 months, the patient manifested epileptic seizures that remain difficult to control. Postnatal MRI showed partial thalamic fusion and polymicrogyria, in addition to severe enlargement of lateral ventricles, multiple deposits of hemosiderin in cerebral and cerebellar hemispheres, and thin optic nerve and chiasma. Virtual gene panel based on whole-exome sequencing data led to a detection of a de novo previously unreported in-frame deletion NM_001845.5:c.4688_4711del in COL4A1 located in the highly conserved NC1 domain initiating collagen helix assembly. The presented case lies one a more severe end of the COL4A1 mutation-related disease spectrum, manifesting as fetal intracranial bleeding, malformation of cortical development, drug-resistant epilepsy, and developmental delay.

BACKGROUND:Immune-mediated mechanisms substantially contribute to the Rasmussen encephalitis (RE) pathology, but for unknown reasons, immunotherapy is generally ineffective in patients who have already developed intractable epilepsy; overall laboratory data regarding the effect of immunotherapy on patients with RE are limited. We analyzed multiple samples from seven differently treated children with RE and evaluated the effects of immunotherapies on neuroinflammation. Immunotherapy was introduced to all patients at the time of intractable epilepsy and they all had to undergo hemispherothomy.METHODS:Immunohistochemistry, flow cytometry, Luminex multiplex bead and enzyme-linked immunosorbent assay techniques were combined to determine: 1) inflammatory changes and lymphocyte subpopulations in 45 brain tissues; 2) lymphocyte subpopulations and the levels of 12 chemokines/cytokines in 24 cerebrospinal fluid (CSF) samples and 30 blood samples; and 3) the dynamics of these parameters in four RE patients from whom multiple samples were collected.RESULTS:Sustained T cell-targeted therapy with cyclophosphamide, natalizumab, alemtuzumab, and intrathecal methotrexate (ITMTX), but not with azathioprine, substantially reduced inflammation in brain tissues. Despite the therapy, the distributions of CD8+ T cells and the levels of C-X-C motif ligand (CXCL) 10, CXCL13, and B cell activating factor (BAFF) in patients' CSF remained increased compared to controls. A therapeutic approach combining alemtuzumab and ITMTX was the most effective in producing simultaneous reductions in histopathological inflammatory findings and in the numbers of activated CD8+ T cells in the brain tissue, as well as in the overall CD8+ T cell population and chemokine/cytokine production in the CSF.CONCLUSIONS:We provide evidence that various T cell-targeted immunotherapies reduced inflammation in the brains of RE patients. The observation that intractable epilepsy persisted in all of the patients suggests a relative independence of seizure activity on the presence of T cells in the brain later in the disease course. Thus, new therapeutic targets must be identified. CXCL10, CXCL13 and BAFF levels were substantially increased in CSF from all patients and their significance in RE pathology remains to be addressed.

BACKGROUND:The recognition of active inflammation in the central nervous system (CNS) in the absence of infectious agents is challenging. The present study aimed to determine the diagnostic relevance of five selected chemo/cytokines in the recognition of CNS inflammation and in the context of traditional cerebrospinal fluid (CSF) biomarkers (white blood cell [WBC] counts, oligoclonal bands, protein levels, CSF/serum albumin ratios) and clinical diagnoses. METHODS:C-C and C-X-C motif ligands (CCL2, CXCL8, 10 and 13) and interleukin (IL) 6 levels in the CSF and serum from 37 control and 87 symptomatic children with ten different (mostly noninfectious) inflammatory CNS disorders (16 of which had follow-up samples after recovery) were determined using Luminex multiple bead technology and software. Nonparametric tests were used; p < 0.05 was considered statistically significant. Receiver operating characteristic curves were constructed to analyze controls and 1) all symptomatic samples or 2) symptomatic samples without CSF pleocytosis. RESULTS:Compared with the control CSF samples, levels of all investigated chemo/cytokines were increased in symptomatic CSF samples, and only IL-6 remained elevated in recovery samples (p ≤ 0.001). CSF CXCL-13 levels (> 10.9 pg/mL) were the best individual discriminatory criterion to differentiate neuroinflammation (specificity/sensitivity: 97/72% and 97/61% for samples without pleocytosis), followed by CSF WBC counts (specificity/sensitivity: 97/62%). The clinical utility of the remaining CSF chemo/cytokine levels was determined in descending order of sensitivities corresponding to thresholds that ensured 97% specificity for neuroinflammation in samples without pleocytosis (pg/mL; sensitivity %): IL-6 (3.8; 34), CXCL8 (32; 26), CXCL10 (317; 24) and CCL2 (387; 10). Different diagnosis-related patterns of CSF chemo/cytokines were observed. CONCLUSIONS:The increased CSF level of CXCL13 was the marker with the greatest predictive utility for the general recognition of neuroinflammation among all of the individually investigated biomarkers. The potential clinical utility of chemo/cytokines in the differential diagnosis of neuroinflammatory diseases was identified.

Objective The impetus for this consensus discussion was to recommend clinical trial designs that can deliver high-quality data for effective therapies for pediatric patients, in a reasonable timeframe, with a key focus on short- and long-term safety. Methods The International Pediatric Multiple Sclerosis Study Group convened a meeting of experts to review the advances in the understanding of pediatric-onset multiple sclerosis (MS) and the advent of clinical trials for this population. Results In the last few years, convincing evidence has emerged that the biological processes involved in MS are largely shared across the age span. As such, treatments proven efficacious for the care of adults with MS have a biological rationale for use in pediatric MS given the relapsing-remitting course at onset and high relapse frequency. There are also ethical considerations on conducting clinical trials in this age group including the use of placebo owing to highly active disease. It is imperative to reconsider study design and implementation based on what information is needed. Are studies needed for efficacy or should safety be the primary goal? Further, there have been major recruitment challenges in recently completed and ongoing pediatric MS trials. Phase 3 trials for every newly approved therapy for adult MS in the pediatric MS population are simply not feasible. Conclusions A primary goal is to ensure high-quality evidence-based treatment for children and adolescents with MS, which will improve our understanding of the safety of these agents and remove regulatory or insurance-based limitations in access to treatment.

Myelitida v dětskem věku je vzacne a zavažne onemocněni. Může se vyskytovat samostatně a mit monofazický průběh, ale může být take prvnim projevem relabujicich onemocněni. Diagnostika se opira o klinický obraz a komplex pomocných vysetřeni, v kterem hraje stěžejni roli magneticka rezonance, vysetřeni likvoru a některých autoprotilatek. Myelitidy na autoimunitnim podkladě převažuji nad infekcnimi. V diferencialni diagnoze je nutno pomýslet zejmena na roztrousenou sklerozu a neuromyelitis optica. Stanoveni spravne diagnozy je důležite nejen pro rychlou a dostatecnou lecbu akutniho zanětu, ale take pro nastaveni chronicke terapie k prevenci relapsů, což může zlepsit celkovou prognozu pacienta a předejit trvale invaliditě. V nasledujicim sděleni představime soubor 20 dětských pacientů s myelitidou se zaměřenim na diagnosticka a lecebna uskali.

Autoimunitní onemocnění centrálního nervového systému jsou potenciálně léčitelná.Jejich výskyt je u dětí vzácný a průběh bývá závažný.Klasifikace prochází vývojem, upravují se diagnostická kritéria a formují se terapeutické přístupy.Cílem je, aby diagnóza autoimunitního postižení byla stanovena co nejdříve a mohla být zahájena adekvátní terapie.Text ve stručnosti přináší aktualizovaný pohled na nejčastější klinické

Rasmussen encephalitis (RE) is a rare but devastating unihemispheric brain disorder that often affects children.1 The clinical picture is characterized by intractable focal epilepsy and progressive decline of functions associated with the affected hemisphere.2 Despite its known inflammatory background and T-cell involvement, immunotherapy appears to slow rather than halt disease progression, and hemispherotomy appears to be the only solution for intractable epilepsy.1–4 A potential early therapeutic window has been suggested, and new therapeutic agents have become available.1 A monoclonal antibody targeting CD52 that leads to long-term depletion of lymphocytes (alemtuzumab) has previously been considered as a possible treatment option for RE, but clinical data are limited.1,5 Acknowledgment: The authors thank Michal Tichy for management of neurosurgery and Vladimir Komarek for his support.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune disorder of the central nervous system (CNS). Its immunopathogenesis has been proposed to include early cerebrospinal fluid (CSF) lymphocytosis, subsequent CNS disease restriction and B cell mechanism predominance. There are limited data regarding T cell involvement in the disease. To contribute to the current knowledge, we investigated the complex system of chemokines and cytokines related to B and T cell functions in CSF and sera samples from anti-NMDAR encephalitis patients at different time-points of the disease. One patient in our study group had a long-persisting coma and underwent extraordinary immunosuppressive therapy.

Immunoglobulin G4-related disease (IgG4-RD) is a novel clinical entity characterized by elevated serum IgG4 levels and histopathologic features of storiform fibrosis, obliterative phlebitis, tissue eosinophilia, and infiltration of IgG4-positive plasma cells. Although it can involve almost any organ, IgG4-RD rarely involves the nervous system. The principal neurologic manifestations include hypophysitis and hypertrophic pachymeningitis (HP). In some patients, previously known idiopathic HP may in fact be IgG4-related. Acknowledgment: The authors thank Dr. Suzanne Z. Powell for her assistance in IgG4 antibody staining.

Rasmussen encephalitis (RE) is a severe immune-mediated neurologic disease characterized by unihemispheric inflammation, progressive neurologic deficits, and intractable focal epilepsy. Functional hemispherectomy is considered to be the only effective intervention for this devastating disease.1,2

Prezentujeme kazuistiku sestileteho chlapce s kongenitalnim hypotonickým syndromem v kombinaci s poruchou sani a opožděnim motorickeho vývoje. Kromě hypotonie byla patrna výrazna distalni hypermobilita kloubů, dale keratosis pilaris a později i mirne kontraktury flexorů kolen. Dalsim přiznakem onemocněni byla vrozena luxace kycli. Mentalni vývoj byl normalni. Aktivita kreatinkinazy byla lehce zvýsena (5,8 μkat/L). Vzhledem k fenotypu a typickemu nalezu na MRI svalů dolnich koncetin pro myopatii typ Ullrich jsme nechali provest molekularně geneticke vysetřeni vsech 3 genů pro kolagen VI, ktere prokazalo již popsanou kauzalni mutaci v COL6A3 genu C6210 + 1 G > A, jedna se o de-novo mutaci. Stanoveni diagnozy umožnilo predikci průběhu a rizik onemocněni, umožnilo geneticke poradenstvi rodině. Pravděpodobně se jedna o prvni připad molekularně geneticky potvrzene kongenitalni svalove dystrofie typu Ullrich v CR.