Search

Competing Interests: The authors declare that they have no conflict of interest.

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., (© 2022 Wiley Periodicals LLC.)

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., Competing Interests: Declaration of competing interest None (for all authors)., (Copyright © 2021 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

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., Competing Interests: The authors have declared that no competing interests exist.

Background: 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., Methods: Twenty-seven paired CSF/serum samples were collected from nine patients during the follow-up period (median 12 months, range 1-26 months). The patient samples were stratified into three periods after the onset of the first disease symptom and compared with the controls. Modified Rankin score (mRS) defined the clinical status. The concentrations of the chemokines (C-X-C motif ligand (CXCL)10, CXCL8 and C-C motif ligand 2 (CCL2)) and the cytokines (interferon (IFN)γ, interleukin (IL)4, IL7, IL15, IL17A and tumour necrosis factor (TNF)α) were measured with Luminex multiple bead technology. The B cell-activating factor (BAFF) and CXCL13 concentrations were determined via enzyme-linked immunosorbent assay. We correlated the disease period with the mRS, pleocytosis and the levels of all of the investigated chemokines and cytokines. Non-parametric tests were used, a P value <0.05 was considered to be significant., Results: The increased CXCL10 and CXCL13 CSF levels accompanied early-stage disease progression and pleocytosis. The CSF CXCL10 and CXCL13 levels were the highest in the most complicated patient. The CSF BAFF levels remained unchanged through the periods. In contrast, the CSF levels of T cell-related cytokines (INFγ, TNFα and IL17A) and IL15 were slightly increased at all of the periods examined. No dynamic changes in chemokine and cytokine levels were observed in the peripheral blood., Conclusions: Our data support the hypothesis that anti-NMDAR encephalitis is restricted to the CNS and that chemoattraction of immune cells dominates at its early stage. Furthermore, our findings raise the question of whether T cells are involved in this disease.

Background: Chemokines and cytokines in cerebrospinal fluid (CSF) and serum have been extensively studied in adults with neuroborreliosis (NB), whereas there are limited data about the pediatric population. In adults, T helper type 1 (Th1) and Th17-related cytokines were observed during acute NB. In children, the Th2 response is thought to moderate the disease course. The aim of this study was to determine the chemokine-cytokine profile in children with acute NB displaying Borrelia-related peripheral facial nerve palsy (PFNP)., Methods: Luminex multiple bead technology was used for the detection of twelve cytokines and chemokines in the CSF and serum of three groups: 1) children with Borrelia-related PFNP (BPFNP); 2) children with non-borrelial "idiopathic" PFNP (NIPFNP); and 3) age-related controls., Results: In BPFNP, cytokines-chemokines related to a non-specific pro-inflammatory activity and specific Th1/Th17 responses were detected in CSF, and elevated IL-7 and IL-10 levels were observed in serum and CSF compared to NIPFNP and to controls. In NIPFNP, CSF findings were similar to controls; however, higher levels of IL-7 and MCP-1 were observed in serum. Higher IL-8, IL-15 and MCP-1 levels were detected in CSF compared to serum in all groups. MCP-1 and IL-8 levels in CSF were strikingly higher in BPFNP compared to the other two groups, while IL-15 levels in CSF showed no difference. In addition, in controls, increased IL-4 level was found in CSF compared to serum., Conclusion: The chemokine-cytokine profile in the CSF of children with acute NB was similar to previous studies in adults. Our data suggests that higher levels of IL-4, IL-15 and MCP-1 levels in CSF compared to serum in controls might represent a potentially protective cytokine milieu in the CNS compartment.