Understanding Childhood Neuroimmune Diseases of the Central Nervous System

Immune-mediated diseases of the central nervous system (CNS) in childhood are a heterogeneous group of rare conditions sharing the inflammatory involvement of the CNS. This review highlights the growing knowledge of childhood neuroimmune diseases that primarily affect the CNS, outlining the clinical and diagnostic features, the pathobiological mechanisms and genetics, current treatment options, and emerging challenges. The clinical spectrum of these conditions is increasingly expanded, and the underlying mechanisms of dysregulation of the immune system could vary widely. Cell-mediated and antibody-mediated disorders, infection-triggered and paraneoplastic conditions, and genetically defined mechanisms can occur in previously healthy children and can contribute to different stages of the disease. The careful evaluation of the clinical presentation and temporal course of symptoms, the specific neuroimaging and immunological findings, and the exclusion of alternative causes are mandatory in clinical practice for the syndromic diagnosis. A common feature of these conditions is that immunotherapeutic agents could modulate the clinical course and outcomes of the disease. Furthermore, specific symptomatic treatments and comprehensive multidisciplinary care are needed in the overall management. We focus on recent advances on immune-mediated demyelinating CNS disorders, autoimmune encephalitis, interferonopathies, and possible neuroimmune disorders as Rasmussen encephalitis. Better knowledge of these conditions could allow prompt diagnosis and targeted immunotherapy, to decrease morbidity and mortality as well as to improve clinical outcomes, reducing the burden of the disease due to possible long-term neuropsychiatric sequelae. Persisting controversies remain in the rigorous characterization of each specific clinical entity because of the relative rarity in children; moreover, in a large proportion of suspected neuroimmune diseases, the immune "signature" remains unidentified; treatment guidelines are mostly based on retrospective cohort studies and expert opinions; then advances in specific molecular therapies are required. In the future, a better characterization of specific immunological biomarkers may provide a useful understanding of the underlying pathobiological mechanisms of these conditions in order to individualize more tailored therapeutic options and paradigms. Multicenter collaborative research on homogeneous groups of patients who may undergo immunological studies and therapeutic trials could improve the characterization of the underlying mechanisms, the specific phenotypes, and tailored management

A study of longitudinal mobile health data through fuzzy clustering methods for functional data: The case of allergic rhinoconjunctivitis in childhood

The use of mobile communication devices in health care is spreading worldwide. A huge amount of health data collected by these devices (mobile health data) is nowadays available. Mobile health data may allow for real-time monitoring of patients and delivering ad-hoc treatment recommendations. This paper aims at showing how this may be done by exploiting the potentialities of fuzzy clustering techniques. In fact, such techniques can be fruitfully applied to mobile health data in order to identify clusters of patients for diagnostic classification and cluster-specific therapies. However, since mobile health data are full of noise, fuzzy clustering methods cannot be directly applied to mobile health data. Such data must be denoised prior to analyzing them. When longitudinal mobile health data are available, functional data analysis represents a powerful tool for filtering out the noise in the data. Fuzzy clustering methods for functional data can then be used to determine groups of patients. In this work we develop a fuzzy clustering method, based on the concept of medoid, for functional data and we apply it to longitudinal mHealth data on daily symptoms and consumptions of anti-symptomatic drugs collected by two sets of patients in Berlin (Germany) and Ascoli Piceno (Italy) suffering from allergic rhinoconjunctivitis. The studies showed that clusters of patients with similar changes in symptoms were identified opening the possibility of precision medicine

Unraveling the enigma of new-onset refractory status epilepticus: a systematic review of aetiologies

Background and purpose: New-onset refractory status epilepticus (NORSE) is a clinical presentation, neither a specific diagnosis nor a clinical entity. It refers to a patient without active epilepsy or other pre-existing relevant neurological disorder, with a NORSE without a clear acute or active structural, toxic or metabolic cause. This study reviews the currently available evidence about the aetiology of patients presenting with NORSE and NORSE-related conditions. Methods: A systematic search was carried out for clinical trials, observational studies, case series and case reports including patients who presented with NORSE, febrile-infection-related epilepsy syndrome or the infantile hemiconvulsion-hemiplegia and epilepsy syndrome. Results: Four hundred and fifty records were initially identified, of which 197 were included in the review. The selected studies were retrospective case–control (n = 11), case series (n = 83) and case reports (n = 103) and overall described 1334 patients both of paediatric and adult age. Aetiology remains unexplained in about half of the cases, representing the so-called ‘cryptogenic NORSE’. Amongst adult patients without cryptogenic NORSE, the most often identified cause is autoimmune encephalitis, either non-paraneoplastic or paraneoplastic. Infections are the prevalent aetiology of paediatric non-cryptogenic NORSE. Genetic and congenital disorders can have a causative role in NORSE, and toxic, vascular and degenerative conditions have also been described. Conclusions: Far from being a unitary condition, NORSE is a heterogeneous and clinically challenging presentation. The development and dissemination of protocols and guidelines to standardize diagnostic work-up and guide therapeutic approaches should be implemented. Global cooperation and multicentre research represent priorities to improve the understanding of NORSE

Stage-related outcome for thymic epithelial tumours

Background: Thymic epithelial tumours (TETs) are characterized by a wide variety of biological behaviors. Radical resection and stage are strong prognostic factors. Aim of this study is to review our Single Center Experience. Methods: One hundred and seventy-seven patients observed in the period from January 2000 to December 2016 were included in the study. Data regarding clinicopathologic features, treatment, and survival were collected. Stage-related clinical standpoints and therapeutic options were also evaluated. Results: Non-surgical treatment was primarily performed in 15 (8.47%), unresectable disease was intraoperatively found in 12 cases (7.4%). The analysis of 150 patients undergoing curative surgery revealed 70 stage I TET (46.66%), 49 stage II (32.66%), 19 stage III (12.66%), 6 stage IVa (4%) and 6 stage IVb (4%) at the first hospital admission. Histology identified 12 A thymoma (8%), 38 AB (25.33%), 24 B1 (16%), 50 B2 (33.33%), 19 B3 (12.66%) and 7 carcinomas (4.66%). The mean follow up time was 84.14 months (sd = 61.68 months). Disease relapse occurred in 13 patients (8.78%) at a mean period of 78.85 months (sd = 60.87 months) after surgery. Exitus due to thymoma happened in 6 cases (4.05%) after a mean survival of 56.02 months (sd = 25.17 months). The 5-year overall survival rate was 0.94 (95%CI 0.88-0.97) and the 5-year disease-free survival rate was 0.90 (95%CI 0.83-0.94). The 5-year overall survival rates were 96.1% (95% CI, 89.9-98.5%) for the early stages and 87.4% (95% CI, 65.6-95.8%) for the advanced stages (p = 0.670). The 5-year disease-free survival rates resulted being 98.8% (95% CI, 92.3-99.8%) for the early stages and 59.8% (95% CI, 37.8-76.2%) for the advanced stages (p < 0.001). Conclusions: Advanced stage TETs are characterized by higher mortality and recurrence rates. Although technically demanding, surgery, as part of multimodality therapy, could prolong survival. Iterative surgical treatment of recurrences is a viable option for selected patients. Trial registration: The study was approved by the Institutional Review Board of Perugia and Terni University Hospitals [Code T1003] and was retrospectively registered

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

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

Pharmacotherapy for Dravet Syndrome: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials

Background: Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy characterized by drug-resistant, lifelong seizures. The management of seizures in DS has changed in recent years with the approval of new antiseizure medications (ASMs). Objective: The aim of this study was to estimate the comparative efficacy and tolerability of the ASMs for the treatment of seizures associated with DS using a network meta-analysis (NMA). Methods: Studies were identified by conducting a systematic search (week 4, January 2023) of the MEDLINE (accessed by PubMed), EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and US National Institutes of Health Clinical Trials Registry (http://www.clinicaltrials.gov) databases. Any randomized, controlled, double- or single-blinded, parallel-group study comparing at least one ASM therapy against placebo, another ASM, or a different dose of the same ASM in participants with a diagnosis of DS was identified. The efficacy outcomes were the proportions of participants with ≥ 50% (seizure response) and 100% reduction (seizure freedom) in baseline convulsive seizure frequency during the maintenance period. The tolerability outcomes included the proportions of patients who withdrew from treatment for any reason and who experienced at least one adverse event (AE). Effect sizes were estimated by network meta-analyses within a frequentist framework. Results: Eight placebo-controlled trials were included, and the active add-on treatments were stiripentol (n = 2), pharmaceutical-grade cannabidiol (n = 3), fenfluramine hydrochloride (n = 2), and soticlestat (n = 1). The studies recruited 680 participants, of whom 409 were randomized to active treatments (stiripentol = 33, pharmaceutical-grade cannabidiol = 228, fenfluramine hydrochloride = 122, and soticlestat = 26) and 271 to placebo. Pharmaceutical-grade cannabidiol was associated with a lower rate of seizure response than fenfluramine hydrochloride (odds ratio [OR] 0.20, 95% confidence interval [CI] 0.07–0.54), and stiripentol was associated with a higher seizure response rate than pharmaceutical-grade cannabidiol (OR 14.07, 95% CI 2.57–76.87). No statistically significant differences emerged across the different ASMs for the seizure freedom outcome. Stiripentol was associated with a lower probability of drug discontinuation for any reason than pharmaceutical-grade cannabidiol (OR 0.45, 95% CI 0.04–5.69), and pharmaceutical-grade cannabidiol was associated with a lower proportion of participants experiencing any AE than fenfluramine hydrochloride (OR 0.22, 95% CI 0.06–0.78). Stiripentol had a higher risk of AE occurrence than pharmaceutical-grade cannabidiol (OR 75.72, 95% CI 3.59–1598.58). The study found high-quality evidence of efficacy and tolerability of the four ASMs in the treatment of convulsive seizures in DS. Conclusions: There exists first-class evidence that documents the efficacy and tolerability of stiripentol, pharmaceutical-grade cannabidiol, fenfluramine hydrochloride, and soticlestat for the treatment of seizures associated with DS, and allows discussion about the expected outcomes regarding seizure frequency reduction and tolerability profiles

Guar gum/borax hydrogel: Rheological, low field NMR and release characterizations

Guar gum (GG) and Guar gum/borax (GGb) hydrogels are studied by means of rheology, Low Field Nuclear Magnetic Resonance (LF NMR) and model drug release tests. These three approaches are used to estimate the mesh size (ζ) of the polymeric network. A comparison with similar Scleroglucan systems is carried out. In the case of GGb, the rheological and Low Field NMR estimations of ζ lead to comparable results, while the drug release approach seems to underestimate ζ. Such discrepancy is attributed to the viscous effect of some polymeric chains that, although bound to the network to one end, can freely fluctuate among meshes. The viscous drag exerted by these chains slows down drug diffusion through the polymeric network. A proof for this hypothesis is given by the case of Scleroglucan gel, where the viscous contribution is not so significant and a good agreement between the rheological and release test approaches was found

Pre-natal and post-natal exposure to respiratory infection and atopic diseases development: a historical cohort study

BACKGROUND: According to the hygiene hypothesis, infections in early life protect from allergic diseases. However, in earlier studies surrogate measures of infection rather than clinical infections were associated with decreased frequencies of atopic diseases. Exposure to infection indicating sub-clinical infection rather than clinical infection might protect from atopic diseases. Objective: to investigate whether exposure to acute respiratory infections within pregnancy and the first year of life is associated with atopic conditions at age 5–14 years and to explore when within pregnancy and the first year of life this exposure is most likely to be protective. METHODS: Historical cohort study: Population level data on acute respiratory infections from the routine reporting system of the former German Democratic Republic were linked with individual data from consecutive surveys on atopic diseases in the same region (n = 4672). Statistical analyses included multivariate logistic regression analysis and polynomial distributed lag models. RESULTS: High exposure to acute respiratory infection between pregnancy and age one year was associated with overall reduced odds of asthma, eczema, hay fever, atopic sensitization and total IgE. Exposure in the first 9 months of life showed the most pronounced effect. Adjusted odds ratio's for asthma, hay fever, inhalant sensitization and total IgE were statistical significantly reduced up to around half. CONCLUSION: Exposure to respiratory infection (most likely indicating sub-clinical infection) within pregnancy and the first year of life may be protective in atopic diseases development. The post-natal period thereby seems to be particularly important

Anti-seizure medications for Lennox-Gastaut syndrome

Background Lennox‐Gastaut syndrome (LGS) is an age‐specific epilepsy syndrome characterised by multiple seizure types. LGS has a characteristic electroencephalogram, an onset before age eight years, and drug resistance. This is an updated version of the Cochrane Review published in 2013. Objectives To assess the efficacy and tolerability of anti‐seizure medications (ASMs) for LGS. Search methods We searched the Cochrane Register of Studies (CRS Web) and MEDLINE (Ovid, 1946 to 28 February 2020) on 2 March 2020. CRS Web includes randomised controlled trials (RCTs) or quasi‐RCTs from the Cochrane Central Register of Controlled Trials (CENTRAL); the Specialised Registers of Cochrane Review Groups, including Cochrane Epilepsy; PubMed; Embase; ClinicalTrials.gov; and the World Health Organization's International Clinical Trials Registry Platform (ICTRP). We imposed no language restrictions. We contacted pharmaceutical companies and colleagues in the field to seek any unpublished or ongoing studies. Selection criteria We considered RCTs, including cross‐over trials, of ASMs for LGS in children and adults. We included studies of ASMs used as either monotherapy or as add‐on (adjunctive) therapy. We excluded studies comparing different doses of the same ASM. Data collection and analysis We used standard Cochrane methodological procedures, including independent, dual assessment for risk of bias, and applying the GRADE approach to rate the evidence certainty for outcomes. Main results We found no trials of ASM monotherapy. The review included 11 trials (1277 participants; approximately 11 weeks to 112 weeks follow‐up after randomisation) using add‐on ASMs for LGS in children, adolescents, and adults. Two studies compared add‐on cannabidiol (two doses) with add‐on placebo in children, adolescents, and adults. Insufficient information was provided for calculation of different response rate proportions in all seizures. We found high‐certainty evidence that 82 more people per 1000 (confidence interval (CI) 19 more to 350 more) had adverse events (AE) leading to study discontinuation with add‐on cannabidiol, compared to add‐on placebo (two studies; 396 participants; risk ratio (RR) 6.62, 95% CI 1.56 to 28.15). One study compared add‐on cinromide with add‐on placebo in children and adolescents only. We found very low‐certainty evidence that 35 more people per 1000 (CI 123 fewer to 434 more) had 50% or greater average reduction of overall seizures with add‐on cinromide compared to add‐on placebo (one study; 56 participants; RR 1.15, 95% CI 0.47 to 2.86). This study did not report participants with AE leading to study discontinuation. One study compared add‐on clobazam (three doses) with add‐on placebo. This study did not report overall seizure cessation or reduction. We found high‐certainty evidence that 106 more people per 1000 (CI 0 more to 538 more) had AE leading to study discontinuation with add‐on clobazam compared to add‐on placebo (one study; 238 participants; RR 4.12, 95% CI 1.01 to 16.87). One study compared add‐on felbamate with add‐on placebo. No cases of seizure cessation occurred in either regimen during the treatment phase (one study; 73 participants; low‐certainty evidence). There was low‐certainty evidence that 53 more people per 1000 (CI 19 fewer to 716 more) with add‐on felbamate were seizure‐free during an EEG recording at the end of the treatment phase, compared to add‐on placebo (RR 2.92, 95% CI 0.32 to 26.77). The study did not report overall seizure reduction. We found low‐certainty evidence that one fewer person per 1000 (CI 26 fewer to 388 more) with add‐on felbamate had AE leading to study discontinuation compared to add‐on placebo (one study, 73 participants; RR 0.97, 95% CI 0.06 to 14.97). Two studies compared add‐on lamotrigine with add‐on placebo. Neither study reported overall seizure cessation. We found high‐certainty evidence that 176 more people per 1000 (CI 30 more to 434 more) had ≥ 50% average seizure reduction with add‐on lamotrigine compared to add‐on placebo (one study; 167 participants; RR 2.12, 95% CI 1.19 to 3.76). We found low‐certainty evidence that 40 fewer people per 1000 (CI 68 fewer to 64 more) had AE leading to study‐discontinuation with add‐on lamotrigine compared to add‐on placebo (one study; 169 participants; RR 0.49, 95% CI 0.13 to 1.82). Two studies compared add‐on rufinamide with add‐on placebo. Neither study reported seizure cessation. We found high‐certainty evidence that 202 more people per 1000 (CI 34 to 567 more) had ≥ 50% average seizure reduction (one study; 138 participants; RR 2.84, 95% CI 1.31 to 6.18). We found low‐certainty evidence that 105 more people per 1000 (CI 17 fewer to 967 more) had AE leading to study discontinuation with add‐on rufinamide compared to add‐on placebo (one study; 59 participants; RR 4.14, 95% CI 0.49 to 34.86). One study compared add‐on rufinamide with another add‐on ASM. This study did not report overall seizure cessation or reduction. We found low‐certainty evidence that three fewer people per 1000 (CI 75 fewer to 715 more) had AE leading to study discontinuation with add‐on rufinamide compared to another add‐on ASM (one study; 37 participants; RR 0.96, 95% CI 0.10 to 9.57). One study compared add‐on topiramate with add‐on placebo. This study did not report overall seizure cessation. We found low‐certainty evidence for ≥ 75% average seizure reduction with add‐on topiramate (one study; 98 participants; Peto odds ratio (Peto OR) 8.22, 99% CI 0.60 to 112.62) and little or no difference to AE leading to study discontinuation compared to add‐on placebo; no participants experienced AE leading to study discontinuation (one study; 98 participants; low‐certainty evidence). Authors' conclusions RCTs of monotherapy and head‐to‐head comparison of add‐on ASMs are currently lacking. However, we found high‐certainty evidence for overall seizure reduction with add‐on lamotrigine and rufinamide, with low‐certainty evidence for AE leading to study discontinuation compared with add‐on placebo or another add‐on ASM. The evidence for other add‐on ASMs for overall seizure cessation or reduction was low to very low with high‐ to low‐certainty evidence for AE leading to study discontinuation. Future research should consider outcome reporting of overall seizure reduction (applying automated seizure detection devices), impact on development, cognition and behaviour; future research should also investigate age‐specific efficacy of ASMs and target underlying aetiologies