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Proton pump inhibitor-responsive esophageal eosinophilia (PPI-REE) is diagnosed in at least one-third of patients with suspected eosinophilic esophagitis (EoE). We aimed to evaluate the durability and factors influencing long-term efficacy of PPI therapy. Retrospective multicenter cohort study of patients with PPI-REE who had at least 12 months of follow-up. PPI therapy was tapered to the lowest dose, which maintained clinical remission. Primary outcomes were the proportion of patients with loss of histological response (<15 eos/HPF) and predictors of loss of response. CYP2C19 polymorphisms were determined from blood samples in a subset of patients. Seventy-five PPI-REE patients were included (mean follow-up 26 months (12-85)), of whom fifty-five (73%) had sustained histological remission on low-dose PPI therapy. Loss of response was significantly higher in those patients with a CYP2C19 rapid metabolizer genotype (36% vs. 6%, P = 0.01) and with rhinoconjunctivitis (40% vs. 13%, P = 0.007). On the multivariate analysis, a CYP2C19 rapid metabolizer genotype (odds ratio (OR) 12.5; 95% confidence interval (CI): 1.3-115.9) and rhinoconjunctivitis (OR 8.6; 95% CI: 1.5-48.7) were independent predictors of loss of response. Among relapsing patients, eosinophilia was limited to the distal esophagus in 14/20 (70%). Nine of ten relapsers, with distal eosinophilia, all showing a CYP2C19 rapid metabolizer genotype, regained histological remission after PPI dose intensification. Most PPI-REE patients remain in long-term remission on low-dose PPI therapy. CYP2C19 rapid metabolizer genotypes and rhinoconjunctivitis were independent predictors of loss of response to PPI, but patients frequently responded to PPI dose escalation.

PurposeThe authors identify the theoretical constructions measuring the intentions to pursue succession as well as the socioemotional wealth theoretical framework, and the authors propose an objective of testing the relationships existing between them so as their importance giving evidence of their relevance.Design/methodology/approachIt is a research with a positivist philosophical position measuring in a quantitative way with a deductive and structured approach applied to 98 CEO owners of Mexican companies, using nonparametric methodologies the authors simulated subsamples with structural equation modeling in SmartPLS 3.3.2, the metrics on the model are described as a functionalist paradigm.FindingsDirectors' attitudes paired up with the intentions of succession are significantly related to the socioemotional aspect of the family business; although the theory proposes three aspects to measure these intentions, the social norm in this research has not been strong enough to be a predictor as an influence on the company's socioemotional wealth.Originality/valueThe authors found this a valuable paper for the complement of theory focused on purely manifesting aspects in family companies, because they identified theoretical and empirical relationships opening up guidelines for new research in socioemotional aspects in accordance with the entrepreneurs attitudes to achieve succession, the differentiation lies in measuring psychological aspects of the director's behavior toward succession and not to the succession per se as done in most research; also, the methodology of data analysis facilitates the reader to easily recognize the relationships between the proposed theoretical constructions, showing the detailed metrics development by researchers in the family business field.

Background Disease-modifying therapies are thought to reduce the conversion rate to secondary progressive multiple sclerosis. Objective To explore the rate, chronology, and contributing factors of conversion to the progressive phase in treated relapsing–remitting multiple sclerosis patients. Methods Our study included 204 patients treated for relapsing–remitting multiple sclerosis between 1995 and 2002, prospectively followed to date. Kaplan–Meier analysis was applied to estimate the time until secondary progressive multiple sclerosis conversion, and multivariate survival analysis with a Cox regression model was used to analyse prognostic factors. Results Relapsing–remitting multiple sclerosis patients were continuously treated for 13 years (SD 4.5); 36.3% converted to secondary progressive multiple sclerosis at a mean age of 42.6 years (SD 10.6), a mean time of 8.2 years (SD 5.2) and an estimated mean time of 17.2 years (range 17.1–18.1). A multifocal relapse, age older than 34 years at disease onset and treatment failure independently predicted conversion to secondary progressive multiple sclerosis but did not influence the time to reach an Expanded Disability Status Scale of 6.0. Conclusions The favourable influence of disease-modifying therapies on long-term disability in relapsing–remitting multiple sclerosis is well established. However, the time to progression onset and the subsequent clinical course in treated patients seem similar to those previously reported in natural history studies. More studies are needed to clarify the effect of disease-modifying therapies once the progressive phase has been reached.

Increasing evidence suggests that seizures and status epilepticus can be immune-mediated. We aimed to describe the clinical features of a new epileptic disorder, and to establish the target antigen and the effects of patients' antibodies on neuronal cultures. In this observational study, we selected serum and CSF samples for antigen characterisation from 140 patients with encephalitis, seizures or status epilepticus, and antibodies to unknown neuropil antigens. The samples were obtained from worldwide referrals of patients with disorders suspected to be autoimmune between April 28, 2006, and April 25, 2013. We used samples from 75 healthy individuals and 416 patients with a range of neurological diseases as controls. We assessed the samples using immunoprecipitation, mass spectrometry, cell-based assay, and analysis of antibody effects in cultured rat hippocampal neurons with confocal microscopy. Neuronal cell-membrane immunoprecipitation with serum of two index patients revealed GABAA receptor sequences. Cell-based assay with HEK293 expressing α1/β3 subunits of the GABAA receptor showed high titre serum antibodies (>1:160) and CSF antibodies in six patients. All six patients (age 3–63 years, median 22 years; five male patients) developed refractory status epilepticus or epilepsia partialis continua along with extensive cortical-subcortical MRI abnormalities; four patients needed pharmacologically induced coma. 12 of 416 control patients with other diseases, but none of the healthy controls, had low-titre GABAA receptor antibodies detectable in only serum samples, five of them also had GAD-65 antibodies. These 12 patients (age 2–74 years, median 26·5 years; seven male patients) developed a broader spectrum of symptoms probably indicative of coexisting autoimmune disorders: six had encephalitis with seizures (one with status epilepticus needing pharmacologically induced coma; one with epilepsia partialis continua), four had stiff-person syndrome (one with seizures and limbic involvement), and two had opsoclonus-myoclonus. Overall, 12 of 15 patients for whom treatment and outcome were assessable had full (three patients) or partial (nine patients) response to immunotherapy or symptomatic treatment, and three died. Patients' antibodies caused a selective reduction of GABAA receptor clusters at synapses, but not along dendrites, without altering NMDA receptors and gephyrin (a protein that anchors the GABAA receptor). High titres of serum and CSF GABAA receptor antibodies are associated with a severe form of encephalitis with seizures, refractory status epilepticus, or both. The antibodies cause a selective reduction of synaptic GABAA receptors. The disorder often occurs with GABAergic and other coexisting autoimmune disorders and is potentially treatable. The National Institutes of Health, the McKnight Neuroscience of Brain Disorders, the Fondo de Investigaciones Sanitarias, Fundació la Marató de TV3, the Netherlands Organisation for Scientific Research (Veni-incentive), the Dutch Epilepsy Foundation.

The role of T cells in autoimmune encephalitis syndromes with autoantibodies against cell surface antigens is still enigmatic. Here we analyzed the T cell receptor repertoires of CD8+ and CD4+ T cells in a patient with “idiopathic” gamma‐aminobutyric‐acid‐A receptor (GABAA‐R) encephalitis by next‐generation sequencing and single‐cell analyses. We identified a CD8+ T cell clone that was strongly expanded in the cerebrospinal fluid and in the hippocampus but not in the operculo‐insular cortex. By contrast, CD4+ T cells were polyclonal in these tissues. Such a strong clonal expansion suggests that CD8+ T cells may play a significant role in the pathogenesis.

IntroductionRituximab is considered as a potential therapeutic option in relapsing-remitting (RRMS) and progressive forms (PMS) of multiple sclerosis (MS).ObjectiveTo investigate the effectiveness and safety of rituximab in MS.Patients and methodsObservational study of effectiveness (clinical and radiological) and safety of rituximab in RRMS and PMS.ResultsA total of 90 rituximab-treated patients were collected: 31 RRMS and 59 PMS All patients had an active disease despite standard treatment. The annualized relapse rate (ARR) the year before rituximab was 0.86, 53.3% of patients had gadolinium enhanced lesion, and mean Expanded Disability Status Scale (EDSS) had increased from 4.2 to 4.9. During treatment, the ARR was reduced an 88.4% (p < 0.001). A significant decrease of EDSS to 4.6 was observed (p = 0.01) after 1 year of treatment, which remained stable during the second year in both groups. There was no evidence of disease activity in 70% of total sample, 74.2% of RRMS, and 67% of the PMS patients. Infusion-related symptoms were the most prevalent side effect (18.8%) and most were mild. Three thrombotic events were detected.ConclusionRituximab could be an effective and safe treatment in aggressive RRMS. Some selected PMS patients could also benefit from this treatment.

Cerebrospinal kappa free light chain (KFLC)-index is a marker of intrathecal immunoglobulin synthesis that aids in the diagnosis of multiple sclerosis (MS). However, little evidence exists on its prognostic role. Our aim is to analyze the relationship between KFLC-index and other MS biomarkers and to explore its prognostic role. This is a monocentric observational study in a cohort of 52 people with relapsing MS (pwRMS) performed on prospectively acquired clinical data and with retrospective evaluation of biomarkers. We measured KFLC-index, immunoglobulin intrathecal synthesis, cerebrospinal fluid (CSF) chitinase 3-like 1 (CHI3L1), and neurofilament light protein (NFL) and reviewed MRI to detect leptomeningeal contrast enhancement (LMCE). We compared time to Expanded Disability Status Scale (EDSS) 3 and to initiation of high-efficacy disease-modifying therapies (heDMTs) by multivariate Cox regression analysis. Median KFLC-index correlated with IgG/IgM indexes ( p < 0.0001/ p < 0.05) and IgG-oligoclonal bands (OCGBs) ( p < 0.001). Patients with IgM-oligoclonal bands (OCMBs) had a higher KFLC-index ( p = 0.049). KFLC-index was higher in patients with LMCE ( p = 0.008) and correlated with CHI3L1 ( p = 0.007), but disease activity had no effect on its value. Bivariate and multivariate analyses confirmed KFLC-index > 58 as an independent risk factor for reaching an EDSS of 3 (hazard ratio (HR) = 12.4; 95% CI = 1.1–147; p = 0.047) and for the need of treatment with heDMTs (HR = 3.0; 95% CI = 1.2–7.1; p = 0.0013). To conclude, our data suggest a potential prognostic role of the KFLC-index during the MS course.

Neuromyelitis optica spectrum disorders (NMOSD) are a group of inflammatory disorders of central nervous system characterized by immune-mediated demyelination and axonal damage, predominantly affecting spinal cord and optic nerves. This case report describes a 47-year-old woman with an aggressive form of seropositive NMOSD who had previously been treated with corticosteroids, plasma exchange, and cyclophosphamide. She experienced a life-threatening relapse that did not respond to conventional treatment, but ultimately showed a positive response to eculizumab. Furthermore, we describe the role of sNfL.

BackgroundSerum neurofilament light chain (sNfL) and serum glial fibrillary acidic protein (sGFAP) have emerged as important biomarkers in multiple sclerosis (MS) and aquaporin-4 seropositive neuromyelitis optica spectrum disorder (AQP4-NMOSD). However, their interest in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) remains unclear. Our aim was to characterise sNfL and sGFAP profile and analyse their usefulness in predicting relapses and disability in MOGAD.MethodsRetrospective study of adult MOGAD patients with serum samples collected at baseline (≤3 months from disease onset) and follow-up (>6 months from baseline sample). sNfL and sGFAP were analysed using Simoa HD-1, and values were compared across time-points. The association between biomarkers and clinical variables and their predictive value for disability and relapses were analysed.ResultsEighty-nine MOGAD patients were included. Baseline sNfL and sGFAP values were high at baseline and decreased over time (p<0.001, p=0.027, respectively). sNfL and sGFAP values were associated with Expanded Disability Status Scale (EDSS) at attacks (β 0.15 (0.06; 0.25), p=0.002; β 0.14 (0.07; 0.21), p<0.001, respectively) and were lower in optic neuritis presentations (β −0.69 (−1.18; −0.19), p=0.007; β −0.42 (−0.76; −0.08), p=0.016). Biomarker deltas[Δ] (baseline values – second samples values) were associated with ΔEDSS (initial EDSS - final EDSS) (ΔsNfL β 0.52 (0.01; 1.04), p=0.046; ΔsGFAP β 1.07 (0.38; 1.75), p=0.003). Finally, sNfL values independently predicted the risk of relapses (HR 2.06 (1.41; 3.01), p<0.001).ConclusionsOur results on sNfL and sGFAP suggest initial neuro-axonal and astrocytic damage in MOGAD and the utility of these biomarkers at onset and follow-up in predicting clinical recovery and relapses.