To minimize the risk of Progressive Multifocal Leukoencephalopathy and rebound in JCV-positive multiple sclerosis (MS) patients after 24 natalizumab doses, it has been proposed to extend the ...administrations interval. The objective is to evaluate the EID efficacy on MRI activity compared with the standard interval dosing (SID).
Observational, multicentre, retrospective cohort study, starting from the 24th natalizumab infusion to the loss of follow-up or 2 years after baseline. Three hundred and sixteen patients were enrolled. The median dose interval (MDI) following the 24th infusion was 5 weeks, with a bimodal distribution (modes at 4 and 6 weeks). Patients were grouped into 2 categories according to the mean number of weeks between doses: <5 weeks, SID; ≥5 weeks, EID.
One hundred and eighty-seven patients were in the SID group (MDI = 4.5 weeks) and 129 in the EID group (MDI 6.1 weeks). The risk to develop active lesions on MRI is similar in SID and EID groups during the 6 and 12 months after the 24th natalizumab infusion, respectively 4.27% (95% CI:0.84–7.70) vs 4.71% (95% CI:0.16–9.25%) p = 0.89 and 8.50% (95% CI:4.05–12.95) vs 6.55% (95% CI:2.11–11.00%) p = 0.56. The EID regimen does not appear to increase the occurrence of MRI activity during follow-up.
There is no evidence of the reduced efficacy of natalizumab in an EID setting regarding the MRI activity. This observation supports the need for a bigger randomized study to assess the need to change the standard of the natalizumab dosing schedule, to better manage JCV-positive patients.
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•Extending the natalizumab interval dose over 4 weeks could reduce Progressive Multifocal Leukoencephalopathy risk.•Extending the administrations interval of natalizumab could increase MRI activity.•In our observational, multicentre, retrospective cohort study over 316 patients with multiple sclerosis, showed that the extended dose regimen does not increase the occurrence of MRI activity after 6 and 12 months.•The extended dose natalizumab regimen could maintain the natalizumab efficacy and could be a useful dosing schedule in JCV-positive patients.
Background and purpose
Longitudinally extensive transverse myelitis (LETM) associated with aquaporin‐4 autoantibodies (AQP4‐IgG) can cause severe disability. Early diagnosis and prompt treatment are ...critical to prevent relapses. A novel score is described based on clinical and neuroimaging characteristics that predicts AQP4‐IgG positivity in patients with LETM.
Methods
Patients were enrolled both retrospectively and prospectively from multiple Italian centers. Clinical and neuroimaging characteristics of AQP4‐IgG positive and negative patients were compared through univariate and multivariate analysis.
Results
Sixty‐six patients were included. Twenty‐seven (41%) were AQP4‐IgG positive and median age at onset was 45.5 years (range 19–81, interquartile range 24). Female sex (odds ratio OR 17.9, 95% confidence interval CI 2.6–381.9; p = 0.014), tonic spasms (OR 45.6, 95% CI 3.1–2197; p = 0.017) and lesion hypointensity on T1‐weighted images (OR 52.9, 95% CI 6.8–1375; p = 0.002) were independently associated with AQP4‐IgG positivity. The AQP4‐IgG positivity in myelitis (AIM) score predicted AQP4‐IgG positivity with 85% sensitivity and 95% specificity. Positive and negative likelihood ratios were 16.6 and 0.2 respectively. The inter‐rater and intra‐rater agreement in the score application were both excellent.
Conclusions
The AIM score predicts AQP4‐IgG positivity with good sensitivity and specificity in patients with a first episode of LETM. The score may assist clinicians in early diagnosis and treatment of AQP4‐IgG positive LETM.
In this multicenter study, a score is developed to predict aquaporin‐4 (AQP4) immunoglobulin G (IgG) positivity in patients with longitudinally extensive myelitis (LETM). The AQP‐4‐IgG positive myelitis (AIM) score was applied both retrospectively and prospectively for 66 LETM patients, and a score ≥5 predicted AQP4‐IgG positivity with 85% sensitivity and 95% specificity. The AIM score appears a reliable tool to aid in the early diagnosis and treatment of AQP4‐IgG positive LETM.
Epigenetics connects genetic and environmental factors: it includes DNA methylation, histone post‐translational modifications and the regulation of chromatin accessibility by non‐coding RNAs, all of ...which control constitutive or inducible gene transcription. This plays a key role in harnessing the transcriptional programs of both innate and adaptive immune cells due to its plasticity and environmental‐driven nature, piloting myeloid and lymphoid cell fate decisions with no change in their genomic sequence. In particular, epigenetic marks at the site of lineage‐specific transcription factors and maintenance of cell type‐specific epigenetic modifications, referred to as ‘epigenetic memory’, dictate cell differentiation, cytokine production and functional capacity following repeated antigenic exposure in memory T cells. Moreover, metabolic and epigenetic reprogramming occurring during a primary innate immune response leads to enhanced responses to secondary challenges, a phenomenon known as ‘trained immunity’. Here, we discuss how stable and dynamic epigenetic states control immune cell identity and plasticity in physiological and pathological conditions. Dissecting the regulatory circuits of cell fate determination and maintenance is of paramount importance for understanding the delicate balance between immune cell activation and tolerance, in healthy conditions and in autoimmune diseases.
External cues (e.g., environment, diet) and age converge on epigenetics that affects gene expression through specific DNA and histone modifications or non‐coding RNAs; this, together with genetic factors, tailors immune cell function. Through complex interactions with transcription factor networks and other transcriptional machinery, epigenetic modifications support the functional exchange between repressed and active states of chromatin to prime immune activation, transcriptional memory, innate immune training and tolerance.
To analyse autoantibody status in a well-defined European multicentre cohort of patients with epilepsy of unknown aetiology and to validate the recently proposed Antibody Prevalence in Epilepsy ...(APE2) and Response to ImmunoTherapy in Epilepsy (RITE2) scores.
We retrospectively collected clinical and paraclinical data of 92 patients referred to the Neurology Units of Verona and Salzburg between January 2014 and July 2019 with new-onset epilepsy, status epilepticus or chronic epilepsy of unknown aetiology. Fixed and live cell-based assays, tissue-based assays, immunoblot, and live rat hippocampal cell cultures were performed in paired serum/cerebrospinal fluid (CSF) to detect antineuronal and antiglial antibodies. The APE2 and RITE2 scores were then calculated and compared with clinical and laboratory data.
Autoantibodies were detected in 29/92 patients (31.5%), with multiple positivity observed in 6/29 cases. The APE2 score (median 5, range 1-15) significantly correlated with antibody positivity (p=0.014), especially for the presence of neuropsychiatric symptoms (p<0.01), movement disorders (p<0.01), dysautonomia (p=0.03), faciobrachial dyskinesias (p=0.03) and cancer history (p<0.01). Status epilepticus was significantly more frequent in antibody-negative patients (p<0.01). Among the items of the RITE2 score, early initiation of immunotherapy correlated with a good treatment response (p=0.001), whereas a cancer history was significantly more common among non-responders (p<0.01). Persistence of neuropsychiatric symptoms and seizures correlated with antiepileptic maintenance after at least 1 year.
This is the first study that independently validates the APE2 and RITE2 scores and includes the largest cohort of patients whose paired serum and CSF samples have been tested for autoantibodies possibly associated with autoimmune epilepsy.
Background
COVID-19 vaccines have been recommended to people with multiple sclerosis (pwMS) and, to ensure durable immunity, a third booster dose has been administered in several countries. Data ...about potential risks associated with the third booster dose in pwMS, such as vaccine-triggered disease exacerbations, are still scarce.
Objective
To investigate whether the administration of a third booster dose of mRNA COVID-19 vaccines was associated with an increased risk of short-term disease reactivation in a large cohort of pwMS.
Methods
We retrospectively selected 1265 pwMS who received a third booster dose of an mRNA COVID-19 vaccine. Demographic and clinical data were collected, including the presence, number and characteristics of relapses in the 60 days prior to and after the third booster dose.
Results
In the selected cohort, the relapse rate in the two months after administration of the third booster dose of mRNA COVID-19 vaccines did not increase when compared with the prior two months. Indeed, the percentage of pwMS experiencing relapses in the 60 days following the administration of the third booster dose was 2.1%, similar to the percentage recorded in 60 days prior to vaccination, which was 1.9%.
Conclusions
The third booster dose of mRNA COVID-19 vaccines appeared to be safe for pwMS.
Chronic neuroinflammation is a key pathological hallmark of multiple sclerosis (MS) that suggests that resolution of inflammation by specialized proresolving molecules is dysregulated in the disease. ...Annexin A1 (ANXA1) is a protein induced by glucocorticoids that facilitates resolution of inflammation through several mechanisms that include an inhibition of leukocyte recruitment and activation. In this study, we investigated the ability of ANXA1 to influence T cell effector function in relapsing/remitting MS (RRMS), an autoimmune disease sustained by proinflammatory Th1/Th17 cells. Circulating expression levels of ANXA1 in naive-to-treatment RRMS subjects inversely correlated with disease score and progression. At the cellular level, there was an impaired ANXA1 production by CD4
CD25
conventional T and CD4
RORγt
T (Th17) cells from RRMS subjects that associated with an increased migratory capacity in an in vitro model of blood brain barrier. Mechanistically, ANXA1 impaired monocyte maturation secondarily to STAT3 hyperactivation and potently reduced T cell activation, proliferation, and glycolysis. Together, these findings identify impaired disease resolution pathways in RRMS caused by dysregulated ANXA1 expression that could represent new potential therapeutic targets in RRMS.
Objective
This study was undertaken to describe and compare disease course and prognosis of early (ie, disease onset before age 11 years) and late (ie, disease onset after age 11 years) onset ...pediatric multiple sclerosis.
Methods
Prospectively collected clinical information from Italian Multiple Sclerosis Register of 1993 pediatric multiple sclerosis patients, of whom 172 had early onset, was analyzed. Cox models adjusted for sex, baseline Expanded Disability Status Scale score, and disease‐modifying treatments and stratified for diagnostic criteria adopted (Poser vs McDonald) were used to assess the risk of reaching irreversible Expanded Disability Status Scale scores of 3, 4, and 6, and conversion to secondary progressive phenotype in early versus late onset pediatric patients. Prognostic factors were also evaluated.
Results
A greater proportion of males, isolated brainstem involvement, and longer time interval between first and second clinical episode were observed in early versus late onset pediatric patients. Compared to late onset, early onset pediatric patients took longer from disease onset to convert to secondary progressive phenotype and to reach all disability milestones. Recovery from first demyelinating event, time to first relapse, annualized relapse rate during the first 3 years of disease, and disease‐modifying treatment exposure were independent predictors for long‐term disability in early onset pediatric patients. In late onset pediatric patients, isolated optic neuritis, multifocal symptoms, and progressive course at disease onset were additional predictors for long‐term disability.
Interpretation
These findings point toward the existence of a different natural history in early versus late onset pediatric multiple sclerosis patients. ANN NEUROL 2022;91:483–495
We investigated the occurrence and relative contribution of relapse-associated worsening (RAW) and progression independent of relapse activity (PIRA) to confirmed disability accrual (CDA) and ...transition to secondary progression (SP) in relapsing multiple sclerosis (MS).
Relapsing-onset MS patients with follow-up > / = 5 years (16,130) were extracted from the Italian MS Registry. CDA was a 6-month confirmed increase in Expanded Disability Status Scale (EDSS) score. Sustained disability accumulation (SDA) was a CDA with no EDSS improvement in all subsequent visits. Predictors of PIRA and RAW and the association between final EDSS score and type of CDA were assessed using logistic multivariable regression and multivariable ordinal regression models, respectively.
Over 11.8 ± 5.4 years, 16,731 CDA events occurred in 8998 (55.8%) patients. PIRA (12,175) accounted for 72.3% of CDA. SDA occurred in 8912 (73.2%) PIRA and 2583 (56.7%) RAW (p < 0.001). 4453 (27.6%) patients transitioned to SPMS, 4010 (73.2%) out of 5476 patients with sustained PIRA and 443 (24.8%) out of 1790 patients with non-sustained PIRA. In the multivariable ordinal regression analysis, higher final EDSS score was associated with PIRA (estimated coefficient 0.349, 95% CI 0.120-0.577, p = 0.003).
In this real-world relapsing-onset MS cohort, PIRA was the main driver of disability accumulation and was associated with higher disability in the long term. Sustained PIRA was linked to transition to SP and could represent a more accurate PIRA definition and a criterion to mark the putative onset of the progressive phase.
Introduction
Neurological disorders are considered rare complications of immune-checkpoint inhibitor.
Case description
We report a 63-year-old man with recurrence of melanoma who presented epilepsy, ...limbic encephalitis, cerebellar ataxia, and stiff person syndrome soon after treatment with nivolumab, an immune-checkpoint inhibitor. On autoimmune screening, serum and CSF GAD65 were detected. Significant response to steroids and intravenous immunoglobulins were observed, but cancer recurred after nivolumab discontinuation in parallel with epileptic seizure and worsening of cognitive impairment and the patient died.
Discussion
This case expands the spectrum of GAD65-associated conditions induced by immune-checkpoint inhibitor and underlines treatment complexity when both neurological complications and tumour recurrence occur.
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