Brain reserve and timing of clinical onset in multiple sclerosis.

BACKGROUND: A latent period of variable length elapses between multiple sclerosis (MS) biological onset and the occurrence of the first clinical episode reflecting a central nervous system (CNS) demyelinating event. Factors affecting the duration of such interval are unknown. OBJECTIVE: To explore whether brain reserve, which moderates the impact of structural damage along MS course, could also affect the timing of MS clinical onset. METHODS: We conducted a time-to-event analysis in 326 relapsing-onset multiple sclerosis patients to ascertain the effect of brain reserve, that is, larger maximal lifetime brain growth (MLBG) estimated as intracranial volume, on the risk of an earlier disease onset. For this purpose, we carried out a Cox proportional hazards regression model stratified by sex and adjusted by site and pre-morbid MS risk factors. All patients reached the event (i.e. the disease onset) with no censored case; the age (years) at disease onset was set as the main time variable. RESULTS: We identified a protective effect of brain reserve on the time to disease onset (HR = 0.11, 95% CI = 0.02-0.83, p = 0.032), unchanged when accounting for MS risk factors. CONCLUSION: Brain reserve might counteract the pathological mechanisms ongoing after biological initiation, thus delaying the disease overt clinical manifestation.

Cortical plasticity in AQP4-positive NMOSD: a transcranial magnetic stimulation study.

Aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4-NMOSD) is an autoimmune disease characterized by suboptimal recovery from attacks and long-term disability. Experimental data suggest that AQP4 antibodies can disrupt neuroplasticity, a fundamental driver of brain recovery. A well-established method to assess brain LTP is through intermittent theta-burst stimulation (iTBS). This study aimed to explore neuroplasticity in AQP4-NMOSD patients by examining long-term potentiation (LTP) through iTBS. We conducted a proof-of-principle study including 8 patients with AQP4-NMOSD, 8 patients with multiple sclerosis (MS), and 8 healthy controls (HC) in which iTBS was administered to induce LTP-like effects. iTBS-induced LTP exhibited significant differences among the 3 groups (p: 0.006). Notably, AQP4-NMOSD patients demonstrated impaired plasticity compared to both HC (p = 0.01) and pwMS (p = 0.02). This pilot study provides the first in vivo evidence supporting impaired neuroplasticity in AQP4-NMOSD patients. Impaired cortical plasticity may hinder recovery following attacks suggesting a need for targeted rehabilitation strategies.

Anti-RBD Antibody Levels and IFN-γ-Specific T Cell Response Are Associated with a More Rapid Swab Reversion in Patients with Multiple Sclerosis after the Booster Dose of COVID-19 Vaccination.

This study investigated the incidence and severity of SARS-CoV-2 breakthrough infections (BIs) and the time to swab reversion in patients with multiple sclerosis (PwMS) after the booster dose of COVID-19 mRNA vaccines. We enrolled 64 PwMS who had completed the three-dose mRNA vaccine schedule and had never experienced COVID-19 before. Among the 64 PwMS, 43.8% had BIs with a median time since the third vaccine dose of 155 days. BIs occurred more frequently in ocrelizumab-treated patients (64.7%). Patients with a relapsing-remitting MS course showed a reduced incidence of BIs compared with those with a primary-progressive disease (p = 0.002). Having anti-receptor-binding domain (RBD) antibodies represented a protective factor reducing the incidence of BIs by 60% (p = 0.042). The majority of BIs were mild, and the only severe COVID-19 cases were reported in patients with a high Expanded Disability Status Scale score (EDSS > 6). The median time for a negative swab was 11 days. Notably, fingolimod-treated patients take longer for a swab-negativization (p = 0.002). Conversely, having anti-RBD antibodies ≥ 809 BAU/mL and an IFN-γ-specific T cell response ≥ 16 pg/mL were associated with a shorter time to swab-negativization (p = 0.051 and p = 0.018, respectively). In conclusion, the immunological protection from SARS-CoV-2 infection may differ among PwMS according to DMTs.

Concomitant Parenchymal, Subarachnoid, and Ventricular Neurocysticercosis in Rome, Italy: A Case Report with a 4-Year Follow-Up.

Neurocysticercosis (NCC) is caused by the larval stage of Taenia solium. This parasitic disease is endemic in many areas of the world and is emerging in Europe. NCC can affect different brain regions, but simultaneous involvement of the parenchymal, subarachnoid, and ventricular regions is rare. We report the case of a 39-year-old woman from Honduras, resident in Rome for 10 years, who presented to the Emergency Department complaining of headaches, transient hemianopsia, and bilateral papilledema. MRI showed a concomitant parenchymal, subarachnoid, and ventricular involvement in the brain. T. solium IgG antibodies were detected in the blood. The etiological diagnosis of NCC was obtained by identifying T. solium in cerebrospinal fluid using Next Generation Sequencing. Endoscopic neurosurgery with the placement of a ventricular shunt and medical long-term anti-parasitic treatment with a cumulative number of 463 days of albendazole and 80 days of praziquantel were performed. A successful 4-year follow-up is reported. NCC is one of the most common parasitic infections of the human CNS, but it is still a neglected tropical disease and is considered to be an emerging disease in Europe. Its diagnosis and clinical management remain a challenge, especially for European clinicians.

Disability patterns in multiple sclerosis: A meta-analysis on RAW and PIRA in the real-world context.

OBJECTIVE: To summarize the current evidence on relapse-associated worsening (RAW) and progression independent of relapse activity (PIRA) through a quantitative synthesis of real-world studies. METHODS: Scientific databases were searched to identify suitable articles. Random-effects meta-analyses, subgroup analyses and meta-regression models were ran to provide pooled estimates of RAW and PIRA events and to identify their potential moderators (PROSPERO registration: CRD42024503895). RESULTS: Eighteen articles met the eligibility criteria, with a pooled sample size of 52,667 patients (93% relapsing-remitting, 6% clinically isolated syndrome and 1% progressive) followed for 2.4 to 12.1 years, yielding to 415,825 patient-years. Pooled event rates for RAW and PIRA were 1.6 (95 confidence interval (CI) = 1.1-2.1) and 3.1 (95% CI = 2.3-3.9) per 100 patient-years, respectively. Less RAW events were found in cohorts including patients with progressive course (ß = -0.069, p = 0.006) and under high-efficacy disease-modifying treatments (DMTs) (ß = -0.031, p = 0.007), while PIRA events were directly related to older age (ß = 0.397, p = 0.027). In addition, we found significant differences in PIRA event rates according to the criteria adopted to define confirmed disability accrual (p < 0.05). DISCUSSION: PIRA accounts for most events causing disability accumulation in the real-world setting, even at the earlier disease stages, whereas RAW represents a less frequent phenomenon, likely due to effective treatments. The detection and statistical analysis of PIRA outcomes pose challenges, raising the risk of erroneous inference. When interpreting our findings, caution is needed given the wide heterogeneity of included studies.

Unusual CLIPPERS presentation with a predominant spinal cord involvement: case report and review of the literature.

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a discrete nosological entity characterized by punctate and curvilinear gadolinium enhancement "peppering" the pons and a strong response to steroids. MRI images typically show pontine and cerebellar punctate-enhancing lesions, which occasionally spread up to the juxtacortical areas and down to the spinal cord. Interestingly, the more distant the lesion is from the pons, the less intense they become. Herein, we describe an extremely rare case of CLIPPERS presenting with predominant spinal cord involvement; then, we searched in the literature the available cases with a similar presentation. Our case focuses attention on a rare MRI CLIPPERS presentation. Since CLIPPERS has a dramatic response to corticosteroid treatment, it is fundamental to promptly recognize its MRI pattern to start treatment as soon as possible.

Incidence and determinants of seizures in multiple sclerosis: a meta-analysis of randomised clinical trials.

BACKGROUND: Seizures are reported to be more prevalent in individuals with multiple sclerosis (MS) compared with the general population. Existing data predominantly originate from population-based studies, which introduce variability in methodologies and are vulnerable to selection and reporting biases. METHODS: This meta-analysis aims to assess the incidence of seizures in patients participating in randomised clinical trials and to identify potential contributing factors. Data were extracted from 60 articles published from 1993 to 2022. The pooled effect size, representing the incidence rate of seizure events, was estimated using a random-effect model. Metaregression was employed to explore factors influencing the pooled effect size. RESULTS: The meta-analysis included data from 53 535 patients and 120 seizure events in a median follow-up of 2 years. The pooled incidence rate of seizures was 68.0 per 100 000 patient-years, significantly higher than the general population rate of 34.6. Generalised tonic-clonic seizures were the most common type reported, although there was a high risk of misclassification for focal seizures with secondary generalisation. Disease progression, longer disease duration, higher disability levels and lower brain volume were associated with a higher incidence of seizures. Particularly, sphingosine-1-phosphate receptor (S1PR) modulators exhibited a 2.45-fold increased risk of seizures compared with placebo or comparators, with a risk difference of 20.5 events per 100 000 patient-years. CONCLUSIONS: Patients with MS face a nearly twofold higher seizure risk compared with the general population. This risk appears to be associated not only with disease burden but also with S1PR modulators. Our findings underscore epilepsy as a significant comorbidity in MS and emphasise the necessity for further research into its triggers, preventive measures and treatment strategies.

Assessing treatment response to oral drugs for multiple sclerosis in real-world setting: a MAGNIMS Study.

BACKGROUND: The assessment of treatment response is a crucial step for patients with relapsing-remitting multiple sclerosis on disease-modifying therapies (DMTs). We explored whether a scoring system developed within the MAGNIMS (MRI in Multiple Sclerosis) network to evaluate treatment response to injectable drugs can be adopted also to oral DMTs. METHODS: A multicentre dataset of 1200 patients who started three oral DMTs (fingolimod, teriflunomide and dimethyl fumarate) was collected within the MAGNIMS network. Disease activity after the first year was classified by the 'MAGNIMS' score based on the combination of relapses (0-≥2) and/or new T2 lesions (<3 or ≥3) on brain MRI. We explored the association of this score with the following 3-year outcomes: (1) confirmed disability worsening (CDW); (2) treatment failure (TFL); (3) relapse count between years 1 and 3. The additional value of contrast-enhancing lesions (CELs) and lesion location was explored. RESULTS: At 3 years, 160 patients experienced CDW: 12% of them scored '0' (reference), 18% scored '1' (HR=1.82, 95% CI 1.20 to 2.76, p=0.005) and 37% scored '2' (HR=2.74, 95% CI 1.41 to 5.36, p=0.003) at 1 year. The analysis of other outcomes provided similar findings. Considering the location of new T2 lesions (supratentorial vs infratentorial/spinal cord) and the presence of CELs improved the prediction of CDW and TFL, respectively, in patients with minimal MRI activity alone (one or two new T2 lesions). CONCLUSIONS: Early relapses and substantial MRI activity in the first year of treatment are associated with worse short-term outcomes in patients treated with some of the oral DMTs.

Stopping Disease-Modifying Treatments in Multiple Sclerosis: A Systematic Review and Meta-Analysis of Real-World Studies.

BACKGROUND: The question of whether multiple sclerosis requires life-long disease-modifying treatments (DMTs) remains unanswered. Some studies suggest that older patients with stable disease may safely discontinue their DMTs, yet comprehensive evidence-based data are scarce and real-world studies have provided mixed results. OBJECTIVE: The aim of this study was to assess the rate of disease reactivation and associated risk factors after discontinuation of DMTs in patients with multiple sclerosis. METHODS: We searched scientific databases (PubMed/MEDLINE, Scopus and Google Scholar) to identify real-world studies published until 31 July, 2023 that reported the number of patients who experienced relapses and/or disability accrual (outcomes of interest) following a therapy discontinuation longer than 12 months. Magnetic resonance activity and treatment re-start after DMT discontinuation were also considered as additional outcomes. We excluded studies where therapy discontinuation was explicitly related to an unintended or planned pregnancy or preceded a treatment switch. We ran random-effects meta-analyses, subgroup analyses and meta-regression models to provide pooled estimates of post-discontinuation relapse and disability events, and to identify their potential moderators (predictors). RESULTS: After an independent screening, 22 articles met the eligibility criteria, yielding a pooled sample size of 2942 patients followed for 1-7 years after discontinuation (11,689 patient-years). The pooled rates for relapse and disability events were 6.7 and 5.8 per 100 patient-years, respectively. However, available data did not allow us to disentangle isolated disability accrual from relapse-associated worsening. Studies including older patients (ß = -0.65, p = 0.006), patients with a longer exposure to DMTs (ß = -2.22, p = 0.001) and patients with a longer period of disease stability (ß = -2.74, p = 0.002) showed a lower risk of relapse events. According to meta-regression equations, the risk of relapse events after DMT discontinuation became negligible (arbitrarily set at < 1% per year) at approximately 60 years of age, and after either 10 years of DMT exposure, or 8 years of disease stability. Additional analyses showed pooled rates for magnetic resonance imaging activity and re-start events of 16.7 and 17.5 per 100 patient-years, respectively. CONCLUSIONS: Based on our quantitative synthesis of real-world data, in the absence of definitive answers from clinical trials, DMT discontinuation appears feasible with a high degree of certainty in selected patients. While our findings are robust regarding relapse events, future efforts are warranted to determine if DMT discontinuation is associated with isolated disability accrual.

Dimethyl Fumarate or Teriflunomide for Relapsing-Remitting Multiple Sclerosis: A Meta-analysis of Post-marketing Studies.

In the absence of head-to-head comparison trials, we aimed to compare the effectiveness of two largely prescribed oral platform disease-modifying treatments for relapsing-remitting multiple sclerosis, namely, dimethyl fumarate (DMF) and teriflunomide (TRF). We searched scientific databases to identify real-world studies reporting a direct comparison of DMF versus TRF. We fitted inverse-variance weighted meta-analyses with random effects models to estimate the risk ratio (RR) of relapse, confirmed disability worsening (CDW), and treatment discontinuation. Quantitative synthesis was accomplished on 14 articles yielding 11,889 and 8133 patients treated with DMF and TRF, respectively, with a follow-up ranging from 1 to 2.8 years. DMF was slightly more effective than TRF in reducing the short-term relapse risk (RR = 0.92, p = 0.01). Meta-regression analyses showed that such between-arm difference tends to fade in studies including younger patients and a higher proportion of treatment-naïve subjects. There was no difference between DMF and TRF on the short-term risk of CDW (RR = 0.99, p = 0.69). The risk of treatment discontinuation was similar across the two oral drugs (RR = 1.02, p = 0.63), but it became slightly higher with DMF than with TRF (RR = 1.07, p = 0.007) after removing one study with a potential publication bias that altered the final pooled result, as also confirmed by a leave-one-out sensitivity analysis. Discontinuation due to side effects and adverse events was reported more frequently with DMF than with TRF. Our findings suggest that DMF is associated with a lower risk of relapses than TRF, with more nuanced differences in younger naïve patients. On the other hand, TRF is associated with a lower risk of treatment discontinuation for side effects and adverse events.

Models of care in emergency neurology: from the Neuro Fast Track to the emergency neurologist-a position paper of the Italian Association for Emergency Neurology (ANEU).

I n the context of an adequate health care organization, the figure of the neurologist as an emergency operator (in the emergency room-ER-and/or in a dedicated outpatient clinic) is crucial for an effective functional connection with the territory (and therefore with general practitioners), a reduction in inappropriate ER accesses, specific diagnostic and therapeutic approaches to neurological emergencies in the ER and a reduction in nonspecific or even unnecessary instrumental investigations. In this position paper of the Italian Association of Emergency Neurology (ANEU: Associazione Neurologia dell'Emergenza Urgenza), these issues are addressed, and two important organizational solutions are proposed: 1) The Neuro Fast Track, as an outpatient organization approach strongly linked to general practitioners and non-neurological specialists and dedicated to cases with deferrable urgency (to be assessed within 72 h) 2) The identification of an emergency neurologist, who is engaged in ER assessments as a consultant and involved in the management of the semi-intensive care unit of the emergency neurology and the stroke unit according to an appropriate rotation, as well as in consultations for patients with neurological emergencies in inpatient wards The possibility of computerizing the screening of patients with deferrable urgency in the Neuro Fast Track is described. A dedicated app represents an important tool that can facilitate the identification of patients for whom deferred assessment is appropriate, the scheduling of neurological examinations and reductions in the booking time through a more rapid approach to specialist assessment and subsequent investigations.

The Italian hub-and-spoke network for the emergency neurology management.

OBJECTIVE: The aim of the present study was to assess emergency neurology management in Italy by comparing patients admitted to the hub and spoke hospitals. METHODS: Data obtained from the annual Italian national survey (NEUDay) investigating the activity and facilities of neurology in the emergency room conducted in November 2021 were considered. Information for each patient who received a neurologic consultation after accessing the emergency room was acquired. Data on facilities were also gathered, including hospital classification (hub vs spoke), number of consultations, presence of neurology and stroke unit, number of beds, availability of neurologist, radiologist, neuroradiologist, and instrumental diagnostic accessibility. RESULTS: Overall, 1,111 patients were admitted to the emergency room and had neurological consultation across 153 facilities (out of the 260 Italian ones). Hub hospitals had significantly more beds, availability of neurological staff, and instrumental diagnostic accessibility. Patients admitted to hub hospital had a greater need for assistance (higher number of yellow/red codes at neurologist triage). A higher propensity to be admitted to hub centers for cerebrovascular problems and to receive a diagnosis of stroke was observed. CONCLUSIONS: The identification of hub and spoke hospitals is strongly characterized by the presence of beds and instrumentation mainly dedicated to acute cerebrovascular pathologies. Moreover, the similarity in the number and type of accesses between hub and spoke hospitals suggests the need to look for adequate identification of all the neurological pathologies requiring urgent treatment.

Informal caregiver's socio demographic profile for community-dwelling women and men with mild to moderate Alzheimer's disease, compliance, and satisfaction to treatment: A post-hoc analysis of the AXEPT study.

In this post-hoc analysis of the AXEPT study, 855 patients were analyzed, 544 (63.6%) females. The mean (± SD) MMSE score in women vs men was 20.8 ± 2.6 vs. 21.2 ± 2.5; p = 0.0087, and women were more likely affected by psychiatric disorders (n = 76, 14.0% women vs. n = 21, 6.8% men; p = 0.0015). Men were mainly assisted by their wives (n = 207, 66.6%), women mainly by their daughters (n = 243, 44.7%) and only in a minority of cases by their husbands (n = 92, 16.9%). Women less frequently cohabited with their caregivers than men (n = 233, 43.1% vs. n = 240, 77.9%, p < 0.0001), and received less daily time of caregiving (mean (± SD): 10.0 ± 7.2 vs. 15.2 ± 8.2; p < 0.0001). No gender differences were highlighted in compliance to treatment and caregiver satisfaction, while gender differences in caregiving were found at disadvantage of women affected by more severe cognitive and psychiatric conditions.

Dynamic Evolution of Humoral and T-Cell Specific Immune Response to COVID-19 mRNA Vaccine in Patients with Multiple Sclerosis Followed until the Booster Dose.

This study characterizes antibody and T-cell immune responses over time until the booster dose of COronaVIrus Disease 2019 (COVID-19) vaccines in patients with multiple sclerosis (PwMS) undergoing different disease-modifying treatments (DMTs). We prospectively enrolled 134 PwMS and 99 health care workers (HCWs) having completed the two-dose schedule of a COVID-19 mRNA vaccine within the last 2-4 weeks (T0) and followed them 24 weeks after the first dose (T1) and 4-6 weeks after the booster (T2). PwMS presented a significant reduction in the seroconversion rate and anti-receptor-binding domain (RBD)-Immunoglobulin (IgG) titers from T0 to T1 (p < 0.0001) and a significant increase from T1 to T2 (p < 0.0001). The booster dose in PwMS showed a good improvement in the serologic response, even greater than HCWs, as it promoted a significant five-fold increase of anti-RBD-IgG titers compared with T0 (p < 0.0001). Similarly, the T-cell response showed a significant 1.5- and 3.8-fold increase in PwMS at T2 compared with T0 (p = 0.013) and T1 (p < 0.0001), respectively, without significant modulation in the number of responders. Regardless of the time elapsed since vaccination, most ocrelizumab- (77.3%) and fingolimod-treated patients (93.3%) showed only a T-cell-specific or humoral-specific response, respectively. The booster dose reinforces humoral- and cell-mediated-specific immune responses and highlights specific DMT-induced immune frailties, suggesting the need for specifically tailored strategies for immune-compromised patients to provide primary prophylaxis, early SARS-CoV-2 detection and the timely management of COVID-19 antiviral treatments.

Longitudinal characterisation of B and T-cell immune responses after the booster dose of COVID-19 mRNA-vaccine in people with multiple sclerosis using different disease-modifying therapies.

BACKGROUND: The decline of humoral response to COVID-19 vaccine led to authorise a booster dose. Here, we characterised the kinetics of B-cell and T-cell immune responses in patients with multiple sclerosis (PwMS) after the booster dose. METHODS: We enrolled 22 PwMS and 40 healthcare workers (HCWs) after 4-6 weeks from the booster dose (T3). Thirty HCWs and 19 PwMS were also recruited 6 months (T2) after the first dose. Antibody response was measured by anti-receptor-binding domain (RBD)-IgG detection, cell-mediated response by an interferon (IFN)-γ release assay (IGRA), Th1 cytokines and T-cell memory profile by flow cytometry. RESULTS: Booster dose increased anti-RBD-IgG titers in fingolimod-treated, cladribine-treated and IFN-ß-treated patients, but not in ocrelizumab-treated patients, although antibody titres were lower than HCWs. A higher number of fingolimod-treated patients seroconverted at T3. Differently, T-cell response evaluated by IGRA remained stable in PwMS independently of therapy. Spike-specific Th1-cytokine response was mainly CD4+ T-cell-mediated, and in PwMS was significantly reduced (p<0.0001) with impaired IL-2 production compared with HCWs at T3. In PwMS, total Th1 and IFN-γ CD4+ T-cell responders to spike protein were increased from T2 to T3.Compared with HCWs, PwMS presented a higher frequency of CD4+ and CD8+ terminally differentiated effector memory cells and of CD4+ effector memory (TEM) cells, independently of the stimulus suggesting the association of this phenotype with MS status. CD4+ and CD8+ TEM cell frequency was further increased at T3 compared with T2. CONCLUSIONS: COVID-19 vaccine booster strengthens humoral and Th1-cell responses and increases TEM cells in PwMS.