Antibody response elicited by the SARS-CoV-2 vaccine booster in patients with multiple sclerosis: Who gains from it?

BACKGROUND AND PURPOSE: Although two doses of COVID-19 vaccine elicited a protective humoral response in most persons with multiple sclerosis (pwMS), a significant group of them treated with immunosuppressive disease-modifying therapies (DMTs) showed less efficient responses. METHODS: This prospective multicenter observational study evaluates differences in immune response after a third vaccine dose in pwMS. RESULTS: Four hundred seventy-three pwMS were analyzed. Compared to untreated patients, there was a 50-fold decrease (95% confidence interval [CI] = 14.3-100.0, p < 0.001) in serum SARS-CoV-2 antibody levels in those on rituximab, a 20-fold decrease (95% CI = 8.3-50.0, p < 0.001) in those on ocrelizumab, and a 2.3-fold decrease (95% CI = 1.2-4.6, p = 0.015) in those on fingolimod. As compared to the antibody levels after the second vaccine dose, patients on the anti-CD20 drugs rituximab and ocrelizumab showed a 2.3-fold lower gain (95% CI = 1.4-3.8, p = 0.001), whereas those on fingolimod showed a 1.7-fold higher gain (95% CI = 1.1-2.7, p = 0.012), compared to patients treated with other DMTs. CONCLUSIONS: All pwMS increased their serum SARS-CoV-2 antibody levels after the third vaccine dose. The mean antibody values of patients treated with ocrelizumab/rituximab remained well below the empirical "protective threshold" for risk of infection identified in the CovaXiMS study (>659 binding antibody units/mL), whereas for patients treated with fingolimod this value was significantly closer to the cutoff.

The PRESTO study: awareness of stroke symptoms and time from onset to intervention.

Timely access to medical assistance is the first crucial step to improving clinical outcomes of stroke patients. Many educational campaigns have been organized with the purpose of making people aware of what a stroke is and what is necessary to do after its clinical onset. The PRESTO campaign was organized in Genoa (Italy) to spread easy messages regarding the management of the acute phase of stroke. Educational material was disseminated to educate people to call the emergency medical services as soon as symptoms appear. Data collected were analyzed in three different phases of the campaign: before the beginning, during, and after the end. We enrolled 1,132 patients with ischemic stroke admitted to hospital within 24 hours of symptoms onset. Our data showed a mild reduction in onset-to-door time (24 minutes) during the months following the end of the campaign and a slight increase in number of patients who arrived at hospitals, in particular with milder symptoms and transient ischemic attack, as opposed to the same period before the campaign. Interestingly, in the months after the end of the campaign, we observed a slight reduction of the percentage of patients who accessed hospitals after 4.5 hours from symptoms onset. In conclusion, our results may suggest that an informative campaign can be successful in making people rapidly aware of stroke onset, with the consequent rapid access to hospitals. Considering the changing of way of access to information, we think that an extensive multimedia campaign should be evaluated in the next future.

SARS-CoV-2 and Stroke Characteristics: A Report From the Multinational COVID-19 Stroke Study Group.

[Figure: see text].

The importance of thinking about Guillain-Barré syndrome during the COVID-19 pandemic: a case with pure dysautonomic presentation.

Guillain-Barré syndrome (GBS) is a peripheral nervous system disease caused by an immune-mediated inflammatory mechanism, usually triggered by a previous infectious process or vaccine; its typical presentation is a rapid and progressive bilateral limb hyposthenia, associated with sensory deficits and reduction or absence of osteotendinous reflexes. However, also autonomic nervous system can be involved with heart rate fluctuations, blood pressure instability, pupillary dysfunction, and urinary retention. Since the beginning of COVID-19 pandemic, GBS has been reported among neurological complications of SARS-CoV-2 infection, although etiopathological mechanisms still have to be clearly defined. We report the case of a 79-year-old man with multiple comorbidities, including diabetes, who was affected by SARS-CoV-2 interstitial pneumonia and developed dysautonomic symptoms after 10 days of hospitalization. A neurological evaluation was performed, and GBS was considered as a possible cause of the clinical manifestations. This hypothesis was confirmed by electrophysiological study and further supported, ex-juvantibus, by the satisfactory response to immunoglobulin treatment. In our opinion, this case of pure dysautonomic presentation of GBS in a SARS-CoV-2 positive patient is relevant because it suggests to consider GBS upon SARS-CoV-2 infection even if the symptoms have uncommon characteristics (e.g., pure vegetative manifestations) and if there are confounding factors which could lead to a misdiagnosis (e.g., old age, SARS-CoV-2 infection consequences and diabetes).

Myasthenia gravis associated with anti-MuSK antibodies developed after SARS-CoV-2 infection.

INTRODUCTION: Since the onset of the novel coronavirus pandemic, several neurological complications secondary to SARS-CoV-2 infection have been reported, affecting central nervous system, peripheral nervous system and neuromuscular junction. CASE REPORT: We present the case of a 77-year-old man who developed bulbar myasthenia gravis (MG) eight weeks after SARS-CoV-2 infection. The search for serum antibodies against the acetylcholine receptor and the muscle-specific tyrosine kinase (MuSK), performed by radioimmunoassay (RIA), and the search of low-density lipoprotein receptor-related protein 4 antibodies, performed by immunohistochemistry, resulted negative, while anti-MuSK antibodies were detected by cell-based assay (CBA). The patient was treated with pyridostigmine (60 mg four times a day) with unsatisfactory clinical response, followed by immunosuppressive therapy (azathioprine 1.5 mg/kg/day) with improvement of MG symptoms after two months of treatment. DISCUSSION: Several viral diseases have been described as associated with the onset of MG, although the underlying mechanisms are not yet fully understood. Similarly, a growing number of scientific reports suggest a correlation between SARS-CoV-2 infection and autoimmune diseases. The interest of our case lies in the timing of the MG onset (after 2 months from infection), together with the unusual late onset of anti-MuSK MG. These elements suggest that coronavirus infection may act as a trigger of the disease. We confirm the importance of CBA in the serological diagnosis of RIA-negative MG.

Clinical baseline factors predict response to natalizumab: their usefulness in patient selection.

BACKGROUND: Optimal patient selection would improve the risk-benefit ratio of natalizumab treatment for relapsing-remitting multiple sclerosis (RR MS). Clinical features of subjects responding to natalizumab have not been univocally recognized. METHODS: Longitudinal data on RR MS patients treated with natalizumab in Liguria, Italy are reported. Predictors of relapse occurrence and disability improvement were analyzed with a logistic regression method in subjects treated for one year (N = 62). A new score, called "Better EDSS Trend (BET)", was devised to describe the impact of the treatment on disability. Changes in annualized relapse rate (ARR) and Expanded Disability Status Scale (EDSS) after one and two years and proportion of disease-free patients were evaluated. RESULTS: Previous EDSS worsening plus ARR ≥ 2 increased the risk of relapse during the treatment [Odds Ratio (OR) 4.12, P = 0.04], but this was not associated with an increase in disability at one year. EDSS 3.0-3.5 or high disease activity were associated with neurological improvement in the first year of treatment (respectively OR 5.78, P = 0.05 and OR 4.80, P = 0.05). Positive BET score, i.e. improvement in the disability trend, was observed in 40.3% of patients, and correlated with high ARR in the year before treatment (OR 1.69, P = 0.03). CONCLUSION: Subjects with EDSS 3.0-3.5 and those with very active disease in the year before treatment are most likely to improve in neurological function under natalizumab. A relapse in the first year of treatment is associated to high pre-treatment disease activity; however, since the occurrence of a relapse did not have a negative impact on clinical improvement at one year, we suggest that it should not lead to treatment discontinuation. We propose BET as an additional endpoint of treatment response in MS.

Brain positron emission tomography in idiopathic normal-pressure hydrocephalus: new 18 F-fluorodeoxyglucose pattern in a long-known syndrome.

AIM: Patients with idiopathic normal-pressure hydrocephalus (iNPH) can show a global reduction in cerebral glucose metabolism at [ 18 F]Fluorodeoxyglucose (FDG) PET. The presence of caudate hypometabolism has been identified as a potential biomarker in iNPH, yet there is limited evidence of hypermetabolic findings in patients with iNPH so far. METHODS: We retrieved retrospectively patients with iNPH and normal cognitive assessment, evaluated before surgery undergoing brain [ 18 F]FDG-PET. The 18 F-FDG-PET brain scans were compared to those of a control group of healthy subjects, matched for age and sex, by statistical parametric mapping (SPM) to identify areas of relative hypo- and hypermetabolism. Furthermore, the existence of a correlation between areas of hypo- and hypermetabolism in the patient group was tested. RESULTS: Seven iNPH patients (mean age 74 ±â€…6 years) were found in the hospital database. SPM group analysis revealed clusters of significant hypometabolism ( P  = 0.001) in the iNPH group in the dorsal striatum, involving caudate and putamen bilaterally. Clusters of significant hypermetabolism ( P  = 0.001) were revealed in the bilateral superior and precentral frontal gyrus (BA 4, 6). A significant inverse correlation between striatal hypometabolism and bilateral superior and precentral frontal gyrus hypermetabolism was revealed ( P  < 0.001 corrected for multiple comparisons). CONCLUSION: In this cohort, patients with iNPH showed subcortical hypometabolism, including bilateral dorsal striatum. To the best of our knowledge, this is the first report demonstrating a hypermetabolic pattern in the primary motor and premotor areas, and showing an inverse correlation between the striatum and motor cortex in patients with iNPH.

Penetrance of the V203I variant of the PRNP gene: report of a patient with stroke-like onset of Creutzfeld-Jacob Disease and review of published cases.

Creutzfeldt-Jakob disease (CJD) is usually sporadic, but 10-15% of cases are caused by autosomal-dominant pathogenic variants in the prion protein gene (PRNP). A few PRNP variants show low penetrance. We report the case of a 64-year-old man, admitted to the ward with acute onset of aphasia; death occurred 6 weeks later. Brain MRI, EEG pattern and brain pathology were consistent with CJD diagnosis. Genetic analysis revealed a heterozygous V203I variant. We summarized the key clinical findings in patients carrying the V203I variant who were described to date. We also discuss the hypothesis as to whether V203I is a risk factor for CJD rather than a Mendelian disease-associated variant, as well as the possible implications of such hypothesis in the clinical scenario.

Breakthrough SARS-CoV-2 infections after COVID-19 mRNA vaccination in MS patients on disease modifying therapies during the Delta and the Omicron waves in Italy.

BACKGROUND: In this study we aimed to monitor the risk of breakthrough SARS-CoV-2 infection in patients with MS (pwMS) under different DMTs and to identify correlates of reduced protection. METHODS: This is a prospective Italian multicenter cohort study, long-term clinical follow-up of the CovaXiMS (Covid-19 vaccine in Multiple Sclerosis) study. 1855 pwMS scheduled for SARS-CoV-2 mRNA vaccination were enrolled and followed up to a mean time of 10 months. The cumulative incidence of breakthrough Covid-19 cases in pwMS was calculated before and after December 2021, to separate the Delta from the Omicron waves and to account for the advent of the third vaccine dose. FINDINGS: 1705 pwMS received 2 m-RNA vaccine doses, 21/28 days apart. Of them, 1508 (88.5%) had blood assessment 4 weeks after the second vaccine dose and 1154/1266 (92%) received the third dose after a mean interval of 210 days (range 90-342 days) after the second dose. During follow-up, 131 breakthrough Covid-19 infections (33 during the Delta and 98 during the Omicron wave) were observed. The probability to be infected during the Delta wave was associated with SARS-CoV-2 antibody levels measured after 4 weeks from the second vaccine dose (HR=0.57, p < 0.001); the protective role of antibodies was preserved over the whole follow up (HR=0.57, 95%CI=0.43-0.75, p < 0.001), with a significant reduction (HR=1.40, 95%CI=1.01-1.94, p=0.04) for the Omicron cases. The third dose significantly reduced the risk of infection (HR=0.44, 95%CI=0.21-0.90,p=0.025) during the Omicron wave. INTERPRETATION: The risk of breakthrough SARS-CoV-2 infections is mainly associated with reduced levels of the virus-specific humoral immune response. FUNDING: Supported by FISM - Fondazione Italiana Sclerosi Multipla - cod. 2021/Special-Multi/001 and financed or co-financed with the '5 per mille' public funding.

MRI activity and extended interval of Natalizumab dosing regimen: a multicentre Italian study.

BACKGROUND: 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). METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Effect of SARS-CoV-2 mRNA vaccination in MS patients treated with disease modifying therapies.

BACKGROUND: In patients with Multiple Sclerosis (pwMS) disease-modifying therapies (DMTs) affects immune response to antigens. Therefore, post-vaccination serological assessments are needed to evaluate the effect of the vaccine on SARS-CoV-2 antibody response. METHODS: We designed a prospective multicenter cohort study enrolling pwMS who were scheduled for SARS-Cov-2 vaccination with mRNA vaccines (BNT162b2, Pfizer/BioNTech,Inc or mRNA-1273, Moderna Tx,Inc). A blood collection before the first vaccine dose and 4 weeks after the second dose was planned, with a centralized serological assessment (electrochemiluminescence immunoassay, ECLIA, Roche-Diagnostics). The log-transform of the antibody levels was analyzed by multivariable linear regression. FINDINGS: 780 pwMS (76% BNT162b2 and 24% mRNA-1273) had pre- and 4-week post-vaccination blood assessments. 87 (11·2%) were untreated, 154 (19·7%) on ocrelizumab, 25 (3·2%) on rituximab, 85 (10·9%) on fingolimod, 25 (3·2%) on cladribine and 404 (51·7%) on other DMTs. 677 patients (86·8%) had detectable post-vaccination SARS-CoV-2 antibodies. At multivariable analysis, the antibody levels of patients on ocrelizumab (201-fold decrease (95%CI=128-317), p < 0·001), fingolimod (26-fold decrease (95%CI=16-42), p < 0·001) and rituximab (20-fold decrease (95%CI=10-43), p < 0·001) were significantly reduced as compared to untreated patients. Vaccination with mRNA-1273 resulted in a systematically 3·25-fold higher antibody level (95%CI=2·46-4·27) than with the BNT162b2 vaccine (p < 0·001). The antibody levels on anti-CD20 therapies correlated to the time since last infusion, and rituximab had longer intervals (mean=386 days) than ocrelizumab patients (mean=129 days). INTERPRETATION: In pwMS, anti-CD20 treatment and fingolimod led to a reduced humoral response to mRNA-based SARS-CoV-2 vaccines. As mRNA-1273 elicits 3·25-higher antibody levels than BNT162b2, this vaccine may be preferentially considered for patients under anti-CD20 treatment or fingolimod. Combining our data with those on the cellular immune response to vaccines, and including clinical follow-up, will contribute to better define the most appropriate SARS-CoV-2 vaccine strategies in the context of DMTs and MS. FUNDING: FISM[2021/Special-Multi/001]; Italian Ministry of Health'Progetto Z844A 5 × 1000'.

Extending the Interval of Natalizumab Dosing: Is Efficacy Preserved?

Extending the natalizumab interval after the 24th administration could reduce the risk of progressive multifocal leukoencephalopathy (PML). The objective is to evaluate the noninferiority of the efficacy of an extended interval dosing (EID) compared with the standard interval dosing (SID) of natalizumab. It is an observational, multicenter (14 Italian centers), retrospective cohort study, starting from the 24th natalizumab infusion to the loss of follow-up or 2 years after baseline. Patients were grouped in 2 categories according to the mean number of weeks between doses: < 5 weeks, SID; ≥ 5 weeks, EID. Three hundred and sixty patients were enrolled. Median dose interval (MDI) following 24th infusion was 4.7 weeks, with a bimodal distribution (modes at 4 and 6 weeks). Two hundred and sixteen patients were in the SID group (MDI = 4.3 weeks) and 144 in the EID group (MDI 6.2 weeks). Annualized relapse rate was 0.060 (95% CI = 0.033-0.087) in the SID group and 0.039 (95% CI = 0.017-0.063) in the EID group. The non-inferiority of EID versus SID was satisfied. In conclusion, there is no evidence of a reduced efficacy of natalizumab in an EID setting. This observation confirms previous results and together with the emerging evidence of a reduced risk of PML associated to an EID, supports the need of a randomized study to assess the need to change the standard of the natalizumab dosing schedule.

A multicentric pharmacovigilance study: collection and analysis of adverse drug reactions in relapsing-remitting multiple sclerosis patients.

PURPOSE: We performed a pharmacovigilance study of 10 drugs used in patients with relapsing-remitting multiple sclerosis (RR-MS). Our aim was to provide an overview of the safety of these drugs by the evaluation of reported expected and unexpected adverse reactions. PATIENTS AND METHODS: We collected and analyzed adverse drug reactions from RR-MS patients belonging to four hospitals in three Italian regions, for a period of 24 months. RESULTS: We received a total of 411 adverse reactions, of which 84.18% were expected and only 15.82% were unexpected. We found no correlation between the number of reported adverse reactions and the route of administration (injectable/intravenous drugs N=224, oral drugs N=187). However, oral agents have caused a greater number of unexpected moderate-to-severe adverse reactions while, in injectable and infusion therapies, they have been evaluated as mild-moderate adverse reactions. CONCLUSION: Our results underscore the importance of monitoring the safety profile of multiple sclerosis therapies, with particular attention to oral agents that have been introduced later in the clinical practice.

Teriflunomide treatment reduces B cells in patients with MS.

OBJECTIVE: To study the immunomodulatory effect of teriflunomide on innate and adaptive immune cell populations through a pilot, open-label, observational study in a cohort of patients with relapsing-remitting MS. METHODS: Blood lymphocytes were isolated from 10 patients with MS before and after 3 or 12 months of treatment. Adaptive and innate immune cell subsets were analyzed by flow cytometry as follows: B cells (memory, regulatory, and mature subsets), T cells (effector and regulatory subsets), and natural killer (NK) cells (CD56dim and CD56bright subsets). RESULTS: Our results show that teriflunomide significantly reduces absolute counts of total CD19+ B cells and mature and regulatory B-cell subsets. T cells were affected to a lesser extent, with a trend in reduction of absolute counts for both T effector CD4+ cells (Th1, Th17 and Th1/17) and T regulatory CD8+ and CD4+ cells. Teriflunomide had no detectable effect on NK-cell numbers. CONCLUSIONS: In our small cohort, teriflunomide treatment affects mainly and significantly on B-cell numbers, while having a milder effect on T-cell numbers. Larger cohorts are necessary to confirm these findings and understand the effect of teriflunomide on the functionality of these cells.

In vitro VLA-4 blockade results in an impaired NK cell-mediated immune surveillance against melanoma.

Natalizumab (NTZ) is a monoclonal antibody targeting the α4ß1 integrin (CD49d/CD29), very late antigen-4 (VLA-4), which is approved for treatment of relapsing-remitting multiple sclerosis (RR-MS). A possible association between NTZ treatment and a higher risk of melanoma is under debate. Natural Killer (NK) cells, which express VLA-4, represent an innate barrier limiting spreading of melanoma under steady state conditions. Indeed, because of their expression of activating receptors, they are very efficient in recognizing and killing melanoma cells without the need of a previous priming. For this reason, we aimed at assessing whether NK-cell functions might be impaired by sustained exposure to NTZ. To investigate this possibility we isolated NK cells from healthy donors and tested their cytotoxic and migratory functions against primary melanoma cells derived from subcutaneous and lymph node metastases. Flow cytometry analysis demonstrated expression of CD49d on both freshly isolated NK cells and activated NK cells. Moreover, VLA-4 and its receptor, vascular cell adhesion protein-1 (VCAM-1) were similarly expressed on freshly isolated NK cells. However, upon a short exposure to NTZ, expression of VLA-4 on NK cells decreased. Analysis of NK receptor expression upon exposure of NK cells from three healthy donors to NTZ indicated that DNAM-1 and NKp46 are apparently decreased, while NKG2A is increased. The degranulation of NK cells towards melanoma cells, which express both VLA-4 and VCAM-1, was not affected when NTZ was added to the co-culture or when both NK cells and melanoma cells were each pre-exposed to NTZ for over 12h. In contrast, degranulation was significantly inhibited after 48h of pre-incubation indicating that NTZ can influence NK-cell degranulation towards melanoma cells only after a prolonged exposure. Using a migration chamber assay, we observed that the migration of NK cells towards melanoma cells was dependent upon the concentration of melanoma cells in the lower chamber, and that it was significantly reduced in presence of NTZ. Our results show that upon exposure to NTZ both cytolytic activity and migration toward melanoma cells were affected, suggesting that binding of NTZ to NK cells affects pathways involved in these NK-cell functions. We analyzed the expression of CD49d on NK cells from MS patients treated with NTZ and observed that it decreases with time of treatment. These data suggest that blockade of VLA-4 on NK-cell surface alters some key functions involved in the immune surveillance toward melanoma by NK cells and may provide a mechanistic explanation for the reported occurrence of melanoma in MS patients treated with NTZ.

Acute disseminated encephalomyelitis with severe neurological outcomes following virosomal seasonal influenza vaccine.

Acute disseminated encephalomyelitis (ADEM) is an inflammatory, usually monophasic, immune mediate, demyelinating disease of the central nervous system which involves the white matter. ADEM is more frequent in children and usually occurs after viral infections, but may follow vaccinations, bacterial infections, or may occur without previous events. Only 5% of cases of ADEM are preceded by vaccination within one month prior to symptoms onset. The diagnosis of ADEM requires both multifocal involvement and encephalopathy and specific demyelinating lesions of white matter. Overall prognosis of ADEM patients is often favorable, with full recovery reported in 23% to 100% of patients from pediatric cohorts, and more severe outcome in adult patients. We describe the first case of ADEM occurred few days after administration of virosomal seasonal influenza vaccine. The patient, a 59-year-old caucasic man with unremarkable past medical history presented at admission decreased alertness, 10 days after flu vaccination. During the 2 days following hospitalization, his clinical conditions deteriorated with drowsiness and fever until coma. The magnetic resonance imaging of the brain showed multiple and symmetrical white matter lesions in both cerebellar and cerebral hemispheres, suggesting demyelinating disease with inflammatory activity, compatible with ADEM. The patient was treated with high dose of steroids and intravenous immunoglobulin with relevant sequelae and severe neurological outcomes.