Relapsing-remitting and primary progressive multiple sclerosis treated with ocrelizumab: A comparative study.

OBJECTIVES: To compare the clinical and radiological effectiveness of ocrelizumab in primary progressive multiple sclerosis (PPMS) and relapsing-remitting multiple sclerosis (RRMS) in a clinical practice setting and describe its tolerability and adverse events. METHODS: A retrospective observational cohort study was conducted comparing clinical and magnetic resonance imaging (MRI) data of all patients with (pw)PPMS and RRMS who had received treatment with ocrelizumab at least one cycle and have been followed up for one year at minimum. RESULTS: 42 patients (27 women) treated with ocrelizumab: 29 had RRMS and 13 PPMS. The follow-up period was 26.4 ± 8.4 months. The proportion of pwRRMS with no evidence of disease activity (NEDA) in the first year was 69.2% and in the second was 80%. In the first year, radiological activity was reduced by 80.0% in pwRRMS and 91.7% in pwPPMS. In the second year, radiological activity was completely reduced in both groups. A statistically significant difference (p<0.05) was observed between the pre-ocrelizumab rate of disability progression vs. the first year rate of progression for pwRRMS and pwPPMS. However, an increase in the disability progression rate in the second year of treatment was found in pwPPMS. Ocrelizumab was mostly well tolerated and some adverse effects were reported: infusion-related reactions (IRRs) were the most frequent adverse event, followed by infections and hematological side effects. Discontinuations were due to infections, hematological complications, and perception of ineffectiveness. CONCLUSIONS: Ocrelizumab was very effective in reducing relapses and MRI activity. The rate of progression was slowed down; however, the effect was more evident for pwRRMS than for pwPPMS over time.

Baseline Inflammatory Status Reveals Dichotomic Immune Mechanisms Involved In Primary-Progressive Multiple Sclerosis Pathology.

Objective: To ascertain the role of inflammation in the response to ocrelizumab in primary-progressive multiple sclerosis (PPMS). Methods: Multicenter prospective study including 69 patients with PPMS who initiated ocrelizumab treatment, classified according to baseline presence [Gd+, n=16] or absence [Gd-, n=53] of gadolinium-enhancing lesions in brain MRI. Ten Gd+ (62.5%) and 41 Gd- patients (77.4%) showed non-evidence of disease activity (NEDA) defined as no disability progression or new MRI lesions after 1 year of treatment. Blood immune cell subsets were characterized by flow cytometry, serum immunoglobulins by nephelometry, and serum neurofilament light-chains (sNfL) by SIMOA. Statistical analyses were corrected with the Bonferroni formula. Results: More than 60% of patients reached NEDA after a year of treatment, regardless of their baseline characteristics. In Gd+ patients, it associated with a low repopulation rate of inflammatory B cells accompanied by a reduction of sNfL values 6 months after their first ocrelizumab dose. Patients in Gd- group also had low B cell numbers and sNfL values 6 months after initiating treatment, independent of their treatment response. In these patients, NEDA status was associated with a tolerogenic remodeling of the T and innate immune cell compartments, and with a clear increase of serum IgA levels. Conclusion: Baseline inflammation influences which immunological pathways predominate in patients with PPMS. Inflammatory B cells played a pivotal role in the Gd+ group and inflammatory T and innate immune cells in Gd- patients. B cell depletion can modulate both mechanisms.

SARS-CoV-2 Infection in Multiple Sclerosis: Results of the Spanish Neurology Society Registry.

OBJECTIVE: To understand COVID-19 characteristics in people with multiple sclerosis (MS) and identify high-risk individuals due to their immunocompromised state resulting from the use of disease-modifying treatments. METHODS: Retrospective and multicenter registry in patients with MS with suspected or confirmed COVID-19 diagnosis and available disease course (mild = ambulatory; severe = hospitalization; and critical = intensive care unit/death). Cases were analyzed for associations between MS characteristics and COVID-19 course and for identifying risk factors for a fatal outcome. RESULTS: Of the 326 patients analyzed, 120 were cases confirmed by real-time PCR, 34 by a serologic test, and 205 were suspected. Sixty-nine patients (21.3%) developed severe infection, 10 (3%) critical, and 7 (2.1%) died. Ambulatory patients were higher in relapsing MS forms, treated with injectables and oral first-line agents, whereas more severe cases were observed in patients on pulsed immunosuppressors and critical cases among patients with no therapy. Severe and critical infections were more likely to affect older males with comorbidities, with progressive MS forms, a longer disease course, and higher disability. Fifteen of 33 patients treated with rituximab were hospitalized. Four deceased patients have progressive MS, 5 were not receiving MS therapy, and 2 were treated (natalizumab and rituximab). Multivariate analysis showed age (OR 1.09, 95% CI, 1.04-1.17) as the only independent risk factor for a fatal outcome. CONCLUSIONS: This study has not demonstrated the presumed critical role of MS therapy in the course of COVID-19 but evidenced that people with MS with advanced age and disease, in progressive course, and those who are more disabled have a higher probability of severe and even fatal disease.

Effect of Ocrelizumab in Blood Leukocytes of Patients With Primary Progressive MS.

OBJECTIVE: To analyze the changes induced by ocrelizumab in blood immune cells of patients with primary progressive MS (PPMS). METHODS: In this multicenter prospective study including 53 patients with PPMS who initiated ocrelizumab treatment, we determined effector, memory, and regulatory cells by flow cytometry at baseline and after 6 months of therapy. Wilcoxon matched paired tests were used to assess differences between baseline and 6 months' results. p Values were corrected using the Bonferroni test. RESULTS: Ocrelizumab reduced the numbers of naive and memory B cells (p < 0.0001) and those of B cells producing interleukin (IL)-6, IL-10, granulocyte-macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor-alpha (TNFα) (p < 0.0001 in all cases). By contrast, the proportions of plasmablasts and B cells producing GM-CSF and TNFα increased significantly, suggesting the need for treatment continuation. We also observed a decrease in CD20+ T-cell numbers (p < 0.0001) and percentages (p < 0.0001), and a clear remodeling of the T-cell compartment characterized by relative increases of the naive/effector ratios in CD4+ (p = 0.002) and CD8+ (p = 0.002) T cells and relative decreases of CD4+ (p = 0.03) and CD8+ (p = 0.004) T cells producing interferon-gamma. Total monocyte numbers increased (p = 0.002), but no changes were observed in those producing inflammatory cytokines. The immunologic variations were associated with a reduction of serum neurofilament light chain (sNfL) levels (p = 0.008). The reduction was observed in patients with Gd-enhanced lesions at baseline and in Gd- patients with baseline sNfL >10 pg/mL. CONCLUSIONS: In PPMS, effector B-cell depletion changed T-cell response toward a low inflammatory profile, resulting in decreased sNfL levels.

Para-infectious anti-GD2/GD3 IgM myelitis during the Covid-19 pandemic: Case report and literature review.

BACKGROUND: Even though SARS-CoV-2 is a predominantly respiratory virus, several reports have described various neurological disorders, from the beginning of the pandemic. The first para-infectious myelitis case was described in Wuhan in February 2020. Nevertheless, data from registries and reviews are scarce. METHODS: A 40-year-old female with T5-T6 SARS-CoV-2 para-infectious myelitis is reported. A literature review of the published literature on the SARS-CoV-2 and para-infectious myelitis was done. Epidemiological, clinical, laboratory, image, treatment, and outcome data are described. RESULTS: Particular findings of our case are that Covid-19 was asymptomatic and anti-GD2/GD3 IgM was found. 18 para-infectious myelitis occurred over a wide age range (Beh et al., 2013-67), mean age 50.7±18.6 years, with 10/18 (55.6%) women. Covid-19 involvement was variable from asymptomatic cases to severe Covid-19 resulting in death. The mean time to establish myelitis from the onset of Covid-19 symptoms was 10.3 ±7.8 days (0-24). The most common clinical form was transverse myelitis (14/18 patients, 77.7%) and the most frequent radiological form was longitudinally extensive myelitis (11/17 patients, 64.7%). In CSF mild lymphocytosis (14/16, 87.5%) with low cellularity (40.9±49.7/µL) and elevated proteins (11/16, 77.8%, mean 145.0 mg±159.0/dL) were frequent. Oligoclonal bands were usually negative (7/9, 77.7%) and mirror pattern was found in 2/7 patients (33.3%). SARS-CoV-2 PCR in CSF was negative in 10/10 cases. CONCLUSION: SARS-CoV-2 can cause myelitis by immune-mediated mechanisms. Clinical-radiological characteristics of Covid-19 para-infectious myelitis were variable and non-specific.

Catastrophic outcome of patients with a rebound after Natalizumab treatment discontinuation.

INTRODUCTION: Natalizumab (NTZ) is an effective drug for the treatment of relapsing-remitting multiple sclerosis. In some patients discontinuation is mandatory due to the risk of progressive multifocal leukoencephalopathy. However, severe clinical and radiological worsening has been described after drug cessation. Our aim was to describe the clinical and radiological features of the rebound phenomenon. MATERIAL AND METHODS: Patients switched from NTZ to Fingolimod (FTY) who had presented a rebound after discontinuation were selected. Clinical and magnetic resonance imaging (MRI) data were collected. RESULTS: Four JC virus positive patients were included. The mean disease duration was 9.5 years (SD: 4.12) with a mean time of 3.1 years on NTZ. All patients started FTY within 3-4 months. Neurological deterioration started in a mean time of 3.5 months (SD: 2.08) with multifocal involvement: 75% motor disturbances, 50% cognitive impairment, 25% seizures. The average worsening in Expanded Disability Status Scale [EDSS] was of 3.25 points (SD: 2.33). The MRI showed a very large increase in T2 and gadolinium-enhanced lesions (mean: 23.67, SD: 18.58). All patients received 5 days of IV methylprednisolone, one patient required plasma exchange. All the patients presented neurological deterioration with an EDSS worsening of 1.13 points (SD: 0.48). After the rebound three patients continued treatment with FTY, only one patient restarted NTZ. CONCLUSION: Discontinuation of NTZ treatment may trigger a severe rebound with marked clinical and radiological worsening. A very careful evaluation of benefit-risk should be considered before NTZ withdrawal, and a close monitoring and a short washout period is recommended after drug withdrawal.

[Takotsubo cardiomyopathy as a complication of an epileptic status]. / Miocardiopatía de Takotsubo como complicación de un estado epiléptico.

INTRODUCTION: Cardiological complications are the most frequent cause of mortality in the epileptic status. Takotsubo cardio-myopathy is a recently reported condition that can appear in a number of medical emergencies, including epileptic status. CASE REPORT: We present a case of Takotsubo cardiomyopathy within the context of an epileptic status and we also review similar cases reported in the literature. Special attention is given to the semiology and aetiology of the epileptic seizures, patients' epidemiological data, the alterations noted in the electrocardiogram and the complications that occurred. The patient, a 43-year-old female, recovered completely both cardiologically and neurologically, and did not suffer any relapses during the one-year follow-up. CONCLUSION: Takotsubo cardiomyopathy is a severe, treatable complication that can occur in the epileptic status.

“Píldora del día después” e ictus: un nuevo caso / Emergency contraception and stroke. A new case report

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Treatment with natalizumab in relapsing-remitting multiple sclerosis patients induces changes in inflammatory mechanism.

Natalizumab is a widely accepted drug for the relapsing-remitting subtype of multiple sclerosis (RRMS). The present longitudinal exploratory study in RRMS patients analyzes the effects of natalizumab treatment on the levels of pro-inflammatory and anti-inflammatory cytokine protein levels and also the frequency and suppressor function of regulatory T cells. Flow cytometry was used to determine cytokines and regulatory T cell frequency while regulatory T cell suppressor function was assayed in vitro at different time-points after starting with natalizumab. Results showed serum levels of pro-inflammatory interferon gamma and interleukin (IL)-12p70, as well as anti-inflammatory IL-4 and IL-10, were elevated just a few hours or days after first IV infusion of natalizumab. Interestingly, other cytokines like IL-5 or IL-13 were also elevated while pro-inflammatory IL-17, IL-2, and IL-1ß increased only after a long-term treatment, suggesting different immune mechanisms. In contrast, we did not observe any effect of natalizumab treatment on regulatory T cell frequency or activity. In conclusion, these results suggest natalizumab has other immunological effects beyond VLA-4 interaction and inhibition of CNS extravasation, the relevance of which is as yet unknown and warrants further investigation.