Real-World Retrospective Analysis of Alemtuzumab Outcomes in Relapsing-Remitting Multiple Sclerosis: The LEMCAM Study.

BACKGROUND: Alemtuzumab is a high-efficacy treatment approved for relapsing-remitting multiple sclerosis (RRMS). Although clinical trials and observational studies are consistent in showing its efficacy and manageable safety profile, further studies under clinical practice conditions are needed to further support its clinical use. OBJECTIVE: The aim of this observational retrospective study was to evaluate the effectiveness and safety of alemtuzumab to add to the current real-world evidence on the drug. METHODS: A cohort of 115 adult patients with RRMS treated with alemtuzumab between 2014 and 2020 was retrospectively followed up in five centers in Spain. Analysis included annualized relapse rate (ARR), 6-month confirmed disability worsening (CDW), 6-month confirmed disability improvement (CDI), radiological activity, no evidence of disease activity (NEDA-3), and safety signals. Given the different follow-up periods among participants, ARR was calculated using the person-years method. CDI was defined as a ≥ 1.0-point decrease in Expanded Disability Status Scale (EDSS) score assessed in patients with a baseline EDSS score ≥ 2.0 confirmed 6 months apart. CDW was defined as a ≥ 1.0-point increase in EDSS score assessed in patients with a baseline EDSS score ≥ 1.0 (≥ 1.5 if baseline EDSS = 0), confirmed 6 months apart. RESULTS: ARR decreased from 1.9 (95% confidence interval 1.60-2.33) in the year prior to alemtuzumab initiation to 0.28 (0.17-0.37) after 1 year of treatment (87% reduction), and to 0.22 (0.13-0.35) after the second year. Over the entire follow-up period, ARR was 0.24 (0.18-0.30). At year 1, 75% of patients showed no signs of magnetic resonance imaging (MRI) activity and 70% at year 5. One percent of patients experienced 6-month CDW at year 1, 2.6% at year 2, 7.4% at year 3, and no patients over years 4 and 5. A total of 7.7% of patients achieved 6-month CDI in year 1, 3.6% in year 2, and maintained it at years 3 and 4. Most patients achieved annual NEDA-3: year 1, 72%; year 2, 79%; year 3, 80%; year 4, 89%; year 5, 75%. Infusion-related reactions were observed in 95% of patients and infections in 74%. Thyroid disorders occurred in 30% of patients, and only three patients developed immune thrombocytopenia. No cases of progressive multifocal leukoencephalopathy were reported. CONCLUSIONS: This study shows that alemtuzumab reduced the relapse rate and disability worsening in real-world clinical practice, with many patients achieving and sustaining NEDA-3 over time. The safety profile of alemtuzumab was consistent with previous findings, and no new or unexpected safety signals were observed. As this was an observational and retrospective study, the main limitation of not having all variables comprehensively available for all patients should be considered when interpreting results.

Analysis of humoral and cellular immunity after SARS-CoV-2 vaccination in patients with multiple sclerosis treated with immunomodulatory drugs.

We analyzed immune response to SARS-CoV-2 vaccination by measuring specific IgG titers and T-cell reactivity to different SARS-CoV-2 peptides in multiple sclerosis patients taking different disease-modifying treatments. Of the 88 patients included, 72 developed any kind of immune response after vaccination. Although DMTs such as fingolimod and anti-CD20+ treatments prevented patients from developing a robust humoral response to the vaccine, most of them were still able to develop a cellular response, which could be crucial for long-term immunity. It is probably advisable that all MS patients take additional/booster doses to increase their humoral and/or cellular immune response to SARS-CoV-2.

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.

Pharmacokinetic variability of eslicarbazepine in real clinical practice.

INTRODUCTION: Eslicarbazepine acetate (ESL) is a sodium channel blocker indicated for partial-onset seizures with or without secondary generalization, at a single daily dose. There are very few publications on the levels of ESL metabolites in real clinical practice. OBJECTIVE: To describe the serum levels of licarbazepine (main metabolite of ESL) in patients with refractory epilepsy in real clinical practice. To evaluate the influence of age, sex, and polytherapy on levels and adverse effects. METHODS: This study involved a retrospective analysis of patients diagnosed with epilepsy treated with ESL for whom plasma levels of licarbazepine were available, measured by spectrophotometry. RESULTS: Sixty-four patients were included. One patient had licarbazepine levels of 0 (admitted not taking the drug) was not analyzed. Mean licarbazepine levels of 7.66 µg/mL (400 mg/day dose), 16.56 µg/mL (800-mg dose), and 20.80 µg/mL (1200 mg) were significantly different. There was a significant correlation between daily dose and serum levels (p < 0.05) and between the concentration/dose ratio and lower to higher doses (p < 0.05). Pharmacokinetic variability (coefficient of variation for the concentration/dose ratio) was 33.2%. We found a decrease in the concentration/dose ratio in the 1200 mg/day dose, compared to lower doses. We did not find differences by sex or intake of other antiepileptic inducers or metabolic inhibitors. Fifteen patients (23.8%) had mild nonsymptomatic hyponatremia. CONCLUSION: These results suggest that it is not necessary to routinely determine licarbazepine levels. In specific cases, licarbazepine levels can be useful to assess adherence to treatment and for personalized dose adjustment.

Acutely altered mental status as the main clinical presentation of multiple strokes in critically ill patients with COVID-19.

BACKGROUND AND AIMS: Cerebral infarction in COVID-19 patients might be associated with a hypercoagulable state related to a systemic inflammatory response. Its diagnosis might be challenging. We present two critically ill patients with COVID-19 who presented acutely altered mental status as the main manifestation of multiple strokes. METHODS: Clinical presentation and diagnostic work-up of the patients. RESULTS: Two patients in their sixties were hospitalized with a bilateral pneumonia COVID-19. They developed respiratory failure and were admitted to ICU for mechanical ventilation and intense medical treatment. They were started on low-molecular-weight heparin since admission. Their laboratory results showed lymphopenia and increased levels of C-reactive protein and D-dimer. Case 1 developed hypofibrinogenemia and presented several cutaneous lesions with biopsy features of thrombotic vasculopathy. Case 2 was performed a CT pulmonary angiogram at ICU showing a bilateral pulmonary embolism. When waking up, both patients were conscious but with a remarkable global altered mental status without focal neurological deficits. A brain MRI revealed multiple acute bilateral ischemic lesions with areas of hemorrhagic transformation in both patients (case 1: affecting the left frontal and temporal lobes and both occipital lobes; case 2: affecting both frontal and left occipital lobes). Cardioembolic source and acquired antiphospholipid syndrome were ruled out. COVID-19-associated coagulopathy was suspected as the possible main etiology of the strokes. CONCLUSION: Acutely altered mental status might be the main manifestation of multiple brain infarctions in critically ill COVID-19 patients. It should be specially considered in those with suspected COVID-19-associated coagulopathy. Full-dose anticoagulation and clinical-radiological monitoring might reduce their neurological consequences.

Assessment of Collateral Circulation Using Perfusion CT in Middle Cerebral Artery Thrombectomy-Treated Patients.

INTRODUCTION: The prognostic value of leptomeningeal collateral circulation in thrombectomy-treated patients remains unclear. We evaluated the construct validity of assessing leptomeningeal collateral circulation using a new regional perfusion CT source image-based approach, the Perfusion Acquisition for THrombectomy Scale (PATHS). We also compared the prognostic value of PATHS with a further 6 scales based on various techniques: CT-angiography, perfusion CT, and digital subtraction angiography. Additionally, we studied the relationship between the scores for the different scales. PATIENTS AND METHODS: We performed a retrospective study of consecutive patients with stroke and M1/terminal carotid occlusion treated with thrombectomy in our center. Leptomeningeal collateral circulation was prospectively evaluated using 7 scales: Tan and Miteff (CT Angiography); Calleja, Cao, American Society of Intervention and Therapeutic Neuroradiology/Society of Interventional Radiology, and PATHS (perfusion); and Christoforidis (Digital Subtraction Angiography). Correlations were studied using the Spearman method. RESULTS: The study population comprised 108 patients. All scales predicted the modified Rankin Scale at 3 months (P ≤ .02) and all but 1 (Christoforidis) correlated with 24-hour brain infarct volume (P ≤ .02). These correlations were higher with PATHS (rho = -0.47, P < .001 for 3-month modified Rankin Scale; rho = -0.35, P < .001 for follow-up infarct volume). The multivariate analysis showed PATHS to be an independent predictor of modified Rankin Scale at 3 months less than equal to 2. A crosscorrelation analysis revealed a better correlation between scales that used the same techniques. CONCLUSIONS: PATHS can be used to assess leptomeningeal collateral circulation. PATHS had better prognostic value than other scales; therefore, it might be considered for assessment of leptomeningeal collateral circulation in candidates for thrombectomy. The moderate correlation between scales suggests that scores are not interchangeable.