mRNA COVID-19 Vaccination Does Not Exacerbate Symptoms or Trigger Neural Antibody Responses in Multiple Sclerosis.

BACKGROUND AND OBJECTIVE: In people with multiple sclerosis (pwMS), concern for potential disease exacerbation or triggering of other autoimmune disorders contributes to vaccine hesitancy. We assessed the humoral and T-cell responses to SARS-CoV-2 after mRNA vaccination, changes in disease activity, and development of antibodies against central or peripheral nervous system antigens. METHODS: This was a prospective 1-year longitudinal observational study of pwMS and a control group of patients with other inflammatory neurologic disorders (OIND) who received an mRNA vaccine. Blood samples were obtained before the first dose (T1), 1 month after the first dose (T2), 1 month after the second dose (T3), and 6 (T4), 9 (T5), and 12 (T6) months after the first dose. Patients were assessed for the immune-specific response, annualized relapse rate (ARR), and antibodies to onconeuronal, neural surface, glial, ganglioside, and nodo-paranodal antigens. RESULTS: Among 454 patients studied, 390 had MS (22 adolescents) and 64 OIND; the mean (SD) age was 44 (14) years; 315 (69%) were female; and 392 (87%) were on disease-modifying therapies. Antibodies to the receptor-binding domain were detected in 367 (86%) patients at T3 and 276 (83%) at T4. After a third dose, only 13 (22%) of 60 seronegative patients seroconverted, and 255 (92%) remained seropositive at T6. Cellular responses were present in 381 (93%) patients at T3 and in 235 (91%) patients at T6 including all those receiving anti-CD20 therapies and in 79% of patients receiving fingolimod. At T3 (429 patients) or T6 (395 patients), none of the patients had developed CNS autoantibodies. Seven patients had neural antibodies that were already present before immunization (3 adult patients with MS had MOG-IgG, 2 with MG and 1 with MS had neuronal cell surface antibodies [unknown antigen], and 1 with MS had myelin antibody reactivity [unknown antigen]. Similarly, no antibodies against PNS antigens were identified at T3 (427 patients). ARR was lower in MS and not significantly different in patients with OIND. Although 182 (40%) patients developed SARS-CoV-2 infection, no cases of severe COVID-19 or serious adverse events occurred. DISCUSSION: In this study, mRNA COVID-19 vaccination was safe and did not exacerbate the autoimmune disease nor triggered neural autoantibodies or immune-mediated neurologic disorders. The outcome of patients who developed SARS-CoV-2 infection was favorable.

Neuroinflammation and gliosis in the injured and contralateral retinas after unilateral optic nerve crush.

The main purpose of this study is to analyze the effects of unilateral optic nerve crush in the gene expression of pro- and anti-inflammatory mediators, and gliosis markers in injured and contralateral retinas. Retinas from intact, unilaterally optic nerve injured or sham-operated C57BL/6J mice were analyzed 1, 3, 9 and 30 days after the surgery (n = 5/group and time point) and the relative expression of TGF-ß1, IL-1ß, TNF-α, Iba1, AQP4, GFAP, MHCII, and TSPO was analyzed in injured and contralateral using qPCR. The results indicated that compared with intact retinas, sham-operated animals showed an early (day 1) upregulation of IL-1ß, TNF-α and TSPO and a late (day 30) upregulation of TNF-α. In sham-contralateral retinas, TNF-α and TSPO mRNA expression were upregulated and day 30 while GFAP, Iba1, AQP4 and MHCII downregulated at day 9. Compared with sham-operated animals, in retinas affected by optic nerve crush GFAP and TSPO upregulated at day 1 and TNF-α, Iba1, AQP4 and MHCII at day 3. In the crushed-contralateral retinas, TGF-ß1, TNF-α, Iba1 and MHCII were upregulated at day 1. TSPO was upregulated up to day 30 whereas TGF-ß1 and Iba1 downregulated after day 9. In conclusion, both sham surgery and optic nerve crush changed the profile of inflammatory and gliosis markers in the injured and contralateral retinas, changes that were more pronounced for optic nerve crush when compared to sham.

Association of Serum Neurofilament Light Chain Levels at Disease Onset With Disability Worsening in Patients With a First Demyelinating Multiple Sclerosis Event Not Treated With High-Efficacy Drugs.

Importance: The value of serum neurofilament light chain (sNfL) levels for predicting long-term disability in patients with multiple sclerosis (MS) remains controversial. Objective: To assess whether high sNfL values are associated with disability worsening in patients who underwent their first demyelinating MS event. Design, Setting, and Participants: This multicenter cohort study included patients who underwent their first demyelinating event suggestive of MS at Hospital Universitario Ramón y Cajal (development cohort; June 1, 1994, to September 31, 2021, with follow-up until August 31, 2022) and 8 Spanish hospitals (validation cohort; October 1, 1995, to August 4, 2020, with follow-up until August 16, 2022). Exposures: Clinical evaluations at least every 6 months. Main Outcomes and Measures: The main outcomes were 6-month confirmed disability worsening (CDW) and an Expanded Disability Status Scale (EDSS) score of 3. Levels of sNfL were measured in blood samples obtained within 12 months after disease onset using a single molecule array kit. The cutoffs used were sNfL level of 10 pg/mL and a standardized score (z score) of 1.5. Multivariable Cox proportional hazards regression models were used to evaluate outcomes. Results: Of the 578 patients included in the study, 327 were in the development cohort (median age at sNfL analysis, 34.1 years [IQR, 27.2-42.7 years]; 226 female [69.1%]) and 251 patients were in the validation cohort (median age at sNfL analysis, 33.3 years [IQR, 27.4-41.5 years]; 184 female [73.3%]). The median follow-up was 7.10 years (IQR, 4.18-10.0 years). Levels of sNfL greater than 10 pg/mL were independently associated with higher risk of 6-month CDW and an EDSS of 3 in the development cohort (6-month CDW: hazard ratio [HR], 2.39; 95% CI, 1.39-4.12; P = .002; EDSS of 3: HR, 4.12; 95% CI, 2.18-7.77; P < .001) and the validation cohort (6-month CDW: HR, 1.61; 95% CI, 1.07-2.42; P = .02; EDSS of 3: HR, 2.03; 95% CI, 1.23-3.33; P = .005). Highly effective disease-modifying treatments were associated with lower risks of 6-month CDW and an EDSS of 3 in patients with high baseline sNfL values. Conclusions and Relevance: This cohort study found that high sNfL values obtained within the first year of disease were associated with long-term disability worsening in MS, suggesting that sNfL level measurement may help identify optimal candidates for highly effective disease-modifying treatments.

Perception of Medical Professionalism among Medical Residents in Spain.

BACKGROUND: Medical professionalism, defined as commitment to the primacy of patient welfare, is the basis for doctor-patient-society relationships, but previous research with medical students has shown that professionalism and social commitment to medicine may be waning. To determine if this trend also appears in recently qualified practicing doctors, we surveyed 90 newly graduated doctors currently working as medical residents in two university hospitals in Murcia, Spain. A previously validated questionnaire that studies the perception of six categories (responsibility, altruism, service, excellence, honesty and integrity, and respect) defining medical professionalism was used. RESULTS: A good perception of professionalism was found among medical residents, with more than 70% positive responses in all these six categories. There is an increasing trend in the number of negative responses as the residency goes on. Altruism was the category with the greatest percentage of negative answers (22.3%) and Respect was the category with the lowest percentage (12.9%). CONCLUSIONS: The results show a good professionalism perception in medical residents, but also a slight decline in positive answers that began during medical school. A significant trend was found when including both students and residents. Although there were some differences between students and residents, these were not statistically significant. Educational interventions are needed both at the level of medical school and postgraduate medical residency.

Axonal Injuries Cast Long Shadows: Long Term Glial Activation in Injured and Contralateral Retinas after Unilateral Axotomy.

BACKGROUND: To analyze the course of microglial and macroglial activation in injured and contralateral retinas after unilateral optic nerve crush (ONC). METHODS: The left optic nerve of adult pigmented C57Bl/6 female mice was intraorbitally crushed and injured, and contralateral retinas were analyzed from 1 to 45 days post-lesion (dpl) in cross-sections and flat mounts. As controls, intact retinas were studied. Iba1+ microglial cells (MCs), activated phagocytic CD68+MCs and M2 CD206+MCs were quantified. Macroglial cell changes were analyzed by GFAP and vimentin signal intensity. RESULTS: After ONC, MC density increased significantly from 5 to 21 dpl in the inner layers of injured retinas, remaining within intact values in the contralateral ones. However, in both retinas there was a significant and long-lasting increase of CD68+MCs. Constitutive CD206+MCs were rare and mostly found in the ciliary body and around the optic-nerve head. While in the injured retinas their number increased in the retina and ciliary body, in the contralateral retinas decreased. Astrocytes and Müller cells transiently hypertrophied in the injured retinas and to a lesser extent in the contralateral ones. CONCLUSIONS: Unilateral ONC triggers a bilateral and persistent activation of MCs and an opposed response of M2 MCs between both retinas. Macroglial hypertrophy is transient.

Bridging Therapy and Occlusion Site Influence Symptomatic Hemorrhage Rate after Thrombectomy: A Daily Practice Study in 623 Stroke Patients.

BACKGROUND: Comparison of symptomatic intracranial hemorrhage (SICH) rates between stroke patients treated with bridging therapy (BT) and primary mechanical thrombectomy (PMT) are scarce and difficult to interpret due to baseline differences between both populations. METHODS: Retrospective analysis of patients with acute ischemic stroke treated with endovascular therapy (BT or PMT) was performed at our center between January 2010 and June 2017. RESULTS: Six hundred twenty-three patients were included. Global SICH rate was 9% overall: 6.8% in the PMT group and 12.6% in the BT group. The following factors significantly associated with SICH after multivariate analysis: MCA occlusion (p: 0.047), stroke of unknown origin (p: 0.025), BT (p: 0.024), and procedural time over 65 min (p: 0.027). The following variables presented a statistically significant higher frequency in patients treated with PMT: atrial fibrillation (p: 0.005), anticoagulant medication (p < 0.001), wake-up strokes (p < 0.001), atherothrombotic etiology (p < 0.05), combined thrombectomy technique (p: 0.008), longer procedural times (p: 0.025), and favorable outcome at 3 months (p: 0.011). The following variables presented a statistically significant higher frequency in patients treated with BT: antiplatelet medication (p: 0.048), MCA occlusions (p: 0.017), cardioembolic etiology (p < 0.05), stent retriever/aspiration technique (p: 0.008), and SICH (p: 0.013). Patients with MCA occlusions had twice the risk of SICH after BT than after PMT (16.4 and 8.6%, p: 0.038). CONCLUSIONS: In this clinical series, the SICH rate was higher in patients treated with BT than in those treated with PMT. Relevant differences in baseline (related to IVT contraindications) were found between both groups. Randomized studies of BT versus PMT in populations with similar baseline characteristics might be of interest.

Prevention of rebound effect after natalizumab withdrawal in multiple sclerosis. Study of two high-dose methylprednisolone schedules.

BACKGROUND: Natalizumab (NTZ) is a disease-modifying treatment (DMT) in multiple sclerosis (MS) whose discontinuation can produce a "rebound effect", consisting of severe clinical deterioration and/or evidence of disease reactivation on magnetic resonance imaging (MRI). OBJECTIVE: To analyze the efficacy of two treatment schedules with intravenous methylprednisolone (IVMP) administered during the washout period of natalizumab (i.e., before starting another DMT) in preventing the rebound phenomenon. METHODS: Five-year retrospective study of NTZ withdrawals after at least 24 uninterrupted doses. Two IVMP schedules were tested. In schedule 1 (3-month washout), 1, 2, and 3 g of IVMP were administered on the first, second, and third month respectively. In schedule 2 (2-month washout), 1 and 2 g of IVMP were administered on the first and second month respectively. A new DMT was started 10 days after the end of each schedule. Rebound was defined as at least one clinical relapse plus rebound activity on MRI (>5 gadolinium-enhanced lesions and a number of new/T2-enhanced and/or gadolinium-enhanced lesions greater than before initiation of NTZ) during washout or at 6 months after new DMT initiation (6M-DMT). Clinical and MRI evaluations were performed at 3, 6, 12, and 24 months after initiation of the new DMT. RESULTS: Fifty patients (68% women) were included, with a mean (SD) age of 37.76 (10.88) years and pre-NTZ annualized relapse rate (ARR) of 1.78 (1.04). During NTZ therapy, mean Expanded Disability Status Scale (EDSS) score was 3.7 (1.73) and ARR was 0.23 (0.39). The ARR (mean of both schedules) was 0.1 (0.71) during washout and 0.32 (0.84) at 6M-DMT. Rebound was observed in 10% of cases (n = 5), with no significant clinical or radiological differences (p>0.05) between the two IVMP schedules. Rebound was observed in younger patients and was associated with new MRI lesions and higher ARR at 3M-DMT and 6M-DMT respectively, with no difference in EDSS after 2 years of follow-up. Neither the ARR before NTZ initiation nor the choice of new DMT after NTZ discontinuation was associated with development of rebound effect. CONCLUSIONS: Both IVMP schedules were well tolerated during NTZ washout and rebound was observed in only 10% of cases. In our experience, administration of IVMP during NTZ washout could reduce the possibility of a rebound effect.

Mechanical Thrombectomy in Acute Stroke Due to Carotid Occlusion: A Series of 153 Consecutive Patients.

BACKGROUND: Strokes due to carotid artery occlusion (CAO) are associated with bad clinical prognosis and poor response to intravenous thrombolysis. Several studies in the past have shown the benefits of mechanical thrombectomy (MT) and compared bridging therapy (BT) and primary MT (PMT) in large vessel occlusions, but only a few studies have focused on the specific population of CAO and their response to endovascular treatment. METHODS: Retrospective review of patients treated at our center between January 2010 and June 2017 that (1) presented with acute ischemic stroke caused by CAO in the first 4.5 h since symptom onset, and (2) were treated with MT (BT or PMT). Baseline characteristics of the population, comparison between BT and PMT, intrahospital mortality, symptomatic intracranial hemorrhage, and functional outcome were investigated. RESULTS: A total of 153 patients were included. Baseline characteristics: 51.6% were male, and the median age was 71 years. The most frequent risk factor was hypertension (71.9%). The main stroke etiology was atherothrombotic (40.5%). The mean admission National Institute of Health Severity Score (NIHSS) was 19, mean discharge NIHSS was 7. Isolated occlusion of the Extracranial or Intracranial Internal Carotid Artery was the most frequent occlusion location (52.3%). TICI 2b-3 was achieved in 87.6%, intrahospital mortality was 26.8%, symptomatic hemorrhage was 8.5%, and 3 months-modified Rankin Score (mRS) 0-2 was 26.8%. Definitive carotid stenting was needed in 33.3% of the cases. BT versus PMT: Patients treated with PMT presented a higher incidence of atrial fibrillation, anticoagulation, and cardioembolic stroke compared to those treated with BT. No differences in TICI 2b-3, 3 months-mRS or symptomatic hemorrhage were found between both groups. Intrahospital mortality: Poor perfusion-CT mismatch (p = 0.005), isolated Internal carotid artery location (p = 0.024), and symptomatic hemorrhage (p < 0.001) were independent predictors. Symptomatic intracranial hemorrhage: Patients with post-treatment symptomatic hemorrhage had higher intrahospital mortality (p < 0.001) and worse 3 months-mRS (p = 0.033). Functional outcome: Admission NIHSS (p = 0.012) independently predicted 3 months-mRS. CONCLUSIONS: In our population, patients with CAO clinically present with severe strokes. Isolated occlusions of the extra- or intracranial segments of the carotid are more frequent than tandem occlusions. Successful recanalization after thrombectomy is achieved in most of the patients, but association with favorable functional outcome is poor. Clinical evolution is similar in patients treated with PMT and BT. Intracranial symptomatic hemorrhage after treatment is associated with higher intrahospital mortality and worse 3 months-mRS. Poor perfusion-CT mismatch, symptomatic hemorrhage, and isolated CAO are independent predictors of intrahospital mortality. Admission NIHSS is an independent predictor of 3 months-mRS.

Difusión de los antibióticos en el sistema nervioso central / Antibiotic diffusion to central nervous system

Las infecciones del sistema nervioso central (SNC) causadas por patógenos mutiresistentes suponen un reto terapéutico. El paso de fluidos y de solutos al SNC está estrechamente regulado a través de la barrera hematoencefálica (BHE).La penetración de cualquier fármaco, inclusive los antibióticos, en el líquido cefalorraquídeo (LCR) depende del tamaño molecular, la lipofilicidad, la unión a proteínas plasmáticas y su afinidadpor transportadores de la BHE. La relación entre el área bajo la curva en el LCR y el suero AUCCSF (Area Bajo la Curva en LCR) / AUCS (Area Bajo la Curva en suero) de una sustancia es el parámetro más preciso para determinar su capacidad de difusión. Linezolid, algunas quinolonas y metronidazol consiguen altas concentraciones en LCR y son útiles para tratar microorganismos sensibles. Algunos antibióticos cuya permeabilidad a través de la BHE es baja pueden ser administrados directamente en el ventrículo a la vez que se realiza infusión intravenosa. El antibiótico ideal para tratar una infección del SNC es pequeño, no tiene alta tasa de unión a proteínas plasmáticas, es moderadamente lipofílico y no es un ligando de alta afinidad a bombas de expulsión de la BHE. Conocer la farmacocinética de los antibióticos y su interacción con la BHE permitirá mejorar el tratamiento de los pacientes con infecciones del SNC. En este artículo se exponen las propiedades físico-químicas de los principales grupos de antibióticos para evaluar cuáles son más prometedores en el tratamiento de las infecciones del SNC y cómo usarlos en la práctica clínica habitual (AU)

Central nervous system (CNS) infections caused by pathogens with a reduced sensitivity to drugs are a therapeutic challenge. Transport of fluid and solutes is tightly controlled within CNS, where vasculature exhibits a blood-brain barrier (BBB).The entry of drugs, including antibiotics, into the cerebro- spinal fluid (CSF) is governed by molecular size, lipophilicity, plasma protein binding and their affinity to transport systems at the BBB. The ratio of the AUCCSF (Area under the curve in CSF)/AUCS (Area under the curve in serum) is the most accurate parameter to characterize drug penetration into the CSF. Linezolid, some fluoroquinolones and metronidazole get high CSF concentrations and are useful for treating susceptible pathogens. Some highly active antibiotic compounds with low BBB permeability can be directly administered into the ventricles together with concomitant intravenous therapy. The ideal antibiotic to treat CNS infections should be that with a small moderately lipophilic molecule, low plasma protein binding and low affinity to efflux pumps at BBB. Knowledge of the pharmacokinetics and pharmacodynamics of antibiotics at the BBB will assist to optimize antibiotic treatment in CNS infections. This article reviews the physicochemical properties of the main groups of antibiotics to assess which compounds are most promising for the treatment of CNS infections and how to use them in the daily clinical practice (AU)