Optical coherence tomography measures correlate with brain and spinal cord atrophy and multiple sclerosis disease-related disability.

BACKGROUND AND PURPOSE: Both optical coherence tomography (OCT) and magnetic resonance imaging (MRI) volumetric measures have been postulated as potential biomarkers of multiple sclerosis (MS)-related disability. The aim of the study was to investigate the association between OCT and brain volume and spinal cord area (SCA) parameters in patients with relapsing MS and to assess their independent associations with disability. METHODS: This was a cross-sectional analysis of 90 patients with MS who underwent OCT and MRI examination. Values of peripapillary retinal nerve fibre layer (pRNFL), ganglion cell/inner plexiform layer (GCIPL) and inner nuclear layer of eyes without previous optic neuritis were obtained. SCA and brain parenchymal fraction (BPF), grey and white matter fractions were obtained. Multivariable regression analyses were conducted with disability as dependent variable. RESULTS: Lower pRNFL thickness and lower GCIPL volume as well as lower BPF, grey matter fraction and SCA were associated with a longer disease duration and a higher Expanded Disability Status Scale score. Lower pRNFL thickness and GCIPL volumes were associated with lower BPF and SCA. In the multivariable logistic regression analyses, pRNFL thickness and GCIPL volume outperformed MRI in predicting disability. CONCLUSIONS: The OCT measures correlate with brain and spinal cord atrophy and appear more closely associated with disability than MRI volumetric measures.

Lesion filling effect in regional brain volume estimations: a study in multiple sclerosis patients with low lesion load.

INTRODUCTION: Regional brain volume estimation in multiple sclerosis (MS) patients is prone to error due to white matter lesions being erroneously segmented as grey matter. The Lesion Segmentation Toolbox (LST) is an automatic tool that estimates a lesion mask based on 3D T2-FLAIR images and then uses this mask to fill the structural MRI image. The goal of this study was (1) to test the LST for estimating white matter lesion volume in a cohort of MS patients using 2D T2-FLAIR images, and (2) to evaluate the performance of the optimized LST on image segmentation and the impact on the calculated grey matter fraction (GMF). METHODS: The study included 110 patients with a clinically isolated syndrome and 42 with a relapsing-remitting MS scanned on a 3.0-T MRI system. In a subset of consecutively selected patients, the lesion mask was semi-manually delineated over T2-FLAIR images. After establishing the optimized LST parameters, the corresponding regional fractions were calculated for the original, filled, and masked images. RESULTS: A high agreement (intraclass correlation coefficient (ICC) = 0.955) was found between the (optimized) LST and the semi-manual lesion volume estimations. The GMF was significantly smaller when lesions were masked (mean difference -0.603, p < 0.001) or when the LST filling technique was used (mean difference -0.598, p < 0.001), compared to the GMF obtained from the original image. CONCLUSION: LST lesion volume calculation seems reliable. GMFs are significantly reduced when a method to correct the contribution of MS lesions is used, and it may have an impact in assessing GMF differences between clinical cohorts.

Brain atrophy in natalizumab-treated patients: A 3-year follow-up.

BACKGROUND: A pseudoatrophy effect has been held responsible for the lack of net impact of natalizumab on brain volume outcomes in 2-year trials, but no data are available beyond 24 months. OBJECTIVE: We aimed to investigate brain volume dynamics in natalizumab-treated patients in up to 3 years after therapy initiation with clinical correlations. METHODS: Patients on natalizumab for at least 3 years were clinically assessed 3-monthly. Magnetic resonance imaging scans were performed at baseline and yearly. Brain volume changes were obtained with SIENA. Multivariate models were used to investigate the association between baseline inflammation and changes in brain volume and disability. RESULTS: Sixty-two patients with multiple sclerosis were analysed. Mean age and disease duration were 34.7 (SD: 8.3) and 10.4 (SD: 6.6) years. Presence of gadolinium enhancement at baseline was not associated with Expanded Disability Status Scale changes (p=0.468), but was associated with larger brain volume decreases (p=0.005) in the first (p=0.024) and second year (p=0.019) but not in the third year (p=0.863). Brain volume changes at 12 and 36 months were marginally associated with disability status at month 12 (p=0.094) and 36 (p=0.084), respectively. CONCLUSIONS: Baseline inflammation affects brain volume measures up to 24 months after natalizumab initiation. A marginal association of brain volume changes with disability is present.

Significant clinical worsening after natalizumab withdrawal: Predictive factors.

We aimed to single out multiple sclerosis (MS) cases with poor outcome after natalizumab withdrawal and to identify predictive variables. We ascertained 47 withdrawals, and compared their pre- and post-natalizumab periods. We objectively defined significant clinical worsening after natalizumab withdrawal as a 2-step increase in Expanded Disability Status Scale (EDSS). We performed regression models. As a group, post-natalizumab annualized relapse rate (ARR) was lower in the post-natalizumab period, and there were no differences in the mean number of gadolinium (Gd)-enhancing lesions between pre- and post-natalizumab magnetic resonance imaging (MRI). Corticosteroid treatment did not change the outcomes. Eight patients (19%) presented significant clinical worsening after natalizumab withdrawal, which was predicted by a higher baseline EDSS and a 1-step EDSS increase while on natalizumab.

Similar biological effect of high-dose oral versus intravenous methylprednisolone in multiple sclerosis relapses.

UNLABELLED: Our aim was to investigate differences in immune mechanisms in multiple sclerosis (MS) relapse, after high-dose oral methylprednisolone (oMP) or intravenous methylprednisolone (ivMP). We measured serum cytokines (IL-2, IL-4, IL-6, IL-10, IL-17, TNF-α and IFN-γ) in 39 of 49 MS patients with moderate-severe relapse, whom were treated with ivMP or oMP in a placebo-controlled, non-inferiority clinical trial. We assessed these cytokine levels at baseline and at 1 and 4 weeks post-treatment. The cytokine levels between oMP and ivMP were similar at any time. Proinflammatory cytokines (IL-6 and IFN-γ) were significantly decreased in both groups at week 1 (p = 0.05 / p = 0.03) and at week 4 (p = 0.04 / p = 0.05). This study provides further confirmatory evidence that oMP is not inferior to ivMP. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT00753792.

A randomized clinical trial of oral versus intravenous methylprednisolone for relapse of MS.

BACKGROUND: Steroids improve multiple sclerosis (MS) relapses but therapeutic window and dose, frequency and administration route remain uncertain. OBJECTIVE: The objective of this paper is to compare the clinical and radiologic efficacy, tolerability and safety of intravenous methylprednisolone (ivMP) vs oral methylprednisolone (oMP), at equivalent high doses, for MS relapse. METHODS: Forty-nine patients with moderate or severe relapse within the previous 15 days were randomized in a double-blind, noninferiority, multicenter trial to receive ivMP or oMP and their matching placebos. Expanded Disability Status Scale (EDSS) scores were determined at baseline and weeks 1, 4 and 12. Brain MRI were assessed at baseline and at weeks 1 and 4. Primary endpoint was a noninferiority assessment of EDSS improvement at four weeks (noninferiority margin of one point), with further key efficacy assessments of number and volume of T1 gadolinium-enhancing (Gd+), and new or enlarged T2 lesions at four weeks' post-treatment initiation. Secondary outcomes were safety and tolerability. RESULTS: The study achieved the main outcome of noninferiority at four weeks for improved EDSS score. No differences were found between ivMP and oMP in the number of Gd+ lesions (0 (0-1) vs 0 (0-0.5), p = 0.630), volume of Gd+ lesions (0 (0-88.0) vs 0 (0-32.9) mm(3), p = 0.735), or new or enlarged T2 lesions (0 (0-194) vs 0 (0-123), p = 0.769). MP was well tolerated, and no serious adverse events were reported. CONCLUSIONS: This study provides confirmatory evidence that oMP is not inferior to ivMP in reducing EDSS, similar in MRI lesions at four weeks for MS relapses and is equally well tolerated and safe. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT00753792.

Scoring treatment response in patients with relapsing multiple sclerosis.

BACKGROUND: We employed clinical and magnetic resonance imaging (MRI) measures in combination, to assess patient responses to interferon in multiple sclerosis. OBJECTIVE: To optimize and validate a scoring system able to discriminate responses to interferon treatment in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: Our analysis included two large, independent datasets of RRMS patients who were treated with interferons that included 4-year follow-up data. The first dataset ("training set") comprised of 373 RRMS patients from a randomized clinical trial of subcutaneous interferon beta-1a. The second ("validation set") included an observational cohort of 222 RRMS patients treated with different interferons. The new scoring system, a modified version of that previously proposed by Rio et al., was first tested on the training set, then validated using the validation set. The association between disability progression and risk group, as defined by the score, was evaluated by Kaplan Meier survival curves and Cox regression, and quantified by hazard ratios (HRs). RESULTS: The score (0-3) was based on the number of new T2 lesions (>5) and clinical relapses (0,1 or 2) during the first year of therapy. The risk of disability progression increased with higher scores. In the validation set, patients with score of 0 showed a 3-year progression probability of 24%, while those with a score of 1 increased to 33% (HR = 1.56; p = 0.13), and those with score greater than or equal to 2 increased to 65% (HR = 4.60; p < 0.001). CONCLUSIONS: We report development of a simple, quantitative and complementary tool for predicting responses in interferon-treated patients that could help clinicians make treatment decisions.

Clinical impact of early brain atrophy in clinically isolated syndromes.

BACKGROUND: The impact of global and tissue-specific brain atrophy on conversion to multiple sclerosis (MS) after a clinically isolated syndrome (CIS) is not fully gauged. OBJECTIVES: We aimed to determine the magnitude and clinical relevance of brain volume dynamics in the first year after a CIS. METHODS: We assessed 176 patients with CIS within 3 months of onset, clinically and by conventional magnetic resonance imaging (MRI) scans, at baseline and 1 year after clinical onset. We determined the percentage of brain volume change (PBVC) and the brain parenchymal (BPF), grey matter (GMF) and white matter (WMF) fractions. RESULTS: The mean follow-up time was 53 months (SD = 16.8): 76 patients (43%) experienced a second attack, 32 (18%) fulfilled MRI-only 2005 McDonald criteria and 68 (39%) remained as CIS. Statistically significant decreases in the volume measures tested were observed in patients with a second attack, for BPF and PBVC; in both MS groups for GMF; whereas in all groups, the WMF was unchanged. Patients with a second attack had larger PBVC decreases (- 0.65% versus + 0.059%; p < 0.001). PBVC decreases below - 0.817% independently predicted shorter times to a second attack. CONCLUSIONS: Global brain and grey matter volume loss occurred within the first year after a CIS; brain volume loss predicted conversion to MS.

Validation of a New Semiautomated Segmentation Pipeline Based on the Spinal Cord Toolbox DeepSeg Algorithm to Estimate the Cervical Canal Area.

BACKGROUND AND PURPOSE: As in the brain reserve concept, a larger cervical canal area may also protect against disability. In this context, a semiautomated pipeline has been developed to obtain quantitative estimations of the cervical canal area. The aim of the study was to validate the pipeline, to evaluate the consistency of the cervical canal area measurements during a 1-year period, and to compare cervical canal area estimations obtained from brain and cervical MRI acquisitions. MATERIALS AND METHODS: Eight healthy controls and 18 patients with MS underwent baseline and follow-up 3T brain and cervical spine sagittal 3D MPRAGE. The cervical canal area was measured in all acquisitions, and estimations obtained with the proposed pipeline were compared with manual segmentations performed by 1 evaluator using the Dice similarity coefficient. The cervical canal area estimations obtained on baseline and follow-up T1WI were compared; brain and cervical cord acquisitions were also compared using the individual and average intraclass correlation coefficients. RESULTS: The agreement between the manual cervical canal area masks and the masks provided by the proposed pipeline was excellent, with a mean Dice similarity coefficient mean of 0.90 (range, 0.73-0.97). The cervical canal area estimations obtained from baseline and follow-up scans showed a good level of concordance (intraclass correlation coefficient = 0.76; 95% CI, 0.44-0.88); estimations obtained from brain and cervical MRIs also had good agreement (intraclass correlation coefficient = 0.77; 95% CI, 0.45-0.90). CONCLUSIONS: The proposed pipeline is a reliable tool to estimate the cervical canal area. The cervical canal area is a stable measure across time; moreover, when cervical sequences are not available, the cervical canal area could be estimated using brain T1WI.

[Esclerosis multiple. Lactancia. Lactante. Planificacion familiar. Posparto. Tratamiento modificador de la enfermedad.] / Fármacos modificadores de la enfermedad en la esclerosis múltiple durante la lactancia: revisión de la evidencia actual.

INTRODUCTION: Multiple sclerosis mainly affects women of childbearing age, and the pregnancy and postpartum period is of special interest because of the peculiarities of the disease course and the therapeutic consequences that derive from it. During the period of breastfeeding (BF), the choice of treatment strategy must weigh up the well-established benefits of BF for both the newborn and the mother against the safety profile and potential adverse effects on the infant resulting from exposure to disease-modifying drugs transferred through breast milk. DEVELOPMENT: The study reviews the current evidence on the safety of disease-modifying drugs available for the treatment of multiple sclerosis during the BF period, and gathers data on the transfer of the different drugs into breast milk, as well as the potential adverse effects described in the infant. The drugs of first choice during this period are interferon beta and glatiramer acetate. The rest of the disease modifying drugs are not accepted for use in the BF period according to their summary of product characteristics. However, in recent years, data from studies of clinical practice and case series have been published suggesting that some of these drugs could be used safely during this period. CONCLUSIONS: Given the recognised health benefits of BF for both mother and infant, exclusive breastfeeding is recommended whenever possible. It is essential to carry out an individualised assessment prior to pregnancy and to evaluate the different treatment options depending on each patient.

TITLE: Fármacos modificadores de la enfermedad en la esclerosis múltiple durante la lactancia: revisión de la evidencia actual.Introducción. La esclerosis múltiple afecta principalmente a mujeres en edad fértil, y el período de gestación y posparto es de especial interés por las peculiaridades que comporta en cuanto a evolución de la enfermedad y por las consecuencias terapéuticas que se derivan. En el período de lactancia materna (LM), la elección de la estrategia de tratamiento debe poner en una balanza, por un lado, los beneficios bien establecidos de la LM para el recién nacido y su madre y, por el otro, el perfil de seguridad y potenciales efectos adversos en el lactante derivados de la exposición a los fármacos modificadores de la enfermedad, por transferencia a través de leche materna. Desarrollo. Se realiza una revisión de la evidencia actual acerca de la seguridad de los fármacos modificadores de la enfermedad disponibles para el tratamiento de la esclerosis múltiple durante el período de LM, y se recogen datos de transferencia de los diferentes fármacos a la leche materna, así como los potenciales efectos adversos descritos en el lactante. Los fármacos considerados de primera elección durante este período son el interferón beta y el acetato de glatiramer. El resto de los fármacos modificadores de la enfermedad no están aceptados para su utilización en el período de LM por ficha técnica. Sin embargo, en los últimos años, se han publicado datos de estudios de práctica clínica y series de casos que indican que algunos de estos fármacos podrían utilizarse con seguridad durante este período. Conclusiones. Teniendo en cuenta los beneficios reconocidos de la LM para la salud tanto de la madre como del lactante, se debe recomendar la LM exclusiva a las pacientes con esclerosis múltiple siempre que sea posible. Es fundamental realizar una evaluación individualizada previa al embarazo y valorar las diferentes opciones de tratamiento en función de cada paciente.

Chitinase 3-like 1 plasma levels are increased in patients with progressive forms of multiple sclerosis.

BACKGROUND: Chitinase 3-like 1 (CHI3L1) is upregulated in a wide variety of inflammatory conditions. Recent studies have pointed to a role of CHI3L1 in multiple sclerosis (MS) pathogenesis. OBJECTIVE: The objective of this study was to investigate the role of plasma CHI3L1 in MS clinical course and disease activity and to evaluate the effect of interferon-beta (IFNß) treatment on protein levels. METHODS: Plasma CHI3L1 levels were determined by ELISA in 57 healthy controls (HC), 220 untreated MS patients [66 primary progressive MS patients (PPMS), 30 secondary progressive MS patients (SPMS), and 124 relapsing-remitting MS patients (RRMS), 94 during clinical remission and 30 during relapse], and 32 MS patients receiving IFNß treatment. A polymorphism of the CHI3L1 gene, rs4950928, was genotyped in 3274 MS patients and 3483 HC. RESULTS: Plasma CHI3L1 levels were significantly increased in patients with progressive forms of MS compared with RRMS patients and HC. CHI3L1 levels were similar between RRMS patients in relapse and remission. A trend towards decreased CHI3L1 levels was observed in IFNß-treated patients. Allele C of rs4950928 was significantly associated with PPMS patients and with higher plasma CHI3L1 levels. CONCLUSIONS: These findings point to a role of CHI3L1 in patients with progressive forms of MS, particularly in those with PPMS.

Change in the clinical activity of multiple sclerosis after treatment switch for suboptimal response.

BACKGROUND: Therapy for multiple sclerosis (MS) has a partial efficacy, and a significant proportion of treated patients will develop a suboptimal response with first-line disease-modifying drugs (DMD). Therapy switch in patients with MS can be a strategy after a treatment failure. We studied the change in clinical activity after switching of first-line DMD because of a treatment failure. METHODS: Relapsing-remitting multiple sclerosis (RRMS) patients treated with interferon-beta (IFNB) or glatiramer acetate (GA) were divided into (i) patients without change in DMD, (ii) patients with a change in DMD because of a poor response, and (iii) those with a change in DMD without relation with response. Annualized relapse rate (ARR) and relapse-free proportions were analyzed. RESULTS: We identified 923 patients with RRMS. Of the 180 who experienced a change because of suboptimal response, 90 switched to another first-line DMT, 38 to mitoxantrone, and 52 to natalizumab. Median ARR in the pre-DMD period on first DMD and second DMD was the following: 1, 1, and 0 for switchers from IFNB to another IFNB (P = 0.0001); 0.67, 1, and 0 for switchers from GA to IFNB (P = 0.01); 1, 1, and 0 for switchers from an IFNB to GA (P = 0.02); 1.1, 1.5, 0.2 for switchers from IFNB or GA to mitoxantrone (P = 0.0001); 0.9, 1, 0 for switchers from IFNB or GA to natalizumab (P = 0.0001). CONCLUSIONS: In patients with RRMS who have a poor response, switch to another DMD may reduce the clinical activity of the disease.

Gadolinium-enhanced brain lesions in multiple sclerosis relapse.

OBJECTIVE: To study the clinico-radiological paradox in multiple sclerosis (MS) relapse by analyzing the number and location of gadolinium-enhanced (Gd+) lesions on brain MRI before methylprednisolone (MP) treatment. METHODS: We analyzed brain MRI from 90 relapsed MS patients in two Phase IV multicenter double-blind randomized clinical trials that showed the noninferiority of different routes and doses of MP administration. A 1.5- or 3-T brain MRI was performed at baseline before MP treatment and within 15 days of symptom onset. The number and location of Gd+ lesions were analyzed. Associations were studied using univariate analysis. RESULTS: Sixty-two percent of patients had at least 1 Gd+ brain lesion; the median number was 1 (interquartile range 0-4), and 41% of patients had 2 or more lesions. The most frequent location of Gd+ lesions was subcortical (41.4%). Gd+ brain lesions were found in 71.4% of patients with brainstem-cerebellum symptoms, 57.1% with spinal cord symptoms and 55.5% with optic neuritis (ON). Thirty percent of patients with brain symptoms did not have Gd+ lesions, and only 43.6% of patients had symptomatic Gd+ lesions. The univariate analysis showed a negative correlation between age and the number of Gd+ lesions (p=0.002). CONCLUSION: Most patients with relapse showed several Gd+ lesions on brain MRI, even when the clinical manifestation was outside of the brain. Our findings illustrate the clinico-radiological paradox in MS relapse and support the value of brain MRI in this scenario.

Consensus statement on the use of alemtuzumab in daily clinical practice in Spain. / Consenso de expertos sobre el uso de alemtuzumab en la práctica clínica diaria en España.

INTRODUCTION: Alemtuzumab is a highly effective drug approved by the European Medicines Agency as a disease-modifying drug for the treatment of relapsing-remitting multiple sclerosis. OBJECTIVE: A consensus document was drafted on the management of alemtuzumab in routine clinical practice in Spain. DEVELOPMENT: A group of multiple sclerosis specialists reviewed articles addressing treatment with alemtuzumab in patients with multiple sclerosis and published before December 2017. The included studies assessed the drug's efficacy, effectiveness, and safety; screening for infections and vaccination; and administration and monitoring aspects. The initial proposed recommendations were developed by a coordinating group and based on the available evidence and their clinical experience. The consensus process was carried out in 2 stages, with the initial threshold percentage for group agreement established at 80%. The final document with all the recommendations agreed by the working group was submitted for external review and the comments received were considered by the coordinating group. CONCLUSION: The present document is intended to be used as a tool for optimising the management of alemtuzumab in routine clinical practice.

Consensus statement on the use of alemtuzumab in daily clinical practice in Spain.

INTRODUCTION: Alemtuzumab is a highly effective drug approved by the European Medicines Agency as a disease-modifying drug for the treatment of relapsing-remitting multiple sclerosis. OBJECTIVE: A consensus document was drafted on the management of alemtuzumab in routine clinical practice in Spain. DEVELOPMENT: A group of multiple sclerosis specialists reviewed articles addressing treatment with alemtuzumab in patients with multiple sclerosis and published before December 2017. The included studies assessed the drug's efficacy, effectiveness, and safety; screening for infections and vaccination; and administration and monitoring aspects. The initial proposed recommendations were developed by a coordinating group and based on the available evidence and their clinical experience. The consensus process was carried out in 2 stages, with the initial threshold percentage for group agreement established at 80%. The final document with all the recommendations agreed by the working group was submitted for external review and the comments received were considered by the coordinating group. CONCLUSION: The present document is intended to be used as a tool for optimising the management of alemtuzumab in routine clinical practice.

Natalizumab for relapsing-remitting multiple sclerosis.

INTRODUCTION: Natalizumab is a monoclonal antibody that inhibits leukocyte migration across the blood-brain barrier and has been approved for the treatment of relapsing-remitting multiple sclerosis. OBJECTIVE: To provide a review and update of the pharmacological and therapeutic characteristics of natalizumab, with special emphasis on the most recently published data on the efficacy, effectiveness and safety of this drug. DEVELOPMENT: Several randomized clinical trials in patients with relapsing forms of multiple sclerosis have demonstrated that natalizumab substantially reduces clinical and radiological disease activity. Post hoc analysis of phase III clinical trials and the results of post-approval observational studies indicate that natalizumab significantly increases the proportion of patients with complete clinical and radiological response and is effective in patients with highly active forms of multiple sclerosis and suboptimal response to other treatments. Like other monoclonal antibodies, natalizumab can cause hypersensitivity reactions, which are severe in 1% of patients. Other adverse effects are generally mild or infrequent. Nevertheless, several cases of progressive multifocal leukoencephalopathy have been detected in patients treated with natalizumab monotherapy. The risk of this severe complication seems to increase with the number of doses administered. CONCLUSION: Natalizumab has a favorable risk-benefit ratio in the treatment of relapsing -remitting multiple sclerosis. However, because of the potential risk of progressive multifocal leukoencephalopathy, patients must be carefully selected and specific protocols must be followed during the drug's administration.

Leadership in times of crisis. School principals facing COVID-19.

This article analyzes the personal leadership resources utilized by a sample of school principals in Catalonia (Spain) during the confinement and post-confinement periods due to the COVID-19 crisis. A questionnaire was designed, validated, and provided to the principals from Primary Education schools to carry out the study. The questionnaire analyzed personal leadership resources used by the principals during the confinement and post-confinement periods, compared to a former ¨normal situation¨. The data analysis results confirmed that the role of the principals was crucial in redirecting the situation and completing the academic course satisfactorily. The principals scored their leadership resources remarkably high in the former normality and maintained proactivity at a similar level during the crisis. However, other resources scored lower during the same period. As a direct result, there was a high degree of adaptation to this situation from the principals. The results indicate that principals do not lead in the same manner in times of crisis as in normal times. Age, experience, and type of school influence the results only in former normal situations but not in times of crisis.

Recommendations for vaccination in patients with multiple sclerosis who are eligible for immunosuppressive therapies: Spanish consensus statement. / Recomendaciones para la vacunación en pacientes con esclerosis múltiple candidatos a terapias inmunosupresoras: documento de consenso español.

BACKGROUND: The recent development of highly effective treatments for multiple sclerosis (MS) and the potential risk of infectious complications require the development of prevention and risk minimisation strategies. Vaccination is an essential element of the management of these patients. This consensus statement includes a series of recommendations and practical scenarios for the vaccination of adult patients with MS who are eligible for highly effective immunosuppressive treatments. METHODOLOGY: A formal consensus procedure was followed. Having defined the scope of the statement, we conducted a literature search on recommendations for the vaccination of patients with MS and specific vaccination guidelines for immunosuppressed patients receiving biological therapy for other conditions. The modified nominal group technique methodology was used to formulate the recommendations. DEVELOPMENT: Vaccination in patients who are candidates for immunosuppressive therapy should be considered before starting immunosuppressive treatment providing the patient's clinical situation allows. Vaccines included in the routine adult vaccination schedule, as well as some specific ones, are recommended depending on the pre-existing immunity status. If immunosuppressive treatment is already established, live attenuated vaccines are contraindicated. For vaccines with a correlate of protection, it is recommended to monitor the serological response in an optimal interval of 1-2 months from the last dose.

Progression on the Multiple Sclerosis Functional Composite in multiple sclerosis: what is the optimal cut-off for the three components?

For the Timed 25-Foot Walk (T25FW) and 9-Hole Peg Test (9HPT), components of the Multiple Sclerosis Functional Composite (MSFC), cut-off points of 20% change have previously been defined as meaningful endpoints of functional decline. Recently, however, a 15% change of MSFC components was introduced. The objective of this study was to determine optimal cut-offs for all MSFC components to indicate clinical disease progression in a primary progressive (PP) multiple sclerosis (MS) population. T25FW, 9HPT and the Paced Auditory Serial Addition Test (PASAT) were performed in 161 patients with PPMS with a 2-year interval. Absolute and relative differences in test scores were calculated. For each cut-off point of relative change, proportions of patients who progressed (deterioration beyond cut-off value) and improved (improvement beyond cut-off value) were calculated. Further, we calculated the ratio of 'improved' versus 'progressed' patients. Line graphs were created indicating: percentage progressed patients, percentage improved patients, and ratio of improved versus progressed patients. The optimal cut-off was determined by searching the cut-off point with the lowest ratio of improved versus progressed patients, while at the same time capturing a substantial amount of progression. For both T25FW and 9HPT, the ratio between patients that improved and worsened clearly decreased between the cut-offs of 15% and 20%. For the PASAT, the ratio between patients improved and worsened was persistently poor. In conclusion, a cut-off of 20% for both T25FW and 9HPT has a better signal-to-noise ratio than lower values (e.g. 15%) and is therefore preferable for the assessment of disease progression. No satisfactory cut-off point for the PASAT could be determined.

Do multimodal evoked potentials add information to MRI in clinically isolated syndromes?

The role of multimodal evoked potentials (MMEPs) in establishing multiple sclerosis (MS) diagnosis and prognosis has diminished nowadays. The objective of this article is to evaluate whether MMEPs add information to MRI in identifying patients with higher risk of relapse or development of disability after a clinically isolated syndrome (CIS). Patients who underwent visual, somato-sensory and brainstem auditory evoked potentials (EPs) were identified from a cohort of consecutive CIS. Patients also underwent brain MRI within 3 months of first attack. We analysed time to second attack and to Expanded Disability Status Scale (EDSS) score of 3.0 according to number of Barkhof criteria and number of abnormal MMEPs. A complete study was performed in 245 patients who were followed for a mean of 76.4 months (interquartile range: 61 to 96). Seventy-one patients (29%) had the three EPs normal, 115 patients (47%) had one abnormal EP; 40 patients (16%) had two; and 19 patients (8%) had three abnormal EPs. Baseline MRI determined the risk for converting to clinically definite MS and correlated with disability according to previous studies. EPs individually did not modify the risk of conversion or disability. However, the presence of three abnormal EPs increased the risk of reaching moderate disability (hazard ratio 7.0; 1.4-34.9) independently of baseline MRI. In conclusion, in the presence of three abnormal EPs could help identify CIS patients with a higher risk of developing disability, independently of MRI findings. However, the utility of MMEPs is limited by the low percentage of CIS patients having the three abnormal at baseline.