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Introduction: Neuromyelitis optica spectrum disorders (NMOSD) and MOG-associated disease (MOGAD) are an increasingly recognized group of demyelinating disorders of the central nervous system. Previous studies suggest that prognosis is predicted by older age at onset, number of relapses, the severity of the first attack and autoantibody status., Objective: To study prognostic factors associated with disability progression and additional relapses in the 3-year follow-up of a national NMOSD/MOGAD cohort., Results: Out of 180 of the initial Portuguese cohort, data on 82 patients was available at the end of the follow-up period (2019-2022). Two patients died. Twenty (24.4%) patients had one or more attack in this period (25 attacks in total), mostly transverse myelitis (TM) (56.0%) or optic neuritis (32.0%). MOGAD was significantly associated with a monophasic disease course (p = 0.03), with milder attacks (p = 0.01), while AQP4 + NMOSD was associated with relapses (p = 0.03). The most common treatment modalities were azathioprine (38.8%) and rituximab (18.8%). AQP4 + NMOSD more frequently required chronic immunosuppressive treatment, particularly rituximab (p = 0.01). Eighteen (22.5%) had an EDSS ≥6 at the end of the follow-up. AQP4 + NMOSD (p < 0.01) and the occurrence of transverse myelitis (TM) during disease (p = 0.04) correlated with an EDSS≥6 at the end of the follow-up period. MOGAD was significantly associated with an EDSS<6 (p < 0.01), and MOG+ cases that reached an EDSS>6 were significantly older (64.0 ± 2.8 versus 31.0 ± 17.1, p = 0.017). A bivariate logistic regression model including the serostatus and TM attacks during disease history successfully predicted 72.2% of patients that progressed to an EDSS≥6., Conclusion: This study highlights that myelitis predict increased disability (EDSS≥6) in NMOSD/MOGAG and AQP4 positivity is associated with increased disability., Competing Interests: Declaration of competing interest Authors declare no conflict of interest regarding this work., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Executive dysfunction occurs in 15% to 20% of multiple sclerosis (MS) patients and verbal fluency tests are frequently used to assess this deficit. The Word List Generation (WLG) is one of the most used measures in MS. This study aims to compare the performance of WLG of MS patients and healthy controls and to analyze the influence of clinical and demographic factors on the performance of MS patients., Methods: One hundred and nine MS patients and an age- and gender-matched group of 138 healthy controls were evaluated with WLG Portuguese version, as well as other tests from the Brief Repeatable Battery of Neuropsychological Tests (BRBN-T), subtests from WAIS, a phonemic fluency test (M, R, and P), and measures of psychological symptomatology and cognitive fatigue. The MS group (70.6% females) was mainly diagnosed with RRMS (89.2%)., Results: The MS group performed significantly lower than healthy controls on the WLG. In the MS group, this performance was significantly correlated with the level of education. Significant differences were found between the two groups regarding cognitive fatigue, with MS patients reporting higher levels than healthy controls. However, this variable was not related to the performance on the WLG for MS patients., Conclusions: This study suggests that MS is associated with large levels of cognitive decline on the phonemic verbal fluency tests. These results are consistent with other studies and highlight the importance of verbal fluency and cognitive speed measures in the neuropsychological assessment of MS. Deficits on this task seem to be highly related to the level of education of the patient rather than other demographic and clinical factors.

Background: Cognitive impairment affects 40-65% of MS patients, encompassing all disease stages and types of clinical courses. This estimation is based on different instruments used and population normative data., Objective: This study aims to assess the cognitive function in a hospital-based cohort of Portuguese MS patients, to allow estimating the prevalence of cognitive impairment in different phenotypes., Methods: Three hundred and thirteen patients with Multiple Sclerosis (MS) underwent neuropsychological assessment with the brief repeatable battery of neuropsychological tests (BRBN-T) and the brief international cognitive assessment for multiple sclerosis (BICAMS)., Results: Differences were observed in the cognitive impairment profile of different disease phenotypes and of the different disease severity stages. RRMS patients performed better in the cognitive test of the BRBN-T and BICAMS than those with progressive disease phenotypes. Relationships between cognitive impairment and disability and professional status were relevant. Although similarities could be observed in the cognitive profile of the MS phenotypes, with predominant involvement of verbal memory, verbal fluency, and information processing speed, the latter was found to be more frequent as the disease progressed., Conclusion: This study contributes to improve knowledge about the cognitive profile of the different MS phenotypes and understand the cognitive characteristics of Portuguese patients.

Objective: Cognitive impairment is experienced by 40-70% of multiple sclerosis patients, with information processing speed and memory most affected. Until now, cognitive results classified patients as impaired and not impaired. With this dichotomous approach, it is difficult to identify, in a heterogeneous group of patients with cognitive impairment, which cognitive domain(s) are most altered. This study aims to identify cognitive phenotypes in a clinical cohort of adult patients with Relapsing-Remitting Multiple Sclerosis (RRMS) using the International Classification of Cognitive Disorders in MS (IC-CoDiMS) and to characterize their clinical features. Methods: Three hundred patients with RRMS underwent neuropsychological assessment with the Brief Repeatable Battery of Neuropsychological Tests (BRBN-T) and the Brief International Cognitive Multiple Sclerosis (BICAMS). Results: In our cohort, the mean age was 41.38 [11.48 SD] years, and 205 [68.3%] were women. At the -1 SD threshold, 49% were cognitively intact, 25% had uni-domain impairment, 17% had bi-domain impairment, and 9% had multi-domain impairment. Processing speed was the most frequent single-domain impairment, followed by memory and verbal fluency. At the -1.5 SD threshold, 74.7% were cognitively intact, 17% had uni-domain impairment, 6% had bi-domain impairment, had bi-domain impairment, and 3.0% had multi-domain impairment. Memory was the most frequent single-domain impairment, followed by processing speed and verbal fluency. Conclusions: This study corroborates the importance of determining cognitive phenotypes through taxonomy (IC-CoDiMS). In addition, it contributes to improving the classification of cognitive phenotypes in patients with RRMS to enhance the development of more effective treatments and cognitive interventions.

Introduction: Optic neuropathies (ON), a broad spectrum of disorders of the optic nerve, are a frequent cause of visual loss, presenting either in isolation or associated to neurological or systemic disorders. They are often first evaluated in the Emergency Room (ER) and a rapid determination of the etiology is imperative for implementing timely and appropriate treatment. We aim to describe ER demographic data and clinical characteristics, as well as the performed imaging exams, of patients subsequently hospitalized and diagnosed with ON. Furthermore, we seek to explore the accuracy of ER discharge diagnosis and evaluate possible predictive factors that may influence it., Methods: We retrospectively reviewed the medical records of 192 patients admitted to the ward of the Neurology Department of Centro Hospitalar Universitário São João (CHUSJ), with a discharge diagnosis of ON. Subsequently, we selected those admitted from the ER, with clinical, laboratory and imaging data, between January 2004 and December 2021., Results: We included 171 patients. All participants were discharged from the ER and admitted in the ward with a main diagnostic suspicion of ON. Patients were stratified according to suspected etiology at the time of discharge: 99 inflammatory (57.9%), 38 ischemic (22.2%), 27 unspecified (15.8%) and 7 other (4.1%). By comparing with current follow-up diagnosis, 125 patients had an accurate ER diagnosis category (73.1%), 27 had an ON diagnosis of unspecified etiology that was defined only during follow-up (15.8%) and 19 had an inaccurate diagnosis category (11.1%). Diagnostic change was more common with ER ischemic diagnosis (21.1%) compared to inflammatory diagnosis (8.1%) (p = 0.034)., Conclusions: Our study reveals that most patients with ON can be accurately diagnosed in the ER through clinical history neurological and ophthalmological evaluation., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

We report a 9-year-old Spanish boy with severe psychomotor developmental delay, short stature, microcephaly and abnormalities of the brain morphology, including cerebellar atrophy. Whole-exome sequencing (WES) uncovered two novel de novo variants, a hemizygous variant in CASK (Calcium/Calmodulin Dependent Serine Protein Kinase) and a heterozygous variant in EEF2 (Eukaryotic Translation Elongation Factor 2). CASK gene encodes the peripheral plasma membrane protein CASK that is a scaffold protein located at the synapses in the brain. The c.2506-6 A > G CASK variant induced two alternative splicing events that account for the 80% of the total transcripts, which are likely to be degraded by NMD. Pathogenic variants in CASK have been associated with severe neurological disorders such as mental retardation with or without nystagmus also called FG syndrome 4 (FGS4), and intellectual developmental disorder with microcephaly and pontine and cerebellar hypoplasia (MICPCH). Heterozygous variants in EEF2, which encodes the elongation factor 2 (eEF2), have been associated to Spinocerebellar ataxia 26 (SCA26) and more recently to a childhood-onset neurodevelopmental disorder with benign external hydrocephalus. The yeast model system used to investigate the functional consequences of the c.34 A > G EEF2 variant supported its pathogenicity by demonstrating it affects translational fidelity. In conclusion, the phenotype associated with the CASK variant is more severe and masks the milder phenotype of EEF2 variant., (© 2023. The Author(s), under exclusive licence to The Japan Society of Human Genetics.)

Background: Neuromyelitis Optica Spectrum Disorder (NMOSD) is an inflammatory disease of the central nervous system. The study aimed to characterize the neuropsychological profile of NMOSD by comparing them with multiple sclerosis (MS) patients and healthy controls., Method: Sixty-four participants were included:19 NMOSD, 27 MS, and 18 healthy controls. The neuropsychological protocol included the Portuguese version of Montreal Cognitive Assessment, the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS), Verbal Fluency (phonemic and semantic), the Hospital Anxiety and Depression Scale, and the Expanded Disability Status Scale for clinical groups., Results: NMOSD patients had significant lower cognitive performance when compared to HC mainly in information processing speed, concentration, language processing, and in executive functions (cognitive flexibility, sustained, and divided attention). No significant differences were observed between NMOSD and MS patients. Three predictors for cognitive impairment, according to BICAMS criteria, were found: depression, disease duration, and the level of disability., Conclusion: The neuropsychological profile found in the present study for NMOSD is consistent with the previous findings. Information regarding the predictors of cognitive impairment in both diseases and their different associations are important for future research and for guiding interventions more suitable for the neuropsychological needs of affected patients.

Objectives: Cladribine is a selective and oral immunological reconstitution treatment, approved in Europe for very active multiple sclerosis (MS) with relapses. Aims were to assess the safety and effectiveness of cladribine in real-world setting, during treatment follow-up., Methods: This was a multicentric, longitudinal, observational study with retrospective and prospective data collection of clinical, laboratory, and imaging data. This interim analysis reports data from July 1, 2018 (study onset), to March 31, 2021., Results: A total of 182 patients were enrolled: 68.7% were female; mean age at onset was 30.1 ± 10.0 years, and mean age at first cycle of cladribine treatment was 41.1 ± 12.1; 88.5% were diagnosed with relapse-remitting MS and 11.5% with secondary progressive MS. Mean disease duration at cladribine start was 8.9 ± 7.7 years. Most patients (86.1%) were not naive, and median number of previous disease-modifying therapies was 2 (interquartile range, 1-3). At 12 months, we observed no significant Expanded Disability Status Scale score worsening ( P = 0.843, Mann-Whitney U test) and a significantly lower annualized relapse rate (0.9 at baseline to 0.2; 78% reduction). Cladribine treatment discontinuation was registered in 8% of patients, mainly (69.2%) due to disease activity persistence. Most frequent adverse reactions were lymphocytopenia (55%), infections (25.2%), and fatigue (10.7%). Serious adverse effects were reported in 3.3%. No patient has discontinued cladribine treatment because of adverse effects., Conclusion: Our study confirms the clinical efficacy and the safety profile of cladribine for treating MS patients with a long-term active disease in the real-world setting. Our data contribute to the body of knowledge of the clinical management of MS patients and the improvement of related clinical outcomes., Competing Interests: Conflicts of Interest and Source of Funding: This article was prepared with the medical writing support of W4Research, financially supported by Merck. Merck had no access to the data or any other role in study design, analysis, or decision to submit for publication. Mónica S., J. Sequeira, P.A., R.G., J.F., F.L., L.L., M.J.S., C.C., and J. de Sá have received honoraria from Merck and others for acting as speakers and for attending scientific meetings. J. Sequeira, P.A., R.G., J.F., F.L., L.L., M.J.S., V.S., C.C., and J. de Sá had also received fees for acting as a consultant and/or for participation in advisory boards from several companies, including Merck. The remaining authors did not receive any financial support and have no conflicts of interest to declare., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Multiple sclerosis is a disease with a heterogeneous evolution. The early identification of secondary progressive multiple sclerosis is a clinical challenge, which would benefit from the definition of biomarkers and diagnostic tools applicable in the transition phase from relapsing-remitting multiple sclerosis to secondary progressive multiple sclerosis. We aimed to reach a Portuguese national consensus on the monitoring of patients with multiple sclerosis and on the more relevant clinical variables for the early identification of its progression., Material and Methods: A Delphi panel which included eleven Portuguese Neurologists participated in two rounds of questions between July and August of 2021. In the first round, 39 questions which belonged to the functional, cognitive, imaging, biomarkers and additional evaluations were included. Questions for which no consensus was obtained in the first round (less than 80% of agreement), were appraised by the panel during the second round., Results: The response rate was 100% in both rounds and consensus was reached for a total of 33 questions (84.6%). Consensus was reached for monitoring time, evaluation scales and clinical variables such as the degree of brain atrophy and mobility reduction, changes suggestive of secondary progressive multiple sclerosis. Additionally, digital devices were considered tools with potential to identify disease progression. Most questions for which no consensus was obtained referred to the cognitive assessment and the remaining referred to both functional and imaging domains., Conclusion: Consensus was obtained for the determination of the monitorization interval and for most of the clinical variables. Most questions that did not reach consensus were related with the confirmation of progression taking into account only one test/domain, reinforcing the multifactorial nature of multiple sclerosis.

Background: Metabolic syndrome and multiple sclerosis [MS] share the presence of chronic inflammation in their pathogenic mechanisms. This study aimed to estimate the prevalence of metabolic syndrome parameters in MS and their association with disease disability, cognitive function, and Neurofilament Light chain [NfL] levels., Methods: Clinical, analytical, and magnetic resonance imaging data were obtained through medical records. Disease disability was measured by the Expanded Disability Status Scale [EDSS], the MS Severity Scale [MSSS] along with cognitive impairment by the Brief International Cognitive Assessment for MS [BICAMS] and Word List Generation test [WLG]. Metabolic syndrome parameters were evaluated by fasting blood glucose, triglycerides, high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol, total cholesterol, blood pressure, and waist circumference [WC]. We also analysed serum leptin and ghrelin and cerebrospinal fluid NfL., Results: Our sample included 51 people with MS, 34 (66.7%) females, mean age of 38.20±12.12 years and median disease duration of 3 years (P25=2.0, P75=5.0). Multivariate linear regression analysis confirmed that WC correlates with EDSS (β=0.04, p=.001) and MSSS (β=0.07, p=.002) as well as Brief Visuospatial Memory Test-Revised (β=-0.29, p=.008), WLG (β=-0.20, p=.039). NfL is also negatively associated with HDL-C (β=-4.51, p=.038)., Conclusions: Waist circumference is associated with disability and deficits in cognitive tests. A decrease in HDL-C is associated with an increase in NfL. This suggests metabolic syndrome might be an important factor in MS disease course., Competing Interests: Declaration of Competing Interest The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2022. Published by Elsevier B.V.)

Background: Early recognition of markers of faster disability worsening in paediatric-onset multiple sclerosis (MS) is a key requisite of personalised therapy for children with MS at the earliest possible time., Objective: To identify early predictors of rapid disability accrual in patients with paediatric-onset MS., Methods: Using the global MSBase registry, we identified patients who were <18 years old at the onset of MS symptoms. The clinico-demographic characteristics examined as predictors of future MS Severity Score (MSSS) included sex, age at symptom onset, absence of disability at the initial assessment, maximum Expanded Disability Status Scale (EDSS) score, relapse frequency and presence of brainstem, pyramidal, visual or cerebellar symptoms in the first year. A Bayesian log-normal generalised linear mixed model adjusted for cumulative proportion of time on higher-efficacy disease-modifying therapies (DMTs) was used to analyse the data., Results: 672 patients (70% female) contributing 9357 visits were included. The median age at symptom onset was 16 (quartiles 15-17) years. Older age at symptom onset (exp(β)=1.10 (95% CI 1.04 to 1.17)), higher EDSS score (1.22 (1.12 to 1.34)) and pyramidal (1.31 (1.11 to 1.55)), visual (1.25 (1.10 to 1.44)) or cerebellar (1.18 (1.01 to 1.38)) symptoms in the first year were associated with higher MSSS. MSSS was reduced by 4% for every 24% increase in the proportion of time on higher-efficacy DMTs (0.96 (0.93 to 0.99))., Conclusions: A relatively later onset of MS in childhood, higher disability and pyramidal, visual or cerebellar symptoms during the first year predicted significant worsening in disability in patients with paediatric-onset MS. Persistent treatment with higher-efficacy DMTs was associated with a reduced rate of disability worsening., Competing Interests: Competing interests: SS has nothing to disclose. CM has nothing to disclose. IR served on scientific advisory boards, received conference travel support and/or speaker honoraria from Roche, Novartis, Merck and Biogen. ID has nothing to disclose. RA received honoraria as a speaker and for serving on scientific advisory boards from Bayer, Biogen, GSK, Merck, Novartis, Roche and Sanofi-Genzyme. SO has nothing to disclose. GI received speaking honoraria from Biogen, Novartis, Sanofi, Merck, Roche, Almirall and Teva. SE received speaker honoraria and consultant fees from Biogen Idec, Novartis, Merck, Bayer, Sanofi Genzyme, Roche and Teva. DH received speaker honoraria and consulting fees from Biogen, Merck, Teva, Roche, Sanofi Genzyme and Novartis, as well as support for research activities from Biogen and Czech Ministry of Education (project Progres Q27/LF1). EKH received honoraria/research support from Biogen, Merck Serono, Novartis, Roche and Teva; has been a member of advisory boards for Actelion, Biogen, Celgene, MS, Novartis and SG; and has been supported by the Czech Ministry of Education research project PROGRES Q27/LF1. FP received speaker honoraria and advisory board fees from Almirall, Bayer, Biogen, Celgene, Merck, Novartis, Roche, Sanofi-Genzyme and TEVA. He received research funding from Biogen, Merck, FISM (Fondazione Italiana Sclerosi Multipla), Reload Onlus Association and University of Catania. MT received travel grants from Novartis, Bayer-Schering, Merck and Teva; and has participated in clinical trials by Sanofi Aventis, Roche and Novartis. CB received conference travel support from Biogen, Novartis, Bayer-Schering, Merck and Teva; and has participated in clinical trials by SA, Roche and Novartis. BY has nothing to disclose. SJK received personal compensation for participation in the Roche MaeStro Exchange Program and in Merck-Serono medical advisory board. MO has nothing to disclose. AL has received personal compensation for consulting, serving on a scientific advisory board, speaking or other activities from Biogen, Bristol Myers Squibb, Merck Serono, Mylan, Novartis, Roche, Sanofi/Genzyme and Teva. Her institutions have received research grants from Novartis (last 4 years). AA received personal fees and speaker honoraria from Teva, Merck, Biogen - Gen Pharma, Roche, Novartis, Bayer and Sanofi-Genzyme; and received travel and registration grants from Merck, Biogen - Gen Pharma, Roche, Sanofi-Genzyme and Bayer. AP has nothing to disclose. MG received consulting fees from Teva Canada Innovation, Biogen, Novartis and Genzyme Sanofi; and lecture payments from Teva Canada Innovation, Novartis and EMD. He has also received a research grant from Canadian Institutes of Health Research. PD served on editorial boards and has been supported to attend meetings by EMD, Biogen, Novartis, Genzyme and TEVA Neuroscience. He holds grants from the CIHR and the MS Society of Canada and has received funding for investigator-initiated trials from Biogen, Novartis and Genzyme. MJS has nothing to disclose. DS received honoraria as a consultant on scientific advisory boards by Bayer-Schering, Novartis and Sanofi-Aventis and compensation for travel from Novartis, Biogen, Sanofi Aventis, Teva and Merck. YS has nothing to disclose. RG has nothing to disclose. AS has nothing to disclose. RT has nothing to disclose. MPA received honoraria as a consultant on scientific advisory boards by Biogen, Bayer-Schering, Merck, Teva and Sanofi-Aventis; and has received research grants by Biogen, Bayer-Schering, Merck, Teva and Novartis. YF has nothing to disclose. TK served on scientific advisory boards for BMS, Roche, Sanofi Genzyme, Novartis, Merck and Biogen, steering committee for Brain Atrophy Initiative by Sanofi Genzyme; received conference travel support and/or speaker honoraria from WebMD Global, Novartis, Biogen, Sanofi-Genzyme, Teva, BioCSL and Merck; and received research or educational event support from Biogen, Novartis, Genzyme, Roche, Celgene and Merck., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Replication of the nuclear genome is an essential step for cell division. Pathogenic variants in genes coding for highly conserved components of the DNA replication machinery cause Meier-Gorlin syndrome (MGORS)., Objective: Identification of novel genes associated with MGORS., Methods: Exome sequencing was performed to investigate the genotype of an individual presenting with prenatal and postnatal growth restriction, a craniofacial gestalt of MGORS and coronal craniosynostosis. The analysis of the candidate variants employed bioinformatic tools, in silico structural protein analysis and modelling in budding yeast., Results: A novel homozygous missense variant NM&#95;016095.2:c.341G>T, p.(Arg114Leu), in GINS2 was identified. Both non-consanguineous healthy parents carried this variant. Bioinformatic analysis supports its classification as pathogenic. Functional analyses using yeast showed that this variant increases sensitivity to nicotinamide, a compound that interferes with DNA replication processes. The phylogenetically highly conserved residue p.Arg114 localises at the docking site of CDC45 and MCM5 at GINS2. Moreover, the missense change possibly disrupts the effective interaction between the GINS complex and CDC45, which is necessary for the CMG helicase complex (Cdc45/MCM2-7/GINS) to accurately operate. Interestingly, our patient's phenotype is strikingly similar to the phenotype of patients with CDC45 -related MGORS, particularly those with craniosynostosis, mild short stature and patellar hypoplasia., Conclusion: GINS2 is a new disease-associated gene, expanding the genetic aetiology of MGORS., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Introduction: Several neuroimmunological disorders have distinct phenotypes according to the age of onset, as in multiple sclerosis or myasthenia gravis. It is also described that late onset NMOSD (LONMOSD) has a different phenotype., Objective: To describe the clinical/demographic characteristics of the LONMOSD and distinguish them from those with early onset (EONMOSD)., Methods: From a nationwide Portuguese NMOSD study we analyzed the clinical/demographic characteristics of the LONMOSD., Results: From the 180 Portuguese patients 45 had disease onset after 50 years old, 80% were female. 23 had anti-AQP4 antibodies (51.1%), 13 anti-MOG antibodies (28.9%) and 9 were double seronegative (20.0%). The most common presenting phenotypes in LONMOSD were transverse myelitis (53.3%) and optic neuritis (26.7%), without difference from EONMOSD (p = 0.074). The mean EDSS for LONMOSD was 6.0 (SD=2.8), after a mean follow-up time of 4.58 (SD=4.47) years, which was significantly greater than the mean EDSS of EONMOSD (3.25, SD=1.80)(p = 0.022). Anti-AQP4 antibodies positive LONMOSD patients had increased disability compared to anti-MOG antibodies positive LONMOSD (p = 0.022). The survival analysis showed a reduced time to use a cane for LONMOSD, irrespective of serostatus (p<0.001)., Conclusions: LONMOSD has increased disability and faster progression, despite no differences in the presenting clinical phenotype were seen in our cohort., (Copyright © 2022. Published by Elsevier B.V.)

Introduction: Cognitive impairment and retinal atrophy have been proposed as two potential markers of neurodegeneration in multiple sclerosis (MS). We aimed at assessing the relation between peripapillary retinal nerve fiber layer (pRNFL) and macular ganglion cell layer (mGCL) atrophy and cognitive performance in early MS., Methods: This is a multicenter cross-sectional study on patients with early MS (clinically isolated syndrome and relapsing-remitting MS), with an EDSS score ≤ 3.0. Patients with previous optic neuritis, other ocular diseases, psychiatric illness, or recent relapse were excluded. All patients underwent standardized optical coherence tomography (OCT) and neuropsychological evaluation with validated tests for MS patients. Cognitive impairment was defined as having two cognitive tasks below age- and education-adjusted norms., Results: We recruited 52 patients with early MS, with an average age of 37 years (SD = 10.5), an average disease duration of 3.69 years (SD = 2.3), and a median EDSS of 1.0 (IQR = 0.5). In this sample, 15/52 patients presented cognitive impairment. Regarding OCT measurements, 7/52 patients had an average pRNFL below the 5th percentile and 2/52 had an average mGCL below the 5th percentile. The average pRNFL thickness was comparable in cognitively impaired and cognitively preserved patients (100.3 μm vs 103.1 μm, p = 0.52); the average mGCL thickness had also similar values between groups (50.5 μm vs 53 μm, p = 0.38)., Conclusions: Cognitive impairment was frequent in our sample of early MS. However, no association with reduced pRNFL or mGCL thickness was found. When compared to OCT, cognitive assessment could provide an earlier marker of neurodegeneration in MS., (© 2022. Fondazione Società Italiana di Neurologia.)

Introduction: Neuromyelitis optica spectrum disorders (NMOSD) are more prevalent in adulthood, with few cases reported in pediatric age (<18 years). In this group, anti-aquaporin 4 (AQP4) antibodies are less frequent, while antibodies against myelin oligodendrocyte glycoprotein (MOG) are more commonly detectable than in adults., Objective and Methods: Description of pediatric NMOSD cases identified in a national multicentric NMOSD Portuguese registry., Results: Twenty (11.1%) NMOSD cases were diagnosed in pediatric age. Twelve (60%) were female, with a median age of onset of 12.5 (6.8-16.5) years. The presenting feature was transverse myelitis in 10 (50%), 4 of which with simultaneous optic neuritis and 2 with concomitant brainstem syndrome. Nine patients (45%) had pleocytosis in the CSF. Six (30.0%) exhibited anti-AQP4 antibodies, 13 (65.0%) anti-MOG antibodies, and one was seronegative for both. Four anti-AQP4 antibodies-positive patients had ≥1 relapse. Most anti-MOG-positive cases were monophasic (53.8%). In the acute phase, all patients received IV methylprednisolone, nine received IVIg and four plasma exchange. One anti-AQP4-positive patient died. Ten patients (5 anti-AQP4-positive/5 anti-MOG-positive) were on maintenance immunosuppressive therapy at the time of data collection., Conclusion: NMOSD may present in pediatric age. It is essential to establish the diagnosis and promptly start therapy to improve the prognosis., (Copyright © 2022 Elsevier B.V. All rights reserved.)

We describe an infant female with a syndromic neurodevelopmental clinical phenotype and increased chromosome instability as cellular phenotype. Genotype characterization revealed heterozygous variants in genes directly or indirectly linked to DNA repair: a de novo X-linked HDAC8 pathogenic variant, a paternally inherited FANCG pathogenic variant and a maternally inherited BRCA2 variant of uncertain significance. The full spectrum of the phenotype cannot be explained by any of the heterozygous variants on their own; thus, a synergic contribution is proposed. Complementation studies showed that the FANCG gene from the Fanconi Anaemia/BRCA (FA/BRCA) DNA repair pathway was impaired, indicating that the variant in FANCG contributes to the cellular phenotype. The patient's chromosome instability represents the first report where heterozygous variant(s) in the FA/BRCA pathway are implicated in the cellular phenotype. We propose that a multigenic contribution of heterozygous variants in HDAC8 and the FA/BRCA pathway might have a role in the phenotype of this neurodevelopmental disorder. The importance of these findings may have repercussion in the clinical management of other cases with a similar synergic contribution of heterozygous variants, allowing the establishment of new genotype-phenotype correlations and motivating the biochemical study of the underlying mechanisms.

Intellectual disability (ID) can be caused by non-genetic and genetic factors, the latter being responsible for more than 1700 ID-related disorders. The broad ID phenotypic and genetic heterogeneity, as well as the difficulty in the establishment of the inheritance pattern, often result in a delay in the diagnosis. It has become apparent that massive parallel sequencing can overcome these difficulties. In this review we address: (i) ID genetic aetiology, (ii) clinical/medical settings testing, (iii) massive parallel sequencing, (iv) variant filtering and prioritization, (v) variant classification guidelines and functional studies, and (vi) ID diagnostic yield. Furthermore, the need for a constant update of the methodologies and functional tests, is essential. Thus, international collaborations, to gather expertise, data and resources through multidisciplinary contributions, are fundamental to keep track of the fast progress in ID gene discovery., (© 2021. The Author(s).)

Introduction: Neuromyelitis optica spectrum disorder (NMOSD) is a rare disorder in which astrocyte damage and/or demyelination often cause severe neurological deficits., Objective: To identify Portuguese patients with NMOSD and assess their epidemiological/clinical characteristics., Methods: This was a nationwide multicenter study. Twenty-four Portuguese adult and 3 neuropediatric centers following NMOSD patients were included., Results: A total of 180 patients met the 2015 Wingerchuk NMOSD criteria, 77 were AQP4-antibody positive (Abs+), 67 MOG-Abs+, and 36 seronegative. Point prevalence on December 31, 2018 was 1.71/100,000 for NMOSD, 0.71/100,000 for AQP4-Abs+, 0.65/100,000 for MOG-Abs+, and 0.35/100,000 for seronegative NMOSD. A total of 44 new NMOSD cases were identified during the two-year study period (11 AQP4-Abs+, 27 MOG-Abs+, and 6 seronegative). The annual incidence rate in that period was 0.21/100,000 person-years for NMOSD, 0.05/100,000 for AQP4-Abs+, 0.13/100,000 for MOG-Abs+, and 0.03/100,000 for seronegative NMOSD. AQP4-Abs+ predominated in females and was associated with autoimmune disorders. Frequently presented with myelitis. Area postrema syndrome was exclusive of this subtype, and associated with higher morbidity/mortality than other forms of NMOSD. MOG-Ab+ more often presented with optic neuritis, required less immunosuppression, and had better outcome., Conclusion: Epidemiological/clinical NMOSD profiles in the Portuguese population are similar to other European countries., (Copyright © 2021. Published by Elsevier B.V.)

Background: Therapeutic inertia (TI) is defined as a failure to initiate or intensify treatments despite evidence of disease activity. Its prevalence and determining factors in Relapsing-Remitting Multiple Sclerosis (RRMS) patients in Portugal are not known. The main objective of this work was to ascertain the prevalence of TI in RRMS and its determining factors., Methods: We conducted a multicentre retrospective observational study of RRMS patients followed in MS Clinics of six Portuguese hospitals with at least one medical appointment in 2018. TI was defined as the absence of treatment initiation or intensification when therapeutic goals were unmet, that is when there was evidence of disease activity based on the definition of "no evidence of disease activity" (NEDA) which refers to absence of clinical relapses, absence of disease progression measured by expanded disability status scale (EDSS) and absence of new disease activity (new T2 lesions/enhancing lesion) on magnetic resonance imaging (MRI) over the period of observation., Results: We included 427 patients with RRMS meeting inclusion criteria, 69.6% females, with a mean age of 41.66 years old. The mean age at diagnosis was 33.17 years old and the average number of years since diagnosis was 8.72. MS relapses were reported on 54 patients. Moderate to severe relapses were reported in 59.3%. Median EDSS score was 1.5. Intention to get pregnant was explicit in 39 patients, representing 18.8% of the women at childbearing age. Among the 365 patients who had an MRI, 23.8% had new T2 lesions and 7.4% had enhancing lesions. Regarding DMT, 72.8% were treated with interferon, glatiramer acetate, teriflunomide, or dimethyl fumarate, 20.6% were under fingolimod, natalizumab, rituximab, and cladribine, and the remaining 6.6% were without treatment. Adverse events were reported in 12.9% of patients, and 10.1% mentioned preferences regarding the treatment. TI was present in 80 (18.7%) patients, representing 54.8% of those with potential to inertia. Patients with a radiologically less active disease, who were already on a DMT and who had no adverse events from their current treatment were more likely to have TI (p<0,05). Also, patients followed in centers classified as higher level of care (level 1) had more TI compared with patients followed in centers of levels 2 and 3., Conclusion: TI was present in 1 in 5 patients, exceeding half of the sample with the potential to inertia, corroborating the high prevalence of TI in other studies. The determining factors of TI were the absence of relapses or the occurrence of mild relapses, being already on DMT, absence of adverse events, and follow-up in higher care level centers. TI is a topic rarely addressed in MS and this work highlights the importance of therapeutic optimization in these patients. Further studies should be held to explore the factors that influence TI once they have a great impact on therapeutic decisions., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system. Prodromal symptoms and higher healthcare use have been suggested in patients who later develop MS., Objectives: Assess the healthcare utilization pattern of relapsing-remitting MS (RRMS) patients in the five years prior to MS diagnosis., Methods: Retrospective, multicentric study. Demographic and clinical data, drug prescriptions and diagnostic tests were collected from electronic health records five-years previous to MS diagnosis and compared with national data., Results: Included 168 patients, 112 (66.7%) female, median age 34±11 years. The mean number of healthcare use per patient per year was 3.14±2,69, most of them in primary healthcare (47%). Most frequent symptoms were musculoskeletal (22%), gastrointestinal (17%), sensitive (14%) and sensory organs (14%). Median number of diagnostic tests per patient was 6 (IQR 7), and drug prescriptions per patient was 6 (IQR 9). Most frequently prescribed drugs were analgesic/anti-inflammatories, antibiotics and anxiolytics and there was a high request rate of MRIs., Conclusion: RRMS patients had a high frequency of healthcare utilization when compared to national data. This supports the current evidence showing a prodromal phase in MS., (Copyright © 2021. Published by Elsevier B.V.)

Background: A delayed onset of treatment effect, termed therapeutic lag, may influence the assessment of treatment response in some patient subgroups., Objectives: The objective of this study is to explore the associations of patient and disease characteristics with therapeutic lag on relapses and disability accumulation., Methods: Data from MSBase, a multinational multiple sclerosis (MS) registry, and OFSEP, the French MS registry, were used. Patients diagnosed with MS, minimum 1 year of exposure to MS treatment and 3 years of pre-treatment follow-up, were included in the analysis. Studied outcomes were incidence of relapses and disability accumulation. Therapeutic lag was calculated using an objective, validated method in subgroups stratified by patient and disease characteristics. Therapeutic lag under specific circumstances was then estimated in subgroups defined by combinations of clinical and demographic determinants., Results: High baseline disability scores, annualised relapse rate (ARR) ⩾ 1 and male sex were associated with longer therapeutic lag on disability progression in sufficiently populated groups: females with expanded disability status scale (EDSS) < 6 and ARR < 1 had mean lag of 26.6 weeks (95% CI = 18.2-34.9), males with EDSS < 6 and ARR < 1 31.0 weeks (95% CI = 25.3-36.8), females with EDSS < 6 and ARR ⩾ 1 44.8 weeks (95% CI = 24.5-65.1), and females with EDSS ⩾ 6 and ARR < 1 54.3 weeks (95% CI = 47.2-61.5)., Conclusions: Pre-treatment EDSS and ARR are the most important determinants of therapeutic lag.

Background: Multiple sclerosis treatment has changed in the last years with the emergence of new disease-modifying therapies (DMTs). Despite a better efficacy profile, these drugs raise concerns about infectious risk, which needs to be mitigated., Objective: To analyze the results of a systematic collaborative approach between Neurology and Infectious Diseases (ID) Departments in the management of infectious risk and complications in MS patients treated with DMT., Methods: Retrospective collection of MS patients' demographic and clinical data from clinical records of MS and ID outpatient clinics (2011-2017)., Results: We included 149 patients: most had evidence of previous contact with Herpesviridae, and half of them were not immune to hepatitis A and B viruses (HAV and HBV). Vaccines for HAV, HBV, and Streptococcus pneumoniae were administered in 91%, 78%, and 88% of non-immune patients, respectively. JC virus serology monitoring prevented natalizumab (NTZ) initiation or prompted its switch in 34/122 patients. Forty patients had latent tuberculosis, in which 88% were treated. Infectious events occurred in 33 patients, mostly mild urinary, respiratory, and herpes virus group infections. Only three patients required inpatient care., Conclusion: Facing the expansion of the new DMT, we highlight the benefits of an interdisciplinary approach for safer use of the chosen treatment., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)

Background: Several disease-modifying therapies (DMTs) have emerged in the last two decades for the treatment of multiple sclerosis (MS). The increasing use of these therapies has enhanced the need to study its impact on long-term disease progression and on the natural history of MS. This study aimed to characterize a Portuguese MS patient cohort in what concerns the natural history of disease by exploring differences throughout 3 decades., Methods: Longitudinal, retrospective, non-interventional study. Patients aged ≥ 18 years old, with confirmed diagnosis of relapsing-remitting MS (RRMS), were included. Biodemographic and clinical characteristics (MS diagnosis, patient follow-up, relapses, treatment, and exams) were assessed and compared according to the first appointment date throughout 10-year spans (1987-1996; 1997-2006; 2007-2016)., Results: 548 patients were included in this analysis. Significant differences were observed between decades for evoked potential (EP) and cerebrospinal fluid (CSF) exams conducted at diagnosis, the first with less expression on the last decade; the median number of relapses per year (higher in the subgroup 07-16); EDSS at baseline and at last appointment (both higher in the subgroup 87-96); and the percentage of patients achieving EDSS 3.0 and EDSS 6.0 (increased in the subgroup 87-96). Additionally, time from diagnosis to first treatment was significantly lower in patients from the most recent decade, and a greater percentage of such patients, compared to the other two subgroups, was, at last appointment, under a second line DMT., Conclusion: In general, our study reflects findings from longitudinal studies on MS progression already published in the literature. In recent years, the growing number of more effective DMTs, along with earlier disease detection, and improvements in access to healthcare appear to have had a positive impact on patients' access to treatment and, consequently, disease progression. Additional studies, with increased follow up time, are needed to further investigate the effect of treatment improvement in the natural history of MS., (Copyright © 2021. Published by Elsevier B.V.)

Understanding the risks of COVID-19 in patients with Multiple Sclerosis (MS) receiving disease-modifying therapies (DMTs) and their immune reactions is vital to analyze vaccine response dynamics. A systematic review on COVID-19 course and outcomes in patients receiving different DMTs was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Emerging data on SARS-CoV-2 vaccines was used to elaborate recommendations. Data from 4417 patients suggest that MS per se do not portend a higher risk of severe COVID-19. As for the general population, advanced age, comorbidities, and higher disability significantly impact COVID-19 outcomes. Most DMTs have a negligible influence on COVID-19 incidence and outcome, while for those causing severe lymphopenia and hypogammaglobulinemia, such as anti-CD20 therapies, there might be a tendency of increased hospitalization, worse outcomes and a higher risk of re-infection. Blunted immune responses have been reported for many DMTs, with vaccination implications. Clinical evidence does not support an increased risk of MS relapse or vaccination failure, but vaccination timing needs to be individually tailored. For cladribine and alemtuzumab, it is recommended to wait 3-6 months after the last cycle until vaccination. For the general anti-CD20 therapies, vaccination must be deferred toward the end of the cycle and the next dose administered at least 4-6 weeks after completing vaccination. Serological status after vaccination is highly encouraged. Growing clinical evidence and continuous surveillance are extremely important to continue guiding future treatment strategies and vaccination protocols.

Objective: To investigate pregnancy-related disease activity in a contemporary multiple sclerosis (MS) cohort., Methods: Using data from the MSBase Registry, we included pregnancies conceived after 31 Dec 2010 from women with relapsing-remitting MS or clinically isolated syndrome. Predictors of intrapartum relapse, and postpartum relapse and disability progression were determined by clustered logistic regression or Cox regression analyses., Results: We included 1998 pregnancies from 1619 women with MS. Preconception annualized relapse rate (ARR) was 0.29 (95% CI 0.27-0.32), fell to 0.19 (0.14-0.24) in third trimester, and increased to 0.59 (0.51-0.67) in early postpartum. Among women who used fingolimod or natalizumab, ARR before pregnancy was 0.37 (0.28-0.49) and 0.29 (0.22-0.37), respectively, and increased during pregnancy. Intrapartum ARR decreased with preconception dimethyl fumarate use. ARR spiked after delivery across all DMT groups. Natalizumab continuation into pregnancy reduced the odds of relapse during pregnancy (OR 0.76 per month [0.60-0.95], p=0.017). DMT re-initiation with natalizumab protected against postpartum relapse (HR 0.11 [0.04-0.32], p<0.0001). Breastfeeding women were less likely to relapse (HR 0.61 [0.41-0.91], p=0.016). 5.6% of pregnancies were followed by confirmed disability progression, predicted by higher relapse activity in pregnancy and postpartum., Conclusion: Intrapartum and postpartum relapse probabilities increased among women with MS after natalizumab or fingolimod cessation. In women considered to be at high relapse risk, use of natalizumab before pregnancy and continued up to 34 weeks gestation, with early re-initiation after delivery is an effective option to minimize relapse risks. Strategies of DMT use have to be balanced against potential fetal/neonatal complications., (© 2021 American Academy of Neurology.)

Background: A significant proportion of pediatric-onset multiple sclerosis (POMS) patients do not respond to first-line disease-modifying therapies. Clinical trials showed that natalizumab is effective and safe in adults, but there are limited clinical trial data for children. Natalizumab is currently prescribed off-label for POMS. We aimed to characterize the effectiveness, safety and tolerability of natalizumab in all POMS cases treated in Portugal (from 2007 to 2018)., Methods: Data from clinical records were retrospectively collected for all POMS cases treated with natalizumab in Portugal., Results: Twenty-one patients were included, 14 (67%) of which were female. The median age at POMS diagnosis was 13 years old. The median duration of treatment with natalizumab was 2 years and 3 months. Median Expanded Disability Status Scale score decreased from 1.5 to 1.0 after 24 months. The Annualized Relapse Rate decreased from 1.31 events/patient/year before treatment with natalizumab to 0 after 12 months of treatment and to 0.04 after 24 months. No gadolinium-enhancing lesions or new or enlarged T2 hyperintense lesions were observed in 8/8 patients (100%) after 12 months, and 4/5 (80%) after 24 months. There was one possible serious adverse event, which did not require dose adjustment. Five patients discontinued treatment due to positive anti-JCV (JC virus) antibody JC serostatus., Conclusion: Natalizumab may be an effective and safe disease-modifying therapy for POMS. Our results are in line with data published for the adult population, as well as with similar observational studies in pediatric populations in other regions., Competing Interests: Declaration of Competing Interest Filipe Palavra: Participates as investigator in clinical trials and observational studies sponsored by Biogen, Novartis, Merck, Roche, Sanofi-Genzyme and Teva. Received clinical research funding from Biogen and Merck. Received personal compensation for participating on advisory boards from Novartis, Biogen, Teva, Sanofi-Genzyme, Merck, Bayer and Roche and for participating as a speaker at meetings and teaching courses sponsored by Biogen, Novartis, Merck, Teva and Sanofi-Genzyme. Sónia Figueiroa: Participates as investigator in clinical trials and observational studies sponsored by Biogen. Received clinical research funding from Biogen. Received personal compensation for participating on advisory boards from Merck. Ana Sofia Correia: Participates as investigator in clinical trials and observational studies sponsored by Biogen, Novartis and Sanofi-Genzyme. Received an educational sponsorship from Merck Serono. Received personal compensation for participating on advisory boards from Novartis, Biogen, Sanofi-Genzyme, Merck and Roche and for participating as a speaker at meetings and teaching courses sponsored by Biogen, Novartis and Merck. Fernando Tapadinhas: Has no conflicts of interest to disclose. João Cerqueira: Participates as investigator in clinical trials and observational studies sponsored by Biogen, Novartis, Merck, Roche, Celgene and J&J. Received research funding from Biogen. Received personal compensation for participating on advisory boards from Novartis, Biogen, Teva, Sanofi-Genzyme, Merck, Bayer and Roche and for participating as a speaker at meetings and teaching courses sponsored by Roche, Biogen, Novartis, Merck, Teva and Sanofi-Genzyme. Rui Pedro Guerreiro: Participates as investigator in clinical trials and observational studies sponsored by Biogen, Novartis, Merck and Sanofi-Genzyme. Received personal compensation for participating on advisory boards from Novartis, Biogen, Sanofi-Genzyme, Merck and Bayer and for participating as a speaker at meetings and teaching courses sponsored by Biogen, Novartis and Merck. João de Sá: Participates as a speaker at meetings and teaching courses sponsored by Biogen, Sanofi-Genzyme, Novartis, Merck and Roche. Maria José Sá: Participates as investigator in clinical trials and observational studies sponsored by Biogen, Novartis, Merck, Roche, Sanofi-Genzyme and Teva. Received personal compensation for participating on advisory boards from Bayer, Biogen, Novartis, Teva, Sanofi-Genzyme, Merck and Roche and for participating as a speaker at meetings and teaching courses. Sofia Almeida: Employee of and hold stock and/or stock options in Biogen. Patrícia Mota: Employee of and hold stock and/or stock options in Biogen. Lívia Sousa: Participates as investigator in clinical trials and observational studies sponsored by Biogen, Novartis, Merck, Roche, Sanofi-Genzyme and Teva. Received personal compensation for participating on advisory boards from Bayer, Biogen, Novartis, Teva, Sanofi-Genzyme, Merck and Roche and for participating as a speaker at meetings and teaching courses., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Introduction: Radiologically isolated syndrome (RIS) refers to the incidental discovery of white matter lesions suggestive of MS, on brain MRI, in asymptomatic patients. Recent studies suggest similar features of cognitive impairment between RIS and MS patients. Also, lower levels of health-related quality of life (QOL) and fatigue are reported in such patients., Aims: characterize and compare the cognitive profile of a multicentric Portuguese cohort of RIS patients with a control group., Methods: multicentric comparative study of a cohort of adult patients with RIS, and age and gender-matched controls followed in the headache outpatient clinic with prior MRI not fulfilling criteria for RIS diagnosis. We conducted interviews with participants, collected clinical data and applied the BICAMS battery and self-reported questionnaires (HADS, MFIS, MSQOL-54)., Results: we evaluated 31 patients with RIS (median age 46 years, IQR [(Dusankova et al., 2012-52], 72% women) and 19 control individuals (median age 32 years, IQR [(O'Jile et al., 2005-48], 71% women). Prevalence of cognitive impairment did not differ between groups (16% of the RIS and 10% of the controls, p=0.579). We found no differences between groups on the BICAMS tests, although the results of the California Verbal Learning Test (CVLT-II) score presented a trend to significance, with a lower value on the RIS group (53.9 vs. 59.3, p=0.066). There were no significant differences regarding fatigue, QOL, anxiety/depression scores., Conclusion: this is the first study on a Portuguese cohort of RIS patients assessing cognitive profile with BICAMS. A non-neglectable part of our cohort presented cognitive impairment. Our findings add to previous studies in suggesting that a more pronounced impairment of verbal memory and learning, evaluated by CVLT-II, may be present in RIS patients compared to controls. BICAMS should be assessed on future studies with larger cohorts., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: The Brief Repeatable Battery of Neuropsychological Tests (BRBN-T) is one of the most sensitive and used measures for detecting cognitive impairment in Multiple Sclerosis (MS)., Objective: The aim of this study was to adapt and validate this battery to the Portuguese population of MS patients., Methods: The Portuguese version of the BRBN-T was applied to a stratified control national sample of 326 individuals considering sex, age, educational level and geographic location and also a clinical sample of 115 MS patients from several national hospitals. Through the exploration of its psychometrics properties, the Portuguese BRBN-T norms were produced., Results: The normative data is presented as a regression-based formula to adjust test scores for gender, education and age, and the results reveal the BRBN-T has the ability to differentiate between MS patients and healthy participant's cognitive performance., Conclusion: This study demonstrated in our clinical population a good ability to detect cognitive impairment. Its clearly contributed to reinforcing the neuropsychological assessment in Portugal in patients with MS, by providing a new set of instruments, which can be used in the clinical practice, and in future studies. Moreover, it will allow a rigorous and precise support in relation to neuropsychological assessment for future longitudinal studies and clinical trials.

Since the introduction of next-generation sequencing, an increasing number of disorders have been discovered to have genetic etiology. To address diverse clinical questions and coordinate research activities that arise with the identification of these rare disorders, we developed the Human Disease Genes website series (HDG website series): an international digital library that records detailed information on the clinical phenotype of novel genetic variants in the human genome (https://humandiseasegenes.info/). Each gene website is moderated by a dedicated team of clinicians and researchers, focused on specific genes, and provides up-to-date-including unpublished-clinical information. The HDG website series is expanding rapidly with 424 genes currently adopted by 325 moderators from across the globe. On average, a gene website has detailed phenotypic information of 14.4 patients. There are multiple examples of added value, one being the ARID1B gene website, which was recently utilized in research to collect clinical information of 81 new patients. Additionally, several gene websites have more data available than currently published in the literature. In conclusion, the HDG website series provides an easily accessible, open and up-to-date clinical data resource for patients with pathogenic variants of individual genes. This is a valuable resource not only for clinicians dealing with rare genetic disorders such as developmental delay and autism, but other professionals working in diagnostics and basic research. Since the HDG website series is a dynamic platform, its data also include the phenotype of yet unpublished patients curated by professionals providing higher quality clinical detail to improve management of these rare disorders., (© 2021 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Eukaryotic translation elongation factor 2 (eEF2) is a key regulatory factor in gene expression that catalyzes the elongation stage of translation. A functionally impaired eEF2, due to a heterozygous missense variant in the EEF2 gene, was previously reported in one family with spinocerebellar ataxia-26 (SCA26), an autosomal dominant adult-onset pure cerebellar ataxia. Clinical exome sequencing identified de novo EEF2 variants in three unrelated children presenting with a neurodevelopmental disorder (NDD). Individuals shared a mild phenotype comprising motor delay and relative macrocephaly associated with ventriculomegaly. Populational data and bioinformatic analysis underscored the pathogenicity of all de novo missense variants. The eEF2 yeast model strains demonstrated that patient-derived variants affect cellular growth, sensitivity to translation inhibitors and translational fidelity. Consequently, we propose that pathogenic variants in the EEF2 gene, so far exclusively associated with late-onset SCA26, can cause a broader spectrum of neurologic disorders, including childhood-onset NDDs and benign external hydrocephalus., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The 5th International Porto Congress of Multiple Sclerosis took place between the 14th and 16th of February 2019 in Porto, Portugal. Its intensive programme covered a wide-range of themes-including many of the hot topics, challenges, pitfalls and yet unmet needs in the field of multiple sclerosis (MS)-led by a number of well-acknowledged world experts. This meeting review summarizes the talks that took place during the congress, which focussed on issues in MS as diverse as the development and challenges of progressive MS, epidemiology, differential diagnosis, medical management, molecular research and imaging tools.

Background: Readmission rate is an important healthcare quality metric and remains a problem in Multiple Sclerosis (MS) patients, nonetheless information about this issue is scarce. We present the first study to estimate hospital readmissions in a MS hospital-based European cohort., Methods: Retrospective cohort study of patients with at least one hospitalization with a primary discharge of MS from August 1, 2009 and July 31, 2015. The primary outcome was hospitalization within 30 days post-discharge (30-DR). The secondary outcomes included length of stay during index and readmission, total hospital readmissions during the study period, predictors and causes of readmission., Results: Forty-four (41.5%) patients had a hospital readmission during the six years of this study, 11.3% of them 30-DR, mainly due to infections (58.5%). The two most common comorbidities in these patients were neurogenic bladder (47.7%) and ischemic heart disease (18.1%). Progressive MS subtype was the main predictor of 30-DR, even after adjustment for therapy (OR: 6.29; p = 0.016), with an area under the curve of 0.73., Conclusion: Progressive MS subtypes and "second-line drugs" carry a higher risk of hospital readmission soon after discharge. The impact and cost-effectiveness of strategies to lower readmission rates in MS should be the focus of upcoming studies., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

In multiple sclerosis, treatment start or switch is prompted by evidence of disease activity. Whilst immunomodulatory therapies reduce disease activity, the time required to attain maximal effect is unclear. In this study we aimed to develop a method that allows identification of the time to manifest fully and clinically the effect of multiple sclerosis treatments ('therapeutic lag') on clinical disease activity represented by relapses and progression-of-disability events. Data from two multiple sclerosis registries, MSBase (multinational) and OFSEP (French), were used. Patients diagnosed with multiple sclerosis, minimum 1-year exposure to treatment, minimum 3-year pretreatment follow-up and yearly review were included in the analysis. For analysis of disability progression, all events in the subsequent 5-year period were included. Density curves, representing incidence of relapses and 6-month confirmed progression events, were separately constructed for each sufficiently represented therapy. Monte Carlo simulations were performed to identify the first local minimum of the first derivative after treatment start; this point represented the point of stabilization of treatment effect, after the maximum treatment effect was observed. The method was developed in a discovery cohort (MSBase), and externally validated in a separate, non-overlapping cohort (OFSEP). A merged MSBase-OFSEP cohort was used for all subsequent analyses. Annualized relapse rates were compared in the time before treatment start and after the stabilization of treatment effect following commencement of each therapy. We identified 11 180 eligible treatment epochs for analysis of relapses and 4088 treatment epochs for disability progression. External validation was performed in four therapies, with no significant difference in the bootstrapped mean differences in therapeutic lag duration between registries. The duration of therapeutic lag for relapses was calculated for 10 therapies and ranged between 12 and 30 weeks. The duration of therapeutic lag for disability progression was calculated for seven therapies and ranged between 30 and 70 weeks. Significant differences in the pre- versus post-treatment annualized relapse rate were present for all therapies apart from intramuscular interferon beta-1a. In conclusion we have developed, and externally validated, a method to objectively quantify the duration of therapeutic lag on relapses and disability progression in different therapies in patients more than 3 years from multiple sclerosis onset. Objectively defined periods of expected therapeutic lag allows insights into the evaluation of treatment response in randomized clinical trials and may guide clinical decision-making in patients who experience early on-treatment disease activity. This method will subsequently be applied in studies that evaluate the effect of patient and disease characteristics on therapeutic lag., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Multiple sclerosis typically affects young women of reproductive age. Therefore, all healthcare professionals involved in the follow-up of multiple sclerosis patients must be prepared to discuss pregnancy and breastfeeding issues and provide the best possible counselling. However, there are still many doubts and heterogeneous clinical approaches partly due to the lack of consensus and guidelines. Concerning the handling of disease modifying therapies during pregnancy and postpartum, existing uncertainties have been complicated by the increase in the number of treatments available in recent years. This article aims to present the state-of-the-art and provide guidance based on the best level of available evidence and expert opinion regarding the management of multiple sclerosis patients at different stages: pregnancy planning, pregnancy, partum, and the postpartum period.

Background: The prevalence of Multiple Sclerosis (MS) has been increasing worldwide and the north-south gradient of prevalence may be disappearing in the Northern hemisphere. The few previous prevalence studies performed in Portugal have reported a lower prevalence than the average for Western Europe. The aim of this study is to estimate the prevalence of MS in the Entre Douro e Vouga region, in Northern Portugal., Methods: Multiple overlapping sources were used to ascertain all cases from the reference population: records from hospitals in the region and neighbouring regions; diagnostic databases of primary care physicians; and applications for disability benefits. The prevalence date was set at 1 January 2014. The reference population was 274,859 inhabitants. Patients' neurologists were contacted to retrieve clinical information and confirm the diagnosis based., Results: A total of 177 patients were identified after eliminating duplicates from different sources. The female to male ratio was 1.9 and the mean age at disease onset was 33.5 (standard deviation: 10.3). Clinically isolated syndrome accounted for 9.0% of patients, relapsing remitting for 58.8%, secondary progressive for 20.3% and primary progressive for 11.8%. The prevalence was estimated in 64.4 patients per 100,000 (95% confidence interval: 54.9;73.9)., Conclusions: In this study we report a higher point prevalence of MS than had been previously described in Portugal, but still far from the higher values recently reported in other Southern European countries.

Purpose: To delineate the genotype-phenotype correlation in individuals with likely pathogenic variants in the CLTC gene., Methods: We describe 13 individuals with de novo CLTC variants. Causality of variants was determined by using the tolerance landscape of CLTC and computer-assisted molecular modeling where applicable. Phenotypic abnormalities observed in the individuals identified with missense and in-frame variants were compared with those with nonsense or frameshift variants in CLTC., Results: All de novo variants were judged to be causal. Combining our data with that of 14 previously reported affected individuals (n = 27), all had intellectual disability (ID), ranging from mild to moderate/severe, with or without additional neurologic, behavioral, craniofacial, ophthalmologic, and gastrointestinal features. Microcephaly, hypoplasia of the corpus callosum, and epilepsy were more frequently observed in individuals with missense and in-frame variants than in those with nonsense and frameshift variants. However, this difference was not significant., Conclusions: The wide phenotypic variability associated with likely pathogenic CLTC variants seems to be associated with allelic heterogeneity. The detailed clinical characterization of a larger cohort of individuals with pathogenic CLTC variants is warranted to support the hypothesis that missense and in-frame variants exert a dominant-negative effect, whereas the nonsense and frameshift variants would result in haploinsufficiency.

Recurrent somatic variants in SPOP are cancer specific; endometrial and prostate cancers result from gain-of-function and dominant-negative effects toward BET proteins, respectively. By using clinical exome sequencing, we identified six de novo pathogenic missense variants in SPOP in seven individuals with developmental delay and/or intellectual disability, facial dysmorphisms, and congenital anomalies. Two individuals shared craniofacial dysmorphisms, including congenital microcephaly, that were strikingly different from those of the other five individuals, who had (relative) macrocephaly and hypertelorism. We measured the effect of SPOP variants on BET protein amounts in human Ishikawa endometrial cancer cells and patient-derived cell lines because we hypothesized that variants would lead to functional divergent effects on BET proteins. The de novo variants c.362G>A (p.Arg121Gln) and c. 430G>A (p.Asp144Asn), identified in the first two individuals, resulted in a gain of function, and conversely, the c.73A>G (p.Thr25Ala), c.248A>G (p.Tyr83Cys), c.395G>T (p.Gly132Val), and c.412C>T (p.Arg138Cys) variants resulted in a dominant-negative effect. Our findings suggest that these opposite functional effects caused by the variants in SPOP result in two distinct and clinically recognizable syndromic forms of intellectual disability with contrasting craniofacial dysmorphisms., (Copyright © 2020 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Objective: To confirm anti-JC virus (JCV) antibody seroprevalence in Portuguese patients with relapsing-remitting multiple sclerosis (RRMS) and to determine their anti-JCV antibody index., Methods: JUSTIFY was a retrospective, multicentre study that included 655 RRMS patients tested at least once with the anti-JCV antibody assay STRATIFY JCV DxSelect. Demographic data, multiple sclerosis history and results of the anti-JCV antibody test were collected, along with physicians' reasons for requesting the test and the impact of the results., Results: Overall anti-JCV antibody seroprevalence was 60.8% (95% confidence interval, 56.9-64.5). Seroprevalence was associated with higher age (P = .030) and was lower in natalizumab-treated patients (P < .001). The mean anti-JCV antibody index of immunosuppressant-naive patients was 1.5 ± 1.3 (n = 378). The main reasons for performing the test were clinical characterization (35.5%) and medication change (26.2%). In patients who switched treatments (n = 109), fingolimod (47.7%) and natalizumab (26.6%) were the most commonly chosen new treatments., Conclusions: The study confirmed the high anti-JCV antibody prevalence in Portuguese RRMS patients and its association with age. These data can be used to better understand the benefit-risk profile of natalizumab treatment in Portuguese patients and to support progressive multifocal leukoencephalopathy risk management strategies., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)