Natalizumab extended interval dosing: what about wearing-off effect?

BACKGROUND: Up to two thirds of patients with multiple sclerosis (MS) under natalizumab report a resurgence of symptoms at the end of the natalizumab cycle (wearing-off (WO) effect). At the outbreak of COVID-19, in line with the international recommendations for MS management, our centre switched all clinically stable patients on natalizumab therapy for more than one year from standard interval dosing (SID) to extended interval dosing (EID) with every six weeks infusions. This study aimed to evaluate the impact of EID in WO in MS patients under natalizumab. METHODS: An observational retrospective study in patients with MS under natalizumab on EID was conducted. A questionnaire regarding current (on EID) and past (on SID) experience of WO effect was applied. RESULTS: Seventy-six patients were included. No significant differences were found in the annual relapse rate after the switch to EID (p = 0.083). However, there was a significant increase in the proportion of patients complaining of WO from 38.2% to 56.6% (p = 0.001). Moreover, patients with WO on SID, referred a significant increase in severity (p = 0.019) and duration of WO symptoms (p = 0.029), due to an anticipation of the symptoms relative to the day of natalizumab infusion (p = 0.019), when switching to EID. Symptoms improved with treatment maintenance in 23.3% of patients; instead, a reduction in interval dosing was needed in 54.8% with symptom improvement. CONCLUSION: WO affects a significant proportion of MS patients under natalizumab. Its prevalence, severity, and duration increase on EID, therefore despite clinical effectiveness maintenance of this posology should be individualized.

Prevalence, Incidence, and Mortality of Multiple Sclerosis in Coimbra, Portugal.

Multiple sclerosis (MS) is the most common chronic inflammatory, demyelinating, and neurodegenerative disease of the central nervous system in young adults, representing the leading cause of nontraumatic disability in this population. The rising prevalence of MS worldwide makes it critical to recognize the absolute number of patients with MS, demanding the execution of a sustainable healthcare policy. In Portugal, only six studies evaluating MS rates were published, disclosing a prevalence of 64 cases per 100,000 persons and an incidence of 3.1 cases per 100,000 persons/year, but the mortality rates have not been reported. Thus, this observational, cross-sectional study aimed to assess MS prevalence, incidence, and mortality in the city of Coimbra, a region in the center of Portugal. Patients who fulfilled McDonald's Diagnosis Criteria (2017) for MS were recruited. Inclusion criteria were defined according to prevalence, incidence, and mortality studies. The baseline demographic and clinical characterization of the prevalence study population was performed. The MS prevalence rate in Coimbra was 143.45 cases per 100,000 inhabitants. Between 2018 and 2021, the cumulative incidence was 8.52 new cases per 100,000 persons/year. The mortality rate between 2018 and 2021 was 2.84 deaths per 100,000 inhabitants. MS prevalence and incidence in Coimbra are higher than reported in previous similar studies and comparable to Europe's mean prevalence and incidence.

It's Never Too Late for a Diagnosis.

BACKGROUND: Zellweger spectrum disorder (ZSD) (OMIM#214100) is a phenotypic continuum ranging from severe to mild presentations. ZSD is now used in all individuals with a defect in one of the 13 ZSD-PEX genes, regardless of phenotype. Diagnosis can be suggested by abnormal levels of very long-chain fatty acids, phytanic acid, pristanic acid, plasmalogens, pipecolic acid, or bile acids. However, false negatives are frequent, mostly in older patients. Definite diagnosis is established in a proband with suggestive clinical findings by identification of biallelic pathogenic variants in one of the 13 ZSD-PEX genes. CASE REPORT: A 39-year-old female patient had a global development delay since her first year of life. Never developed oral language but had sphincter control and was able to walk and laugh. At 8 years old, she had her first seizure and lost sphincter control when she was 20 years old. At 28 years old, she had an episode of status epilepticus, with severe prostration and became bedridden. She is currently mute, without capacity for communication or motor control. She has no consanguineous parents, has a 35 year old brother with global developmental delay and their mother had a history of an abortion, without other relevant family history. Brain MRI of the patient revealed severe leukodystrophy mainly periventricular, bilateral and symmetric, and less prominent in the cerebellar white matter, with severe cerebral and corpus callosum atrophy. Molecular study with a leukodystrophy gene panela identified a homozygotic pathogenic variant on PEX 1 gene (NM_000466.3) - c.2528G>A (p.(Gly843Asp)), confirming the diagnosis of ZSD. CONCLUSION: Homozygosity for PEX1 p.Gly843Asp seems to be associated with an intermediate/milder ZSD phenotype,with survival until adulthood. Some patients develop progressive degeneration of CNS myelin, a leukodystrophy pattern, like this patient, which may lead to regression. This girl with ZSD had a rapid and severe loss of previous skills after a seizure. Even though there is no specific treatment for this disease, a correct diagnosiswas very important for the parents and for family genetic counselling.

SERAC1 Deficiency- A New Phenotype.

Introduction - SERAC1 deficiency phenotype range from MEGD(H)EL syndrome, the most severe, to juvenile complicated spastic paraplegia, to adult-onset dystonic features (in only one patient). The MEGD(H)EL syndrome is characterized by (3-methylglutaconic aciduria with deafness-dystonia, [hepatopathy], encephalopathy, and Leigh-like syndrome). Biochemical abnormalities: elevated urinary 3 - metilglutaconic and 3-metilglutaric acids, high lactate and alanine in serum. Diagnosis is confirmed when biallelic pathogenic variants in SERAC1 gene are found. Brain MRI: basal ganglia lesions and generalized atrophy. Results/Case report - A 30-year-old patient with a moderate intellectual disability, developed, since the age of 25, a progressive loss of previous capacities (hand dexterity, oral language), and later subacute generalized dystonic features. Currently he has spastic tetraparesis, dystonia, scoliosis and autistic behavior, with bilateral basal ganglia lesions on brain MRI. Genetic study revealed biallelic pathogenic variants in SERAC1 gene, confirm MEGD(H)EL. A 73 years old patient with cognitive impairment and progressive spastic tetraparesis had multiple periventricular T2 hyperintense lesions. She has a homozygotic SERAC1 variant NM_032861: exon4:c.T139A: p.F471 (rs112780453), considered benign. Biochemical study revealed elevated plasmatic alanine and urinary3-metilglutaconic and 3-metilglutaric acid. This profile is concordant with mitochondrial dysfunction and SERAC1 Deficit. Conclusion - The first patient has the clinical symptoms associated to the MEGD(H)EL syndrome, and the biochemical and genetic confirmation of the diagnosis, without reservations. However, in the second patient, the progressive paraparesis and cognitive impairment did not appear to be caused by multiple sclerosis nor subcortical vascular leukoencephalopathy (without vascular risk factors). The abnormal biochemical profile is suggestive of SERAC1 Deficiency, even without genetic confirmation. In what should we believe?

Outcomes on Social and Classic Cognition in adults with Pediatric-onset Multiple Sclerosis.

BACKGROUND: Cognitive impairment affecting classic and social domains has been consistently reported in patients with Multiple Sclerosis (MS). However, little is known about the cognitive outcomes, particularly on social cognition, in adults with pediatric-onset multiple sclerosis (POMS). OBJECTIVES: To compare the performance in classic and social cognitive domains between adults with POMS and adult-onset MS (AOMS). METHODS: A group of 30 patients with POMS (age onset <18 years) was compared with age-matched (AOAMS, n=30) and disease duration-matched (AODMS, n= 30) patients who developed MS after the age of 18 years. Cognitive performance was assessed using the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) and Theory of Mind (ToM) tests. RESULTS: Cognitive impairment was more prevalent in POMS patients (40% vs. 16.7%, p=0.045), independently of age or disease duration, affecting more severely information-processing speed and visual memory domains. No statistically significant differences were found in ToM performance between patients with POMS and AOMS. When analyzing ToM performance according to age of disease onset (≤15 years; 15-20 years; ≥20 years), patients with disease onset ≤15 years old had significantly lower scores on ToM tests when compared to the other groups. CONCLUSION: Patients with POMS were more prone to develop impairment on classic cognitive domains than on ToM ability, when compared with AOMS patients. The interference of POMS with critical neurodevelopmental periods, specific for each cognitive domain, may explain different outcomes at adulthood on social and classic cognition.

Protective effects of cognitive and brain reserve in multiple sclerosis: Differential roles on social cognition and 'classic cognition'.

BACKGROUND: According to cognitive reserve (CR) and brain reserve (BR) theories, lifetime intellectual enrichment and maximal brain volume protect against cognitive decline. OBJECTIVE: To examine the effects of CR and BR on social cognition in multiple sclerosis (MS), and compare it with 'classic cognition'. METHODS: We included 60 MS patients and 60 healthy controls matched on age, sex, and education. Education was used has a proxy of CR and intracranial volume (ICV) as a proxy of BR. Participants underwent Theory of Mind (ToM) testing (Eyes Test, Videos Test), comprehensive neuropsychological assessment and 3Tesla brain MRI. Cortical and subcortical grey matter (GM) volumes were calculated. RESULTS: We found positive effects of education and ICV on general cognitive status and ToM performance, respectively. Higher education moderated the impact of subcortical GM atrophy on 'classic' cognitive status (R2=0.219, p=<0.001). Conversely, greater ICV attenuated the impact of cortical GM atrophy on Eyes Test (R2=0.158, p=0.002) and Videos Test (R2=0.198, p=0.001). Stratification for disease duration showed that the protective effect of education/ICV occurred in early stages of disease (<10 years). CONCLUSION: CR and BR have differential protective roles in MS, with BR having a positive effect on social cognition and CR on 'classic' cognitive domains.

Clinical effectiveness of reduced fingolimod dose in relapsing remitting multiple sclerosis-a Portuguese cohort.

BACKGROUND: Fingolimod is an oral daily treatment for relapsing remitting multiple sclerosis (RRMS). A decrease in lymphocytes count is a common side effect, whereby clinicians occasionally propose a reduced dose rather than its discontinuation. However, current data on the effectiveness of these regimens are scarce and contradictory. Our objective was to investigate if the fingolimod effectiveness is maintained with reduction in dosing frequency. METHODS: Retrospective and observational study of RRMS patients taking fingolimod-nondaily (FTY-ND) for at least 6 months. Propensity score-based matching was performed to select patients taking daily dose (FTY-ED) with comparable baseline characteristics: age, sex, disease duration, annualized relapse rate (ARR), and expanded disability status scale (EDSS). Afterwards, clinical and laboratorial assessment was evaluated in both groups. RESULTS: Thirty-six patients were included in each group (FTY-ED vs. FTY-ND). Decrease in lymphocytes count was the main reason for switching to FTY-ND (88.9%). Previous treatment with natalizumab was inversely associated with risk of reducing dose (OR 0.253, 95%CI = 0.08-0.807, p = 0.016). There were no significant differences in clinical disease activity between patients FTY-ED vs. FTY-ND: mean ARR 0.4 vs. 0.3 (p = 0.247), median EDSS 2.0 vs. 2.0 (p = 0.687), and proportion of patients with EDSS increase 8.3% vs. 13.9% (p = 0.453). FTY-ND was overall well tolerated and was associated with an increase in the mean lymphocytes count (362 ± 103 cells/mm3 to 541 ± 183 cells/mm3, p < 0.001). CONCLUSION: These data suggest that the effectiveness of FTY is maintained despite the reduction of the dose, minimizing the most common adverse events. These findings warrant further confirmation, ideally with randomized clinical trials.

The neural basis of fatigue in multiple sclerosis: A multimodal MRI approach.

BACKGROUND: Fatigue is a frequent disabling symptom in multiple sclerosis (MS), but its pathophysiology remains incompletely understood. This study aimed to explore the underlying neural basis of fatigue in patients with MS. METHODS: We enrolled 60 consecutive patients with MS and 60 healthy controls (HC) matched on age, sex, and education. Fatigue was assessed using the Portuguese version of the Modified Fatigue Impact Scale (MFIS). All participants underwent 3T brain MRI (conventional and diffusion tensor imaging [DTI] sequences). White matter (WM) focal lesions were identified and T1/T2 lesion volumes were computed. Tract-based spatial statistics were applied for voxel-wise analysis of DTI metrics fractional anisotropy and mean diffusivity (MD) on normal-appearing WM (NAWM). Using Freesurfer software, total and regional volumes of cortical and subcortical gray matter (GM) were calculated. RESULTS: Compared to HC, patients with MS scored significantly higher on MFIS (33.8 ± 19.7 vs 16.5 ± 15.1, p < 0.001). MFIS scores were not significantly correlated with T1/T2 lesion volumes, total GM volume, or any regional volume of cortical and subcortical GM. Significant correlations were found between global scores of MFIS and MD increase of the NAWM skeleton, including corona radiata, internal capsule, external capsule, corticospinal tract, cingulum, corpus callosum, fornix, superior longitudinal fasciculus, superior fronto-occipital fasciculus, sagittal stratum, posterior thalamic radiation, cerebral peduncle, and uncinate fasciculus. CONCLUSIONS: In this study, fatigue was associated with widespread NAWM damage but not with lesion load or GM atrophy. Functional disconnection, caused by diffuse microstructural WM damage, might be the main neural basis of fatigue in MS.

Theory of Mind and Executive Functions are Dissociated in Multiple Sclerosis.

OBJECTIVES: To investigate the relationship of executive functions (EF) and theory of mind (ToM) in multiple sclerosis (MS), clarifing whether ToM impairment in MS is related to EF dysfunction or whether they represent dissociable processes which can be independently impaired in MS. METHODS: We enrolled 60 consecutive MS patients and 60 healthy controls (HC) matched on age, gender, and education level. All participants underwent ToM testing using the Eyes Test and the Videos Test and neuropsychological testing tapping different EF subdomains. A correlation analysis and a hierarchical cluster analysis were used to determine the similarity between explained variance between EF measures and ToM tests. RESULTS: MS patients had lower scores on both tasks of ToM compared to HC, i.e., Eyes Test (21.1 ± 5.0 vs. 29.5 ± 3.8, p < .001; Cohen's d: 1.9) and Videos Test (19.6 ± 2.4 vs. 22.9 ± 1.8, p < .001; Cohen's d: 1.6). They also performed significantly worse on different measures of EF. ToM performance was not significantly correlated with EF tests. The hierarchical cluster analysis showed that ToM measures in MS were clustered separately from the EF measures, revealing three executive clusters (Attention/working memory cluster; Inhibitory control/shifting ability cluster; Verbal Initiative/Abstract reasoning cluster) and one ToM cluster. CONCLUSION: This study suggests a dissociation of EF and ToM in MS, meaning that the MS-related neurobehavioral symptoms may be associated with a significant impairment in ToM independent of the level of EF performance. Ultimately, this discrimination of ToM deficits in MS may help to identify the appropriate cognitive and behavioral interventions.

Plasma exchange in severe acute relapses of multiple sclerosis - Results from a Portuguese cohort.

BACKGROUND: Relapses in Multiple Sclerosis (MS) are often associated with significant disability impairment which is resultant from poor response to corticosteroids. In such severe cases, plasma exchange (PLEX) may be used, although only a few studies with MS patients have been reported. Our objective was to evaluate the effectiveness of PLEX in severe relapses of MS. METHODS: Retrospective study of MS patients treated with PLEX in acute relapses. Data regarding EDSS, annualized relapse rate (ARR), treatment with corticosteroids, number of PLEX sessions, adverse events, and gadolinium enhancement in brain MRI were analysed. RESULTS: Included 46 patients, 76.09% female (n = 35) with mean age of 38.76 years and mean disease duration of 5.99 years, of which 84.78% had a Relapsing Remitting MS (n = 39), 15.22% Secondary Progressive MS (n = 7). The previous ARR was 1.1 and in 28.26% of the cases (n = 13) PLEX was used in the relapse that led to MS diagnosis. The majority of relapses had motor impairment (69.6%, n = 32), with a median EDSS increase of 1.5 points from baseline (maximum of 6.5) and higher than 1.5 points in 45.65% of cases (n = 21). Brain MRI was available in 69.57% of the cases (n = 32), and gadolinium enhancing lesions were present in 68.75% of cases (n = 22). Corticosteroids were used before PLEX in all patients for a mean of 6.09 days, without any immediate benefit in 41.30% of cases (n = 19), with the remaining cases showing only mild disability recovery. After a mean of 7.39 PLEX sessions, there was clinical benefit with complete EDSS recovery in 41.30% of patients (n = 19), and partial in 39.13% (n = 18). There were no adverse events related to PLEX in 89.13% of patients (n = 41) and in the remaining patients the reported adverse events included deep venous thrombosis (n = 1), anaemia (n = 1), fever (n = 1), hypoalbuminemia (n = 1) and arterial hypotension (n = 1). CONCLUSION: Our results support the use of PLEX in severe relapses unresponsive to corticosteroids, since it was an effective and relatively safe treatment for most of our patients.

Pregnancy in Multiple Sclerosis: A Portuguese cohort study.

BACKGROUND: Pregnancy in Multiple Sclerosis (MS) has been a controversial issue, without international standardized treatment recommendations. The goal of our study was to evaluate the clinical course of MS during pregnancy and the respective therapeutic options, obstetrical outcomes and breastfeeding data. METHODS: This was a retrospective study including women with a diagnosis of relapsing-remitting MS at least one year before pregnancy. Three periods were evaluated: one year prior to pregnancy, pregnancy and one year postpartum. Information acquired included demographic and disease activity data, treatment options, and obstetrical and breastfeeding data. RESULTS: From a cohort of 1134 patients and 777 women, we included 127 pregnancies in 97 women (111 deliveries of a live infant, 11 spontaneous abortions, 3 fetal deaths and 2 voluntary abortions). The annualized relapse rate (ARR) decreased during pregnancy, mainly in the third trimester (prior to pregnancy 0.6 ± 0.8 vs. during pregnancy 0.3 ± 0.6, p = 0.006). There were no significant changes in the ARR in the year after delivery compared to baseline (0.6 ± 0.8 vs. 0.6 ± 0.8, p = 0.895). Patients with relapses in the postpartum period had a shorter disease duration at conception (5.4 ± 3.9 vs. 7.4 ± 4.7; p = 0.029) and breastfed less (53.5% vs. 72.1%, p = 0.046). In the multivariate analysis, relapses during pregnancy predicted postpartum relapses (OR = 4.9, p < 0.005). Neither the previous use of disease modifying therapy (DMT), given to 80.2% of women, nor breastfeeding, caesarean delivery (CD) or epidural analgesia (EA) had an impact on the presence of postpartum relapses. Compared to baseline, the Expanded Disability Status Scale (EDSS) increased in pregnancy and the postpartum period (1.6 ± 0.7 vs. 1.7 ± 0.9 vs. 2.1 ± 1.0, p < 0.001). CD was performed in 43.3% of patients, mainly because of fetal-pelvic incompatibility (35.7%) and EA was performed in 63.9%. The most frequent complications were restriction of fetal growth (4.5%) and gestational diabetes mellitus (3.6%). Concerning newborns, 6.4% had birth asphyxia and 6.1% low birth weight. No malformations were registered. CONCLUSION: Despite a reduction in the relapse rate during pregnancy, the presence of relapses during pregnancy predicted postpartum relapses, with impact on disability. DMT appeared to have no influence on clinical or obstetrical outcome. MS did not have a deleterious effect on the pregnancy course. CD and EA were safe procedures, with a tendency towards CD in MS patients, compared to Portuguese women in general. Breastfeeding did not influence MS activity.

Family Phenotypic Heterogeneity Caused by Mitochondrial DNA Mutation A3243G.

Maternally inherited diabetes and deafness is a rare form of diabetes caused by a mitochondrial DNA mutation. The index case is a 55-year-old woman who was admitted with hypertrophic cardiomyopathy. She had a history of diabetes mellitus and hearing loss. The patient's mother, two brothers and two sisters also had a history of diabetes and hearing loss. This pattern suggests a maternally inherited disorder. All siblings carried the A3243G mitochondrial DNA mutation. The identification of people with monogenic forms of diabetes mellitus is a diagnostic challenge. This condition should be considered whenever there is a history of diabetes associated with hearing loss and a relevant family history. Cardiopathy is also known to be an important feature of mitochondrial disease. In order to identify this aetiology, family screening, genetic counselling and screening of associated comorbidities are encouraged.

A síndrome diabetes e surdez de transmissão materna é uma forma rara de diabetes que resulta da mutação A3243G do ADN mitocondrial. Expõe-se o caso de uma doente do sexo feminino, 55 anos de idade, admitida por cardiomiopatia hipertrófica. A doente possui antecedentes de diabetes mellitus e surdez. Da história familiar, destaca-se a mãe e os seus dois irmãos e duas irmãs, que apresentam diabetes e surdez. Este padrão sugere uma doença de herança maternal. Todos são portadores da mutação A3243G do ADN mitocondrial. A identificação de pessoas com formas monogénicas de diabetes mellitus é um desafio diagnóstico. Deve ser considerado sempre que há história de diabetes associada a surdez e história familiar de diabetes. A cardiomiopatia hipertrófica é uma característica importante da patologia mitocondrial. Nestes doentes deve ser considerada a avaliação da família, aconselhamento genético e triagem de comorbilidades associadas.

Disconnection as a mechanism for social cognition impairment in multiple sclerosis.

OBJECTIVE: To assess the contribution of microstructural normal-appearing white matter (NAWM) damage to social cognition impairment, specifically in the theory of mind (ToM), in multiple sclerosis (MS). METHODS: We enrolled consecutively 60 patients with MS and 60 healthy controls (HC) matched on age, sex, and education level. All participants underwent ToM testing (Eyes Test, Videos Test) and 3T brain MRI including conventional and diffusion tensor imaging sequences. Tract-based spatial statistics (TBSS) were applied for whole-brain voxel-wise analysis of fractional anisotropy (FA) and mean diffusivity (MD) on NAWM. RESULTS: Patients with MS performed worse on both tasks of ToM compared to HC (Eyes Test 58.7 ± 13.8 vs 81.9 ± 10.4, p < 0.001, Hedges g -1.886; Videos Test 75.3 ± 9.3 vs 88.1 ± 7.1, p < 0.001, Hedges g -1.537). Performance on ToM tests was correlated with higher values of FA and lower values of MD across widespread white matter tracts. The largest effects (≥90% of voxels with statistical significance) for the Eyes Test were body and genu of corpus callosum, fornix, tapetum, uncinate fasciculus, and left inferior cerebellar peduncle, and for the Videos Test genu and splenium of corpus callosum, fornix, uncinate fasciculus, left tapetum, and right superior fronto-occipital fasciculus. CONCLUSIONS: These results indicate that a diffuse pattern of NAWM damage in MS contributes to social cognition impairment in the ToM domain, probably due to a mechanism of disconnection within the social brain network. Gray matter pathology is also expected to have an important role; thus further research is required to clarify the neural basis of social cognition impairment in MS.

Cerebrovascular Dissemination in Time and Space as a Predictor of Cardioembolism.

BACKGROUND: Cardioembolism has tendency to recur and cause lesions in distinct cerebrovascular territories. Using the imaging characteristics of cerebral lesions to determine dissemination in time and space (DTS) is a concept already used in other neurologic conditions; however, it has never been applied as a diagnostic tool in ischemic stroke etiology. AIM: This study aimed to assess DTS as a diagnostic marker of cardioembolism. METHODS: We enrolled consecutive patients with acute ischemic stroke of various etiologies admitted in a cerebrovascular disease nursery from a university hospital in a retrospective cohort study. We excluded patients with coexisting etiologies, incomplete study, or without an acute vascular lesion on computed tomography scan. Lacunar infarctions were not considered. Cerebrovascular territory was divided into right anterior, left anterior, and posterior. Localization of the acute vascular lesion(s), existence of previous vascular lesions, and their respective areas were analyzed. The presence of dissemination in time, space, or DTS was determined. RESULTS: We included 661 patients (mean age: 74.05 years (SD: 13.01)). Cardioembolism was the etiology with most DTS (30.47% of cardioembolic strokes); DT occurred more frequently within the atherosclerotic subtype (9.88%); DS was more prevalent within the arterial dissection group (3.33%). There was a statistically significant difference in stroke etiology between patients with DTS and patients without dissemination (P < .001). DTS had 81.67% specificity, 30.47% sensitivity, 66.67% positive predictive value, and 49.40% negative predictive value for the identification of cardioembolism. CONCLUSION: DTS is a specific diagnostic predictor of cardioembolic stroke and may be helpful in guiding etiologic investigation.

Impairment of social cognition in multiple sclerosis: Amygdala atrophy is the main predictor.

BACKGROUND: Patients with multiple sclerosis (MS) frequently reveal social behavior disturbance. Nevertheless, little is known regarding the impact of MS on social cognition, particularly theory of mind (ToM), and its neural basis. OBJECTIVES: To explore how ToM is affected in MS and its neural correlates. METHODS: Enrolled 60 consecutive MS patients and 60 healthy controls (HC) matched on age, sex, and education. Participants underwent ToM testing (Eyes Test, Videos Test) and 3 T brain magnetic resonance imaging (MRI). Using Freesurfer software, cortical and subcortical gray matter (GM) volumes were calculated. RESULTS: MS patients performed worse on Eyes Test (58.7% ± 13.8% vs 81.9% ± 10.4%, p < 0.001) and Videos Test (75.3% ± 9.3% vs 88.1% ± 7.1%, p < 0.001). Eyes Test performance in MS was positively correlated with the volume of subcortical structures (amygdala, putamen) and cortical regions (entorhinal cortex, fusiform gyrus, superior temporal gyrus, superior parietal gyrus, supramarginal gyrus, medial orbitofrontal cortex, anterior and posterior cingulate gyrus). In regression analysis, amygdala volume was the single predictor of performance ( R2 change = 0.064, p = 0.031), and a mediation analysis indicated that it contributes for the differences observed between MS and HC. CONCLUSION: Patients with MS have impairment on social cognition. Amygdala atrophy was the main predictor probably due to its central position within the "social brain" network.

Predictors of first-line treatment persistence in a Portuguese cohort of relapsing-remitting multiple sclerosis.

Treatment persistence in first-line injectable disease-modifying therapies (DMT) for relapsing-remitting multiple sclerosis (RRMS) is an important indicator of effectiveness. Identifying predictors of treatment discontinuation is important as there are other therapies currently available and a growing range of emerging drugs. We report a retrospective study of RRMS and clinically isolated syndrome patients followed in a University Hospital during a 13-year period with the objective of identifying predictors of treatment persistence. An evaluation of persistence on the first DMT, rates of DMT discontinuation, and reasons and predictors of discontinuation was performed. A total of 410 patients were included, 69% female, with mean disease duration of 37.8months, mean age of 34.2years and mean follow-up time of 6.1years. The first DMT was glatiramer acetate (GA) in 27.56% of patients, interferon (IFN) ß-1a intramuscular in 26.34%, IFNß-1b in 26.10%, IFNß-1a22 in 13.66% and IFNß-1a44 in 6.34%. Treatment was discontinued in 16.34% of patients after 1year of treatment and in 50.24% of patients in the total follow-up time, with a mean time for discontinuation of 39.80months. Higher baseline Expanded Disability Status Scale score was an independent predictor of treatment discontinuation (hazard ratio 1.35, p=0.002). After the first year, treatment persistence was 90.74% for IFNß-1a-IM, 88.46% for IFNß-1a44, 83.18% for IFNß-1b, 83.19% for GA and 69.64% for IFNß-1a22 (p=0.014). Lower frequency of administration was associated with higher persistence rates. The most common reason for treatment discontinuation was lack of efficacy in all DMT subgroups.

Apathy in multiple sclerosis: gender matters.

Apathy has been recognized as a frequent symptom in multiple sclerosis (MS) but uncertainty remains about its prevalence and clinical correlates. Therefore, the objective of this work was to assess the prevalence of apathy in patients with MS and to identify clinical and demographic correlates. A case-control study with 30 patients and 30 healthy controls matched for age, gender and education was performed. Apathy diagnosis was established using Robert et al.'s criteria. Additionally, apathy was assessed using the 10-item short version of the clinical-rated Apathy Evaluation Scale (AES-C-10). The Beck Depression Inventory (BDI), Modified Fatigue Impact Scale (MFIS), and Montreal Cognitive Assessment (MoCA) were used to evaluate depression, fatigue and cognitive impairment, respectively. Apathy prevalence in MS patients was 43.3%. Patients with MS had higher AES-C-10 scores than controls (13.9 vs. 12.0, p=0.015). Patients with apathy presented a higher proportion of males (53.8% vs. 11.8%, p=0.02), lower educational level (53.8% vs. 11.8% of patients with up to 9years of education), higher scores on cognitive dimension of MFIS (18.0 vs. 8.0, p=0.048) and BDI (13.0 vs. 7.0, p=0.035) and worse performance on MoCA (24.0 vs. 26.0, p=0.028). Gender was the only independent predictor of apathy, with men presenting a higher risk compared to women (OR: 9.62; 95%CI: 1.02-90.61; p=0.048). In conclusion, apathy is a common neuropsychiatric disorder in MS and it is probably underdiagnosed. Male patients seem to have an increased risk of apathy, and this finding may be related to the generally more unfavorable course of MS in men.

Clinical predictors of an optimal response to natalizumab in multiple sclerosis.

Despite the high level of effectiveness of natalizumab (NTZ) in the treatment of patients with multiple sclerosis (MS), concerns about its high direct cost and its safety have restricted its use. Our aim was to identify and quantify the clinical factors that predict an optimal response to NTZ. Patients with MS undergoing treatment with NTZ for at least 12 months were classified as optimal responders if, during treatment, they sustained a reduction in their Kurtzke Expanded Disability Status Scale (EDSS) score of 1 point or more or experienced a reduction in annualised relapse rate (ARR) of more than 1. The remaining patients were classified as suboptimal responders and non-responders. Our subject pool included 48 patients. The variables associated with optimal response included: ARR in the previous year of at least 2, an age at first administration of 37.5 years or less, a baseline EDSS score of 4.5 points or less, a disease duration of 9.5 years or less and, in patients with secondary-progressive MS, a progressive-phase duration of 4.5 years or less. The characteristics of the disease at its onset did not affect responsiveness, indicating that patients with highly active disease and low disability are the ideal candidates for NTZ treatment, regardless of previous clinical characteristics.