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Cladribine tablets have been granted marketing authorization in Europe and approved by the Food and Drug Administration (FDA) in the USA to treat relapsing forms of multiple sclerosis (MS). However, people with MS (PwMS) may be more familiar, and therefore more confident, with treatments requiring long-term and frequent dosing. Differences in such treatment strategies can lead to questions relating to how short-course non-continuous treatments, such as cladribine tablets, can work and how well they are tolerated. In response to this, we aimed to create an evidence-based report on patient-focused aspects of treatment with cladribine. To inform development, MS experts, including healthcare professionals (HCPs) and PwMS, proposed topics that PwMS and their families and caregivers would most like to discuss with HCPs during consultations to help them better understand cladribine treatment. The statements regarding each topic were then ranked by PwMS and used to inform the topics covered in this report. We explain here the use of cladribine tablets, which includes explanations of how cladribine tablets work, how to take cladribine tablets, and considerations required prior to and while taking cladribine tablets. We also describe how cladribine tablets affect relapse rate and quality of life and detail side effects, when they are likely to happen, and for how long. We also discuss how cladribine tablets affect family planning, fertility, and the use of vaccines. Alongside each section is a brief, plain language description of what is covered and an accompanying visual to aid conversations between HCPs and PwMS. Improved understanding by PwMS of treatments, such as cladribine, can empower them to play a bigger role in shared decision-making regarding their treatment. Additionally, the open dialogue we aim to promote with this type of report could lead to treatment choices being better tailored for individuals with chronic diseases on the basis of personal experiences, preferences, and circumstances. [ABSTRACT FROM AUTHOR]

Vesicular transport is essential for delivering cargo to intracellular destinations. Evi5 is a Rab11-GTPase-activating protein involved in endosome recycling. In humans, Evi5 is a high-risk locus for multiple sclerosis, a debilitating disease that also presents with excess iron in the CNS. In insects, the prothoracic gland (PG) requires entry of extracellular iron to synthesize steroidogenic enzyme cofactors. The mechanism of peripheral iron uptake in insect cells remains controversial. We show that Evi5-depletion in the Drosophila PG affected vesicle morphology and density, blocked endosome recycling and impaired trafficking of transferrin-1, thus disrupting heme synthesis due to reduced cellular iron concentrations. We show that ferritin delivers iron to the PG as well, and interacts physically with Evi5. Further, ferritin-injection rescued developmental delays associated with Evi5-depletion. To summarize, our findings show that Evi5 is critical for intracellular iron trafficking via transferrin-1 and ferritin, and implicate altered iron homeostasis in the etiology of multiple sclerosis. Vesicle transport ensures cargo delivery to cellular targets. Here, Soltani et al. show that Drosophila Evi5, a multiple sclerosis risk gene in humans, controls vesicular transport of iron-bound transferrins and physically interacts with ferritin. [ABSTRACT FROM AUTHOR]

Background: In relapsing–remitting multiple sclerosis (RRMS) the connection between cognitive impairment (CI) and white matter lesion load (WM-LL) and location is still unclear. This study aimed to identify the relationship between CI in RRMS patients and WM-LL and locations using a fully automated platform. CI and WM-LL were evaluated in 90 patients with RRMS using the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) and Automated MRI volumetric measures of WM-LL and lesion distribution. Regression analysis of BICAMS as a dependent variable with different clinical and radiological parameters was performed. Results: Data were obtained from 90 patients with RRMS who had a mean age of 32.74 ± 8.43 years and a female-to-male ratio of 3:1. The mean (± SD) cognitive rating scores for the BICAMS subtests were 28.07 ± 11.78 for the Symbol Digit Modalities Test (SDMT), 42.32 ± 12.46 for the California Verbal Learning Test-II (CVLT-II), and 16.13 ± 8.17 for the Brief Visuospatial Memory Test-Revised (BVMT-R). According to the BICAMS criteria, 29 cases (32.2%) had CI. BICAMS scores were significantly correlated with age, education level, relapse frequency, disease duration, and time to start disease-modifying therapies. Whole WM-LL and periventricular lesion load were significantly associated with CI. After controlling for age, sex, and education, logistic regression analysis revealed that total WM-LL was the best predictor for CI together with duration of illness and years of education. The cut-off value of 12.85 cc for total WM-LL predicted CI. Conclusions: Whole WM-LL and periventricular lesion load are the best anatomical predictors for CI probably due to the effect on the anterior commissural fibers while years of education and duration of disease are the best demographic predictors for CI. [ABSTRACT FROM AUTHOR]

Socio-cognitive impairment is frequent in multiple sclerosis (MS). However, little is known about the relationship between other potentially relevant clinical symptoms (i.e., cognition, depression, fatigue) and the degree of socio-cognitive impairment, and neural mechanisms underlying socio-cognitive deficits in MS. Therefore, we meta-analytically quantified socio-cognitive impairment in MS. A systematic literature search in MEDLINE Ovid, Web of Science Core Collection, CENTRAL, and PsycInfo was conducted until December 2022. Studies investigating affective or cognitive theory of mind (a/cToM), visual perspective taking (VPT) and social decision making (SDM) in MS patients relative to healthy controls were included. Risk-of-bias (RoB) was assessed using the CLARITY group "Tool for Assessing RoB in Cohort Studies". Mediation analysis investigated the contribution of clinical symptoms to socio-cognitive impairment. In total, n = 8534 studies were screened, 58 were included in the systematic review, 27 in the meta-analyses. Most studies were rated with a moderate RoB. Meta-analyses confirmed impairment of both aToM and cToM in MS patients, with larger effect sizes for aToM. Mediation analysis demonstrated that higher levels of fatigue selectively predicted the degree of cToM impairment. There was insufficient data available to quantify impairment in other socio-cognitive domains. Fourteen structural and functional imaging studies were identified and characterized by substantial heterogeneity. Summarized, this study confirmed substantial socio-cognitive impairment in MS and highlights the potential exacerbating role of comorbid clinical symptoms. We identify several evidence gaps that need to be addressed in future large-scale studies using comprehensive and coordinated assessments of socio-cognitive parameters, potential mediators, and neural correlates. Trial registration: The pre-registered review protocol can be assessed at www.crd.york.ac.uk/PROSPERO/ (ID: CRD42020206225). [ABSTRACT FROM AUTHOR]

Background: Cognitive impairment (CI) is a common and disabling symptom during the disease even in the earliest "preclinical" phase of patients with MS (pwMS). This study aims to assess cognitive function by measuring P300 event-related potential (ERP) and to look into the relationship between P300 abnormalities with the severity of the physical disability, education level, and disease duration. Methods: Fifty pwMS (28 females and 22 males) aged 20–54 years and fifty healthy subjects comprised of 21 females and 29 males aged 18–50 years serves as the control group was studied. All participants underwent medical history, neurological examination, cognitive functions using the Montreal Cognitive Assessment scale (MoCA) and the P300 ERP. Results: In this study, 48% of pwMS had CI. They had a longer P300 latency and a lower amplitude. Those with impaired cognition had a longer duration of illness and higher Expanded Disability Status Scale (EDSS), whereas those with intact cognition had a higher education level. P300 latency was correlated positively with EDSS and disease duration, but negatively with education level. P300 amplitude was found to be negatively correlated with EDSS, and disease duration but positively to the education level. Conclusions: P300, as a non-invasive test, would support the presence of CI in pwMS patients and could be used for screening in daily practice. P300 has a strong relationship with illness duration, disease subtypes, EDSS, and education level. [ABSTRACT FROM AUTHOR]

Background: Multiple sclerosis is a chronic neuro-inflammatory disease of the brain and central nervous system. We aimed at assessing the cognitive functions present in adult patients with multiple sclerosis in remission phase of the disease comparing them to healthy control group. Results: This is a cross sectional study using Penn Computerized Neurocognitive Battery (CNB) to measure performance accuracy and speed on specific neurobehavioral domains comparing MS group to healthy group. The MS group showed lower statistically significant difference in the accuracy of spatial memory, the motor speed, Non-verbal reasoning, Spatial orientation, social cognition, and working memory. Also, MS group showed statistically significant longer reaction time in facial memory, attention, spatial orientation, and non-verbal reasoning. Conclusions: Attention, spatial orientation, non- verbal reasoning, Facial memory, working memory, social cognition and spatial memory were affected in patients with MS during their remission phase. cognitive evaluation should constitute a major part of the clinical examination in MS, especially when impairment seems likely. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a chronic, neurodegenerative, inflammatory condition usually associated with physical disability. Clinical care has been skewed toward the physical manifestations of the disease, yet a range of silent symptoms occurs including the cognitive aspects of MS. In a 2018 meeting of MS in the 21st Century (MS21), an international steering committee comprising both specialists and patient experts recognised that the 'invisible symptoms' of MS pose a significant challenge to patient engagement. These findings prompted the European Charcot Foundation (ECF) MS21 symposium (2020), where a panel consisting of two leading MS clinicians and an MS patient expert (who were all members of the MS21 steering group) gathered to discuss the impact of cognitive impairment on the everyday lives of people with MS. The perspectives and experiences of the panellists are summarised in this paper. The key points raised were that (1) the cognitive manifestations of MS are under-recognised and have consequently been undermanaged from a clinical perspective and (2) cognitive impairment due to MS has a significant impact upon daily living and patient quality of life. During discussions about how these challenges can be addressed, the panel advocated for an improvement in education about cognitive symptoms for people living with MS and healthcare professionals (HCPs) to raise awareness about this aspect of MS. Furthermore, the panel emphasised the importance of open and proactive communication between HCPs and their patients with MS about cognitive symptoms to reduce the stigma attached to these symptoms. In the opinion of the panel, future clinical trials which include cognitive outcomes as key endpoints are needed. Reflecting this point, cognitive impairment in MS care also needs to be treated as an important disease symptom, as is done with physical symptoms of the disease. Implementing early and routine cognition screening and promoting measures for protecting cognition to people living with MS, such as cognitive rehabilitation and a 'brain-healthy' lifestyle, are actions which can drive forward the recognition of cognitive impairment as a care priority. If prioritised as highly as physical disability in both the MS care and clinical drug development setting, and proactively discussed in conversations between HCPs and patients with MS, the 'invisibility' of cognitive impairment in MS can be lifted and a better quality of life can be promoted for people living with MS. Plain Language Summary: Multiple sclerosis is a long-term condition which affects the brain and nervous system. Multiple sclerosis care has often focused more on the physical aspects of the disease than its mental challenges. Examples of mental challenges are brain fog, which can make it hard to organise thoughts, and memory problems. In 2020, the Multiple Sclerosis in the 21st Century group held a meeting at a medical conference called the European Charcot Foundation. In this conference, a patient expert living with multiple sclerosis, together with a neuropsychologist and neurologist both specialising in multiple sclerosis, discussed its mental symptoms and why they are not always recognised and addressed by people with multiple sclerosis and their healthcare teams. The group emphasised that these symptoms can considerably affect the day-to-day lives of people who experience them, stressing that this is a key reason why mental symptoms need to be better prioritised in care. The group advocated for early and frequent cognition testing to be a part of the standard care approach, as is the case with physical symptoms. They also urged healthcare professionals to promote a 'brain-healthy' lifestyle to their patients with multiple sclerosis and to encourage participation in cognitive rehabilitation programmes to maintain their mental abilities in the long run. Finally, the group discussed that more drug development studies that specifically assess how a treatment can reduce mental symptoms are needed: in this way, research and healthcare approaches can better prioritise mental symptoms. [ABSTRACT FROM AUTHOR]

Background: Cognitive impairment (CI) is a common and disabling symptom during the disease even in the earliest "preclinical" phase of patients with MS (pwMS). This study aims to assess cognitive function by measuring P300 event-related potential (ERP) and to look into the relationship between P300 abnormalities with the severity of the physical disability, education level, and disease duration. Methods: Fifty pwMS (28 females and 22 males) aged 20–54 years and fifty healthy subjects comprised of 21 females and 29 males aged 18–50 years serves as the control group was studied. All participants underwent medical history, neurological examination, cognitive functions using the Montreal Cognitive Assessment scale (MoCA) and the P300 ERP. Results: In this study, 48% of pwMS had CI. They had a longer P300 latency and a lower amplitude. Those with impaired cognition had a longer duration of illness and higher Expanded Disability Status Scale (EDSS), whereas those with intact cognition had a higher education level. P300 latency was correlated positively with EDSS and disease duration, but negatively with education level. P300 amplitude was found to be negatively correlated with EDSS, and disease duration but positively to the education level. Conclusions: P300, as a non-invasive test, would support the presence of CI in pwMS patients and could be used for screening in daily practice. P300 has a strong relationship with illness duration, disease subtypes, EDSS, and education level. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a severely debilitating disease which requires accurate and timely diagnosis. MRI is the primary diagnostic vehicle; however, it is susceptible to noise and artifact which can limit diagnostic accuracy. A myriad of denoising algorithms have been developed over the years for medical imaging yet the models continue to become more complex. We developed a lightweight algorithm which utilizes the image's inherent noise via dictionary learning to improve image quality without high computational complexity or pretraining through a process known as orthogonal matching pursuit (OMP). Our algorithm is compared to existing traditional denoising algorithms to evaluate performance on real noise that would commonly be encountered in a clinical setting. Fifty patients with a history of MS who received 1.5 T MRI of the spine between the years of 2018 and 2022 were retrospectively identified in accordance with local IRB policies. Native resolution 5 mm sagittal images were selected from T2 weighted sequences for evaluation using various denoising techniques including our proposed OMP denoising algorithm. Peak signal to noise ratio (PSNR) and structural similarity index (SSIM) were measured. While wavelet denoising demonstrated an expected higher PSNR than other models, its SSIM was variable and consistently underperformed its comparators (0.94 ± 0.10). Our pilot OMP denoising algorithm provided superior performance with greater consistency in terms of SSIM (0.99 ± 0.01) with similar PSNR to non-local means filtering (NLM), both of which were superior to other comparators (OMP 37.6 ± 2.2, NLM 38.0 ± 1.8). The superior performance of our OMP denoising algorithm in comparison to traditional models is promising for clinical utility. Given its individualized and lightweight approach, implementation into PACS may be more easily incorporated. It is our hope that this technology will provide improved diagnostic accuracy and workflow optimization for Neurologists and Radiologists, as well as improved patient outcomes. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is regarded as a chronic inflammatory disease that leads to demyelination and eventually to neurodegeneration. Activation of innate immune cells and other inflammatory cells in the brain and spinal cord of people with MS has been well described. However, with the innovation of technology in glial cell research, we have a deep understanding of the mechanisms of glial cells connecting inflammation and neurodegeneration in MS. In this review, we focus on the role of glial cells, including microglia, astrocytes, and oligodendrocytes, in the pathogenesis of MS. We mainly focus on the connection between glial cells and immune cells in the process of axonal damage and demyelinating neuron loss. [ABSTRACT FROM AUTHOR]

Based on the results of the pivotal CLARITY study, cladribine tablets were approved for use in the European Union in 2017 as a high-efficacy therapy for highly active relapsing-remitting multiple sclerosis (MS). Cladribine tablets are used as an induction therapy: half of the total dose is given in year 1 and the other half in year 2. In the CLARITY Extension trials, repeating the dose routinely in years 3 and 4, was not associated with significantly improved disease control. However, there is very limited evidence on how to manage people with MS (pwMS) beyond year 4, which is increasingly important because more and more patients are now ≥ 4 years after cladribine treatment. Overall, postapproval data show that treatment with two cladribine cycles effectively controls disease activity in the long term. However, there is general agreement that some pwMS with suboptimal response could benefit from retreatment. This study reviews the practical aspects of using cladribine tablets, summarizes the evidence from clinical trials and real-world studies on the safety and efficacy of cladribine, and proposes a treatment algorithm developed by expert consensus for pwMS previously treated with cladribine. In brief, we propose that additional courses of cladribine tablets should be considered in patients with minimal (no relapses, 1–2 new lesions) or moderate (1 relapse, 3–4 new lesions) disease activity, while significant disease activity (> 1 relapse, > 3 new lesions) or progression should warrant a switch to another high-efficacy treatment (HET). More evidence is needed to improve the treatment guidelines for pwMS who previously received cladribine. [ABSTRACT FROM AUTHOR]

Insufficient remyelination due to impaired oligodendrocyte precursor cell (OPC) differentiation and maturation is strongly associated with irreversible white matter injury (WMI) and neurological deficits. We analyzed whole transcriptome expression to elucidate the potential role and underlying mechanism of action of lipocalin-2 (LCN2) in OPC differentiation and WMI and identified the receptor SCL22A17 and downstream transcription factor early growth response protein 1 (EGR1) as the key signals contributing to LCN2-mediated insufficient OPC remyelination. In LCN-knockdown and OPC EGR1 conditional-knockout mice, we discovered enhanced OPC differentiation in developing and injured white matter (WM); consistent with this, the specific inactivation of LCN2/SCl22A17/EGR1 signaling promoted remyelination and neurological recovery in both atypical, acute WMI due to subarachnoid hemorrhage and typical, chronic WMI due to multiple sclerosis. This potentially represents a novel strategy to enhance differentiation and remyelination in patients with white matter injury. [ABSTRACT FROM AUTHOR]

Background: Though abnormal iron deposition has been reported in specific brain regions in multiple sclerosis (MS), no data exist about whether the overall quantity of iron in the brain is altered or not. We aimed to determine whether the noted aberrant iron deposition in MS brains was a problem of overall load or regional distribution in a cohort of MS patients. Methods: An experienced neuroradiologist, a radiology software engineer, and four neurologists analysed data from quantitative susceptibility maps reconstructed from 3-T magnetic resonance brain images of 30 MS patients and 15 age- and sex-matched healthy controls. Global brain iron load was calculated, and the regional iron concentrations were assessed in 1,000 regions of interest placed in MS lesions in different locations, normal appearing white matter, thalami, and basal ganglia. Results: Global brain iron load was comparable between patients and controls after adjustment for volume (p = 0.660), whereas the regional iron concentrations were significantly different in patients than in control (p ≤ 0.031). There was no significant correlation between global iron load and clinical parameters, whereas regional iron concentrations correlated with patients’ age, disease duration, and disability grade (p ≤ 0.039). Conclusions: The aberrant iron deposition noted in MS seems to be a problem of regional distribution rather than an altered global brain iron load. [ABSTRACT FROM AUTHOR]

Introduction: Fatigue, cognitive impairment, depression, and pain are highly prevalent symptoms in multiple sclerosis (MS). These often co-occur and may be explained by a common etiology. By reviewing existing literature, we aimed to identify potential underlying biological processes implicated in the interconnectivity between these symptoms. Methods: A literature search was conducted to identify articles reporting research into the biological mechanisms responsible for the manifestation of fatigue, cognitive impairment, depression, and pain in MS. PubMed was used to search for articles published from July 2011 to July 2021. We reviewed and assessed findings from the literature to identify biological processes common to the symptoms of interest. Results: Of 693 articles identified from the search, 252 were selected following screening of titles and abstracts and assessing reference lists of review articles. Four biological processes linked with two or more of the symptoms of interest were frequently identified from the literature: (1) direct neuroanatomical changes to brain regions linked with symptoms of interest (e.g., thalamic injury associated with cognitive impairment, fatigue, and depression), (2) pro-inflammatory cytokines associated with so-called 'sickness behavior,' including manifestation of fatigue, transient cognitive impairment, depression, and pain, (3) dysregulation of monoaminergic pathways leading to depressive symptoms and fatigue, and (4) hyperactivity of the hypothalamic–pituitary-adrenal (HPA) axis as a result of pro-inflammatory cytokines promoting the release of brain noradrenaline, serotonin, and tryptophan, which is associated with symptoms of depression and cognitive impairment. Conclusion: The co-occurrence of fatigue, cognitive impairment, depression, and pain in MS appears to be associated with a common set of etiological factors, namely neuroanatomical changes, pro-inflammatory cytokines, dysregulation of monoaminergic pathways, and a hyperactive HPA axis. This association of symptoms and biological processes has important implications for disease management strategies and, eventually, could help find a common therapeutic pathway that will impact both inflammation and neuroprotection. [ABSTRACT FROM AUTHOR]

Background: The prevalence of cognitive impairment (CI) can reach up to 65% among multiple sclerosis (MS) patients. Self-administered screening questionnaires can offer a valuable solution for screening MS patients for cognitive complaints. The cognitive screening questionnaire for neurological disorders (CSQND) is an Arabic self-administered questionnaire that has been developed to screen patients with various neurological disorders attending neurology clinics. The aim of this study was to assess cognitive complaints and to validate the CSQND as a screening tool among Egyptian MS patients. Results: Four-hundred MS patients and 400 controls were included in this study. All 400 patients and 400 controls were subjected to the CSQND, only 50 out of the 400 patients and 50 out of the 400 controls retook the CSQND 1 week later to establish test–retest reliability. Fifty patients and 50 controls were assessed by the symbol digit modalities test (SDMT) to establish concurrent validity. Thirty-four percent of patients complained of memory problems, 51% complained of concentration difficulties, 34% complained of language difficulties and 22.5% complained of space and time disorientation. Multiple sclerosis patients had significantly more cognitive complaints (12.4 ± 12.6) compared to controls (6.2 ± 6.8) when screened using the CSQND (P < 0.000001). Total scores of CSQND were positively significantly correlated to age at onset, total disease duration, EDSS scores and total number of relapses, (r = 0.14; 0.275; 0.3; 0.167, respectively), P < 0.05 for all. Agreement was found between CSQND results and the SDMT results, where the line of equality lied within the 95% confidence interval of the mean. A significant positive correlation was found between the CSQND results at the first application and upon retesting both in patients (R = 0.9, P = 0.0001) and controls (R = 0.85, P = 0.0001). Conclusions: The CSQND was found to be a simple, valid, and reliable self-administered questionnaire to screen for cognitive complaints in MS patients. [ABSTRACT FROM AUTHOR]

Introduction: It is important to confirm the effectiveness and tolerability of disease-modifying treatments for relapsing–remitting multiple sclerosis (RRMS) in real-world treatment settings. This prospective observational cohort study (VIRGILE) was performed at the request of the French health authorities. The primary objective was to evaluate the effectiveness of fingolimod 0.5 mg in reducing the annualised relapse rate (ARR) in patients with RRMS. Methods: Participating neurologists enrolled all adult patients with RRMS starting fingolimod treatment between 2014 and 2016, who were followed for 3 years. Follow-up consultations took place at the investigator's discretion. The primary outcome measure was the change in ARR at month 24 after fingolimod initiation. Relapses and adverse events were documented at each consultation; disability assessment (EDSS) and magnetic resonance imagery were performed at the investigator's discretion. Results: Of 1055 eligible patients, 633 patients were assessable at month 36; 405 (64.0%) were treated continuously with fingolimod for 3 years. The ARR decreased from 0.92 ± 0.92 at inclusion to 0.31 ± 0.51 at month 24, a significant reduction of 0.58 [95% CI − 0.51 to − 0.65] relapses/year (p < 0.001). Since starting fingolimod, 461 patients (60.9%) remained relapse-free at month 24 and 366 patients (55.5%) at month 36. In multivariate analysis, no previous disease-modifying treatment, number of relapses in the previous year and lower EDSS score at inclusion were associated with a greater on-treatment reduction in ARR. The mean EDSS score remained stable over the course of the study. Sixty-one out of 289 (21.1%) patients presented new radiological signs of disease activity. Treatment-related serious adverse events were lymphopenia (N = 21), bradycardia (N = 19), elevated transaminases (N = 9) and macular oedema (N = 9). Conclusions: The effectiveness and tolerability of fingolimod in everyday clinical practice are consistent with findings of previous phase III studies. Our study highlights the utility of fingolimod for the long-term management of patients with multiple sclerosis. [ABSTRACT FROM AUTHOR]

Background: Pediatric onset multiple sclerosis (POMS), defined as an age at onset younger than 18 years, which occurs in 5% of patients with MS. cognitive dysfunction is one of the prominent disabling sequelae of Multiple sclerosis. Brain volumetric studies by magnetic resonance images revealed the decline of whole and regional brain volumes along the disease course. This work aimed to investigate the relationship between cognitive impairment in pediatric MS patients with thalamic atrophy and cortical thickness of temporal lobe. This study included 50 patients who were diagnosed as POMS and 50 healthy control participants matched for age and sex. Both groups were compared for volumetric measurements of thalamic volumes and temporal lobes cortical thickness using a computerized program called FreeSurfer.MS group was evaluated for cognitive dysfunction using Arabic version of fifth edition of Standford–Benit test. A correlation between volumetric results and neuropsychological evaluation of MS group was done. Results: Our study showed that the MS group has the lowest value regarding their thalamic volumes and their cortical thickness of temporal lobes in relation to the healthy control group, while there was a significant relation between cognitive impairment and decrease in thalamic volume and specific areas in cortical thickness, such as superior temporal thickness, middle temporal thickness, inferior temporal thickness, fusiform thickness and para hippocampal thickness of temporal lobe in pediatric onset MS patients. Conclusions: POMS affects specific brain areas such as thalamus and cortical thickness of temporal lobes regarding their volume and thickness which influence the neuropsychological evaluation detected by Standford–Benit test. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a complex condition with numerous physical, cognitive and emotional symptoms. These may necessitate significant, permanent lifestyle changes for people with multiple sclerosis (PwMS) and their caregivers and families, meaning it is important in contemporary neurological practice to consider including families and/or caregivers in the management of MS. However, existing evidence suggests that family involvement is not always beneficial; for example, it can exert either a strong positive or negative influence on the ability of PwMS to achieve optimal outcomes from their treatment and disease management. This paper, based on a live debate between neurologists and PwMS, examines the current perceptions on constructive involvement of families and caregivers in consultations for and management of MS, and reveals several areas where additional studies are warranted. Shared decision-making in MS has historically been a collaboration solely between healthcare professionals (HCPs) and PwMS, but PwMS are now more frequently being accompanied to appointments by a support person. This paper encourages HCPs to understand the dynamics between PwMS and their support person, and to individualize consultations and information accordingly. Family and caregiver involvement in the provision of care for PwMS needs to be for the benefit of, and at the discretion of, the PwMS. Support for families of PwMS, although important, may be more effectively and appropriately delivered through other channels outside of the clinical setting. Educating HCPs on the current patient experience to enable them to provide improved personalized care will ensure a mutualistic, patient-centred relationship with PwMS, which will help to optimize outcomes. Communication tools may also facilitate these interactions. Plain Language Summary: Multiple sclerosis (MS) is a highly variable condition. The uncertainty this brings can affect the mental well-being of the entire family of someone living with MS. Additionally, people with MS may need help administering and remembering to use medicines, and require changes to the way they live their life (e.g. employment decisions, home adjustments and care), which can also disrupt the family's lifestyle. The family undoubtedly needs to be involved in certain decisions, such as family planning, or when caring for very young or old people with MS. However, extensive family involvement may not always be a good thing for all people with MS. Therefore, it is the responsibility of healthcare professionals to understand the pivotal role of the caregiver and seek appropriate opportunities to engage with family and support persons on a case-by-case basis. To highlight the importance of family members in the management of MS, an international group of expert neurologists and people with MS discussed the best ways to involve families in consultations and decision-making, without disrupting care or undermining the independence of the people with MS. The group stresses that a family's involvement in the provision of care needs to be for the benefit of the people with MS and that many factors can influence whether family involvement is perceived positively or negatively by the people with MS. Support for the family is important; however, it may be more appropriately delivered outside the healthcare professional consultation, and instead provided by a patient or caregiver organization. [ABSTRACT FROM AUTHOR]

Background: About 40–70% of patients with multiple sclerosis (MS) develop cognitive impairment (CI) throughout their life. We aim to study the influence of MS on cognitive changes. This is a case–control study of fifty patients with MS who met the revised 2017 Mc Donald Criteria and fifty age- and sex-matched healthy subjects. The Expanded Disability Status Scale (EDSS) was used to assess the degree of disability, and the Montreal Cognitive Assessment (MoCA) scoring system was used to assess cognitive function. Results: MS patients show low total MoCA score than the controls. Total MoCA scores were lower in patients with CI versus those with intact cognition. CI was higher in those with a longer duration of illness and a high EDSS. MoCA was positively correlated with education level but negatively with EDSS and disease duration. Conclusion: MoCA scale has optimal psychometric properties for routine clinical use in patients with MS, even in those with mild functional disability. The longer the disease duration and the higher the EDSS, the lower the MoCA score and the higher the education level, the higher the MoCA score. As for the profile of cognitive dysfunction in patients with MS, the domains most frequently failed by the patients were memory, attention, visuospatial learning, and language. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a chronic autoimmune inflammatory disease of the central nervous system, leading to neurodegeneration and manifesting as a variety of symptoms. These can include "invisible" symptoms, not externally evident to others, such as fatigue, mood disorders, cognitive impairments, pain, bladder/bowel dysfunction, sexual dysfunction, and vision changes. Invisible symptoms are highly prevalent in people living with MS, with multifactorial etiology and potential to impact the disease course. Patient experiences of these symptoms include both physical and psychosocial elements, which when unaddressed negatively influence many aspects of quality of life and perception of health. Despite the high impact on patient lives, gaps persist in awareness and management of these hidden symptoms. The healthcare provider and patient author experiences brought together here serve to raise the profile of invisible symptoms and review strategies for a team-based approach to comprehensive MS care. We summarize the current literature regarding the prevalence and etiology of invisible symptoms to convey the high likelihood that a person living with MS will contend with one or more of these concerns. We then explore how open communication between people living with MS and their care team, stigma mitigation, and shared decision-making are key to comprehensive management of invisible symptoms. We recommend validated screening tools and technological advancements that may be incorporated into MS care to regularly monitor these symptoms, offering insight into how healthcare providers can both educate and listen to patients, with the goal of improved patient quality of life. By pairing clinical knowledge with an understanding and consideration of the patient perspective, providers will be equipped to foster a patient-centered dialogue that encourages shared decision-making. CobCdBdg-4RS3rqX92xoSZ Invisible symptoms of MS Graphical Plain Language Summary: [ABSTRACT FROM AUTHOR]

Magnetization transfer ratio (MTR) and brain volumetric imaging are (semi-)quantitative MRI markers capturing demyelination, axonal degeneration and/or inflammation. However, factors shaping variation in these traits are largely unknown. In this study, we collected a longitudinal cohort of 33 multiple sclerosis (MS) patients and extended it cross-sectionally to 213. We measured MTR in lesions, normal-appearing white matter (NAWM), normal-appearing grey matter (NAGM) and total brain, grey matter, white matter and lesion volume. We also calculated the polygenic MS risk score. Longitudinally, inter-patient differences at inclusion and intra-patient changes during follow-up together explained > 70% of variance in MRI, with inter-patient differences at inclusion being the predominant source of variance. Cross-sectionally, we observed a moderate correlation of MTR between NAGM and NAWM and, less pronounced, with lesions. Age and gender explained about 30% of variance in total brain and grey matter volume. However, they contributed less than 10% to variance in MTR measures. There were no significant associations between MRI traits and the genetic risk score. In conclusion, (semi-)quantitative MRI traits change with ongoing disease activity but this change is modest in comparison to pre-existing inter-patient differences. These traits reflect individual variation in biological processes, which appear different from those involved in genetic MS susceptibility. [ABSTRACT FROM AUTHOR]

Predictors of multiple sclerosis (MS) activity during disease-modifying treatment are being extensively investigated. The aim of this study was to assess the prognosis of NEDA (no evidence of disease activity) status during IFN-β (interferon-β) treatment, using apparent diffusion coefficient (ADC) measurements obtained at initial MRI (magnetic resonance imaging). In 87 MS patients treated with IFN-β, ADC values were calculated for 13 regions of normal-appearing white and grey matter (NAWM, NAGM) based on MRI performed with a 1.5 T magnet before (MS0, n = 45) or after one year of therapy (MS1, n = 42). Associations were evaluated between ADC, conventional MRI findings, demographic and clinical factors and NEDA status within the following 3 years using logistic, Cox and multinomial logistic regression models. NEDA rates in the MS0 group were 64.4%, 46.5% and 33.3% after the 1st, 2nd and 3rd year of treatment, respectively and in MS1 patients 71.4% and 48.7% for the periods 1st–2nd and 1st–3rd years of treatment, respectively. ADC values in the NAWM regions contributed to loss of NEDA and its clinical and radiological components, with a 1–3% increase in the risk of NEDA loss (p = 0.0001–0.0489) in both groups. ADC measurements may have an additional prognostic value with regard to NEDA status. [ABSTRACT FROM AUTHOR]

Abstract: Multiple sclerosis (MS) is a neurological disease of the central nervous system which can lead to a range of severe physical disabilities. A large proportion of those affected will experience cognitive impairment, which is associated with a worse prognosis. Effective assessment of cognition in MS has been problematic due to a lack of suitable scales. The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) was developed in 2010 as part of an international endeavour to facilitate cognitive assessment.Aim: The aim of this systematic review and meta-analysis was to synthesise the available literature published as part of the BICAMS international validation protocol.Methods: A literature search conducted using PubMed, PsycINFO and Google Scholar identified 16 studies for inclusion in the systematic review, 14 of which could be included in a meta-analysis.Results: BICAMS has been widely validated across 11 languages and 14 individual cultures and locations. The meta-analysis demonstrated that BICAMS identified significantly reduced cognitive functioning in adults with MS compared to healthy controls. This was true for all three cognitive domains assessed by BICAMS: information processing speed (g = 0.943, 95% CI 0.839, 1.046, g < 0.001), immediate verbal recall memory (g = 0.688, 95% CI 0.554, 0.822, p < 0.001) and immediate visual recall memory (g = 0.635, 95% CI 0.534, 0.736, p < 0.001).Conclusion: BICAMS has been widely applied across cultures and languages to assess cognition in MS. BICAMS offers a feasible, cost-effective means of assessing cognition in MS worldwide. Further validation studies are underway to support this project. [ABSTRACT FROM AUTHOR]

Conventional magnetic resonance imaging (MRI) at 1.5 Tesla (T) is limited by modest spatial resolution and signal-to-noise ratio (SNR), impeding the identification and classification of inflammatory central nervous system changes in current clinical practice. Gaining from enhanced susceptibility effects and improved SNR, ultrahigh field MRI at 7 T depicts inflammatory brain lesions in great detail. This review summarises recent reports on 7 T MRI in neuroinflammatory diseases and addresses the question as to whether ultrahigh field MRI may eventually improve clinical decision-making and personalised disease management. [ABSTRACT FROM AUTHOR]

Conventional magnetic resonance imaging (MRI) at 1.5 Tesla (T) is limited by modest spatial resolution and signal-to-noise ratio (SNR), impeding the identification and classification of inflammatory central nervous system changes in current clinical practice. Gaining from enhanced susceptibility effects and improved SNR, ultrahigh field MRI at 7 T depicts inflammatory brain lesions in great detail. This review summarises recent reports on 7 T MRI in neuroinflammatory diseases and addresses the question as to whether ultrahigh field MRI may eventually improve clinical decision-making and personalised disease management. [ABSTRACT FROM AUTHOR]

Objective:Idiopathic transverse myelitis (I-TM) is typically monophasic, while relapsing forms are usually referred to spinal cord-restricted neuromyelitis optica (NMO), atypical multiple sclerosis (MS), or myelitis during the course of infections and connectivitis. Our objective was to evaluate the frequency of recurrent I-TM; to clarify the nosology of these forms through comparison with NMO and post-infectious TM (P-TM).Design:Prospective cohort study on patients presenting with I-TM was carried out inpatients of Infectious and Neurologic Disease Clinics, Italy.Methods:Over an 8-year period, we recruited 13 patients with I-TM and 16 with P-TM. The patients were followed-up for at least 3 years with repeated brain and spinal cord magnetic resonance imaging (MRI) examinations, multimodal evoked potentials and serum screen for connectivitis. Relapses were defined on clinical and imaging criteria.Results:Four patients with I-TM (31%) had a relapsing course . They were all males with age >50, and severe at-onset disability. The final outcome was poor in three out of four patients. Serum NMO-immunoglobulin G was undetectable in all patients. Longitudinally extensive myelitis was not predictive of relapses. I-TM and P-TM shared clinical, cerebrospinal fluid (CSF) and MRI features, as well as a similar rate (54 vs 38%) of peripheral nervous system involvement (polyradiculoneuritis), and an identical rate of relapses (31% for both forms).Conclusions:Our series support the existence of relapsing I-TM as a disease entity that does not appear related to NMO, nor to MS, cannot be further specified and shares many features with P-TM. The likelihood of relapses was unpredictable based on clinical, CSF and MRI findings.Spinal Cord (2009) 47, 531–537; doi:10.1038/sc.2008.157; published online 23 December 2008 [ABSTRACT FROM AUTHOR]

Discrepant findings have been reported regarding an association of the apolipoprotein E (APOE) gene with the clinical course of multiple sclerosis (MS). To resolve these discrepancies, we examined common sequence variation in six candidate genes residing in a 380-kb genomic region surrounding and including the APOE locus for an association with MS severity. We genotyped at least three polymorphisms in each of six candidate genes in 1540 Caucasian MS families (729 single-case and multiple-case families from the United States, 811 single-case families from the UK). By applying the quantitative transmission/disequilibrium test to a recently proposed MS severity score, the only statistically significant (P=0.003) association with MS severity was found for an intronic variant in the Herpes Virus Entry Mediator-B Gene (PVRL2). Additional genotyping extended the association to a 16.6 kb block spanning intron 1 to intron 2 of the gene. Sequencing of PVRL2 failed to identify variants with an obvious functional role. In conclusion, the analysis of a very large data set suggests that genetic polymorphisms in PVRL2 may influence MS severity and supports the possibility that viral factors may contribute to the clinical course of MS, consistent with previous reports.Genes and Immunity (2006) 7, 384–392. doi:10.1038/sj.gene.6364311; published online 1 June 2006 [ABSTRACT FROM AUTHOR]

Background: Montreal Cognitive Assessment test (MoCA) is a brief, sensitive test that has been recommended as a reliable tool to detect mild cognitive impairment. Associations between brain imaging measures and cognitive functioning have been observed in patients with multiple sclerosis (MS). Objectives: To evaluate cognitive dysfunction and physical disability in MS patients by making correlation between magnetic resonance imaging (MRI), MoCA test, and Expanded Disability Status Scale (EDSS). Methods: Fifty MS patients and 25 controls underwent clinical evaluation and assessment of cognitive functions using the MoCA test. In addition, all MS patients underwent conventional MRI brain and Expanded Disability Status Scale (EDSS). Results: The scores for trail making test, memory, attention, serial seven subtractions, fluency, naming, and orientation in MS patients were significantly different from control (p < 0.05). There was significant inverse correlation between number of MS plaques in the temporal lobe and abstraction (p < 0.001, r = − 0.52). Less inverse correlation was found between total number of MRI plaques and concentration, total number of MRI plaques and abstraction, and infratentorial lesions and clock drawing test. No correlations were found between the number of MS plaques in frontal, parietal, occipital, corpus callosum, and neuropsychological tests. Conclusion: Although conventional MRI techniques are crucial in the MS diagnostic workup, their accuracy in evaluating and predicting cognitive dysfunction is less relevant. The MoCA test would provide a brief screen for cognitive dysfunction in MS. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system characterized by focal or diffuse inflammation, demyelination, axonal loss and neurodegeneration. Brain atrophy can be seen in the earliest stages of MS, progresses faster compared to healthy adults, and is a reliable predictor of future physical and cognitive disability. In addition, it is widely accepted to be a valid, sensitive and reproducible measure of neurodegeneration in MS. Reducing the rate of brain atrophy has only recently been incorporated as a critical endpoint into the clinical trials of new or emerging disease modifying drugs (DMDs) in MS. With the advent of easily accessible neuroimaging softwares along with the accumulating evidence, clinicians may be able to use brain atrophy measures in their everyday clinical practice to monitor disease course and response to DMDs. In this review, we will describe the different mechanisms contributing to brain atrophy, their clinical relevance on disease presentation and course and the effect of current or emergent DMDs on brain atrophy and neuroprotection. [ABSTRACT FROM AUTHOR]

Background: Brain PET imaging with different tracers is mainly clinically used in the field of neurodegenerative diseases and brain tumors. In recent years, the potential usefulness of PET has also gained attention in the field of MS. In fact, MS is a complex disease and several processes can be selected as a target for PET imaging. The use of PET with several different tracers has been mainly evaluated in the research setting to investigate disease pathophysiology (i.e. phenotypes, monitoring of progression) or to explore its use a surrogate end-point in clinical trials. Results: We have reviewed PET imaging studies in MS in humans and animal models. Tracers have been grouped according to their pathophysiological targets (ie. tracers for myelin kinetic, neuroinflammation, and neurodegeneration). The emerging clinical indication for brain PET imaging in the differential diagnosis of suspected tumefactive demyelinated plaques as well as the clinical potential provided by PET images in view of the recent introduction of PET/MR technology are also addressed. Conclusion: While several preclinical and fewer clinical studies have shown results, full-scale clinical development programs are needed to translate molecular imaging technologies into a clinical reality that could ideally fit into current precision medicine perspectives. [ABSTRACT FROM AUTHOR]