KG-LIME: predicting individualized risk of adverse drug events for multiple sclerosis disease-modifying therapy.

OBJECTIVE: The aim of this project was to create time-aware, individual-level risk score models for adverse drug events related to multiple sclerosis disease-modifying therapy and to provide interpretable explanations for model prediction behavior. MATERIALS AND METHODS: We used temporal sequences of observational medical outcomes partnership common data model (OMOP CDM) concepts derived from an electronic health record as model features. Each concept was assigned an embedding representation that was learned from a graph convolution network trained on a knowledge graph (KG) of OMOP concept relationships. Concept embeddings were fed into long short-term memory networks for 1-year adverse event prediction following drug exposure. Finally, we implemented a novel extension of the local interpretable model agnostic explanation (LIME) method, knowledge graph LIME (KG-LIME) to leverage the KG and explain individual predictions of each model. RESULTS: For a set of 4859 patients, we found that our model was effective at predicting 32 out of 56 adverse event types (P < .05) when compared to demographics and past diagnosis as variables. We also assessed discrimination in the form of area under the curve (AUC = 0.77 ± 0.15) and area under the precision-recall curve (AUC-PR = 0.31 ± 0.27) and assessed calibration in the form of Brier score (BS = 0.04 ± 0.04). Additionally, KG-LIME generated interpretable literature-validated lists of relevant medical concepts used for prediction. DISCUSSION AND CONCLUSION: Many of our risk models demonstrated high calibration and discrimination for adverse event prediction. Furthermore, our novel KG-LIME method was able to utilize the knowledge graph to highlight concepts that were important to prediction. Future work will be required to further explore the temporal window of adverse event occurrence beyond the generic 1-year window used here, particularly for short-term inpatient adverse events and long-term severe adverse events.

Electrical stimulation of the vagus nerve ameliorates inflammation and disease activity in a rat EAE model of multiple sclerosis.

Multiple sclerosis (MS) is a demyelinating central nervous system (CNS) disorder that is associated with functional impairment and accruing disability. There are multiple U.S. Food and Drug Administration (FDA)-approved drugs that effectively dampen inflammation and slow disability progression. However, these agents do not work well for all patients and are associated with side effects that may limit their use. The vagus nerve (VN) provides a direct communication conduit between the CNS and the periphery, and modulation of the inflammatory reflex via electrical stimulation of the VN (VNS) shows efficacy in ameliorating pathology in several CNS and autoimmune disorders. We therefore investigated the impact of VNS in a rat experimental autoimmune encephalomyelitis (EAE) model of MS. In this study, VNS-mediated neuroimmune modulation is demonstrated to effectively decrease EAE disease severity and duration, infiltration of neutrophils and pathogenic lymphocytes, myelin damage, blood-brain barrier disruption, fibrinogen deposition, and proinflammatory microglial activation. VNS modulates expression of genes that are implicated in MS pathogenesis, as well as those encoding myelin proteins and transcription factors regulating new myelin synthesis. Together, these data indicate that neuroimmune modulation via VNS may be a promising approach to treat MS, that not only ameliorates symptoms but potentially also promotes myelin repair (remyelination).

RNF213 promotes Treg cell differentiation by facilitating K63-linked ubiquitination and nuclear translocation of FOXO1.

Autoreactive CD4+ T helper cells are critical players that orchestrate the immune response both in multiple sclerosis (MS) and in other neuroinflammatory autoimmune diseases. Ubiquitination is a posttranslational protein modification involved in regulating a variety of cellular processes, including CD4+ T cell differentiation and function. However, only a limited number of E3 ubiquitin ligases have been characterized in terms of their biological functions, particularly in CD4+ T cell differentiation and function. In this study, we found that the RING finger protein 213 (RNF213) specifically promoted regulatory T (Treg) cell differentiation in CD4+ T cells and attenuated autoimmune disease development in an FOXO1-dependent manner. Mechanistically, RNF213 interacts with Forkhead Box Protein O1 (FOXO1) and promotes nuclear translocation of FOXO1 by K63-linked ubiquitination. Notably, RNF213 expression in CD4+ T cells was induced by IFN-ß and exerts a crucial role in the therapeutic efficacy of IFN-ß for MS. Together, our study findings collectively emphasize the pivotal role of RNF213 in modulating adaptive immune responses. RNF213 holds potential as a promising therapeutic target for addressing disorders associated with Treg cells.

Value of Optic Nerve MRI in Multiple Sclerosis Clinical Management: A MAGNIMS Position Paper and Future Perspectives.

The optic nerve is frequently involved in multiple sclerosis (MS). However, MRI of the optic nerve is considered optional in the differential diagnosis of optic neuropathy symptoms either at presentation or in established MS. In addition, unlike spinal cord imaging in comparable scenarios, no role is currently recommended for optic nerve MRI in patients presenting with optic neuritis for its confirmation, to plan therapeutic strategy, within the MS diagnostic framework, nor for the detection of subclinical activity in established MS. In this article, evidence related to these 3 aspects will be summarized and gaps in knowledge will be highlighted, including (1) the acquisition challenges and novel sequences that assess pathologic changes within the anterior visual pathways; (2) the clinical implications of quantitative magnetic resonance studies of the optic nerve, focusing on atrophy measures, magnetization transfer, and diffusion tensor imaging; and (3) the relevant clinical studies performed to date. Finally, an algorithm for the application of optic nerve MRI will be proposed to guide future studies aimed at addressing our knowledge gaps.

Portable multi-focal visual evoked potential diagnostics for multiple sclerosis/optic neuritis patients.

PURPOSE: Multiple sclerosis (MS) is a neuro-inflammatory disease affecting the central nervous system (CNS), where the immune system targets and damages the protective myelin sheath surrounding nerve fibers, inhibiting axonal signal transmission. Demyelinating optic neuritis (ON), a common MS symptom, involves optic nerve damage. We've developed NeuroVEP, a portable, wireless diagnostic system that delivers visual stimuli through a smartphone in a headset and measures evoked potentials at the visual cortex from the scalp using custom electroencephalography electrodes. METHODS: Subject vision is evaluated using a short 2.5-min full-field visual evoked potentials (ffVEP) test, followed by a 12.5-min multifocal VEP (mfVEP) test. The ffVEP evaluates the integrity of the visual pathway by analyzing the P100 component from each eye, while the mfVEP evaluates 36 individual regions of the visual field for abnormalities. Extensive signal processing, feature extraction methods, and machine learning algorithms were explored for analyzing the mfVEPs. Key metrics from patients' ffVEP results were statistically evaluated against data collected from a group of subjects with normal vision. Custom visual stimuli with simulated defects were used to validate the mfVEP results which yielded 91% accuracy of classification. RESULTS: 20 subjects, 10 controls and 10 with MS and/or ON were tested with the NeuroVEP device and a standard-of-care (SOC) VEP testing device which delivers only ffVEP stimuli. In 91% of the cases, the ffVEP results agreed between NeuroVEP and SOC device. Where available, the NeuroVEP mfVEP results were in good agreement with Humphrey Automated Perimetry visual field analysis. The lesion locations deduced from the mfVEP data were consistent with Magnetic Resonance Imaging and Optical Coherence Tomography findings. CONCLUSION: This pilot study indicates that NeuroVEP has the potential to be a reliable, portable, and objective diagnostic device for electrophysiology and visual field analysis for neuro-visual disorders.

Mesenchymal stem cells and their derived exosomes in multiple sclerosis disease: from paper to practice.

Multiple sclerosis (MS) is a chronic neurodegenerative, inflammatory, and demyelinating disease of the central nervous system (CNS). Current medicines are not sufficient to control the inflammation and progressive damage to the CNS that is known in MS. These drawbacks highlight the need for novel treatment options. Cell therapy can now be used to treat complex diseases when conventional therapies are ineffective. Mesenchymal stem cells (MSCs) are a diverse group of multipotential non-hematopoietic stromal cells which have immunomodulatory, neurogenesis, and remyelinating capacity. Their advantageous effects mainly rely on paracrine, cell-cell communication and differentiation properties which introduced them as excellent candidates for MS therapy. Exosomes, as one of the MSCs secretomes, have unique properties that make them highly promising candidates for innovative approach in regenerative medicine. This review discusses the therapeutic potential of MSCs and their derived exosomes as a novel treatment for MS, highlighting the differences between these two approaches.

Efficient segmentation of active and inactive plaques in FLAIR-images using DeepLabV3Plus SE with efficientnetb0 backbone in multiple sclerosis.

This research paper introduces an efficient approach for the segmentation of active and inactive plaques within Fluid-attenuated inversion recovery (FLAIR) images, employing a convolutional neural network (CNN) model known as DeepLabV3Plus SE with the EfficientNetB0 backbone in Multiple sclerosis (MS), and demonstrates its superior performance compared to other CNN architectures. The study encompasses various critical components, including dataset pre-processing techniques, the utilization of the Squeeze and Excitation Network (SE-Block), and the atrous spatial separable pyramid Block to enhance segmentation capabilities. Detailed descriptions of pre-processing procedures, such as removing the cranial bone segment, image resizing, and normalization, are provided. This study analyzed a cross-sectional cohort of 100 MS patients with active brain plaques, examining 5000 MRI slices. After filtering, 1500 slices were utilized for labeling and deep learning. The training process adopts the dice coefficient as the loss function and utilizes Adam optimization. The study evaluated the model's performance using multiple metrics, including intersection over union (IOU), Dice Score, Precision, Recall, and F1-Score, and offers a comparative analysis with other CNN architectures. Results demonstrate the superior segmentation ability of the proposed model, as evidenced by an IOU of 69.87, Dice Score of 76.24, Precision of 88.89, Recall of 73.52, and F1-Score of 80.47 for the DeepLabV3+SE_EfficientNetB0 model. This research contributes to the advancement of plaque segmentation in FLAIR images and offers a compelling approach with substantial potential for medical image analysis and diagnosis.

Re-establishing immune tolerance in multiple sclerosis: focusing on novel mechanisms of mesenchymal stem cell regulation of Th17/Treg balance.

The T-helper 17 (Th17) cell and regulatory T cell (Treg) axis plays a crucial role in the development of multiple sclerosis (MS), which is regarded as an immune imbalance between pro-inflammatory cytokines and the maintenance of immune tolerance. Mesenchymal stem cell (MSC)-mediated therapies have received increasing attention in MS research. In MS and its animal model experimental autoimmune encephalomyelitis, MSC injection was shown to alter the differentiation of CD4+T cells. This alteration occurred by inducing anergy and reduction in the number of Th17 cells, stimulating the polarization of antigen-specific Treg to reverse the imbalance of the Th17/Treg axis, reducing the inflammatory cascade response and demyelination, and restoring an overall state of immune tolerance. In this review, we summarize the mechanisms by which MSCs regulate the balance between Th17 cells and Tregs, including extracellular vesicles, mitochondrial transfer, metabolic reprogramming, and autophagy. We aimed to identify new targets for MS treatment using cellular therapy by analyzing MSC-mediated Th17-to-Treg polarization.

'There's Nothing Wrong With You; You Just Need to Lose Weight'-A Qualitative Exploration of Pelvic Floor Dysfunction Among Women With Multiple Sclerosis and Their Interaction in Seeking Pelvic Healthcare.

INTRODUCTION: Within 10 years of multiple sclerosis (MS) progression, nearly all women will have experienced symptoms associated with bladder, bowel and/or sexual health. Yet despite the impact these symptoms have on physical, psychological and social well-being, it remains an underserved area within the UK healthcare system. STUDY AIM: This research employs a participatory research approach framed within the principles of intersectional feminism to collaboratively investigate the lived experiences of pelvic floor dysfunction (PFD) and healthcare interactions among UK-based women with MS. SETTING AND PARTICIPANTS: Women residing in the United Kingdom with MS were invited to participate in online interviews facilitated by the primary author. ANALYSIS: A thematic framework analysis offering a structured yet adaptable approach to data collection and interpretation. RESULTS: One focus group involving four women with MS and seven individual, one-to-one interviews with women with MS provided insights into the challenges associated with navigating both MS and PFD. Four main themes included: Navigating MS and PFD; Cycles of Control; Mind, Mobility and Bladder Embodiment; Silenced Voices: The Impact of Taboos/Stigma/Dismissal on Preventing Access and Resistance through Collective Community. Six subthemes were also identified. Taken together, these themes cumulatively reflect PFD as an unmet healthcare need. CONCLUSION: Our findings underscore negative healthcare experiences, inadequate information provision and unmet needs related to PFD, emphasising the compounding effects of gender and disability biases. IMPACT: We hope that these insights can lay the groundwork for developing tailored therapeutic interventions and improved PFD healthcare for women with MS. Potential solutions include using existing MS support communities. PUBLIC CONTRIBUTIONS: Women with MS were actively involved in co-producing interview scripts for one-to-one interviews. The primary author shared study findings at an MS group event, engaging in discussions with over 30 individuals, including people with MS and their loved ones. MS advocates played a pivotal role in contextualising the study within the broader lived experience of MS.

Sodium-glucose cotransporter 1/2 inhibition and risk of neurodegenerative disorders: A Mendelian randomization study.

INTRODUCTION: This study aims to evaluate the effects of sodium-glucose cotransporter 1 inhibitors (SGLT1i) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) on neurodegenerative disorders and to investigate the role of hemoglobin A1c (HbA1c) levels. METHODS: Utilizing drug target Mendelian randomization, we employed single nucleotide polymorphisms (SNPs) proximal to the SLC5A1 and SLC5A2 genes to analyze the influence of SGLT1i and SGLT2i on Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), frontotemporal dementia (FTD), Lewy body dementia (LBD), and amyotrophic lateral sclerosis (ALS), with type 2 diabetes (T2D) as a positive control. An additional analysis examined the impact of HbA1c levels on the same disorders. RESULTS: SGLT1i exhibited a significant association with decreased risk for ALS and MS. Conversely, SGLT2i were linked to an increased risk of AD, PD, and MS. Elevated HbA1c levels, independent of SGLT1 and SGLT2 effects, were associated with an increased risk of PD. Sensitivity analyses supported the robustness of these findings. CONCLUSION: Our study suggests that SGLT1i may confer protection against ALS and MS, whereas SGLT2i could elevate the risk of AD, PD, and MS. Additionally, elevated HbA1c levels emerged as a risk factor for PD. These findings underscore the importance of personalized approaches in the utilization of SGLT inhibitors, considering their varying impacts on the risks of neurodegenerative diseases.

Explainable machine learning on baseline MRI predicts multiple sclerosis trajectory descriptors.

Multiple sclerosis (MS) is a multifaceted neurological condition characterized by challenges in timely diagnosis and personalized patient management. The application of Artificial Intelligence (AI) to MS holds promises for early detection, accurate diagnosis, and predictive modeling. The objectives of this study are: 1) to propose new MS trajectory descriptors that could be employed in Machine Learning (ML) regressors and classifiers to predict patient evolution; 2) to explore the contribution of ML models in discerning MS trajectory descriptors using only baseline Magnetic Resonance Imaging (MRI) studies. This study involved 446 MS patients who had a baseline MRI, at least two measurements of Expanded Disability Status Scale (EDSS), and a 1-year follow-up. Patients were divided into two groups: 1) for model development and 2) for evaluation. Three descriptors: ß1, ß2, and EDSS(t), were related to baseline MRI parameters using regression and classification XGBoost models. Shapley Additive Explanations (SHAP) analysis enhanced model transparency by identifying influential features. The results of this study demonstrate the potential of AI in predicting MS progression using the proposed patient trajectories and baseline MRI scans, outperforming classic Multiple Linear Regression (MLR) methods. In conclusion, MS trajectory descriptors are crucial; incorporating AI analysis into MRI assessments presents promising opportunities to advance predictive capabilities. SHAP analysis enhances model interpretation, revealing feature importance for clinical decisions.

Very low monomethyl fumarate exposure via human milk: a case report-a contribution from the ConcePTION project.

Introduction: While breastfeeding is recommended, knowledge regarding medicine transfer to human milk and its safety for nursing infants is limited. Only one paper has previously described dimethyl fumarate (DMF) transfer during breastfeeding in two patients at 5 and 6 months postpartum, respectively. The current case report describes maternal pharmacokinetic data of monomethyl fumarate (MMF), the active metabolite of DMF, and infant exposure estimations of MMF at 3 months postpartum. Methods: A 32-year-old Caucasian woman started DMF therapy (120 mg, 2x/day) for multiple sclerosis at 3 months postpartum, after weaning her infant from breastfeeding. On day 99 after birth, the patient collected four milk samples over 24 h after 6 days of treatment at the initial dose. Additionally, a single maternal blood sample was collected to calculate the milk-to-plasma (M/P) ratio. The samples were analyzed using liquid chromatography coupled with the mass spectrometry method. Results: A wide range of measured steady-state concentrations of MMF (5.5-83.5 ng/mL) was observed in human milk samples. Estimated daily infant dosage values for MMF, calculated with 150 and 200 mL/kg/day human milk intake, were 5.76 and 7.68 µg/kg/day, and the relative infant doses were 0.16 and 0.22%. The observed mean M/P ratio was 0.059, similar to the M/P ratio predicted using the empirical Koshimichi model (0.06). Discussion: Combining this case report with the two previously described cases, the estimated infant exposure is low, albeit with relevant intra- and inter-patient variabilities. Research should further focus on infant exposure and safety.

Efficacy and Safety of Mirabegron Add-on Therapy After Failure With Solifenacin in Multiple Sclerosis Patients With Overactive Bladder: A Pilot Study.

OBJECTIVES: Multiple sclerosis (MS) is a chronic neuroinflammatory and neurodegenerative progressive disease of central nervous system that mostly affects young adults. (1) Because of involvement of spinal cord and brain, lower urinary dysfunction symptoms are commonly encountered. MS patients mostly show overactive bladder symptoms like urgency, frequent daytime urination, and urgency incontinence. Among MS patients, antimuscarinic therapy is the first-line treatment with overactive bladder symptoms as well as in general population yet 30% of the patients show insufficient improvement or intolerance to the treatment (2). In our study, our aim is to evaluate the efficacy and safety of mirabegron add-on treatment in MS patients after inadequate response to antimuscarinic monotherapy. METHODS: University of Kyrenia and Dr Burhan Nalbantoglu State hospital's databases were screened for the study. Seventy patients who were residents diagnosed with MS according to McDonald criteria were questioned. Among these patients, a total of 22 of them were included in the study. Inclusion criteria was at least 3 years of MS diagnosis, score of <6 at Expanded Disability Status Scale, and a score of ≥3 at Overactive Bladder Symptom Score Scale. RESULTS: Among selected patients, 10 mg solifenacin treatment was daily started and followed for 4 weeks. Mirabegron add-on treatment was initiated to the 11 patient who had inadequate improvement in overactive bladder symptom score. After mirabegron add-on treatment among 11 patient, there was a sufficient improvement in overactive bladder symptom score ( P < 0.008). CONCLUSIONS: In our study, we have found that antimuscarinic and mirabegron combination causes improved efficacy for overactive bladder in MS population.

SLO-Net: Enhancing Multiple Sclerosis Diagnosis Beyond Optical Coherence Tomography Using Infrared Reflectance Scanning Laser Ophthalmoscopy Images.

Purpose: Several machine learning studies have used optical coherence tomography (OCT) for multiple sclerosis (MS) classification with promising outcomes. Infrared reflectance scanning laser ophthalmoscopy (IR-SLO) captures high-resolution fundus images, commonly combined with OCT for fixed B-scan positions. However, no machine learning research has utilized IR-SLO images for automated MS diagnosis. Methods: This study utilized a dataset comprised of IR-SLO images and OCT data from Isfahan, Iran, encompassing 32 MS and 70 healthy individuals. A number of convolutional neural networks (CNNs)-namely, VGG-16, VGG-19, ResNet-50, ResNet-101, and a custom architecture-were trained with both IR-SLO images and OCT thickness maps as two separate input datasets. The highest performing models for each modality were then integrated to create a bimodal model that receives the combination of OCT thickness maps and IR-SLO images. Subject-wise data splitting was employed to prevent data leakage among training, validation, and testing sets. Results: Overall, images of the 102 patients from the internal dataset were divided into test, validation, and training subsets. Subsequently, we employed a bootstrapping approach on the training data through iterative sampling with replacement. The performance of the proposed bimodal model was evaluated on the internal test dataset, demonstrating an accuracy of 92.40% ± 4.1% (95% confidence interval [CI], 83.61-98.08), sensitivity of 95.43% ± 5.75% (95% CI, 83.71-100.0), specificity of 92.82% ± 3.72% (95% CI, 81.15-96.77), area under the receiver operating characteristic (AUROC) curve of 96.99% ± 2.99% (95% CI, 86.11-99.78), and area under the precision-recall curve (AUPRC) of 97.27% ± 2.94% (95% CI, 86.83-99.83). Furthermore, to assess the model generalization ability, we examined its performance on an external test dataset following the same bootstrap methodology, achieving promising results, with accuracy of 85.43% ± 0.08% (95% CI, 71.43-100.0), sensitivity of 97.33% ± 0.06% (95% CI, 83.33-100.0), specificity of 84.6% ± 0.10% (95% CI, 71.43-100.0), AUROC curve of 99.67% ± 0.02% (95% CI, 95.63-100.0), and AUPRC of 99.65% ± 0.02% (95% CI, 94.90-100.0). Conclusions: Incorporating both modalities improves the performance of automated diagnosis of MS, showcasing the potential of utilizing IR-SLO as a complementary tool alongside OCT. Translational Relevance: Should the results of our proposed bimodal model be validated in future work with larger and more diverse datasets, diagnosis of MS based on both OCT and IR-SLO can be reliably integrated into routine clinical practice.

[Optical coherence tomography in the diagnosis of multiple sclerosis]. / Opticheskaya kogerentnaya tomografiya v diagnostike rasseyannogo skleroza.

Multiple sclerosis (MS) is a chronic autoimmune-inflammatory and neurodegenerative disease. PURPOSE: This study explores the main structural changes in patients with MS and their relationships with the activity and type of disease course. MATERIAL AND METHODS: This prospective study included 159 patients (318 eyes) with an established diagnosis of MS: group (44 eyes; 13.84%) - relapsing-remitting type MS (RRMS) lasting up to 1 year without a history of optic neuritis (ON); group 2 (30 eyes; 9.43%) - RRMS up to 1 year with ON; group 3 (56 eyes; 17.61%) - RRMS lasting from 1 to 10 years without ON; group 4 (38 eyes; 11.95%) - RRMS from 1 to 10 years with ON; group 5 (49 eyes; 15.41%) - RRMS >10 years without ON; group 6 (37 eyes; 11.63%) - RRMS >10 years with ON; group 7 (34 eyes; 10.69%) - secondary progressive multiple sclerosis (SPMS) without ON; group 8 (30 eyes; 9.43%) - SPMS with ON. Patients underwent standard ophthalmological examinations, including optical coherence tomography. RESULTS: A decrease in structural parameters was diagnosed, progressing with the duration of the disease and the presence of ON: the minimum values of mGCL+IPL (65.83±9.14 µm) and mSNFL (76.37±14.77 µm) were detected in the group with SPMS with ON. High inverse correlations of EDSS with mGCL+IPL and mRNFL were demonstrated, with maximum in the group with the longest duration of MS without ON (-0.48 and -0.52 (p=0.01), respectively). CONCLUSION: Changes in the thickness of the structural parameters of the retina, measured by OCT, can be considered as a predictor of the course of MS.

[A study of the correlation between gray matter atrophy in multiple sclerosis and impairment of cognitive function domains].

Objective: To quantify cerebral cortical and deep gray matter atrophy in patients with multiple sclerosis (MS) and explore its correlation with impairment in domains of cognitive function. Methods: Twenty patients with MS and 16 healthy controls (HC) matched for age, sex, and education level were included. Using FreeSurfer software, based on 3D-MRI technology, the differences in cortical thickness and deep gray matter volume between the two groups were comparatively analyzed. A neuropsychological scale that included six domains of cognitive function was scored on both study groups to analyze the correlation between cortical thickness and volume of deep gray matter in MS patients with impairment in cognitive function domains. Results: Impairment in domains of cognitive function: cognitive impairment was present in 60% MS patients in this study, mainly manifesting as impairment of verbal memory, verbal fluency, visuospatial memory, and information processing speed function (all P<0.05). Of these, the majority had impaired visuospatial memory function (55.0%), and the least number of patients had impaired information processing speed (15.0%). Changes in cortical thickness: compared with the HC group, the MS group showed that cortical atrophy was mainly concentrated in the frontoparietal region, including significant thinning of cortical thickness in the left inferior parietal gyrus, right superior frontal gyrus, and the right superior parietal gyrus (all P<0.05). Among them, atrophy of the left inferior parietal gyrus was significantly positively correlated with the impairment of verbal memory, verbal fluency, and information processing speed (all P<0.05). There was a significant positive correlation between the right superior frontal gyrus atrophy and verbal memory, verbal fluency, and visuospatial memory impairment (all P<0.05). Changes in deep gray matter volume: compared with the HC group, deep gray matter volume in the MS group decreased significantly in the bilateral thalamus, bilateral putamen, bilateral pallidum (all P<0.01), and right nucleus accumbens (P<0.05). Among them, left thalamus atrophy was significantly positively correlated with visuospatial memory impairment (r=0.45, P=0.046), and left putamen atrophy was both significantly positively correlated with visuospatial memory (r=0.45, P=0.047) and information processing speed impairment (r=0.50, P=0.026). Conclusions: Early structural brain changes in MS are dominated by gray matter atrophy. Deep gray matter is more prominent than cortical atrophy.

Tumefactive demyelinating lesions: A literature review of recent findings.

Tumefactive demyelinating lesion is a variant of multiple sclerosis that is a diagnostic challenge. Tumefactive demyelinating lesion requires extensive work-up as its clinical and radiological features are often indistinguishable from other central nervous system lesions, such as tumors. Diagnosis is further complicated by the increasing recognition that tumefactive demyelinating lesions can occur alongside, evolve into, or develop from numerous conditions other than multiple sclerosis, pointing to a possible overlapping etiology. We review herein relevant studies from 2017 onwards to provide a current view on the pathogenesis, clinical and imaging findings, novel diagnostic techniques for differential diagnoses, and management of tumefactive demyelinating lesions.

No one really plans to have multiple sclerosis: Transition readiness and quality of life in paediatric multiple sclerosis.

AIM: We sought to explore the experiences and perceptions of the quality of life of adolescents with pediatric-onset multiple sclerosis and assess their readiness for academic, employment and/or health care-related transitions. BACKGROUND: Adolescents with pediatric-onset multiple sclerosis face unique challenges in managing a chronic illness while navigating future scholastic, social and occupational goals. We conducted a qualitative study with in-depth, semi-structured interviews from July 2017 to March 2019. Adolescents with pediatric-onset multiple sclerosis were recruited from a pediatric neurology subspeciality practice until reaching data saturation. A total of 17 interviews were completed via telephone with participants ages 15 through 26. RESULTS: Through content analysis of the interviews, we identified five major themes: (1) receiving a new diagnosis; (2) adapting to life with pediatric-onset multiple sclerosis; (3) evaluating education/career transition preparedness; (4) adjusting within family life and establishing support systems; and (5) assessing current medical services and preparedness for adult medical care. CONCLUSIONS: Autonomy in health care management, adequate control of physical symptoms and sufficient family support impacted perceptions of quality of life. Implementing a dedicated transition visit, including the parent(s) of those with pediatric-onset multiple sclerosis, early in adolescence may provide an avenue for appropriate anticipatory guidance regarding available services, independent medical management and continuity of care.

The use of modafinil for the treatment of fatigue in multiple sclerosis: A systematic review and meta-analysis of controlled clinical trials.

INTRODUCTION: Multiple sclerosis (MS) is a debilitating neurological condition affecting nearly one million people across the United States. Among the most prominent symptoms of the condition are excessive fatigue and daytime sleepiness. Numerous clinical trials have investigated the efficacy of modafinil in addressing fatigue among these patients. OBJECTIVE: The objective of the present study is to assess the safety and efficacy of modafinil for the treatment of fatigue in MS. METHODOLOGY: An electronic search of PUBMED, ScienceDirect, and Cochrane Central was conducted for articles published from inception to December 2023 using search terms such as "modafinil," "fatigue," and "MS." RESULTS: Seven studies were included in our analysis. Modafinil leads to a meaningful reduction in fatigue when compared with placebo, as measured by Modified Fatigue Impact Scale [mean difference (MD) = -4.42 [-8.01, -.84]; I2 = 45%; p = .02] and Epworth Sleepiness Scale [MD = -.87 [-1.64, -.10]; I2 = 0%; p = .03]. Modafinil also demonstrated a greater risk of precipitating adverse events (e.g., insomnia, gastrointestinal symptoms) when compared with placebo [RR = 1.30 [1.03, 1.66]; I2 = 0%; p = .03]. In quality-of-life assessments, modafinil was associated with overall improvement in well-being [standardized mean difference = .18 [.01, .35]; I2 = 56%; p = .04]. CONCLUSION: The data indicates that modafinil confers a therapeutic benefit when treating fatigue in patients with MS and improves overall quality of life; however, there is a risk of precipitating adverse events. Ultimately, higher quality of evidence may be required to better inform clinical management.

Actual and imagined music-cued gait training for people with multiple sclerosis: a multicentre qualitative study.

OBJECTIVES: To explore the experiences and acceptability of music-cued motor imagery (MCMI), music-cued gait training (MCGT), and combined MCMI and MCGT (MCMI-MCGT) in people with multiple sclerosis (pwMS). We also aimed to explore participants' self-rated health status postintervention and gather recommendations for further programme development. DESIGN: Qualitative study alongside the double-blind randomised controlled real and imagined gait training with music-cueing (RIGMUC) multicentre trial of MCMI, MCGT and MCMI-MCGT. SETTING: PwMS recruited for the RIGMUC trial from Departments of Neurology at Medical Universities of Innsbruck and Graz and Clinic for Rehabilitation Muenster, Austria. PARTICIPANTS: All 132 pwMS with mild to moderate disability randomised into the trial were included in the analysis. METHODS: Participants practised home-based MCMI, MCGT or MCMI-MCGT for 30 min, 4×/week, for 4 weeks. Three trained researchers conducted weekly semistructured telephone interviews during the intervention period, supporting adherence, addressing problems, sharing experiences and assessing intervention acceptability. Follow-up interviews at 4-week postintervention aimed to understand participants' self-rated changes in walking, fatigue and overall health compared with their prestudy condition. Investigator triangulation was employed among the researchers to enhance trustworthiness and credibility. RESULTS: Using thematic analysis, we identified five themes: (1) empowerment, (2) remaining in sync, (3) interconnection between imagined and actual walking, (4) sustaining focus and (5) real-world transfer. Participants appreciated and found the imagined and actual MCGT innovative. Problems included concentration issues, early fatigue in advanced disability and difficulty synchronising with music cues. Positive changes in walking, fatigue and overall health postinterventions were reported offering valuable insights for programme development. CONCLUSIONS: A participatory study to codevelop a music-cued exercise programme for pwMS seems appropriate as participants appreciated the innovation and effectiveness of both imagined and actual MCGT. Future studies should also investigate pwMS' potential and limitations in enhancing their MCMI abilities with intensive therapist-supported practice. TRIAL REGISTRATION NUMBER: DRKS00023978.