Effects of a 6-Week Treadmill Training With and Without Virtual Reality on Frailty in People With Multiple Sclerosis.

OBJECTIVE: To examine the effects of a cognitive-motor rehabilitation program consisting of treadmill training (TT) augmented by virtual reality (TT+VR) on frailty in people with multiple sclerosis (pwMS). DESIGN: Secondary analysis from a multicenter randomized controlled trial investigating the effects of TT+VR, compared with TT only, on measures of mobility and cognitive function in pwMS. SETTING: Four university research laboratories in 3 countries. PARTICIPANTS: A total of 124 pwMS were randomized into the parent trial. Here, we studied a subset of n = 83 participants (mean age, 49.4±9.3y; 73.5% female; expanded disability status scale range, 2.0-6.0), who completed the intervention and had complete preintervention and postintervention frailty data. INTERVENTIONS: Participants were randomly allocated to TT+VR (n=44) or TT (n=39). Both groups trained 3 times a week for 6 weeks. MAIN OUTCOME MEASURES: Frailty was assessed using a 40-item frailty index (FI) through standard validated procedures and represented the primary study outcome. Two exploratory frailty indices were also computed by isolating health-related deficits involving the cognitive (FI-physical) or physical (FI-cognitive) domains from the main FI. The assessments were performed at baseline and after 6 weeks, upon intervention completion. RESULTS: The mean FI of study participants at baseline was 0.33±0.13, indicating a moderate average level of frailty. FI scores improved in both TT+VR and TT groups participants (pooled mean ΔFI, 0.024; 95% CI, 0.010-0.038; F=10.49; P=.002; ηp2=0.115), without any group-by-time interaction (F=0.82; P=.367; ηp2=0.010). However, a significant group-by-time interaction was found for pretraining and posttraining changes in FI-cognitive (F=5.74; P=.019; ηp2=0.066), suggesting a greater improvement for TT+VR group participants than for TT group participants. CONCLUSIONS: TT with or without virtual reality can reduce frailty levels in pwMS. While both TT and TT+VR had a positive effect on overall frailty, only TT+VR improved cognitive aspects of frailty and may represent an appropriate strategy for counteracting frailty in pwMS.

Effect of GBA1 Mutations and APOE Polymorphisms on Survival and Progression Among Ashkenazi Jews with Dementia with Lewy Bodies.

BACKGROUND: Glucocerebrosidase 1 (GBA1) mutations are associated with reduced survival in Parkinson's disease but their effect on survival in dementia with Lewy bodies (DLB) is unclear. OBJECTIVE: To assess the impact of GBA1 mutations on survival among Ashkenazi Jews with DLB, while controlling for APOE status. METHODS: One hundred and forty participants from Tel Aviv Medical Center, Israel were genotyped for GBA1 mutations and APOE polymorphisms. Survival rates and follow-up cognitive screening scores were analyzed. RESULTS: GBA1 mutation carriers had a two-fold increased risk of death (HR = 1.999), while APOE status did not independently affect survival. In a subset of patients with available clinical data (N = 63), carriers of the APOE ε4 allele showed faster cognitive deterioration, while GBA1 mutation carriers also declined more rapidly albeit not significantly. CONCLUSION: Understanding the genetic effects on survival and progression is crucial for patient counseling and inclusion in clinical trials. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Long-term cognitive outcomes in Susac syndrome: A case series.

Susac syndrome (SuS) presents with encephalopathy, visual disturbances, and hearing loss from immune-mediated microvascular occlusion. While acute SuS is well-described, long-term cognitive outcomes with current treatments are underknown. We assessed ten SuS patients treated in accordance with evidence-based guidelines using immunotherapies targeting humoral and cell-mediated pathways. Patients were followed for a median 3.6 years. Initially, cognition inversely correlated with corpus callosum lesions on MRI. All reported cognitive improvement; 5/10 patients had residual deficits in visual attention and executive function. Early, aggressive treatment was associated with good outcomes; extensive early corpus callosum lesions may identify patients at-risk of persistent cognitive deficits.

The effect of COVID-19 vaccination on multiple sclerosis activity as reflected by MRI.

INTRODUCTION: Examining the safety of theBNT162b2 mRNA vaccine in multiple sclerosis (MS) patients remains inconclusive, particularly regarding the potential for disease exacerbations. This study aims to assess the effects of BNT162b2 COVID-19 vaccination on disease activity in MS patients through sequential MRI imaging. METHODS: A retrospective study of 84 MS patients from five Israeli hospitals was conducted. MS lesion load was determined from three brain MRI scans, one postvaccination and two prevaccination scans. A post hoc analysis compared subgroups featuring vaccinated and unvaccinated patients respectively, with early onset MS. RESULTS: The cohort included 70 women with early onset (mean age 16.4 ± 0.8 years) and adult onset (mean age 34.9 ± 1.1 years) MS. Among the early onset group, vaccinated patients showed an increased risk of new lesions (p = .00026), while there was no increased risk among adult-onset patients. Additionally, a comparison between early onset vaccinated and nonvaccinated groups revealed a higher risk of increased lesions in the vaccinated group (p = .024). DISCUSSION: Overall, the study suggests that the BNT162b2 vaccine is generally safe in MS patients, with no association found between vaccination and new lesions in most patients. However, close MRI follow-up is recommended for early-onset MS cases to monitor lesion development.

Gait and heart rate: do they measure trait or state physical fatigue in people with multiple sclerosis?

BACKGROUND: Trait and state physical fatigue (trait-PF and state-PF) negatively impact many people with multiple sclerosis (pwMS) but are challenging symptoms to measure. In this observational study, we explored the role of specific gait and autonomic nervous system (ANS) measures (i.e., heart rate, HR, r-r interval, R-R, HR variability, HRV) in trait-PF and state-PF. METHODS: Forty-eight pwMS [42 ± 1.9 years, 65% female, EDSS 2 (IQR: 0-5.5)] completed the Timed Up and Go test (simple and with dual task, TUG-DT) and the 6-min walk test (6MWT). ANS measures were measured via a POLAR H10 strap. Gait was measured using inertial-measurement units (OPALs, APDM Inc). Trait-PF was evaluated via the Modified Fatigue Impact Scale (MFIS) motor component. State-PF was evaluated via a Visual Analog Scale (VAS) scale before and after the completion of the 6MWT. Multiple linear regression models identified trait-PF and state-PF predictors. RESULTS: Both HR and gait metrics were associated with trait-PF and state-PF. HRV at rest was associated only with state-PF. In models based on the first 3 min of the 6MWT, double support (%) and cadence explained 47% of the trait-PF variance; % change in R-R explained 43% of the state-PF variance. Models based on resting R-R and TUG-DT explained 39% of the state-PF. DISCUSSION: These findings demonstrate that specific gait measures better capture trait-PF, while ANS metrics better capture state-PF. To capture both physical fatigue aspects, the first 3 min of the 6MWT are sufficient. Alternatively, TUG-DT and ANS rest metrics can be used for state-PF prediction in pwMS when the 6MWT is not feasible.

Real-World experience with efgartigimod in patients with myasthenia gravis.

Recommendations for the treatment of myasthenia gravis (MG) have been difficult to develop because of limited evidence from large randomized controlled trials. New drugs and treatment approaches have recently been shown to be effective in phase 3 studies in seropositive generalized (g) MG. One such drug is efgartigimod, a human-Fc-fragment of IgG1, with a high affinity for the endosomal FcRn. We conducted a multicenter study to evaluate the real-world clinical and safety effects of efgartigimod in 22 gMG patients. We evaluated the strategies for the timing of re-treatment with it. The participants received a total of 59 efgartigimod -treatment cycles. The median number of cycles was 2 (range 1-6). Twenty patients (86.3%) improved by at least 2 MG-ADL points after the first treatment cycle. The median MG-ADL score at baseline was 6.5 (range: 3-17) and 2.5 (range: 0-9) post-treatment (p < 0.001). A consistent improvement of at least 2 points in the MG-ADL score after each cycle occurs in 18 patients. The effect duration of the treatment was usually between 4 and 12 weeks. Two major clinical patterns of treatment response were found. Treatment with efgartigimod was also associated with significant reductions of prednisone doses Overall, the treatment was safe and associated with only minor adverse events. The single fatality was apparently due tosevere respiratory failure. We found that efgartigimod is clinically effective, may be used as a steroid sparing agent and is generally safe for gMG patients. We recommend a personalized preventive treatment approach until clinical stabilization, followed by discontinuation and periodic evaluations.

Smartphone-based gait assessment for multiple sclerosis.

INTRODUCTION: Multiple Sclerosis causes gait alteration, even in the early stages of the disease. Traditional methods to quantify gait impairment, such as performance-based measures, lab-based motion analyses, and self-report, have limited ecological relevance. The Mon4t® app is a digital tool that uses sensors embedded in standard smartphones to measure various gait parameters. OBJECTIVES: To evaluate the use of Mon4t® technology in monitoring MS patients. METHODS: 100 MS patients and age-matched healthy controls were evaluated using both a human rater and the Mon4t Clinic™ app. Three motor tasks were performed: 3m Timed up and go test (TUG), 10m TUG, and tandem walk. The digital markers were used to compare MS vs. HC, MS with EDSS=0 vs. HC, and MS with EDSS=0 vs. MS with EDSS>0. Within the MS EDSS>0 group, correlations between digital gait markers and the EDSS score were calculated. RESULTS: Significant differences were found between MS patients and HC in multiple gait parameters. When comparing MS patients with minimal disability (EDSS=0) and HC: On the 3m TUG task, MS patients took longer to complete the task (mean difference 0.167seconds, p =0.034), took more steps (mean difference 1.32 steps, p =0.003), and had a weaker ML step-to-step correlation (mean difference 0.1, p = 0.001). The combination of features from the three motor tasks allowed distinguishing a nondisabled MS patient from a HC with high confidence (AUC of 85.65 on the ROC). When comparing MS patients with minimal disability (EDSS=0) to those with higher disability (EDSS>0): On the tandem walk task, patients with EDSS>0 took significantly longer to complete 10 steps than those with EDSS=0 (mean difference 4.63 seconds, p < 0.001), showed greater ML sway (mean difference 0.2, p < 0.001), and had larger angular velocity in the SI axis on average (mean difference 2.31 degrees/sec, p = 0.01). A classification model achieved 81.79 ROC AUC. In the subgroup of patients with EDSS>0, gait features significantly correlated with EDSS score in all three tasks. CONCLUSION: The findings demonstrate the potential of digital gait assessment to augment traditional disease monitoring and support clinical decision making. The Mon4t® app provides a convenient and ecologically relevant tool for monitoring MS patients and detecting early changes in gait impairment.

Olfactory function in Susac syndrome.

OBJECTIVES: Susac syndrome is a rare autoimmune endotheliopathy involving the brain, retina, and inner ear. Olfactory dysfunction is a common early manifestation of several central nervous system diseases, including neurodegenerative diseases and autoimmune-mediated diseases such as Multiple Sclerosis. While the literature is abundant about the Susac syndrome classic triad of encephalopathy, branch retinal artery occlusion, and low-frequency sensorineural hearing loss, little is known about the extent of olfactory sense involvement. METHODS: Using the Sniffin' Sticks test, this study evaluated olfactory function (identification and threshold) in ten recovering Susac syndrome patients under our clinic surveillance with a median of 3.1 (SD=1.53) years post-disease onset. RESULTS: olfactory assessment by threshold and odor identification were within the normal range. No differences between recovering Susac syndrome patients to standard norms of odor identification and threshold were found. CONCLUSIONS: Our findings do not support olfactory dysfunction in Susac syndrome and thereby, do not support olfactory assessment as a reliable biomarker for this condition.

Practical recommendations on treatment of multiple sclerosis with Cladribine: an Israeli Experts Group Viewpoint.

Cladribine tablets (Mavenclad®) were approved by the European Union in 2017 as high-efficacy therapy for highly active relapsing-remitting multiple sclerosis. In Israel, Mavenclad® was approved in 2018. Real-life experience has confirmed the efficacy of cladribine tablets over at least 4 years from the initial course. During the last years, several questions were raised concerning the management of people with MS who show disease activity during years 3 and 4 post-cladribine initiation and what treatment decisions are needed beyond year 4. A few expert boards have tried to provide insight based on research data and to suggest recommendations on the therapeutic dilemmas and treatment decisions with cladribine. However, there is currently no widely accepted consensus about these issues. The vast clinical experience gained in Israel in the past 5 years in several MS centers across the country allows for a broad perspective of the outcomes with long-term cladribine use. This article summarizes previously published recent recommendations and describes the insights of Israeli neurology key opinion leaders that convened for an advisory board meeting on January 29th, 2023, with the aim of reaching a consensus regarding cladribine long-term treatment and follow-up.

Association Between Frailty and Free-Living Walking Performance in People With Multiple Sclerosis.

OBJECTIVE: The purpose of this study was to examine the association between frailty and the quantity and quality of free-living walking and the mediating effect of frailty on the relationship between disability and walking performance in people with multiple sclerosis (MS). METHODS: Ninety-nine people with relapsing-remitting MS (mean age = 49.3 [SD = 9.8] years; 73.7% women; Expanded Disability Status Scale [EDSS] score range = 2.0-6.0) wore a triaxial accelerometer for 7 days. Recorded measures reflected the quantity (daily step counts, number of 30-second walking bouts, and signal vector magnitude [SVM]) and quality (gait speed, step cadence, step and stride regularity, and sample entropy) of walking. For each walking quality measure, the typical (median), best (90th percentile), and worst (10th percentile) values were calculated. Frailty was evaluated through a 38-item frailty index. RESULTS: Participants were classified as not frail (n = 31), moderately frail (n = 34), and severely frail (n = 34) on the basis of established procedures. Patients who were moderately and severely frail exhibited poorer performance in all measures of walking quantity and quality, except for sample entropy, than individuals who were not frail. No differences in free-living walking performance were observed between the moderately and severely frail groups. Frailty did not mediate the relationship between disability (EDSS) and measures of walking quality. Conversely, frailty had a significant mediating effect on the relationship between disability and measures of walking quantity, such as daily step counts (indirect effect: b = -220.42, 95% CI = -452.03 to -19.65) and SVM (indirect effect: b = -1.00, 95% CI = -1.86 to -0.30). CONCLUSION: Frailty is associated with poorer free-living walking performance in people with MS. The study findings suggest that frailty, rather than disability, may be primarily responsible for the lower amount of physical activity performed by people with MS in the real world. IMPACT: The observation that frailty and disability are differently related to measures of walking quality and quantity underscores the importance of a targeted approach to rehabilitation in people with MS.

New Insights on DR and DQ Human Leukocyte Antigens in Anti-LGI1 Encephalitis.

BACKGROUND AND OBJECTIVES: To explore the clinical characteristics and HLA associations of patients with anti-leucine-rich glioma-inactivated 1 encephalitis (LGI1E) from a large single center in Israel. Anti-LGI1E is the most commonly diagnosed antibody-associated encephalitic syndrome in adults. Recent studies of various populations reveal significant associations with specific HLA genes. We examined the clinical characteristics and HLA associations of a cohort of Israeli patients. METHODS: Seventeen consecutive patients with anti-LGI1E diagnosed at Tel Aviv Medical Center between the years 2011 and 2018 were included. HLA typing was performed using next-generation sequencing at the tissue typing laboratory of Sheba Medical Center and compared with data from the Ezer Mizion Bone Marrow Donor Registry, containing over 1,000,000 samples. RESULTS: Our cohort displayed a male predominance and median age at onset in the 7th decade, as previously reported. The most common presenting symptom was seizures. Notably, paroxysmal dizziness spells were significantly more common than previously reported (35%), whereas faciobrachial dystonic seizures were found only in 23%. HLA analysis revealed overrepresentation of DRB1*07:01 (OR: 3.18, CI: 20.9 p < 1.e-5) and DRB1*04:02 (OR: 3.8, CI: 20.1 p < 1.e-5), as well as of the DQ allele DQB1*02:02 (OR: 2.8, CI: 14.2 p < 0.0001) as previously reported. A novel overrepresentation observed among our patients was of the DQB1*03:02 allele (OR: 2.3, CI: 6.9 p < 0.008). In addition, we found DR-DQ associations, among patients with anti-LGI1E, that showed complete or near-complete linkage disequilibrium (LD). By applying LD analysis to an unprecedentedly large control cohort, we were able to show that although in the general population, DQB*03:02 is not fully associated with DRB1*04:02, in the patient population, both alleles are always coupled, suggesting the DRB1*04:02 association to be primary to disease predisposition. In silico predictions performed for the overrepresented DQ alleles reveal them to be strong binders of LGI1-derived peptides, similarly to overrepresented DR alleles. These predictions suggest a possible correlation between peptide binding sites of paired DR-DQ alleles. DISCUSSION: Our cohort presents distinct immune characteristics with substantially higher overrepresentation of DRB1*04:02 and slightly lower overrepresentation of DQB1*07:01 compared with previous reports implying differences between different populations. DQ-DR interactions found in our cohort may shed additional light on the complex role of immunogenetics in the pathogenesis of anti-LGI1E, implying a possible relevance of certain DQ alleles and DR-DQ interactions.

Treadmill training with virtual reality to enhance gait and cognitive function among people with multiple sclerosis: a randomized controlled trial.

BACKGROUND: Motor and cognitive impairments impact the everyday functioning of people with MS (pwMS). The present randomized controlled trial (RCT) evaluated the benefits of a combined motor-cognitive virtual reality training program on key motor and cognitive symptoms and related outcomes in pwMS. METHODS: In a single-blinded, two-arm RCT, 124 pwMS were randomized into a treadmill training with virtual reality (TT + VR) group or a treadmill training alone (TT) (active-control) group. Both groups received three training sessions per week for 6 weeks. Dual-tasking gait speed and cognitive processing speed (Symbol Digit Modalities Test, SDMT, score) were the primary outcomes. Secondary outcomes included additional tests of cognitive function, mobility, and patient-reported questionnaires. These were measured before, after, and 3 months after training. RESULTS: Gait speed improved (p < 0.005) in both groups, similarly, by about 10 cm/s. The TT + VR group (n = 53 analyzed per-protocol) showed a clinically meaningful improvement of 4.4 points (95% CI 1.9-6.8, p = 0.001) in SDMT, compared to an improvement of only 0.8 points in the TT (n = 51 analyzed per-protocol) group (95% CI 0.9-2.5 points, p = 0.358) (group X time interaction effect p = 0.027). Furthermore, TT + VR group-specific improvements were seen in depressive symptoms (lowered by 31%, p = 0.003), attention (17%, p < 0.001), and verbal fluency (11.6% increase, p = 0.002). DISCUSSION: These findings suggest that both TT and TT + VR improve usual and dual-task gait in pwMS. Nonetheless, a multi-modal approach based on VR positively impacts multiple aspects of cognitive function and mental health, more than seen after treadmill-treading alone. Trial registered at ClinicalTrials.Gov NCT02427997.

Fragmentation, circadian amplitude, and fractal pattern of daily-living physical activity in people with multiple sclerosis: Is there relevant information beyond the total amount of physical activity?

BACKGROUND: Physical activity is lower in people with multiple sclerosis (pwMS) compared to healthy controls. Previous work focused on studying activity levels or activity volume, but studies of daily-living rest-activity fragmentation patterns, circadian rhythms, and fractal regulation in pwMS are limited. Based on findings in other cohorts, one could suggest that these aspects of daily-living physical activity will provide additional information about the health and well-being of pwMS. Therefore, here, we aimed to (1) identify which fragmentation, fractal, and circadian amplitude measures differ between pwMS and healthy controls, (2) evaluate the relationship between fragmentation, fractal, and circadian amplitude measures and disease severity, and (3) begin to evaluate the added value of those measures, as compared to more conventional measures of physical activity (e.g., mean signal vector magnitude (SVM). A global measure of the overall volume of physical activity). METHODS: 132 people with relapsing-remitting MS (47±11 yrs, 69.7% female, Expanded Disability Status Scale, EDSS, median (IQR): 3 (2-4)) and 90 healthy controls (46±11 yrs, 47.8% female) were asked to wear a 3D accelerometer on their lower back for 7 days. Rest-activity fragmentation, circadian amplitude, fractal regulation, and mean SVM metrics were extracted. PwMS and healthy controls were compared using independent samples t-tests and linear regression, including comparisons adjusted for mean SVM to control for the effect of physical activity volume. Spearman correlations between measures and logistic regressions were used to identify the clinical condition based on the measures that differed significantly after adjusting for SVM. All analyses included adjustments for demographic and clinical parameters (e.g., age, sex). RESULTS: Multiple measures of activity fragmentation significantly differed between pwMS and healthy controls, reflecting a more fragmented active behavior in pwMS. PwMS had a lower circadian rhythm amplitude, indicating a smaller amplitude in the circadian changes of daily activity, and weaker temporal correlations as based on the fractal analysis. When taking into account physical activity volume, one circadian amplitude measure and one fractal measure remained significantly different in pwMS and controls. Fragmentation measures and circadian amplitude measures were significantly associated with disability level as measured by the EDSS; the association with circadian amplitude remained significant, even after adjusting for the mean SVM. CONCLUSION: The physical activity patterns of pwMS differ from those of healthy individuals in rest-activity fragmentation, the amplitude of the circadian rhythm, and fractal regulation. Measures describing these aspects of activity provide information that is not captured in the total volume of physical activity and could, perhaps, augment the monitoring of disease progression and evaluation of the response to interventions.

CTGF/CCN2 has a possible detrimental role in the inflammation and the remyelination failure in the early stages of multiple sclerosis.

Connective tissue growth factor (CTGF/CCN2) is a proinflammatory and an oligodendrocyte-differentiating blocking agent. It is found in MS lesions, which raises the possibility of involvement in MS pathogenesis. We found that its CSF and serum levels were higher in RR-MS patients than in controls and for serum compared to PP and SP-MS. Immune cells of both RR-MS and controls secreted CTGF/CCN2, which was enhanced by CD3/CD28 stimulation or by LPS. Anti-CTGF treatment of mice with experimental autoimmune encephalitis ameliorated its clinical severity. CTGF/CCN2 may play a role in the immune pathogenesis of MS and in remyelination failure in early stages of MS.

BNT162b2 mRNA COVID-19 vaccine three-dose safety and risk of COVID-19 in patients with myasthenia gravis during the alpha, delta, and omicron waves.

COVID-19 affects the respiratory parenchyma and may potentially contribute to the tendency of myasthenia gravis (MG) patients to develop respiratory failure. It is, therefore, important to study the safety of vaccines against SARS-CoV-2 and to assess the risk of COVID-19 in MG patients. The safety of the three-dose BNT162b2 mRNA vaccine and outcomes of COVID-19 during the alpha, delta, and omicron waves were studied in MG patients as well as the rate of exacerbations and safety for a period of up to 6 weeks from each vaccine dose and patient morbidity and mortality during COVID-19 compared to the general population. 430 vaccine doses were administered across 150 patients. Thirteen patients (8.7%) complained of exacerbation within 6 weeks of each vaccine dose. Both MG onset rate and exacerbation rate were similar to previous years. MG exacerbation rate among fifteen patients who had COVID-19 was significantly higher (40%) compared to the rate following vaccination. During the alpha and delta waves, COVID-19 mortality and severe disease were significantly higher (26.7%) compared to the general population (0.96%). All of them were unvaccinated and had generalized MG. During the omicron wave, all the MG patients who contracted COVID-19 were vaccinated and had mild disease. We concluded that COVID-19 is hazardous for generalized MG patients, while the vaccination did not raise the risk for either exacerbation or new onset of MG and was associated with a reduced risk for severe COVID-19. Hence, it is recommended for generalized MG patients to get vaccinated.

Differences in MS clinical and epidemiological characteristics between Ashkenazi and non-Ashkenazi Jewish patients in Israel: a retrospective single center study.

The prevalence and severity of Multiple Sclerosis (MS) varies across different ethnicities, with a tendency to a more severe phenotype in non-Caucasian populations.  Our objective was to evaluate the differences in disease phenotype between Ashkenazi Jewish and Non-Ashkenazi Jewish patients in Israel. We conducted a single center retrospective cohort study in which subjects were assigned to Ashkenazi or Non-Ashkenazi groups according to self-reported ancestry and disease severity was assessed using the expanded disability status (EDSS), MS severity score (MSSS), progression index (PI) and MRI metrics. 330 Ashkenazi Jewish (AJ) and 207 Non-Ashkenazi Jewish patients (Non-AJ) were included. Non-AJ had a younger age of disease onset (32.7 years vs. 35.7 years, p = 0.05), with a lower proportion of females (62.3% vs. 73.3%, p = 0.01). These differences were maintained within the subgroup of Israeli native patients. Ethnicity was a significant predictor of MSSS (ß = 0.601, p = 0.003), with a higher estimate than that of other epidemiological factors. To conclude, Non-AJ patients had an earlier age of onset and a more disabling disease as well as having a more balanced female to male ratio compared to AJ patients. These findings demonstrate variability of disease phenotype within Caucasian patient's dependent on their ethnicity despite equivalent access to healthcare services.

Frailty and Falls in People Living With Multiple Sclerosis.

OBJECTIVE: To explore the association between frailty and history of falls in people living with multiple sclerosis (MS). DESIGN: Secondary analysis. SETTING: University research laboratories in the United States and Israel. PARTICIPANTS: A total of 118 people (N=118) with relapsing-remitting MS (mean age, 48.9±10.0 years; 74.6% female; Expanded Disability Status Scale [EDSS] range, 1.0-6.0) were studied in this cross-sectional analysis. INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: A frailty index was calculated from 40 health deficits by following standard validated procedures. The number of falls (12-month history) was recorded. RESULTS: Overall, 33.9%, 29.7%, and 36.4% of participants were classified as nonfrail, moderately frail, and severely frail, respectively. The frailty index was significantly correlated (ρ=0.37, P<.001) with higher scores on the EDSS. In univariable negative binomial regression analysis, the frailty index was associated with a higher number of falls (incidence rate ratio [IRR]=3.33; 95% CI, 1.85-5.99; P<.001). After adjustment for age, sex, and EDSS, frailty remained strongly associated with history of falls (IRR=2.78; 95% CI, 1.51-5.10; P=.001). CONCLUSIONS: The current study identifies a significant relationship between frailty and history of falls in MS, independent of age, sex, and disease severity. These findings support the notion that frailty is a syndrome related to but independent of disability in MS.

Susac's syndrome - A new ocular finding and disease outcome.

BACKGROUND: Susac's syndrome, a rare autoimmune vasculo-occlusive disease, may pose a diagnostic challenge and result in a devastating ocular and systemic outcome. Our study identifies a new retinal finding and evaluates disease outcome. We aimed to assess clinical and imaging findings, systemic manifestations and disease outcome in patients with ocular Susac's syndrome under immunosuppressive/immunomodulation therapies. METHODS: Retrospective tertiary center study including patients with a diagnosis of Susac's syndrome with >12 months follow up. Medical record review including ocular, neurological and auditory clinical and imaging findings, and treatment modalities. Main outcome measures were clinical manifestations and disease outcome. RESULTS: Seven patients (14 eyes) with a mean age of 34.1 years were included. Mean follow-up was 31.9 months (12.4-72.4). All had bilateral ocular disease. Retinal microaneurysms, a new ocular finding, were demonstrated in 5 patients and persisted at the final visit. In 5 eyes, they further extended during follow-up. All were treated with immunosuppressive drugs and 5/7 additional immunomodulation therapy. At last examination, best corrected visual acuity was >20/40 in all eyes, 1/10 eyes had visual field deterioration, no eye had active ocular disease, all patients achieved neurological stability, and 1 patient had auditory deterioration. CONCLUSION: Retinal microaneurysms, a new ocular finding in Susac's syndrome, were present in most of our patients, indicating ischemic retinal damage. Immunosuppressive and immunomodulation therapies seem to be highly effective in the control of disease activity.

Mutations in GBA and LRRK2 Are Not Associated with Increased Inflammatory Markers.

BACKGROUND: Inflammation is an integral part of neurodegeneration including in Parkinson's disease (PD). Ashkenazi Jews have high rates of genetic PD with divergent phenotypes among GBA-PD and LRRK2-PD. The role of inflammation in the prodromal phase of PD and the association with disease phenotype has yet to be elucidated. OBJECTIVE: To assess central and peripheral cytokines among PD patients with mutations in the LRRK2 and GBA genes and among non-manifesting carriers (NMC) of these mutations in order to determine the role of inflammation in genetic PD. METHODS: The following cytokines were assessed from peripheral blood and cerebrospinal fluid (CSF): TNF-α, IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10 and INF- γ. A comprehensive intake including general medical conditions, use of anti-inflammatory treatments, motor and cognitive assessments and additional laboratory measures were recorded, enabling the construction of the MDS probable prodromal score. RESULTS: Data from 362 participants was collected: 31 idiopathic PD (iPD), 30 LRRK2-PD, 77 GBA-PD, 3 homozygote GBA-PD, 3 GBA-LRRK2-PD, 67 LRRK2-NMC, 105 GBA-NMC, 14 LRRK2-GBA-NMC, and 32 healthy controls. No between-group differences in peripheral or CSF cytokines were detected. No correlation between disease characteristics or risk for prodromal PD could be associated with any inflammatory measure. CONCLUSION: In this study, we could not detect any evidence on dysregulated immune response among GBA and LRRK2 PD patients and non-manifesting mutation carriers.

Increased Expression of Ephrins on Immune Cells of Patients with Relapsing Remitting Multiple Sclerosis Affects Oligodendrocyte Differentiation.

The effect of the inflammatory response on regenerative processes in the brain is complex. This complexity is even greater when the cause of the tissue damage is an autoimmune response. Multiple sclerosis (MS) is an immune-mediated disease in which demyelination foci are formed in the central nervous system. The degree of repair through oligodendrocyte regeneration and remyelination is insufficient. Ephrins are membrane-bound ligands activating tyrosine kinase signaling proteins that are known to have an inhibitory effect on oligodendrocyte regeneration. In this study, we examined the expression of ephrins on immune cells of 43 patients with relapsing-remitting (RR) MS compared to 27 matched healthy controls (HC). We found an increased expression of ephrin-A2, -A3 and -B3, especially on T cell subpopulations. We also showed overexpression of ephrins on immune cells of patients with RR-MS that increases the forward signaling pathway and that expression of ephrins on immune cells has an inhibitory effect on the differentiation of oligodendrocyte precursor cells (OPCs) in vitro. Our study findings support the concept that the immune activity of T cells in patients with RR-MS has an inhibitory effect on the differentiation capacity of OPCs through the expression and forward signaling of ephrins.