A highly reproducible and efficient method for retinal organoid differentiation from human pluripotent stem cells.

Human pluripotent stem cell (hPSC)-derived retinal organoids are three-dimensional cellular aggregates that differentiate and self-organize to closely mimic the spatial and temporal patterning of the developing human retina. Retinal organoid models serve as reliable tools for studying human retinogenesis, yet limitations in the efficiency and reproducibility of current retinal organoid differentiation protocols have reduced the use of these models for more high-throughput applications such as disease modeling and drug screening. To address these shortcomings, the current study aimed to standardize prior differentiation protocols to yield a highly reproducible and efficient method for generating retinal organoids. Results demonstrated that through regulation of organoid size and shape using quick reaggregation methods, retinal organoids were highly reproducible compared to more traditional methods. Additionally, the timed activation of BMP signaling within developing cells generated pure populations of retinal organoids at 100% efficiency from multiple widely used cell lines, with the default forebrain fate resulting from the inhibition of BMP signaling. Furthermore, given the ability to direct retinal or forebrain fates at complete purity, mRNA-seq analyses were then utilized to identify some of the earliest transcriptional changes that occur during the specification of these two lineages from a common progenitor. These improved methods also yielded retinal organoids with expedited differentiation timelines when compared to traditional methods. Taken together, the results of this study demonstrate the development of a highly reproducible and minimally variable method for generating retinal organoids suitable for analyzing the earliest stages of human retinal cell fate specification.

Multiple sclerosis.

Multiple sclerosis remains one of the most common causes of neurological disability in the young adult population (aged 18-40 years). Novel pathophysiological findings underline the importance of the interaction between genetics and environment. Improvements in diagnostic criteria, harmonised guidelines for MRI, and globalised treatment recommendations have led to more accurate diagnosis and an earlier start of effective immunomodulatory treatment than previously. Understanding and capturing the long prodromal multiple sclerosis period would further improve diagnostic abilities and thus treatment initiation, eventually improving long-term disease outcomes. The large portfolio of currently available medications paved the way for personalised therapeutic strategies that will balance safety and effectiveness. Incorporation of cognitive interventions, lifestyle recommendations, and management of non-neurological comorbidities could further improve quality of life and outcomes. Future challenges include the development of medications that successfully target the neurodegenerative aspect of the disease and creation of sensitive imaging and fluid biomarkers that can effectively predict and monitor disease changes.

Establishing the consistency of a voice recognition symbol digit modalities test analogue.

BACKGROUND: We previously demonstrated the convergent validity of a fully automated voice recognition analogue of the Symbol Digit Modalities Test (VR-SDMT) for evaluating processing speed in people with multiple sclerosis (pwMS). OBJECTIVE/METHODS: We aimed to replicate these results in 54 pwMS and 18 healthy controls (HCs), demonstrating the VR-SDMT's reliability. RESULTS: Significant correlations were found between the VR-SDMT and the traditional oral SDMT in the multiple sclerosis (MS) (r = -0.771, p < 0.001) and HC (r = -0.785, p < 0.001) groups. CONCLUSION: Taken collectively, our two studies demonstrate the reliability and validity of the VR-SDMT for assessing processing speed in pwMS.

A national case-control study investigating demographic and environmental factors associated with NMOSD.

BACKGROUND: Risk factors for aquaporin-4 (AQP4+) antibody neuromyelitis optica spectrum disorder (NMOSD) are not well-established. OBJECTIVE: To investigate demographic and environmental factors associated with NMOSD using a validated questionnaire and case-control design. METHODS: We enrolled patients with AQP4 + NMOSD through six Canadian Multiple Sclerosis Clinics. Participants completed the validated Environmental Risk Factors in Multiple Sclerosis Study (EnvIMS) questionnaire. Their responses were compared to those of 956 unaffected controls from the Canadian arm of EnvIMS. We calculated odds ratios (ORs) for the association between each variable and NMOSD using logistic regression and Firth's procedure for rare events. RESULTS: In 122 participants (87.7% female) with NMOSD, odds of NMOSD in East Asian and Black participants were ⩾8 times that observed in White participants. Birthplace outside Canada was associated with an increased risk of NMOSD (OR = 5.5, 95% confidence interval (CI) = 3.6-8.3) as were concomitant autoimmune diseases (OR = 2.7, 95% CI = 1.4-5.0). No association was observed with reproductive history or age at menarche. CONCLUSION: In this case-control study, risk of NMOSD in East Asian and Black versus White individuals was greater than that observed in many previous studies. Despite the preponderance of affected women, we did not observe any association with hormonal factors such as reproductive history or age at menarche.

Detecting isolated cognitive relapses in persons with MS.

BACKGROUND: The existence of isolated cognitive relapses (ICRs) in persons with MS (PwMS) has been debated. OBJECTIVE: To examine relapses with decline on Symbol Digit Modalities Test (SDMT) but no change on Expanded Disability Status Scale (EDSS). METHODS: This 3-year prospective cohort study identified PwMS experiencing a relapse with decrease on SDMT. Participants with SDMT decline/stable EDSS were labeled "ICR," while those with a corresponding decrease on EDSS were classified "Relapse with Cognitive Decline (RCD)." Two definitions of SDMT decline were explored: (1) ⩾ 8 points, and (2) ⩾ 4 points. Logistic regression was used to analyze the relationship between ICR and RCD. RESULTS: The full cohort had 592 participants: 83 experienced relapses; 22 (26.5%) had an SDMT decrease of ⩾ 8 points; 14 (63.6%) met ICR criteria. Logistic regression (X2(1) = 5.112, p = 0.024) using demographics and disease characteristics explained 28.4% of the variance in ICR versus RCD. Only the MS Neuropsychological Questionnaire was associated with ICR (odds ratio (OR): 8.6; 95% confidence interval (CI): 1.1-16.4) 40 relapsing participants with SDMT decrease of ⩾ 4 points were identified: 26 (65%) had a stable EDSS (ICR). Logistic regression did not find any variable predictive of ICR. CONCLUSION: This prospective study demonstrates evidence of ICR in PwMS.

Importance of Identifying Cognitive Impairment in Multiple Sclerosis.

This article aims to highlight the impact of cognitive impairment on outcomes and quality of life for people with multiple sclerosis (MS) and to review current evidence for the efficacy of disease-modifying therapies (DMTs) and other interventions. In addition, we provide clinical practice insights regarding screening and management of cognitive impairment in people with MS. Evidence suggests that cognitive deterioration often accompanies magnetic resonance imaging changes. Neocortical volume and deep grey matter atrophy correlate with cognitive impairment. Similarly, cognitive decline is predictive of a higher lesion burden. Cognitive impairment is an important clinical measure of disability and negatively impacts quality of life. Phase 3 studies suggest that DMTs such as natalizumab, ozanimod and fingolimod may provide long-lasting, clinically meaningful effects on cognition in people with MS. Further data are needed to support the use of adjunct cognitive behavioural and exercise interventions for people with MS who have cognitive impairment. More data are needed to define appropriate management strategies for cognitive impairment in people with MS. Baseline and periodic screening for cognitive impairment and inclusion of cognitive impairment as a clinical trial endpoint will help to inform efforts to manage this important aspect of MS.

Recommendation to update the British Society for Cutaneous Allergy corticosteroid series.

BACKGROUND: Patch testing is an important investigation when dermatitis is unresponsive to, or worsened by, topical corticosteroid treatment. There is a balance to be struck between testing too many allergens, which is expensive, time consuming and risks causing sensitization, and testing too few, which risks missing the diagnosis. The current British Society for Cutaneous Allergy (BSCA) corticosteroid series comprises eight allergens and was last updated in February 2007. AIM: To review and update the BSCA corticosteroid series. METHODS: We retrospectively analysed data from 16 patch test centres in the UK and Ireland for all patients who were patch tested to a corticosteroid series between August 2017 and July 2019. We recorded the allergens tested, the number and percentage tested to a corticosteroid series and the number of positive results for each allergen. We identified the allergens that test positive in ≥ 0.1% of selectively tested patients. RESULTS: Overall, 3531 patients were tested to a corticosteroid series in the 16 centres. The number of allergens tested ranged from 7 to 18 (mean 10). The proportion of patch test patients who were tested to a corticosteroid series ranged from 1% to 99%. Six allergens in the 2017 BSCA series tested positive in ≥ 0.1% of patients. Nine allergens not in the BSCA corticosteroid series tested positive in ≥ 0.1% of patients. CONCLUSION: This audit demonstrates the importance of regular review of recommended series and the significant variations in practice. The new BSCA corticosteroid series that we recommend contains 13 haptens, with the addition of the patient's own steroid creams as appropriate.

Interpreting change on the Symbol Digit Modalities Test in people with relapsing multiple sclerosis using the reliable change methodology.

BACKGROUND: The Symbol Digit Modalities Test (SDMT) is increasingly utilized in clinical trials. A SDMT score change of 4 points is considered clinically important, based on association with employment anchors. Optimal thresholds for statistically reliable SDMT changes, accounting for test reliability and measurement error, are yet to be applied to individual cases. OBJECTIVE: The aim of this study was to derive a statistically reliable marker of individual change on the SDMT. METHODS: This prospective, case-control study enrolled 166 patients with multiple sclerosis (MS). SDMT scores at baseline, relapse, and 3-month follow-up were compared between relapsing and stable patient groups. Using data from the stable group and three previously published studies, candidate thresholds for reliable decline were calculated and validated against other tests and a clinically meaningful anchor-cognitive relapse. RESULTS: Candidate thresholds for reliable decline at the 80% confidence level varied between 6 and 11 points. An SDMT change of 8 or more raw score points was deemed to offer the best balance of discriminatory power and external validity for estimating cognitive decline. CONCLUSION: This study illustrates the feasibility and usefulness of reliable change methodology for identifying statistically meaningful cognitive decline that could be implemented to identify change in individual patients, for both clinical management and clinical trial outcomes.

Clinical predictors of driving simulator performance in drivers with multiple sclerosis.

BACKGROUND: Drivers with multiple sclerosis (MS) may experience visual-cognitive impairment that affects their fitness to drive. Due to limitations associated with the on-road assessment, an alternative assessment that measures driving performance is warranted. Whether clinical indicators of on-road outcomes can also predict driving performance outcomes on a driving simulator are not fully understood. OBJECTIVE: This study examined if deficits in immediate verbal/auditory recall (California Verbal Learning Test-Second Edition; CVLT2-IR) and/or slower divided attention (Useful Field of View™; UFOV2) predicted deficits in operational, tactical, or strategic maneuvers assessed on a driving simulator, in drivers with and without MS. METHODS: Participants completed the CVLT2-IR, UFOV2, and a driving simulator assessment of operational, tactical, and strategic maneuvers. RESULTS: Deficits in immediate verbal/auditory recall and slower divided attention predicted adjustment to stimuli errors, pertaining to tactical maneuvers only, in 36 drivers with MS (vs 20 drivers without MS; F(3, 51) = 6.1, p = 0.001, R2 = 0.3, Radj2=0.2). CONCLUSION: The CVLT2-IR and UFOV2 capture the visual and verbal/auditory recall, processing speed, and divided attention required to appropriately adjust to stimuli in a simulated driving environment. Clinicians may use the CVLT2-IR and UFOV2 as precursors to driving performance deficits in drivers with MS.

Concussion in adolescence and the risk of multiple sclerosis: A retrospective cohort study.

BACKGROUND: Physical trauma, specifically concussions sustained during adolescence, has been hypothesized to be a risk factor for multiple sclerosis (MS). OBJECTIVE: To examine the association between adolescent concussions and future MS diagnosis. METHODS: This retrospective study using linked administrative databases from Ontario, Canada, identified 97,965 adolescents (age 11-18 years) who sustained ⩾1 concussion and presented to an emergency department between 1992 and 2011. Cases were matched 1:3 with individuals who had not sustained a concussion based on age, sex, address, and index date. The primary outcome was MS diagnosis, using a validated MS diagnosis definition: ⩾1 hospitalization or ⩾5 physician billings within 2 years. RESULTS: A concussion during adolescence was associated with a significantly increased risk of MS (hazard ratio (HR) = 1.29, p = 0.03). Sex-specific analysis revealed that only males who sustained a concussion in adolescence had a raised risk of MS (HR = 1.41, p = 0.04). CONCLUSION: This study supports an association between concussions in adolescence and future MS diagnoses, highlighting the potentially serious long-term effects of concussions.

Quantifying cognition and fatigue to enhance the sensitivity of the EDSS during relapses.

BACKGROUND: Cognition is affected by relapses in persons with multiple sclerosis (PwMS), yet the Expanded Disability Status Scale (EDSS) does not readily detect cognitive changes. OBJECTIVE: The objective of this study is to improve the detection of cognitive decline during relapses, by incorporating the Symbol Digit Modalities Test (SDMT) into the cerebral Functional System Score (CFSS) of the EDSS. METHODS: This prospective study recruited PwMS from three dedicated MS centers. All subjects had EDSS, SDMT, and Fatigue Severity Scale (FSS) administered. Subjects experiencing a relapse were assigned to the relapse group (RG). Matched controls from the larger cohort were assigned to the stable group (SG). RG and SG subjects underwent the same evaluation at relapse and 3 months later. Our main outcomes were a modified CFSS (m-CFSS) and modified EDSS (m-EDSS), incorporating SDMT and FSS, accounting for cognitive performance and fatigue rating, during relapse. RESULTS: The full cohort included 592 subjects; 80 qualified for RG and 72 were matched to the SG. The m-CFSS was significantly higher than CFSS at baseline (median = 2 vs. median = 0, p < 0.001) and relapse (median = 2 vs. median = 1, p < 0.001). The m-EDSS was higher than EDSS (median 3.0 vs. 2.5, p = 0.02) at relapse, where 35 RG subjects (43.8%) had higher m-EDSS than EDSS at relapse. CONCLUSION: This study demonstrates that incorporating the SDMT and FSS improves the accuracy of the EDSS, by accounting for cognitive changes, during relapse activity.

Recovery of cognitive function after relapse in multiple sclerosis.

BACKGROUND: Cognitive impairment is common in multiple sclerosis (MS) but its manifestation as acute disease activity is underappreciated. OBJECTIVE: The aim of this study is to examine recovery after MS relapse on multiple tests of cognitive and motor function and explore correlates of change with Expanded Disability Status Scale (EDSS), magnetic resonance imaging (MRI), and cognitive reserve. METHODS: Fifty relapsing group (RG) and matched stable participants were examined at baseline, during relapse, and at 3-month follow-up. Tests of cognitive processing speed (Symbol Digit Modalities Test (SDMT)) and consensus opinion measures of memory, ambulation, and manual dexterity were administered. All RG patients were treated with a 5-day course of Acthar Gel (5 mL/80 IU). RESULTS: In RG patients, SDMT declined from 55.2 to 44.6 at relapse and recovered to 51.7, a slope differing from stable controls (p = 0.001). A statistical trend (p = 0.07) for the same effect was observed for verbal memory and was significant for ambulation (p = 0.03). The Cerebral Function Score from the EDSS also changed in the RG and recovered incompletely relative to controls (p = 0.006). CONCLUSION: These results replicate earlier reports of cognitive worsening during relapse in MS. Clinically meaningful improvements followed relapse on SDMT and ambulation. Cognitive decline during relapse can be appreciated on neurological exam but not patient-reported outcomes.

Blood pressure changes during alemtuzumab infusion for multiple sclerosis patients.

BACKGROUND AND PURPOSE: Blood pressure (BP) changes during alemtuzumab infusions are poorly understood. The aim of this study was to examine BP changes during alemtuzumab infusions in persons with multiple sclerosis (PwMS). METHODS: This was a retrospective cohort review of systolic (S) and diastolic (D) BP in PwMS receiving alemtuzumab. RESULTS: Thirty-one patients were identified; 22 (64.5%) were women. Mean age and disease duration were 35.2 ± 7.1 and 9.2 ± 5.4 years, respectively. There was no history of hypertension or vascular events. Mean baseline SBP was 119.8 ± 15.1 mmHg, 118.8 ± 14.3 mmHg and 106.5 ± 6.1 mmHg whilst mean DBP was 75.3 ± 9.2 mmHg, 74.1 ± 12.4 mmHg and 69.2 ± 4.3 mmHg at doses 1, 6 and 9, respectively. During the first cycle, SBP increased by 19.2 ± 9.4 mmHg, with comparable percentage increases over the five infusions (16%, 22%, 17%, 11%, 13%, respectively). DBP increased by 6.2 ± 3.8 mmHg with similar percentage increases over the five infusions (8.4%, 11.5%, 5.5%, 7%, 3%). For the second cycle, SBP increased by 16.9 ± 3.2 mmHg, with similar increases over the 3 days (12%, 15%, 17%). DBP increased by 5.4 ± 4.2 mmHg (11%, 9%, 12.8%). The third cycle demonstrated increased mean and percentage of SBP and DBP by 8.9 ± 2.3 mmHg (10%, 70%, 11.8%) and 4.2 ± 1.9 mmHg (3%, 2%, 6.5%), respectively. Collectively, for 31 patients, in the first cycle, mean SBP increased from 119.8 ± 15.1 mmHg to 138.8 ± 13 mmHg (p Ë‚ 0.001), whilst mean DBP increased from 74.5 ± 9.2 mmHg to 79.2 ± 9.1 mmHg (p = 0.007). Overall, 17 (54.8%) patients had increasing BP by ≥20% and nine (29%) had increasing BP by ≥20 mmHg from baseline. CONCLUSIONS: This demonstrates significant increases in BP during alemtuzumab infusions in PwMS.

Lymphocytic colitis in the setting of teriflunomide use for relapsing multiple sclerosis.

Teriflunomide is an oral monotherapy used to treat relapsing multiple sclerosis. Although teriflunomide may be associated with gastrointestinal symptoms, these events are mild and self-limiting. We present a 39-year-old female who developed severe diarrhea and lost 20 pounds within 3 weeks of starting teriflunomide. Despite discontinuing teriflunomide and undergoing cholestyramine washout, her symptoms persisted. Celiac disease on genetic testing was positive, but no anti-transglutaminase and anti-endomysial antibodies were detected. She underwent colonoscopy and biopsy was consistent with lymphocytic colitis. Remission was achieved within days of starting budenoside. Our case describes a rare, but serious, gastrointestinal adverse event of teriflunomide.

Treatment Optimization in Multiple Sclerosis: Canadian MS Working Group Recommendations.

The Canadian Multiple Sclerosis Working Group has updated its treatment optimization recommendations (TORs) on the optimal use of disease-modifying therapies for patients with all forms of multiple sclerosis (MS). Recommendations provide guidance on initiating effective treatment early in the course of disease, monitoring response to therapy, and modifying or switching therapies to optimize disease control. The current TORs also address the treatment of pediatric MS, progressive MS and the identification and treatment of aggressive forms of the disease. Newer therapies offer improved efficacy, but also have potential safety concerns that must be adequately balanced, notably when treatment sequencing is considered. There are added discussions regarding the management of pregnancy, the future potential of biomarkers and consideration as to when it may be prudent to stop therapy. These TORs are meant to be used and interpreted by all neurologists with a special interest in the management of MS.

Depressive Symptoms Are Associated With More Negative Functional Outcomes Than Anxiety Symptoms in Persons With Multiple Sclerosis.

Depression and anxiety are common among persons with multiple sclerosis (MS), and both negatively affect functional status. However, studies rarely account for overlap in depressive and anxiety symptoms on functional outcomes among people with MS. The authors aimed to examine the differential impact of depression and anxiety, measured by the Anxiety and Depression subscales of the Hospital Anxiety and Depression Scale (HADS-A and HADS-D), on functional outcomes among people with MS. Using a retrospective chart review of 128 people with MS, the authors used exploratory structural equation modeling to examine the relation of HADS-A and HADS-D to functional outcomes, namely employment status, fatigue (with the Fatigue Severity Scale), disability (with the Expanded Disability Status Scale [EDSS]), and cognition (with the Symbol Digit Modalities Test [SDMT]). After the authors controlled for the effects of covariates, HADS-A was negatively associated with EDSS (ß=-0.22, p<0.05) and positively associated with vocation (ß=0.23, p<0.05). In contrast, HADS-D was positively correlated with fatigue (ß=0.37, p<0.05) and EDSS (ß=0.26, p<0.05) and negatively correlated with vocation (ß=-0.32, p<0.05) and SDMT (ß=-0.28, p<0.05). HADS-A and HADS-D explained 5% of the variability in employment, 14.5% in fatigue, 1.6% in EDSS, and 4.3% in SDMT, beyond the effects of the covariates. Depressive symptoms have a significant negative impact on functional outcomes among people with MS, relative to anxiety symptoms. These findings support the importance of identifying and treating depressive symptoms among people with MS.