Updated Multiple Sclerosis Incidence, 2015-2022.

This cohort study uses population-based claims data to provide an update of multiple sclerosis incidence in Germany.

Heterophoria in multiple sclerosis patients: a proof of principle cross-sectional study.

Objectives: The pathophysiology of multiple sclerosis (MS) involves inflammatory neurodegeneration in the brainstem, cerebellum, and retina. The clinical relevance of oculomotor involvement in MS, however, remains uncertain. Methods: In this cross-sectional study, we evaluated heterophoria as a (sub)clinical tool in 54 MS patients and 55 age-matched healthy controls (HCs). We quantified heterophoria in prism diopters for distance and near range with orthoptic examination. Our primary outcome was high degrees of horizontal heterophoria (HDHH) defined as measurements beyond ±2 standard deviations from the mean prism diopter of heterophoria of our HCs. Results: More than one-third (37%, n=20/54) of MS patients but only 11% (n=6/55) of HCs were classified as HDHH [distance, MS=9% (n=5/54) versus HC=6% (n=3/55); near, MS=19% (n=10/54) versus HC=5% (n=3/55)]. Our MS patients presented more combined vertical and horizontal deviations at near range [MS 19% (n=10/54) versus for HC 7% (n=4/55)]. We observed the combination of HDHH both at distance and at near testing in 9% (n=5/54) of MS patients but not at all in HCs (n=0/55). Discussion: Despite the high prevalence of heterophoria, HDHH may be an additional (sub)clinical tool of subclinical involvement in MS. Thus, orthoptic examination may be an additional tool to improve MS diagnostic procedures.

Disease-modifying drugs, multiple sclerosis and infection-related healthcare use in British Columbia, Canada: a population-based study.

Background: Much remains unknown surrounding the disease-modifying drugs (DMDs) used to treat multiple sclerosis and infection-related healthcare use in the 'real-world' setting. We examined if DMD exposure was associated with altered infection-related healthcare use. Methods: We assessed if DMD (versus no) exposure was associated with altered infection-related hospitalizations, physician claims, and prescriptions filled in British Columbia, Canada (1996-2017). Healthcare use was assessed using negative binomial and proportional means regression models, reported as sex-/age-/comorbidity-/calendar year-/socioeconomic-adjusted rate and hazard ratios [aRR, aHR], with 95% confidence intervals [CIs]). Findings: We identified 19,360 multiple sclerosis cases (13,940/19,360; 72.0% women; mean age at study start = 44.5 standard deviation, SD = 13.3; mean follow-up = 11.7 [SD = 7.3] years). Relative to unexposed periods, exposure to any DMD was associated with a lower infection-related rate of physician claims (aRR = 0.88; 95% CI:0.85-0.92) and hazard of hospitalization (aHR = 0.64; 95% CI:0.56-0.73), and a higher rate of infection-related prescriptions (aRR = 1.14; 95% CI:1.08-1.20). Exposure to any injectable or oral DMD was associated with a lower infection-related rate of physician claims (injectable aRR = 0.88; 95% CI:0.84-0.92, oral aRR = 0.83; 95% CI:0.77-0.90) and hazard of hospitalization (injectable aHR = 0.65; 95% CI:0.56-0.75, oral aHR = 0.54; 95% CI:0.38-0.77), whereas intravenous DMD exposure was not (aRR = 0.99; 95% CI:0.86-1.14, aHR = 0.73; 95% CI:0.49-1.09). Exposure to any injectable or intravenous DMD was associated with a higher rate of infection-related prescriptions (injectable aRR = 1.15; 95% CI:1.08-1.22, intravenous = 1.34; 95% CI:1.15-1.56), whereas oral DMDs were not (aRR = 0.98; 95% CI:0.91-1.05). Interpretation: DMD exposure for the treatment of MS was associated with differences in infection-related healthcare use. While infection-related hospitalizations and physician visits were lower, prescription fills were higher. How these differences in infection-related healthcare use affect outcomes in persons with multiple sclerosis warrants consideration. Funding: Canadian Institutes of Health Research (CIHR); German Research Foundation (DFG).

Multiple sclerosis disease-modifying drug use by immigrants: a real-world study.

Little is known about disease-modifying drug (DMD) initiation by immigrants with multiple sclerosis (MS) in countries with universal health coverage. We assessed the association between immigration status and DMD use within 5-years after the first MS-related healthcare encounter. Using health administrative data, we identified MS cases in British Columbia (BC), Canada. The index date was the first MS-related healthcare encounter (MS/demyelinating disease-related diagnosis or DMD prescription filled), and ranged from 01/January/1996 to 31/December/2012. Those included were ≥ 18 years old, BC residents for ≥ 1-year pre- and ≥ 5-years post-index date. Persons becoming permanent residents 1985-2012 were defined as immigrants, all others were long-term residents. The association between immigration status and any DMD prescription filled within 5-years post-index date (with the latest study end date being 31/December/2017) was assessed using logistic regression, reported as adjusted odds ratios (aORs) with 95% confidence intervals (CIs). We identified 8762 MS cases (522 were immigrants). Among immigrants of lower SES, odds of filling any DMD prescription were reduced, whereas they did not differ between immigrants and long-term residents across SES quintiles (aOR 0.96; 95%CI 0.78-1.19). Overall use (odds) of a first DMD within 5 years after the first MS-related encounter was associated with immigration status.

Emergency department use by persons with MS: A population-based descriptive study with a focus on infection-related visits.

We described emergency department (ED) visits (all visits and infection-related) by persons with multiple sclerosis (MS) in British Columbia, Canada (1 April 2012 to 31 December 2017). We identified 15,350 MS cases using health administrative data; 73.4% were women, averaging 51.4 years at study entry. Over 4.9 years of follow-up (mean), 56.0% of MS cases visited an ED (mean = 0.6 visits/person/year; total = 37,072 visits). A diagnosis was documented for 25,698 (69.3%) ED visits, and 18.4% (4725/25,698) were infection-related. Inpatient admissions were reported for 20.4% (5238/25,698) of all and 29.2% (1380/4725) of infection-related ED visits. Findings suggest that the ED plays a substantial role in MS healthcare and infection management.

The degree of cortical plasticity correlates with cognitive performance in patients with Multiple Sclerosis.

BACKGROUND: Cortical reorganization and plasticity may compensate for structural damage in Multiple Sclerosis (MS). It is important to establish sensitive methods to measure these compensatory mechanisms, as they may be of prognostic value. OBJECTIVE: To investigate the association between the degree of cortical plasticity and cognitive performance and to compare plasticity between MS patients and healthy controls (HCs). METHODS: The amplitudes of the motor evoked potential (MEP) pre and post quadripulse stimulation (QPS) applied over the contralateral motor cortex served as measure of the degree of cortical plasticity in 63 patients with relapsing-remitting MS (RRMS) and 55 matched HCs. The main outcomes were the correlation coefficients between the difference of MEP amplitudes post and pre QPS and the Symbol Digit Modalities Test (SDMT) and Brief Visuospatial Memory Test-Revised (BVMT-R), and the QPSxgroup interaction in a mixed model predicting the MEP amplitude. RESULTS: SDMT and BVMT-R correlated significantly with QPS-induced cortical plasticity in RRMS patients. Plasticity was significantly reduced in patients with cognitive impairment compared to patients with preserved cognitive function and the degree of plasticity differentiated between both patient groups. Interestingly, the overall RRMS patient cohort did not show reduced plasticity compared to HCs. CONCLUSIONS: We provide first evidence that QPS-induced plasticity may inform about the global synaptic plasticity in RRMS which correlates with cognitive performance as well as clinical disability. Larger longitudinal studies on patients with MS are needed to investigate the relevance and prognostic value of this measure for disease progression and recovery.

CNS Involvement in Chronic Inflammatory Demyelinating Polyneuropathy: Subtle Retinal Changes in Optical Coherence Tomography.

BACKGROUND AND OBJECTIVES: Chronic inflammatory demyelinating polyneuropathy (CIDP) is an autoimmune disease primarily affecting the peripheral nervous system. However, several noncontrolled studies have suggested concomitant inflammatory CNS demyelination similar to multiple sclerosis. The aim of this study was to investigate an involvement of the visual pathway in patients with CIDP. METHODS: In this prospective cross-sectional study, we used high-resolution spectral-domain optical coherence tomography to compare the thickness of the peripapillary retinal nerve fiber layer and the deeper macular retinal layers as well as the total macular volume (TMV) in 22 patients with CIDP and 22 age-matched and sex-matched healthy control (HC) individuals. Retinal layers were semiautomatically segmented by the provided software and were correlated with clinical measures and nerve conduction studies. RESULTS: In patients with CIDP compared with healthy age-matched and sex-matched controls, we found slight but significant volume reductions of the ganglion cell/inner plexiform layer complex (CIDP 1.86 vs HC 1.95 mm3, p = 0.015), the retinal pigment epithelium (CIDP 0.38 vs HC 0.40 mm3, p = 0.02), and the TMV (CIDP 8.48 vs HC 8.75 mm3, p = 0.018). The ganglion cell layer volume and motor nerve conduction velocity were positively associated (B = 0.002, p = 0.02). DISCUSSION: Our data reveal subtle retinal neurodegeneration in patients with CIDP, providing evidence for visual pathway involvement, detectable by OCT. The results need corroboration in independent, larger cohorts.

Relapse-independent multiple sclerosis progression under natalizumab.

The objective of this study was to investigate confirmed progression independent of relapse activity in relapsing-remitting multiple sclerosis patients under long-term natalizumab treatment. We performed a retrospective, cross-sectional study of clinical data captured between 1994 and 2019 at two German multiple sclerosis tertiary referral centres. Data files of all relapsing-remitting multiple sclerosis patients treated with natalizumab for ≥24 months were analysed. Confirmed progression independent of relapse activity was defined as ≥12 week confirmed disability progression on a roving Expanded Disability Status Scale reference score by 1 point in patients with an Expanded Disability Status Scale score ≤3 or 0.5 in patients with an Expanded Disability Status Scale score ≥3.5 in the absence of a relapse. Cox proportional hazard models were used to analyse the probability of developing confirmed progression independent of relapse activity depending on both disease and natalizumab treatment duration. Among the 184 patients identified, 44 (24%) developed confirmed progression independent of relapse activity under natalizumab irrespective of the Expanded Disability Status Scale score at natalizumab onset. Time to confirmed progression independent of relapse activity was not affected by Expanded Disability Status Scale at natalizumab onset (categorized by Expanded Disability Status Scale score ≤3.5 versus >3.5) nor by duration of disease nor by duration of therapy. Confirmed progression independent of relapse activity occurred earlier in the disease course in patients with an earlier natalizumab therapy onset with regard to disease duration. A stepwise forward regression analysis revealed disease duration as the main factor for confirmed progression independent of relapse activity development (P = 0.005). Taken together, confirmed progression independent of relapse activity occurs in a substantial proportion of patients on long-term natalizumab treatment and independent of Expanded Disability Status Scale score at natalizumab onset. Our findings suggest that patients who are initiated on natalizumab early during disease course, usually in order to treat an aggressive clinical phenotype, have a higher risk of early confirmed progression independent of relapse activity.

Introduction of a rapid sequence induction checklist and its effect on compliance to guidelines and complications.

BACKGROUND: Current evidence for the conduct of rapid sequence induction (RSI) is weak. This increases the risk of clinicians modifying the RSI procedure according to personal preferences. Checklists may help increase compliance to best practice guidelines and reduce complication rates. Their value during RSI, a critical procedure in anaesthesia, is unknown. The aim of this study was to investigate compliance to local guidelines and frequency of RSI-related complications before and after introduction of an RSI checklist. METHODS: This was a prospective, observational, pre- and post-intervention study conducted at two hospitals. There were two interventions: the first was a standardized educational lecture to all staff at both hospitals, consisting of an educational instruction of the checklist and general information about RSI, and the second intervention was the introduction of a RSI checklist. The checklist consisted of 16 items. Compliance to guidelines was categorized as high, moderate and low, and was assessed pre- and post-intervention. The frequency of RSI-related complications was also measured. RESULTS: We registered 811 RSI procedures of which 412 were pre-intervention. After intervention, the proportion of procedures with high compliance to RSI guidelines increased from 49% to 70% (P < .001). The proportion with partial and low compliance decreased from 37% to 26% (P < .001) and 13% to 3.3% (P < .001) respectively. No change in RSI-related complication rates was detectable post-intervention (16.6%-16.7% P = .56). CONCLUSION: The introduction of a structured RSI checklist significantly increased compliance to RSI guidelines. A change in RSI-related complications could not be detected due to the size of the study. A checklist may be a useful tool to reduce variance during the RSI procedure.

Association of Retinal Layer Thickness With Cognition in Patients With Multiple Sclerosis.

OBJECTIVE: Retinal layer thickness (RLT) measured by optical coherence tomography (OCT) is considered a noninvasive, cost-efficient marker of neurodegeneration in multiple sclerosis (MS). We aimed to investigate associations of RLT with cognitive performance and its potential as indicator of cognitive status in patients with MS by performing generalized estimating equation (GEE) analyses. METHODS: In this cross-sectional study, patients with at least mild signs of cognitive impairment were examined by OCT as well as by the Brief International Cognitive Assessment for MS and tests assessing attention and executive functions (Trail Making Test [TMT] A and B). Associations of these factors were investigated using GEE models controlling for demographic and disease-related factors and correcting for multiple testing. RESULTS: A total of 64 patients entered the study. In the final sample (n = 50 [n = 14 excluded due to missing data or drop-outs]; n = 44 relapsing-remitting MS and n = 6 secondary progressive MS, mean Expanded Disability Status Scale score = 2.59 [SD = 1.17], disease duration [median] = 7.34 [interquartile range = 12.1]), 36.0% were cognitively impaired. RLT of the macular retinal nerve fiber layer was associated with performance in TMT-B (ß = -0.259). Analyses focusing on the upper and lower tertile of RLT additionally revealed associations between macular ganglion cell-inner plexiform layer and TMT-B and verbal short-term memory and learning, respectively. CONCLUSION: In patients with MS, at less advanced disease stages, RLT was especially associated with cognitive flexibility promoting OCT as a potential marker advocating further extensive neuropsychological examination.

Targeting B Cells to Modify MS, NMOSD, and MOGAD: Part 1.

Ocrelizumab, rituximab, ofatumumab, ublituximab, inebilizumab, and evobrutinib are immunotherapies that target various B cell-related proteins. Most of these treatments have proven efficacy in relapsing and progressive forms of MS and neuromyelitis optica spectrum disease (NMOSD), or are in advanced stages of clinical development. Currently, ocrelizumab, ofatumumab, and inebilizumab are licensed for treatment of MS and NMOSD, respectively. This review focuses on the current state of knowledge about the role of B lymphocytes in immune-mediated pathophysiology and its implications for the mode of action. To understand the significance of this breakthrough in the context of the current MS therapeutic armamentarium, this review more closely examines the clinical development of CD20 depletion and the pioneering contribution of rituximab. Phase 3 and the recently published postmarketing studies will be highlighted to better understand the relevant efficacy data and safety aspects of long-term B-cell depletion.

Targeting B cells to modify MS, NMOSD, and MOGAD: Part 2.

Ocrelizumab, rituximab, ofatumumab, ublituximab, inebilizumab, and evobrutinib are immunotherapies that target various B cell-related proteins. Most of these treatments have proven efficacy in relapsing and progressive forms of MS and neuromyelitis optica spectrum disease (NMOSD) or are in advanced stages of clinical development. Currently, ocrelizumab and inebilizumab are licensed for treatment of MS and NMOSD, respectively. This part of the review focuses on monoclonal antibody B cell-depleting strategies in NMOSD and the emerging related myelin oligodendrocyte glycoprotein (MOG) immunoglobulin G-associated disease (MOGAD). Case series and phase 2/3 studies in these inflammatory disorders are assessed. The safety profile of long-term B-cell depletion in MS, NMOSD, and MOGAD will be highlighted. Finally implications of the current coronavirus disease 2019 pandemic on the management of patients with these disorders and the use of B cell-depleting agents will be discussed.

Disease-Modifying Drug Uptake and Health Service Use in the Ageing MS Population.

Background: Evidence regarding the efficacy or effectiveness of the disease-modifying drugs (DMDs) in the older multiple sclerosis (MS) population is scarce. This has contributed to a lack of evidence-based treatment recommendations for the ageing MS population in practice guidelines. We examined the relationship between age (<55 and ≥55 years), DMD exposure and health service use in the MS population. Methods: We conducted a population-based observational study using linked administrative health data from British Columbia, Canada. We selected all persons with MS and followed from the most recent of their first MS or demyelinating event, 18th birthday or 01-January-1996 (index date) until the earliest of emigration, death or 31-December-2017 (study end). We assessed DMD exposure status over time, initially as any versus no DMD, then by generation (first or second) and finally by each individual DMD. Age-specific analyses were conducted with all-cause hospitalizations and number of physician visits assessed using proportional means model and negative binomial regression with generalized estimating equations. Results: We included 19,360 persons with MS (72% were women); 10,741/19,360 (56%) had ever reached their 55th birthday. Person-years of follow-up whilst aged <55 was 132,283, and 93,594 whilst aged ≥55. Any DMD, versus no DMD in the <55-year-olds was associated with a 23% lower hazard of hospitalization (adjusted hazard ratio, aHR0.77; 95%CI 0.72-0.82), but not in the ≥55-year-olds (aHR0.95; 95%CI 0.87-1.04). Similar patterns were observed for the first and second generation DMDs. Exposure to any (versus no) DMD was not associated with rates of physician visits in either age group (<55 years: adjusted rate ratio, aRR1.02; 95%CI 1.00-1.04 and ≥55 years: aRR1.00; 95%CI 0.96-1.03), but variation in aRR was observed across the individual DMDs. Conclusion: Our study showed beneficial effects of the DMDs used to treat MS on hospitalizations for those aged <55 at the time of exposure. In contrast, for individuals ≥55 years of age exposed to a DMD, the hazard of hospitalization was not significantly lowered. Our study contributes to the broader understanding of the potential benefits and risks of DMD use in the ageing MS population.

Retinal layers and visual conductivity changes in a case series of microangiopathic ischemic stroke patients.

BACKGROUND: It is unknown whether microangiopathic ischemic strokes outside the visual pathway go along with subclinical changes of the retinal structure or the visual system. The objectives of this prospective non-interventional case series were to investigate if spectral-domain optical coherence tomography (SD-OCT) or multifocal visual evoked potentials (mfVEPs) can detect structural retinal changes or functional impairment of the visual system in patients with microangiopathic ischemic stroke. METHODS: We used SD-OCT to cross-sectionally analyze the retinal morphology of 15 patients with microangiopathic ischemic stroke according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification not affecting the visual pathway. We employed semi-automated segmentation of macular volume scans to analyze the thickness of the macular retinal layers and peripapillary ring scans to investigate the retinal morphology in comparison to a control group without stroke. Visual function was assessed by the mfVEP technique in 13 microangiopathic ischemic stroke patients. RESULTS: First peak latency of mfVEPs was significantly delayed in the microangiopathic ischemic stroke group compared to the control patients. Neither the retinal layers nor the mfVEPs' amplitude differed between the microangiopathic ischemic stroke patients and the control group. CONCLUSIONS: In conclusion, microangiopathic ischemic stroke patients presented a delayed first peak latency in mfVEPs as a sign of subclinical functional impairment of the visual pathway. However, our case series suggests no influence on retinal structure resulting from microangiopathic ischemic stroke outside the visual system. Larger and longitudinal studies are needed to confirm these mfVEP findings.

Serum neurofilament light chain: No clear relation to cognition and neuropsychiatric symptoms in stable MS.

OBJECTIVE: To explore the hypothesis that serum neurofilament light chain (sNfL) indicative of neuroaxonal damage may improve precise disease profiling with regard to cognition and neuropsychiatric symptoms, we analyzed potential associations of sNfL levels with cognitive test scores, fatigue, depression, and anxiety. METHODS: Patients with relapsing-remitting and secondary progressive MS (SPMS) underwent an elaborated assessment including MRI, various cognitive tests, and patient-reported outcomes. We determined sNfL levels by single molecule array (Simoa) assay. Relationships between sNfL, cognition, neuropsychiatric symptoms, and demographical data were analyzed using correlations, group comparisons, and regressions. RESULTS: In 45 clinically stable patients with MS (Expanded Disability Status Scale = 2.73 ± 1.12, disease duration = 10.03 ± 7.49 years), 40.0% were cognitively impaired. Mean sNfL levels were 16.02 ± 10.39 pg/mL, with higher levels in the SPMS subgroup (p = 0.038). sNfL levels did reliably link neither with the investigated cognitive and affective parameters nor with fatigue levels. The only relationship found in a small subgroup of patients with SPMS (n = 7) with visuospatial learning (r = -0.950, p = 0.001) and memory (r = -0.813; p = 0.026) disappeared when further controlling for age, educational level, and sex. CONCLUSIONS: In patients with stable MS at less advanced disease stages, sNfL did not convincingly relate to cognitive performance, fatigue, depression, or anxiety and thus may not serve as a surrogate biomarker for neuropsychological status in such populations.

[Ocrelizumab for treatment of multiple sclerosis]. / Ocrelizumab zur Behandlung der Multiplen Sklerose.

Ocrelizumab is a monoclonal antibody directed against the differentiation antigen CD20, which leads to an effective long-term depletion of lymphocytes, in particular B cells. Recently published phase 3 studies confirmed that ocrelizumab is effective in the treatment of both relapsing multiple sclerosis (RMS) and primary progressive multiple sclerosis (PPMS). Based on these results, ocrelizumab was the first drug to be approved for primary chronic progressive MS. To place this therapeutic breakthrough in the context of the current MS therapeutic landscape, it is worthwhile taking a look back at the development of antibody-mediated CD20 depletion, the studies underlying the approval of ocrelizumab and their open extension phases. This review article discusses the available data on the efficacy and safety of long-term B­cell depletion in MS patients and reviews current knowledge on the role of B­lymphocytes in the immunopathogenesis of MS.

Long-term follow-up of multiple sclerosis studies and outcomes from early treatment of clinically isolated syndrome in the BENEFIT 11 study.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) with a diverse disease course involving inflammation and degeneration of neurons and axons. Multiple sclerosis results from a complex interaction of genetic and environmental factors and clinically several disease subtypes with marked variation in symptoms can be discerned. Disease-modifying therapies (DMTs) impact disease activity and outcome. Long-term follow-up studies of DMTs in MS have generally shown that the short-term effects in clinical trials are maintained for up to 21 years, e.g. in the case of interferon beta-1b. However, attainment can be a problem in these studies. On the one hand, so-called real-world studies can augment clinical trials by providing data on the long-term effectiveness and safety of DMTs but lack, on the other hand, randomization and may, in addition, also yield biased findings as a result of compliance issues. Long-term data from clinical trials in clinically isolated syndrome (CIS) patients have been limited but in the case of interferon beta-1b this aspect has been addressed over 11 years in the BENEFIT 11 trial. The results suggest that early treatment results in persistent long-term benefits including conversion to clinically definite MS (CDMS) as well as time to and risk of a first relapse. Here we primarily review the findings of the BENEFIT 11 trial in the context of long-term studies.

Longitudinal optic neuritis-unrelated visual evoked potential changes in NMO spectrum disorders.

OBJECTIVE: To investigate if patients with neuromyelitis optica spectrum disorder (NMOSD) develop subclinical visual pathway impairment independent of acute attacks. METHODS: A total of 548 longitudinally assessed full-field visual evoked potentials (VEP) of 167 patients with NMOSD from 16 centers were retrospectively evaluated for changes of P100 latencies and P100-N140 amplitudes. Rates of change in latencies (RCL) and amplitudes (RCA) over time were analyzed for each individual eye using linear regression and compared using generalized estimating equation models. RESULTS: The rates of change in the absence of optic neuritis (ON) for minimal VEP intervals of ≥3 months between baseline and last follow-up were +1.951 ms/y (n = 101 eyes; SD = 6.274; p = 0.012) for the P100 latencies and -2.149 µV/y (n = 64 eyes; SD = 5.013; p = 0.005) for the P100-N140 amplitudes. For minimal VEP intervals of ≥12 months, the RCL was +1.768 ms/y (n = 59 eyes; SD = 4.558; p = 0.024) and the RCA was -0.527 µV/y (n = 44 eyes; SD = 2.123; p = 0.111). The history of a previous ON >6 months before baseline VEP had no influence on RCL and RCA. ONs during the observational period led to mean RCL and RCA of +11.689 ms/y (n = 16 eyes; SD = 17.593; p = 0.003) and -1.238 µV/y (n = 11 eyes; SD = 3.708; p = 0.308), respectively. CONCLUSION: This first longitudinal VEP study of patients with NMOSD provides evidence of progressive VEP latency delay occurring independently of acute ON. Prospective longitudinal studies are needed to corroborate these findings and help to interpret the clinical relevance.