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.

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.

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.

[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.

Diagnosis of multiple sclerosis: revisions of the McDonald criteria 2017 - continuity and change.

PURPOSE OF REVIEW: The purpose of this review is to describe the new 2017 revisions of the McDonald diagnostic criteria for multiple sclerosis and review first experiences in their application to different patient populations. RECENT FINDINGS: The 2017 revisions agreed on by an international expert panel, as the precursors, define criteria needed to fulfill dissemination in time and space in the clinically isolated syndrome after exclusion of alternative diagnoses. One major change is the inclusion of cerebrospinal fluid (CSF) oligoclonal bands as evidence of dissemination in time in a patient with dissemination in space gathered by clinical or magnetic resonance examination. The distinction between asymptomatic and symptomatic lesions in counting for evidence of dissemination in space or time in supra, infratentorial, and spinal cord syndrome has been abandoned. Finally, cortical lesions can be used to demonstrate dissemination in space. Major differential diagnoses, in particular, the still-evolving concept of neuromyelitis optica spectrum disorders and the myelin oligodendrocyte glycoprotein-IgG-related demyelinating central nervous system disorders. SUMMARY: The new 2017 revisions will simplify the application of the MRI criteria for dissemination in space and include CSF findings as evidence for dissemination in time in clinically isolated syndrome.

Meningitis gone viral: description of the echovirus wave 2013 in Germany.

BACKGROUND: Aseptic meningitis epidemics may pose various health care challenges. METHODS: We describe the German enterovirus meningitis epidemics in the university hospital centers of Düsseldorf, Cologne and Berlin between January 1st and December 31st, 2013 in order to scrutinize clinical differences from other aseptic meningitis cases. RESULTS: A total of 72 enterovirus (EV-positive) meningitis cases were detected in our multicenter cohort, corresponding to 5.8% of all EV-positive cases which were voluntarily reported within the National Enterovirus surveillance (EVSurv, based on investigation of patients with suspected aseptic meningitis/encephalitis and/or acute flaccid paralysis) by physicians within this period of time. Among these 72 patients, 38 (52.8%) were enterovirus positive and typed as echovirus (18 pediatric and 20 adult cases, median age 18.5 years; echovirus 18 (1), echovirus 2 (1), echovirus 30 (31), echovirus 33 (1), echovirus 9 (4)). At the same time, 45 aseptic meningitis cases in our cohort were excluded to be due to enteroviral infection (EV-negative). Three EV-negative patients were tested positive for varicella zoster virus (VZV) and 1 EV-negative patient for herpes simplex virus 2. Hospitalization was significantly longer in EV-negative cases. Cerebrospinal fluid analysis did not reveal significant differences between the two groups. After discharge, EV-meningitis resulted in significant burden of sick leave in our pediatric cohort as parents had to care for the children at home. CONCLUSIONS: Voluntary syndromic surveillance, such as provided by the EVSurv in our study may be a valuable tool for epidemiological research. Our analyses suggest that EV-positive meningitis predominantly affects younger patients and may be associated with a rather benign clinical course, compared to EV-negative cases.

Factors associated with headache in intravenous immunoglobulin treatment for neurological diseases.

OBJECTIVES: To identify possible risk factors influencing the incidence of intravenous immunoglobulin (IVIg) treatment-related cephalalgia in neurological diseases. MATERIALS & METHODS: Retrospective chart review of neurological patients receiving IVIg treatment between July 13, 2017, and August 14, 2017. Patients with MS receiving natalizumab in the same setting were observed as a reference group. RESULTS: Patients with headache after IVIg infusion (n = 22 infusions) showed a reduced heart rate (by 6.0 ± 8.5 beats per minute [bpm]), but no significant difference in blood pressure. Patients without headache after IVIg infusion (n = 69 infusions) showed a higher systolic blood pressure increase and a stronger reduction in the heart rate (by 5.7 ± 8.6 bpm), compared to patients with headache after IVIg infusion. The infusion rate was significantly slower and age significantly lower in patients developing headache after IVIg infusion. Body temperature was unchanged in both groups. Binary logistic regression analysis revealed that blood pressure at baseline and age significantly influence the occurrence of cephalalgia. In reference, patients receiving natalizumab (ie, shorter infusions/smaller infusion volume), systolic blood pressure, and heart rate decreased, while body temperature increased. Here, one patient developed headache. CONCLUSIONS: Intravenous immunoglobulin-associated headache is not associated with an increased blood pressure after infusion but with a reduced heart rate, a slower infusion rate, female sex and seems to be influenced by baseline systolic blood pressure and age. A reaction to immunoglobulin aggregates, stabilizers, or vasoactive mediators are possible explanations. The absence of an association with body temperature does not suggest a systemic immune response as a cause for headache.

Nimodipine confers clinical improvement in two models of experimental autoimmune encephalomyelitis.

Multiple sclerosis is characterised by inflammatory neurodegeneration, with axonal injury and neuronal cell death occurring in parallel to demyelination. Regarding the molecular mechanisms responsible for demyelination and axonopathy, energy failure, aberrant expression of ion channels and excitotoxicity have been suggested to lead to Ca2+ overload and subsequent activation of calcium-dependent damage pathways. Thus, the inhibition of Ca2+ influx by pharmacological modulation of Ca2+ channels may represent a novel neuroprotective strategy in the treatment of secondary axonopathy. We therefore investigated the effects of the L-type voltage-gated calcium channel blocker nimodipine in two different models of mouse experimental autoimmune encephalomyelitis (EAE), an established experimental paradigm for multiple sclerosis. We show that preventive application of nimodipine (10 mg/kg per day) starting on the day of induction had ameliorating effects on EAE in SJL/J mice immunised with encephalitic myelin peptide PLP139-151 , specifically in late-stage disease. Furthermore, supporting these data, administration of nimodipine to MOG35-55 -immunised C57BL/6 mice starting at the peak of pre-established disease, also led to a significant decrease in disease score, indicating a protective effect on secondary CNS damage. Histological analysis confirmed that nimodipine attenuated demyelination, axonal loss and pathological axonal ß-amyloid precursor protein accumulation in the cerebellum and spinal cord in the chronic phase of disease. Of note, we observed no effects of nimodipine on the peripheral immune response in EAE mice with regard to distribution, antigen-specific proliferation or activation patterns of lymphocytes. Taken together, our data suggest a CNS-specific effect of L-type voltage-gated calcium channel blockade to inflammation-induced neurodegeneration.

Acute sarcoidosis in a multiple sclerosis patient after alemtuzumab treatment.

BACKGROUND: Understanding the long-term effect of alemtuzumab on the immune system of multiple sclerosis (MS) patients is crucial. OBJECTIVE: To report a case of acute sarcoidosis (Löfgren's syndrome) in a relapsing-remitting MS patient, 1.5 years after the second course of alemtuzumab treatment. CASE REPORT: Sarcoidosis was confirmed dermatohistologically, radiologically, and serologically. Analysis of the lymphocyte subpopulations showed a persistent effect of alemtuzumab treatment (CD4/CD8 ratio increased, absolute lymphocyte count of CD19-positive cells increased while CD3/4/8-positive cells were decreased). CONCLUSION: Our case highlights the profound effect of alemtuzumab on the immune system and its possible risk for autoimmune complications.

Sublingual administration of atropine eyedrops in children with excessive drooling - a pilot study.

BACKGROUND: Drooling can be a severe disability and have high impact on daily life. Reversible treatment is preferable. AIM: To analyse whether sublingual administration of atropine eyedrops is a useful reversible treatment option for severe drooling in children with disabilities. DESIGN: The study had a prospective, single-system research design. The participants served as their own controls. The study period was 3 weeks without treatment, 4 weeks with atropine eyedrop solution 10 mg/mL one drop a day followed by 4 weeks of one drop twice a day. Parents' rating of their child's drooling was assessed on a 100-mm VAS, and unstimulated salivary secretion rate measurement was performed together with notations about side effects and practicality. RESULTS: Parents' VAS assessment of drooling decreased from a median (range) of 74 (40-98) at baseline to 48 (18-88) (P = 0.05) and 32 (12-85) (P = 0.004) after 4 weeks of atropine once a day and another 4 weeks of atropine twice a day, respectively (n = 11). Unstimulated salivary secretion rates decreased from baseline to end of study (P = 0.032). Several parents complained about difficult administration. No irreversible side effects were noted. CONCLUSIONS: Sublingual atropine eyedrops may be an alternative for treatment of severe drooling in children with disabilities.

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).

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.

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.

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.

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.

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.

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.