Differential diagnosis of suspected multiple sclerosis: an updated consensus approach.

Accurate diagnosis of multiple sclerosis requires careful attention to its differential diagnosis-many disorders can mimic the clinical manifestations and paraclinical findings of this disease. A collaborative effort, organised by The International Advisory Committee on Clinical Trials in Multiple Sclerosis in 2008, provided diagnostic approaches to multiple sclerosis and identified clinical and paraclinical findings (so-called red flags) suggestive of alternative diagnoses. Since then, knowledge of disorders in the differential diagnosis of multiple sclerosis has expanded substantially. For example, CNS inflammatory disorders that present with syndromes overlapping with multiple sclerosis can increasingly be distinguished from multiple sclerosis with the aid of specific clinical, MRI, and laboratory findings; studies of people misdiagnosed with multiple sclerosis have also provided insights into clinical presentations for which extra caution is warranted. Considering these data, an update to the recommended diagnostic approaches to common clinical presentations and key clinical and paraclinical red flags is warranted to inform the contemporary clinical evaluation of patients with suspected multiple sclerosis.

Comparative effectiveness of cladribine tablets versus fingolimod in the treatment of highly active multiple sclerosis: A real-world study.

BACKGROUND: Cladribine tablets and fingolimod have similar marketing authorisations in Europe for the treatment of patients with highly active relapsing multiple sclerosis (HA-RMS). In the absence of direct head-to-head studies, real-world data are important to assess the comparative effectiveness of these oral disease-modifying therapies (DMTs). The primary objective of the present study was to compare relapse rates between patients who received either cladribine tablets or fingolimod. METHODS: This multicentre retrospective study conducted in the United Kingdom and Germany assessed non-inferiority in relapse rates of cladribine tablets versus fingolimod in HA-RMS patients over a 12-month period. Eligible patients who initiated treatment with cladribine tablets or fingolimod at least 12 months prior to the screening date were sampled consecutively until the target sample size was reached. Patients were censored at discontinuation of study treatment, commencement of another DMT, death, loss to follow-up, or at 12 months post-baseline, whichever happened earliest. The primary analytic timeframe for physician-confirmed relapse outcomes was the study effectiveness period (nine months of follow-up after an initial 12 weeks of treatment). Propensity score analysis was applied based on the inverse probability of treatment weighting approach. RESULTS: The primary analytic cohort consisted of 1,095 HA-RMS patients: 610 (55.7%) receiving cladribine tablets and 485 (44.3%) receiving fingolimod. Fewer patients discontinued cladribine tablets and/or switched to another DMT compared with fingolimod (0.2% versus 3.5%, respectively). The primary endpoint, adjusted annualised relapse rate (ARR), was 0.10 (95% confidence interval [CI]: 0.07-0.14) for cladribine tablets and 0.14 (95% CI: 0.10-0.20) for fingolimod. The adjusted ARR ratio of cladribine tablets versus fingolimod was 0.68 (95% CI: 0.42-1.11). Given the entire 95% CI was less than the non-inferiority margin of 1.2, cladribine tablets was non-inferior to fingolimod. CONCLUSIONS: In this real-world retrospective cohort study, cladribine tablets demonstrated comparable effectiveness to fingolimod at one year following treatment initiation. The full treatment dosage of cladribine tablets is completed over two years and so these results may be conservative.

HLA-DRB1*1501 influences long-term disability progression and tissue damage on MRI in relapse-onset multiple sclerosis.

BACKGROUND: Whether genetic factors influence the long-term course of multiple sclerosis (MS) is unresolved. OBJECTIVE: To determine the influence of HLA-DRB1*1501 on long-term disease course in a homogeneous cohort of clinically isolated syndrome (CIS) patients. METHODS: One hundred seven patients underwent clinical and MRI assessment at the time of CIS and after 1, 3, 5 and 15 years. HLA-DRB1*1501 status was determined using Sanger sequencing and tagging of the rs3135388 polymorphism. Linear/Poisson mixed-effects models were used to investigate rates of change in EDSS and MRI measures based on HLA-DRB1*1501 status. RESULTS: HLA-DRB1*1501 -positive (n = 52) patients showed a faster rate of disability worsening compared with the HLA-DRB1*1501 -negative (n = 55) patients (annualised change in EDSS 0.14/year vs. 0.08/year, p < 0.025), and a greater annualised change in T2 lesion volume (adjusted difference 0.45 mL/year, p < 0.025), a higher number of gadolinium-enhancing lesions, and a faster rate of brain (adjusted difference -0.12%/year, p < 0.05) and spinal cord atrophy (adjusted difference -0.22 mm2/year, p < 0.05). INTERPRETATION: These findings provide evidence that the HLA-DRB1*1501 allele plays a role in MS severity, as measured by long-term disability worsening and a greater extent of inflammatory disease activity and tissue loss. HLA-DRB1*1501 may provide useful information when considering prognosis and treatment decisions in early relapse-onset MS.

The prognostic significance of early blood neurofilament light chain concentration and magnetic resonance imaging variables in relapse-onset multiple sclerosis.

BACKGROUND: Improved prognostication remains vital in multiple sclerosis to inform personalized treatment approaches. Blood neurofilament light (bNfL) is a promising prognostic biomarker, but to what extent it provides additional information, independent of established MRI metrics, is yet to be established. METHODS: We obtained all available bNfL data for 133 patients from a longitudinal observational cohort study. Patients were dichotomized into good or poor outcome groups based upon clinical and cognitive assessments performed 15 years after a clinically isolated syndrome. We performed longitudinal modeling of early NfL and MRI variables to examine differences between outcome groups. RESULTS: The bNfL dataset was incomplete, with one to three (mean 1.5) samples available per participant. Within 3 months of onset, bNfL was similar between groups. The bNfL concentration subsequently decreased in those with a good outcome, and remained persistently elevated in those with a poor outcome. By year 5, NfL in the poor outcome group was approximately double that of those with a good outcome (14.58 [10.40-18.77] vs. 7.71 [6.39-9.04] pg/ml, respectively). Differences were reduced after adjustment for longitudinal changes in T2LV, but trends persisted for a greater rate of increase in NfL in those with a poor outcome, independent of T2LV. CONCLUSIONS: This analysis requires replication in cohorts with more complete bNfL datasets, but suggests that persistently elevated blood NfL may be more common in patients with a poor long-term outcome. Persistent elevation of blood NfL may provide additional prognostic information not wholly accounted for by standard monitoring techniques.

Use of follow-on disease-modifying treatments for multiple sclerosis: Consensus recommendations.

BACKGROUND: As patents for multiple sclerosis (MS) therapies expire, follow-on disease-modifying treatments (FO-DMTs) become available at reduced cost. Concerns exist that cheaper FO-DMTs are used simply to reduce healthcare costs. However, the well-being of people with MS should take priority. OBJECTIVES: To identify best practices for FO-DMT development and use by agreeing on principles and consensus statements through appraisal of published evidence. METHODS: Following a systematic review, we formulated five overarching principles and 13 consensus statements. Principles and statements were voted on by a multidisciplinary panel from 17 European countries, Argentina, Canada and the United States. RESULTS: All principles and statements were endorsed by >80% of panellists. In brief, FO-DMTs approved within highly regulated areas can be considered effective and safe as their reference products; FO-DMTs can be evaluated case by case and do not always require Phase III trials; long-term pharmacovigilance and transparency are needed; there is lack of evidence for multiple- and cross-switching among FO-DMTs; and education is needed to address remaining concerns. CONCLUSION: Published data support the use of FO-DMTs in MS. The consensus may aid shared decision-making. While our consensus focused on Europe, the results may contribute to enhanced quality standards for FO-DMTs use elsewhere.

Longitudinal Assessment of Multiple Sclerosis with the Brain-Age Paradigm.

OBJECTIVE: During the natural course of multiple sclerosis (MS), the brain is exposed to aging as well as disease effects. Brain aging can be modeled statistically; the so-called "brain-age" paradigm. Here, we evaluated whether brain-predicted age difference (brain-PAD) was sensitive to the presence of MS, clinical progression, and future outcomes. METHODS: In a longitudinal, multicenter sample of 3,565 magnetic resonance imaging (MRI) scans, in 1,204 patients with MS and clinically isolated syndrome (CIS) and 150 healthy controls (mean follow-up time: patients 3.41 years, healthy controls 1.97 years), we measured "brain-predicted age" using T1-weighted MRI. We compared brain-PAD among patients with MS and patients with CIS and healthy controls, and between disease subtypes. Relationships between brain-PAD and Expanded Disability Status Scale (EDSS) were explored. RESULTS: Patients with MS had markedly higher brain-PAD than healthy controls (mean brain-PAD +10.3 years; 95% confidence interval [CI] = 8.5-12.1] versus 4.3 years; 95% CI = 2.1 to 6.4; p < 0.001). The highest brain-PADs were in secondary-progressive MS (+13.3 years; 95% CI = 11.3-15.3). Brain-PAD at study entry predicted time-to-disability progression (hazard ratio 1.02; 95% CI = 1.01-1.03; p < 0.001); although normalized brain volume was a stronger predictor. Greater annualized brain-PAD increases were associated with greater annualized EDSS score (r = 0.26; p < 0.001). INTERPRETATION: The brain-age paradigm is sensitive to MS-related atrophy and clinical progression. A higher brain-PAD at baseline was associated with more rapid disability progression and the rate of change in brain-PAD related to worsening disability. Potentially, "brain-age" could be used as a prognostic biomarker in early-stage MS, to track disease progression or stratify patients for clinical trial enrollment. ANN NEUROL 2020 ANN NEUROL 2020;88:93-105.

A practical approach to assessing and managing sexual dysfunction in multiple sclerosis.

Sexual dysfunction is common in both men and women with multiple sclerosis but is often under-reported and undertreated. Neurologists report that a major barrier to discussing sexual dysfunction with patients is their lack of knowledge. Here we review the common presentations of sexual dysfunction, discuss its causes in people with multiple sclerosis, and provide a practical approach for neurologists to assess and manage these problems.

Longitudinal spinal cord atrophy in multiple sclerosis using the generalized boundary shift integral.

OBJECTIVE: Spinal cord atrophy is a clinically relevant feature of multiple sclerosis (MS), but longitudinal assessments on magnetic resonance imaging using segmentation-based methods suffer from measurement variability, especially in multicenter studies. We compared the generalized boundary shift integral (GBSI), a registration-based method, with a standard segmentation-based method. METHODS: Baseline and 1-year spinal cord 3-dimensional T1-weighted images (1mm isotropic) were obtained from 282 patients (52 clinically isolated syndrome [CIS], 196 relapsing-remitting MS [RRMS], 34 progressive MS [PMS]), and 82 controls from 8 MAGNIMS (Magnetic Resonance Imaging in Multiple Sclerosis) sites on multimanufacturer and multi-field-strength scans. Spinal Cord Toolbox was used for C2-5 segmentation and cross-sectional area (CSA) calculation. After cord straightening and registration, GBSI measured atrophy based on the probabilistic boundary-shift region of interest. CSA and GBSI percentage annual volume change was calculated. RESULTS: GBSI provided similar rates of atrophy, but reduced measurement variability compared to CSA in all MS subtypes (CIS: -0.95 ± 2.11% vs -1.19 ± 3.67%; RRMS: -1.74 ± 2.57% vs -1.74 ± 4.02%; PMS: -2.29 ± 2.40% vs -1.29 ± 3.20%) and healthy controls (0.02 ± 2.39% vs -0.56 ± 3.77%). GBSI performed better than CSA in differentiating healthy controls from CIS (area under the curve [AUC] = 0.66 vs 0.53; p = 0.03), RRMS (AUC = 0.73 vs 0.59; p < 0.001), PMS (AUC = 0.77 vs 0.53; p < 0.001), and patients with disability progression from patients without progression (AUC = 0.59 vs 0.50; p = 0.04). Sample size to detect 60% treatment effect on spinal cord atrophy over 1 year was lower for GBSI than CSA (CIS: 106 vs 830; RRMS: 95 vs 335; PMS: 44 vs 215; power = 80%; alpha = 5%). INTERPRETATION: The registration-based method (GBSI) allowed better separation between MS patients and healthy controls and improved statistical power, when compared with a conventional segmentation-based method (CSA), although it is still far from perfect. ANN NEUROL 2019 ANN NEUROL 2019;86:704-713.

Early imaging predictors of long-term outcomes in relapse-onset multiple sclerosis.

The clinical course of relapse-onset multiple sclerosis is highly variable. Demographic factors, clinical features and global brain T2 lesion load have limited value in counselling individual patients. We investigated early MRI predictors of key long-term outcomes including secondary progressive multiple sclerosis, physical disability and cognitive performance, 15 years after a clinically isolated syndrome. A cohort of patients with clinically isolated syndrome (n = 178) was prospectively recruited within 3 months of clinical disease onset and studied with MRI scans of the brain and spinal cord at study entry (baseline) and after 1 and 3 years. MRI measures at each time point included: supratentorial, infratentorial, spinal cord and gadolinium-enhancing lesion number, brain and spinal cord volumetric measures. The patients were followed-up clinically after ∼15 years to determine disease course, and disability was assessed using the Expanded Disability Status Scale, Paced Auditory Serial Addition Test and Symbol Digit Modalities Test. Multivariable logistic regression and multivariable linear regression models identified independent MRI predictors of secondary progressive multiple sclerosis and Expanded Disability Status Scale, Paced Auditory Serial Addition Test and Symbol Digit Modalities Test, respectively. After 15 years, 166 (93%) patients were assessed clinically: 119 (72%) had multiple sclerosis [94 (57%) relapsing-remitting, 25 (15%) secondary progressive], 45 (27%) remained clinically isolated syndrome and two (1%) developed other disorders. Physical disability was overall low in the multiple sclerosis patients (median Expanded Disability Status Scale 2, range 0-10); 71% were untreated. Baseline gadolinium-enhancing (odds ratio 3.16, P < 0.01) and spinal cord lesions (odds ratio 4.71, P < 0.01) were independently associated with secondary progressive multiple sclerosis at 15 years. When considering 1- and 3-year MRI variables, baseline gadolinium-enhancing lesions remained significant and new spinal cord lesions over time were associated with secondary progressive multiple sclerosis. Baseline gadolinium-enhancing (ß = 1.32, P < 0.01) and spinal cord lesions (ß = 1.53, P < 0.01) showed a consistent association with Expanded Disability Status Scale at 15 years. Baseline gadolinium-enhancing lesions was also associated with performance on the Paced Auditory Serial Addition Test (ß = - 0.79, P < 0.01) and Symbol Digit Modalities Test (ß = -0.70, P = 0.02) at 15 years. Our findings suggest that early focal inflammatory disease activity and spinal cord lesions are predictors of very long-term disease outcomes in relapse-onset multiple sclerosis. Established MRI measures, available in routine clinical practice, may be useful in counselling patients with early multiple sclerosis about long-term prognosis, and personalizing treatment plans.

Cortical grey matter sodium accumulation is associated with disability and secondary progressive disease course in relapse-onset multiple sclerosis.

OBJECTIVE: Sodium (23Na)-MRI is an emerging imaging technique to investigate in vivo changes in tissue viability, reflecting neuroaxonal integrity and metabolism. Using an optimised 23Na-MRI protocol with smaller voxel sizes and improved tissue contrast, we wanted to investigate whether brain total sodium concentration (TSC) is a biomarker for long-term disease outcomes in a cohort of patients with relapse-onset multiple sclerosis (MS), followed from disease onset. METHODS: We performed a cross-sectional study in 96 patients followed up ~ 15 years after a clinically isolated syndrome (CIS) and 34 healthy controls. Disease course was classified as CIS, relapsing-remitting MS or secondary progressive MS (SPMS). We acquired 1H-MRI and 23Na-MRI and calculated the TSC in cortical grey matter (CGM), deep grey matter, normal-appearing white matter (WM) and WM lesions. Multivariable linear regression was used to identify independent associations of tissue-specific TSC with physical disability and cognition, with adjustment for tissue volumes. RESULTS: TSC in all tissues was higher in patients with MS compared with healthy controls and patients who remained CIS, with differences driven by patients with SPMS. Higher CGM TSC was independently associated with Expanded Disability Status Scale (R2=0.26), timed 25-foot walk test (R2=0.23), 9-hole peg test (R2=0.23), Paced Auditory Serial Addition Test (R2=0.29), Symbol Digit Modalities Test (R2=0.31) and executive function (R2=0.36) test scores, independent of grey matter atrophy. CONCLUSIONS: Sodium accumulation in CGM reflects underlying neuroaxonal metabolic abnormalities relevant to disease course heterogeneity and disability in relapse-onset MS. TSC and should be considered as an outcome measure in future neuroprotection trials.