Prospective trial of natalizumab personalised extended interval dosing by therapeutic drug monitoring in relapsing-remitting multiple sclerosis (NEXT-MS).

BACKGROUND: Extended interval dosing (EID) of natalizumab is a promising strategy to optimise treatment in multiple sclerosis (MS). Personalised EID by therapeutic drug monitoring can enable further extension of treatment intervals. METHODS: The NEXT-MS trial is an investigator-initiated prospective phase IV non-randomised study. Adults with a diagnosis of relapsing-remitting MS who received ≥6 natalizumab infusions were included in three groups: personalised EID with a target drug trough concentration of 10 µg/mL (EID10), an exploratory group of personalised EID with a target of 5 µg/mL (EID5) and standard interval dosing (SID) of 4 weeks. The primary outcome is radiological disease activity (new/newly enlarged T2 lesions) comparing the EID10 group to a historical cohort of SID (HSID). RESULTS: Results of the first phase of the NEXT-MS trial are reported here (n=376) as the study will continue with an amended protocol. In the EID10 group (n=251), incidence rate of radiological activity was 10.0 per 1000 person-years, which was non-inferior to the HSID cohort (24.7 per 1000 person-years (n=87), incidence rate difference 14.7, 90% CI -4.5 to 34.0). Incidence rate of radiological activity was 10.0 per 1000 person-years in the EID5 group (n=65), and 47.0 per 1000 person-years in the SID group (n=60). Serum neurofilament light levels did not increase over time within the EID groups. There were no cases of progressive multifocal leukoencephalopathy. CONCLUSIONS: MS disease activity is adequately controlled with personalised natalizumab EID. Interval extension to a drug trough concentration of 5 µg/mL is likely a safe target to extend natalizumab treatment intervals >6 weeks. TRIAL REGISTRATION NUMBER: NCT04225312.

Multicenter Evaluation of AI-generated DIR and PSIR for Cortical and Juxtacortical Multiple Sclerosis Lesion Detection.

Background Cortical multiple sclerosis lesions are clinically relevant but inconspicuous at conventional clinical MRI. Double inversion recovery (DIR) and phase-sensitive inversion recovery (PSIR) are more sensitive but often unavailable. In the past 2 years, artificial intelligence (AI) was used to generate DIR and PSIR from standard clinical sequences (eg, T1-weighted, T2-weighted, and fluid-attenuated inversion-recovery sequences), but multicenter validation is crucial for further implementation. Purpose To evaluate cortical and juxtacortical multiple sclerosis lesion detection for diagnostic and disease monitoring purposes on AI-generated DIR and PSIR images compared with MRI-acquired DIR and PSIR images in a multicenter setting. Materials and Methods Generative adversarial networks were used to generate AI-based DIR (n = 50) and PSIR (n = 43) images. The number of detected lesions between AI-generated images and MRI-acquired (reference) images was compared by randomized blinded scoring by seven readers (all with >10 years of experience in lesion assessment). Reliability was expressed as the intraclass correlation coefficient (ICC). Differences in lesion subtype were determined using Wilcoxon signed-rank tests. Results MRI scans of 202 patients with multiple sclerosis (mean age, 46 years ± 11 [SD]; 127 women) were retrospectively collected from seven centers (February 2020 to January 2021). In total, 1154 lesions were detected on AI-generated DIR images versus 855 on MRI-acquired DIR images (mean difference per reader, 35.0% ± 22.8; P < .001). On AI-generated PSIR images, 803 lesions were detected versus 814 on MRI-acquired PSIR images (98.9% ± 19.4; P = .87). Reliability was good for both DIR (ICC, 0.81) and PSIR (ICC, 0.75) across centers. Regionally, more juxtacortical lesions were detected on AI-generated DIR images than on MRI-acquired DIR images (495 [42.9%] vs 338 [39.5%]; P < .001). On AI-generated PSIR images, fewer juxtacortical lesions were detected than on MRI-acquired PSIR images (232 [28.9%] vs 282 [34.6%]; P = .02). Conclusion Artificial intelligence-generated double inversion-recovery and phase-sensitive inversion-recovery images performed well compared with their MRI-acquired counterparts and can be considered reliable in a multicenter setting, with good between-reader and between-center interpretative agreement. Published under a CC BY 4.0 license. Supplemental material is available for this article. See also the editorial by Zivadinov and Dwyer in this issue.

Serum glial fibrillary acidic protein in natalizumab-treated relapsing-remitting multiple sclerosis: An alternative to neurofilament light.

BACKGROUND: There is a need in Relapsing-Remitting Multiple Sclerosis (RRMS) treatment for biomarkers that monitor neuroinflammation, neurodegeneration, treatment response, and disease progression despite treatment. OBJECTIVE: To assess the value of serum glial fibrillary acidic protein (sGFAP) as a biomarker for clinical disease progression and brain volume measurements in natalizumab-treated RRMS patients. METHODS: sGFAP and neurofilament light (sNfL) were measured in an observational cohort of natalizumab-treated RRMS patients at baseline, +3, +12, and +24 months and at the last sample follow-up (median 5.17 years). sGFAP was compared between significant clinical progressors and non-progressors and related to magnetic resonance imaging (MRI)-derived volumes of the whole brain, ventricle, thalamus, and lesion. The relationship between sGFAP and sNfL was assessed. RESULTS: A total of 88 patients were included, and 47.7% progressed. sGFAP levels at baseline were higher in patients with gadolinium enhancement (1.3-fold difference, p = 0.04) and decreased in 3 months of treatment (adj. p < 0.001). No association was found between longitudinal sGFAP levels and progressor status. sGFAP at baseline and 12 months was significantly associated with normalized ventricular (positively), thalamic (negatively), and lesion volumes (positively). Baseline and 12-month sGFAP predicted annualized ventricle volume change rate after 1 year of treatment. sGFAP correlated with sNfL at baseline (p < 0.001) and last sample follow-up (p < 0.001) but stabilized earlier. DISCUSSION: sGFAP levels related to MRI markers of neuroinflammation and neurodegeneration.

Serum contactin-1 as a biomarker of long-term disease progression in natalizumab-treated multiple sclerosis.

BACKGROUND: Natalizumab treatment provides a model for non-inflammation-induced disease progression in multiple sclerosis (MS). OBJECTIVE: To study serum contactin-1 (sCNTN1) as a novel biomarker for disease progression in natalizumab-treated relapsing-remitting MS (RRMS) patients. METHODS: Eighty-nine natalizumab-treated RRMS patients with minimum follow-up of 3 years were included. sCNTN1 was analyzed at baseline (before natalizumab initiation), 3, 12, 24 months (M) and last follow-up (median 5.2 years) and compared to 222 healthy controls (HC) and 15 primary progressive MS patients (PPMS). Results were compared between patients with progressive, stable, or improved disability according to EDSS-plus criteria. RESULTS: Median sCNTN1 levels (ng/mL,) in RRMS (baseline: 10.7, 3M: 9.7, 12M: 10.4, 24M: 10.8; last follow-up: 9.7) were significantly lower compared to HC (12.5; p ⩽ 0.001). It was observed that 48% of patients showed progression during follow-up, 11% improved, and 40% remained stable. sCNTN1 levels were significantly lower in progressors both at baseline and at 12M compared to non-progressors. A 1 ng/mL decrease in baseline sCNTN1 was consistent with an odds ratio of 1.23 (95% confidence interval 1.04-1.45) (p = 0.017) for progression during follow-up. CONCLUSION: Lower baseline sCNTN1 concentrations were associated with long-term disability progression during natalizumab treatment, making it a possible blood-based prognostic biomarker for RRMS.

Neurofilament-light and contactin-1 association with long-term brain atrophy in natalizumab-treated relapsing-remitting multiple sclerosis.

BACKGROUND: Despite highly effective treatment strategies for patients with relapsing-remitting multiple sclerosis (RRMS), long-term neurodegeneration and disease progression are often considerable. Accurate blood-based biomarkers that predict long-term neurodegeneration are lacking. OBJECTIVE: To assess the predictive value of serum neurofilament-light (sNfL) and serum contactin-1 (sCNTN1) for long-term magnetic resonance imaging (MRI)-derived neurodegeneration in natalizumab-treated patients with RRMS. METHODS: sNfL and sCNTN1 were measured in an observational cohort of natalizumab-treated patients with RRMS at baseline (first dose) and at 3 months, Year 1, Year 2, and last follow-up (median = 5.2 years) of treatment. Disability progression was quantified using "EDSS-plus" criteria. Neurodegeneration was measured by calculating annualized percentage brain, ventricular, and thalamic volume change (PBVC, VVC, and TVC, respectively). Linear regression analysis was performed to identify longitudinal predictors of neurodegeneration. RESULTS: In total, 88 patients (age = 37 ± 9 years, 75% female) were included, of whom 48% progressed. Year 1 sNfL level (not baseline or 3 months) was associated with PBVC (standardized (std.) ß = -0.26, p = 0.013), VVC (standardized ß = 0.36, p < 0.001), and TVC (standardized ß = -0.24, p = 0.02). For sCNTN1, only 3-month level was associated with VVC (standardized ß = -0.31, p = 0.002). CONCLUSION: Year 1 (but not baseline) sNfL level was predictive for long-term brain atrophy in patients treated with natalizumab. sCNTN1 level did not show a clear predictive value.

Personalized B-cell tailored dosing of ocrelizumab in patients with multiple sclerosis during the COVID-19 pandemic.

In this observational study, 159 patients with multiple sclerosis received personalized dosing of ocrelizumab incentivized by the COVID-19 pandemic. Re-dosing was scheduled when CD19 B-cell count was ⩾10 cells/µL (starting 24 weeks after the previous dose, repeated 4-weekly). Median interval until re-dosing or last B-cell count was 34 [30-38] weeks. No clinical relapses were reported and a minority of patients showed Expanded Disability Status Scale (EDSS) progression. Monthly serum neurofilament light levels remained stable during extended intervals. Two (1.9%) of 107 patients with a follow-up magnetic resonance imaging (MRI) scan showed radiological disease activity. Personalized dosing of ocrelizumab could significantly extend intervals with low short-term disease activity incidence, encouraging future research on long-term safety and efficacy.

Smartphone-derived keystroke dynamics are sensitive to relevant changes in multiple sclerosis.

BACKGROUND: To investigate smartphone keystroke dynamics (KD), derived from regular typing, on sensitivity to relevant change in disease activity, fatigue, and clinical disability in multiple sclerosis (MS). METHODS: Preplanned interim analysis of a cohort study with 102 MS patients assessed at baseline and 3-month follow-up for gadolinium-enhancing lesions on magnetic resonance imaging, relapses, fatigue and clinical disability outcomes. Keyboard interactions were unobtrusively collected during typing using the Neurokeys App. From these interactions 15 keystroke features were derived and aggregated using 16 summary and time series statistics. Responsiveness of KD to clinical anchor-based change was assessed by calculating the area under the receiver operating characteristic curve (AUC). The optimal cut-point was used to determine the minimal clinically important difference (MCID) and compared to the smallest real change (SRC). Commonly used clinical measures were analyzed for comparison. RESULTS: A total of 94 patients completed the follow-up. The five best performing keystroke features had AUC-values in the range 0.72-0.78 for change in gadolinium-enhancing lesions, 0.67-0.70 for the Checklist Individual Strength Fatigue subscale, 0.66-0.79 for the Expanded Disability Status Scale, 0.69-0.73 for the Ambulation Functional System, and 0.72-0.75 for Arm function in MS Questionnaire. The MCID of these features exceeded the SRC on group level. KD had higher AUC-values than comparative clinical measures for the study outcomes, aside from ambulatory function. CONCLUSIONS: Keystroke dynamics demonstrated good responsiveness to changes in disease activity, fatigue, and clinical disability in MS, and detected important change beyond measurement error on group level. Responsiveness of KD was better than commonly used clinical measures.

Infratentorial and spinal cord lesions: Cumulative predictors of long-term disability?

OBJECTIVE: The objective of the study was to determine whether early infratentorial and/or spinal cord lesions are long-term cumulative predictors of disability progression in multiple sclerosis (MS). METHODS: We selected 153 MS patients from the longitudinal Amsterdam MS cohort. Lesion analysis was performed at baseline and year 2. Disability progression after 6 and 11 years was measured using the Expanded Disability Status Scale (EDSS) and EDSS-plus (including 25-foot walk and 9-hole peg test). Patients with spinal cord or infratentorial lesions were compared for the risk of 6- and 11-year disability progression to patients without spinal cord or infratentorial lesions, respectively. Subsequently, patients with lesions on both locations were compared to patients with only spinal cord or only infratentorial lesions. RESULTS: Baseline spinal cord lesions show a higher risk of 6-year EDSS progression (odds ratio (OR): 3.6, p = 0.007) and EDSS-plus progression (OR: 2.5, p = 0.028) and 11-year EDSS progression (OR: 2.8, p = 0.047). Patients with both infratentorial and spinal cord lesions did not have a higher risk of 6-year disability progression than patients with only infratentorial or only spinal cord lesions. CONCLUSION: The presence of early spinal cord lesions seems to be a dominant risk factor of disability progression. Simultaneous presence of early infratentorial and spinal cord lesions did not undisputedly predict disability progression.

The role of diet in multiple sclerosis onset and course: results from a nationwide retrospective birth-year cohort.

OBJECTIVE: To examine (1) the association between childhood diet and developing MS, age of onset and onset type and (2) the association between diet at age 50 and disability and MRI volumes in people with MS (PwMS). METHODS: The study enrolled 361 PwMS born in 1966 and 125 age- and sex-matched healthy controls (HCs). Information on individual dietary components (fruit, vegetables, red meat, oily fish, whole-grain bread and candy, snacks and fast food) and MS risk factors at the age of 10 and 50 years were collected using questionnaires. Overall diet quality score was calculated for each participant. Multivariable regression analyses were used to evaluate the association between diet at childhood and developing MS, age of onset and onset type and to evaluate diet at age 50, disability and MRI outcomes. RESULTS: Poorer overall diet quality and individual dietary components during childhood (less whole-grain bread, more candy, snacks and fast food and oily fish) were associated with developing MS and onset type (all p < 0.05), but not with the age of onset. Fruit consumption at age 50 was associated with lower disability (Q3 vs. Q1: -0.51; 95% CI: -0.89 to -0.13). Furthermore, several individual dietary components at age 50 were associated with MRI volumetric measures. Higher-diet quality at age 50 was only associated with lower lesion volumes in PwMS (Q2 vs. Q1: -0.3 mL; 95% CI: -0.5 to -0.02). INTERPRETATION: We demonstrate significant associations between dietary factors in childhood and developing MS, age of onset and onset type and between dietary factors at age 50 and disability and MRI-derived volumes.

Neuroaxonal and Glial Markers in Patients of the Same Age With Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: The specificity of novel blood biomarkers for multiple sclerosis (MS)-related neurodegeneration is unclear because neurodegeneration also occurs during normal aging. To understand which aspects of neurodegeneration the serum biomarkers neurofilament light (sNfL), serum glial fibrillary acidic protein (sGFAP), and serum contactin-1 (sCNTN1) reflect, we here explore their cross-sectional association with disability outcome measures and MRI volumes in a unique cohort of people with MS (PwMS) of the same age. METHODS: sNfL, sGFAP (both singe-molecule array technology) and sCNTN1 (Luminex) were measured in serum samples of 288 PwMS and 125 healthy controls (HCs) of the Project Y cohort, a population-based cross-sectional study of PwMS born in the Netherlands in 1966 and age-matched HC. RESULTS: sNfL (9.83 pg/mL [interquartile range {IQR}: 7.8-12.0]) and sGFAP (63.7 pg/mL [IQR: 48.5-84.5]) were higher in PwMS compared with HC (sNfL: 8.8 pg/mL [IQR: 7.0-10.5]; sGFAP: 51.7 pg/mL [IQR: 40.1-68.3]) (p < 0.001), whereas contactin-1 (7,461.3 pg/mL [IQR: 5,951.8-9,488.6]) did not significantly differ between PwMS compared with HC (7,891.2 pg/mL [IQR: 6,120.0-10,265.8]) (p = 0.068). sNfL and sGFAP levels were 1.2-fold higher in secondary progressive patients (SPMS) compared with relapsing remitting patients (p = 0.009 and p = 0.043). Stratified by MS subtype, no relations were seen for CNTN1, whereas sNfL and sGFAP correlated with the Expanded Disability Status Scale (ρ = 0.43 and ρ = 0.39), Nine-Hole Peg Test, Timed 25-Foot Walk Test, and Symbol Digit Modalities Test (average ρ = 0.38) only in patients with SPMS. Parallel to these clinical findings, correlations were only found for sNfL and sGFAP with MRI volumes. The strongest correlations were observed between sNfL and thalamic volume (ρ = -0.52) and between sGFAP with deep gray matter volume (ρ = - 0.56) in primary progressive patients. DISCUSSION: In our cohort of patients of the same age, we report consistent correlations of sNfL and sGFAP with a range of metrics, especially in progressive MS, whereas contactin-1 was not related to clinical or MRI measures. This demonstrates the potential of sNfL and sGFAP as complementary biomarkers of neurodegeneration, reflected by disability, in progressive MS.

Association of volumetric MRI measures and disability in MS patients of the same age: Descriptions from a birth year cohort.

BACKGROUND AND OBJECTIVES: Although MRI-based markers of neuroinflammation have proven crucial for the diagnosis of multiple sclerosis (MS), predicting clinical progression with inflammation remains difficult. Neurodegenerative markers such as brain volume loss show stronger clinical (predictive) correlations, but also harbor age-related variation that must be disentangled from disease duration. In this study we investigated how clinical disability is related to volumetric MRI measures in a cohort of MS patients and healthy controls (HC) of the same age: Project Y. METHODS: This study included 234 MS patients born in 1966 and 112 HC born between 1965 and 1967 in the Netherlands. Disability was quantified using the expanded disability status scale (EDSS), nine hole peg test (9HPT), and timed 25 foot walking test (T25FWT). Volumes were quantified on 3T MRI as normalized whole brain (NBV) and regional gray matter (GM) volumes using the same scanner and MRI protocol: cortical (normalized cortical gray matter volume; NCGMV), deep (NDGMV), thalamic (NThalV), and cerebellar (NCbV) GM volumes. In addition, mean upper cervical cord area (MUCCA), white matter lesion volume (LV), and spinal cord lesions were assessed. These measures were compared between patients and HC, and related to disability measures using linear regression. RESULTS: Mean age of people with MS (PwMS) was 52.8 years (SD 0.9) and median disease duration 15.8 years (IQR 8.7-24.8). All global and regional brain measures were lower in MS patients compared to HC. Univariate regression models showed that NDGMV (ß = -0.20) and MUCCA (ß = -0.38) were most strongly related to the EDSS in all PwMS. After subtype stratification, MUCCA was most strongly related to the EDSS (ß = -0.60) and 9HPT (ß = -0.55) in secondary progressive PwMS. Multivariate regression models demonstrated that in all PwMS, the EDSS was best explained by lower MUCCA, longer disease durations and a progressive disease course (adjusted-R (Sastre-Garriga et al., 2017) = 0.26, p < 0.001). MUCCA was a consistent correlate in separate models of the EDSS for all PwMS, relapsing and progressive onset PwMS. The 9HPT (adjusted-R (Sastre-Garriga et al., 2017) = 0.20, p < 0.001) was best explained by lower MUCCA, higher LV and pack years, while lower limb disability (adjusted-R (Sastre-Garriga et al., 2017) = 0.11, p < 0.001) was best explained by lower MUCCA, progressive onset MS and female sex. DISCUSSION: Our results indicate that in a cohort unbiased by age differences, spinal cord and deep gray matter volumes best related to physical disability. Our results support the use of these measures in clinical practice and trials.

A multimodal marker for cognitive functioning in multiple sclerosis: the role of NfL, GFAP and conventional MRI in predicting cognitive functioning in a prospective clinical cohort.

BACKGROUND: Cognitive impairment in people with MS (PwMS) has primarily been investigated using conventional imaging markers or fluid biomarkers of neurodegeneration separately. However, the single use of these markers do only partially explain the large heterogeneity found in PwMS. OBJECTIVE: To investigate the use of multimodal (bio)markers: i.e., serum and cerebrospinal fluid (CSF) levels of neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) and conventional imaging markers in predicting cognitive functioning in PwMS. METHODS: Eighty-two PwMS (56 females, disease duration = 14 ± 9 years) underwent neuropsychological and neurological examination, structural magnetic resonance imaging, blood sampling and lumbar puncture. PwMS were classified as cognitively impaired (CI) if scoring ≥ 1.5SD below normative scores on ≥ 20% of test scores. Otherwise, PwMS were defined as cognitively preserved (CP). Association between fluid and imaging (bio)markers were investigated, as well as binary logistics regression to predict cognitive status. Finally, a multimodal marker was calculated using statistically important predictors of cognitive status. RESULTS: Only higher NfL levels (in serum and CSF) correlated with worse processing speed (r = - 0.286, p = 0.012 and r = - 0.364, p = 0.007, respectively). sNfL added unique variance in the prediction of cognitive status on top of grey matter volume (NGMV), p = 0.002). A multimodal marker of NGMV and sNfL yielded most promising results in predicting cognitive status (sensitivity = 85%, specificity = 58%). CONCLUSION: Fluid and imaging (bio)markers reflect different aspects of neurodegeneration and cannot be used interchangeably as markers for cognitive functioning in PwMS. The use of a multimodal marker, i.e., the combination of grey matter volume and sNfL, seems most promising for detecting cognitive deficits in MS.

Upper cervical cord atrophy is independent of cervical cord lesion volume in early multiple sclerosis: A two-year longitudinal study.

BACKGROUND: Upper cervical cord atrophy and lesions have been shown to be associated with disease and disability progression already in early relapsing-remitting multiple sclerosis (RRMS). However, their longitudinal relationship remains unclear. OBJECTIVE: To investigate the cross-sectional and longitudinal relation between focal T2 cervical cord lesion volume (CCLV) and regional and global mean upper cervical cord area (UCCA), and their relations with disability. METHODS: Over a two-year interval, subjects with RRMS (n = 36) and healthy controls (HC, n = 16) underwent annual clinical and MRI examinations. UCCA and CCLV were obtained from C1 through C4 level. Linear mixed model analysis was performed to investigate the relation between UCCA, CCLV, and disability over time. RESULTS: UCCA at baseline was significantly lower in RRMS subjects compared to HCs (p = 0.003), but did not decrease faster over time (p ≥ 0.144). UCCA and CCLV were independent of each other at any of the time points or cervical levels, and over time. Lower baseline UCCA, but not CCLV, was related to worsening of both upper and lower extremities function over time. CONCLUSION: UCCA and CCLV are independent from each other, both cross-sectionally and longitudinally, in early MS. Lower UCCA, but not CCLV, was related to increasing disability over time.

Project Y: The search for clues explaining phenotype variability in MS.

BACKGROUND: To study phenotypic variability in MS patients, well-defined unbiased cohort studies are necessary. The most common and probably most important confounding factor when studying disease phenotype in MS is age. OBJECTIVE: To describe study design and subject characteristics of a unique birth cohort (Project Y). The overall aim of Project Y is to identify determinants associated with phenotypic variability in MS, eliminating the possibility of confounding by age. METHODS: Project Y is a population-based cross-sectional study of all people with MS born in the Netherlands in 1966. Patients and healthy controls were subjected to comprehensive examinations: functional and static imaging, physical and cognitive measurements, and lifestyle factors early and later in life. In addition body fluids were collected and stored for future biomarker research. RESULTS: 452 eligible MS patients were identified. Between December 2017 and January 2021, 367 MS patients and 125 healthy controls participated. The total number of identified cases results in a current prevalence of at least 189/100.000 for people born in the year 1966 in The Netherlands. CONCLUSION: Project Y is a unique cohort designed to identify factors associated with phenotypic variability in MS patients without the confounding effects of age. This first description of the Project Y cohort indicates that the prevalence of MS in the Netherlands might be higher than previously presumed. Various studies using Project Y data are ongoing and results will be published in upcoming years.

Long-interval T2-weighted subtraction magnetic resonance imaging: a powerful new outcome measure in multiple sclerosis trials.

OBJECTIVE: To compare long-interval T2-weighted subtraction (T2w-Sub) imaging with monthly gadolinium-enhanced T1-weighted (Gd-T1w) imaging for (1) detection of active lesions, (2) assessment of treatment efficacy, and (3) statistical power, in a multiple sclerosis (MS), phase 2, clinical trial setting. METHODS: Magnetic resonance imaging (MRI) data over 9 months from 120 patients (61 treatment, 59 placebo) from the oral temsirolimus trial were used. T2w-Sub images were scored for active lesions, independent of the original reading of the monthly Gd-T1w images. Treatment efficacy was evaluated using the nonparametric Mann-Whitney U test, and parametric negative binomial (NB)-regression and power calculations were conducted. RESULTS: Datasets from 116 patients (58 treatment, 58 placebo) were evaluated. The mean number of T2w-Sub lesions in the treatment group was 3.0 (+/-4.6) versus 5.9 (+/-8.8) for placebo; the mean cumulative number of new Gd-T1w lesions in the treatment group was 5.5(+/-9.1) versus 9.1(+/-17.2) for placebo. T2w-Sub imaging showed increased power to assess treatment efficacy compared with Gd-T1w imaging, when evaluated by Mann-Whitney U test (p = 0.017 vs p = 0.177), or NB-regression without (p = 0.011 vs p = 0.092) or with baseline adjustment (p < 0.001 vs p = 0.002). Depending on the magnitude of the simulated treatment effect, sample size calculations showed reductions of 22 to 34% in the number of patients (translating into reductions of 81-83% in the number of MRI scans) needed to detect a significant treatment effect in favor of T2w-Sub imaging. INTERPRETATION: Compared with monthly Gd-T1w imaging, long-interval T2w-Sub MRI exhibited increased power to assess treatment efficacy, and could greatly increase the cost-effectiveness of phase 2 MS trials by limiting the number of patients, contrast injections, and MRI scans needed.

Diagnosis of Progressive Multiple Sclerosis From the Imaging Perspective: A Review.

Importance: Although magnetic resonance imaging (MRI) is useful for monitoring disease dissemination in space and over time and excluding multiple sclerosis (MS) mimics, there has been less application of MRI to progressive MS, including diagnosing primary progressive (PP) MS and identifying patients with relapsing-remitting (RR) MS who are at risk of developing secondary progressive (SP) MS. This review addresses clinical application of MRI for both diagnosis and prognosis of progressive MS. Observations: Although nonspecific, some spinal cord imaging features (diffuse abnormalities and lesions involving gray matter [GM] and ≥2 white matter columns) are typical of PPMS. In patients with PPMS and those with relapse-onset MS, location of lesions in critical central nervous system regions (spinal cord, infratentorial regions, and GM) and MRI-detected high inflammatory activity in the first years after diagnosis are risk factors for long-term disability and future progressive disease course. These measures are evaluable in clinical practice. In patients with established MS, GM involvement and neurodegeneration are associated with accelerated clinical worsening. Subpial demyelination and slowly expanding lesions are novel indicators of progressive MS. Conclusions and Relevance: Diagnosis of PPMS is more challenging than diagnosis of RRMS. No qualitative clinical, immunological, histopathological, or neuroimaging features differentiate PPMS and SPMS; both are characterized by imaging findings reflecting neurodegeneration and are also impacted by aging and comorbidities. Unmet diagnostic needs include identification of MRI markers capable of distinguishing PPMS from RRMS and predicting the evolution of RRMS to SPMS. Integration of multiple parameters will likely be essential to achieve these aims.

Serum Neurofilament Light Association With Progression in Natalizumab-Treated Patients With Relapsing-Remitting Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: To investigate the potential of serum neurofilament light (NfL) to reflect or predict progression mostly independent of acute inflammatory disease activity in patients with relapsing-remitting multiple sclerosis (RRMS) treated with natalizumab. METHODS: Patients were selected from a prospective observational cohort study initiated in 2006 at the VU University Medical Center Amsterdam, the Netherlands, including patients with RRMS treated with natalizumab. Selection criteria included an age of 18 years or older and a minimum follow-up of 3 years from natalizumab initiation. Clinical and MRI assessments were performed on a yearly basis, and serum NfL was measured at 5 time points during the follow-up, including on the day of natalizumab initiation (baseline), 3 months, 1 year, and 2 years after natalizumab initiation, and on last follow-up visit. Using general linear regression models, we compared the longitudinal dynamics of NfL between patients with and without confirmed Expanded Disability Status Scale (EDSS) progression between year 1 visit and last follow-up, and between individuals with and without EDSS+ progression, a composite endpoint including the EDSS, 9-hole peg test, and timed 25-foot walk. RESULTS: Eighty-nine natalizumab-treated patients with RRMS were included. Median follow-up time was 5.2 years (interquartile range [IQR] 4.3-6.7, range 3.0-11.0) after natalizumab initiation, mean age at time of natalizumab initiation was 36.9 years (SD 8.5), and median disease duration was 7.4 years (IQR 3.8-12.1). Between year 1 and the last follow-up, 28/89 (31.5%) individuals showed confirmed EDSS progression. Data for the EDSS+ endpoint was available for 73 out of the 89 patients and 35/73 (47.9%) showed confirmed EDSS+ progression. We observed a significant reduction in NfL levels 3 months after natalizumab initiation, which reached its nadir of close to 50% of baseline levels 1 year after treatment initiation. We found no difference in the longitudinal dynamics of NfL in progressors vs nonprogressors. NfL levels at baseline and 1 year after natalizumab initiation did not predict progression at last follow-up. CONCLUSION: In our cohort of natalizumab-treated patients with RRMS, NfL fails to capture or predict progression that occurs largely independently of clinical or radiologic signs of acute focal inflammatory disease activity. Additional biomarkers may thus be needed to monitor progression in these patients. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that serum NfL levels are not associated with disease progression in natalizumab-treated patients with RRMS.

A multidisciplinary neuro-oncological triage panel reduces the time to referral and treatment for patients with a brain tumor.

BACKGROUND: Regional collaboration and appropriate referral management are crucial in neuro-oncological care. Lack of electronic access to medical records across health care organizations impedes interhospital consultation and may lead to incomplete and delayed referrals. To improve referral management, we have established a multidisciplinary neuro-oncological triage panel (NOTP) with digital image exchange and determined the effects on lead times, costs, and time investment. METHODS: A prospective cohort study was conducted from February 2019 to March 2020. All newly diagnosed patients referred to Brain Tumor Center Amsterdam were analyzed according to referral pathway: (1) standard referral (SR), (2) NOTP. The primary outcome was lead time, defined as time-to-referral, time-to-treatment, and total time (median days [interquartile range]). Secondary outcomes were costs and time investment. RESULTS: In total, 225 patients were included, of whom 153 had SR and 72 NOTP referral. Patients discussed in the NOTP were referred more frequently for first neurosurgical consultation (44.7% vs 28.8%) or combined neurological and neurosurgical consultation (12.8% vs 2.5%, P = .002). Time-to-referral was reduced for NOTP referral compared to SR (1 [0.25-4] vs 6 [1.5-10] days, P < .001). Total time decreased from 27 [14-48] days for the standard group to 15 [12-38.25] days for the NOTP group (P = .040). Costs and time investment were comparable for both groups. CONCLUSION: Implementation of digital referral to a multidisciplinary NOTP is feasible and leads to more swift patient-tailored referrals at comparable costs and time investment as SR. This quality improvement initiative has the potential to improve collaboration and coordination of multidisciplinary care in the field of neuro-oncology.

Improved detection of active multiple sclerosis lesions: 3D subtraction imaging.

PURPOSE: To examine the benefits of using near-isotropic single-slab three-dimensional (3D) magnetic resonance (MR) imaging for the creation of subtraction images and to evaluate their performance in the detection of active multiple sclerosis (MS) brain lesions in comparison with two-dimensional (2D) subtraction images. MATERIALS AND METHODS: The study protocol was approved by the local ethics review board and all subjects gave written informed consent before investigation. Three-dimensional MR sequences, including double inversion-recovery, fluid-attenuated inversion recovery, T2-weighted, and T1-weighted magnetization-prepared rapid acquisition gradient-echo (MP-RAGE), and corresponding 2D sequences were performed twice in 14 patients (eight women, six men; mean age, 37.6 years) with MS and nine age-matched healthy control subjects (three women, six men; mean age, 31.7 years). Active lesions were scored by two independent raters, followed by a consensus reading. Lesion counts were evaluated by using negative binomial regression; interrater agreement was evaluated by using intraclass correlation coefficient. RESULTS: Three-dimensional subtraction images had less residual misregistration and flow artifacts and depicted higher numbers of active lesions with greater interobserver agreement compared with 2D subtraction images. Among the 3D sequences, MP-RAGE subtraction imaging enabled detection of a significantly higher mean number of positive active MS lesions compared with 2D subtraction imaging (2.8 versus 1.7, P = .012), particularly infratentorial lesions (0.6 vs 0.1, P < .05), and a substantially higher (nonsignificant) mean number of small (<3 mm) lesions (0.6 vs 0.1, P > .05). CONCLUSION: Three-dimensional subtraction imaging, after image registration, produced better image quality, leading to increased detection of active MS lesions with greater interobserver agreement in comparison with 2D subtraction imaging; 3D MP-RAGE subtraction imaging represents a promising technique to increase sensitivity in ascertaining lesion dissemination in time and increase the power of MR imaging metrics for the evaluation of treatment effects in clinical trials.

Early central atrophy rate predicts 5 year clinical outcome in multiple sclerosis.

OBJECTIVE: To examine the predictive value of central atrophy in early multiple sclerosis (MS) patients, for medium term clinical outcome. METHODS: In 54 patients with recently diagnosed MS, clinical and MRI parameters were obtained at baseline, and after 2 and 5.5 years of follow-up. In addition to conventional MRI parameters and the annualised percentage brain volume change (aPBVC), the annualised percentage ventricular volume change (aPVVC) was quantified. Main outcome measure was disease progression, defined by an increase in Expanded Disability Status Scale of ≥1 after 5.5 years. RESULTS: Disease progression occurred in 29 patients. aPVVC within the first two years was significantly higher in these progressing patients (median 4.76%; IQR 3.05-9.17) compared with stable patients (median 3.23%; IQR -0.1-6.02) (p=0.02). A logistic regression model selected aPVVC within the first 2 years as the only MRI marker predicting progression after 5.5 years (OR 1.17, 95% CI 1.02 to 1.35). When entering all MRI and clinical markers, again aPVVC within the first 2 years was the only MRI marker selected. While aPVVC was correlated between the two consecutive time intervals (ρ=0.41, p<0.01), aPBVC was not. Furthermore, baseline T2 lesion load and gadolinium enhancing lesion load were correlated with aPVVC in the second time interval (2-5.5 years) but not with aPBVC. CONCLUSION: The rate of ventricular enlargement seems to be even more strongly predictive of disease progression after medium term follow-up than whole brain atrophy rate, and also outperforms lesion measures. Central atrophy rate could therefore be an important prognostic marker, especially in the early stages of MS.