Grey Matter Atrophy and its Relationship with White Matter Lesions in Patients with Myelin Oligodendrocyte Glycoprotein Antibody-associated Disease, Aquaporin-4 Antibody-Positive Neuromyelitis Optica Spectrum Disorder, and Multiple Sclerosis.

OBJECTIVE: To evaluate: (1) the distribution of gray matter (GM) atrophy in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4+NMOSD), and relapsing-remitting multiple sclerosis (RRMS); and (2) the relationship between GM volumes and white matter lesions in various brain regions within each disease. METHODS: A retrospective, multicenter analysis of magnetic resonance imaging data included patients with MOGAD/AQP4+NMOSD/RRMS in non-acute disease stage. Voxel-wise analyses and general linear models were used to evaluate the relevance of regional GM atrophy. For significant results (p < 0.05), volumes of atrophic areas are reported. RESULTS: We studied 135 MOGAD patients, 135 AQP4+NMOSD, 175 RRMS, and 144 healthy controls (HC). Compared with HC, MOGAD showed lower GM volumes in the temporal lobes, deep GM, insula, and cingulate cortex (75.79 cm3); AQP4+NMOSD in the occipital cortex (32.83 cm3); and RRMS diffusely in the GM (260.61 cm3). MOGAD showed more pronounced temporal cortex atrophy than RRMS (6.71 cm3), whereas AQP4+NMOSD displayed greater occipital cortex atrophy than RRMS (19.82 cm3). RRMS demonstrated more pronounced deep GM atrophy in comparison with MOGAD (27.90 cm3) and AQP4+NMOSD (47.04 cm3). In MOGAD, higher periventricular and cortical/juxtacortical lesions were linked to reduced temporal cortex, deep GM, and insula volumes. In RRMS, the diffuse GM atrophy was associated with lesions in all locations. AQP4+NMOSD showed no lesion/GM volume correlation. INTERPRETATION: GM atrophy is more widespread in RRMS compared with the other two conditions. MOGAD primarily affects the temporal cortex, whereas AQP4+NMOSD mainly involves the occipital cortex. In MOGAD and RRMS, lesion-related tract degeneration is associated with atrophy, but this link is absent in AQP4+NMOSD. ANN NEUROL 2024.

Clinical and MRI measures to identify non-acute MOG-antibody disease in adults.

MRI and clinical features of myelin oligodendrocyte glycoprotein (MOG)-antibody disease may overlap with those of other inflammatory demyelinating conditions posing diagnostic challenges, especially in non-acute phases and when serologic testing for MOG antibodies is unavailable or shows uncertain results. We aimed to identify MRI and clinical markers that differentiate non-acute MOG-antibody disease from aquaporin 4 (AQP4)-antibody neuromyelitis optica spectrum disorder and relapsing remitting multiple sclerosis, guiding in the identification of patients with MOG-antibody disease in clinical practice. In this cross-sectional retrospective study, data from 16 MAGNIMS centres were included. Data collection and analyses were conducted from 2019 to 2021. Inclusion criteria were: diagnosis of MOG-antibody disease; AQP4-neuromyelitis optica spectrum disorder and multiple sclerosis; brain and cord MRI at least 6 months from relapse; and Expanded Disability Status Scale (EDSS) score on the day of MRI. Brain white matter T2 lesions, T1-hypointense lesions, cortical and cord lesions were identified. Random forest models were constructed to classify patients as MOG-antibody disease/AQP4-neuromyelitis optica spectrum disorder/multiple sclerosis; a leave one out cross-validation procedure assessed the performance of the models. Based on the best discriminators between diseases, we proposed a guide to target investigations for MOG-antibody disease. One hundred and sixty-two patients with MOG-antibody disease [99 females, mean age: 41 (±14) years, median EDSS: 2 (0-7.5)], 162 with AQP4-neuromyelitis optica spectrum disorder [132 females, mean age: 51 (±14) years, median EDSS: 3.5 (0-8)], 189 with multiple sclerosis (132 females, mean age: 40 (±10) years, median EDSS: 2 (0-8)] and 152 healthy controls (91 females) were studied. In young patients (<34 years), with low disability (EDSS < 3), the absence of Dawson's fingers, temporal lobe lesions and longitudinally extensive lesions in the cervical cord pointed towards a diagnosis of MOG-antibody disease instead of the other two diseases (accuracy: 76%, sensitivity: 81%, specificity: 84%, P < 0.001). In these non-acute patients, the number of brain lesions < 6 predicted MOG-antibody disease versus multiple sclerosis (accuracy: 83%, sensitivity: 82%, specificity: 83%, P < 0.001). An EDSS < 3 and the absence of longitudinally extensive lesions in the cervical cord predicted MOG-antibody disease versus AQP4-neuromyelitis optica spectrum disorder (accuracy: 76%, sensitivity: 89%, specificity: 62%, P < 0.001). A workflow with sequential tests and supporting features is proposed to guide better identification of patients with MOG-antibody disease. Adult patients with non-acute MOG-antibody disease showed distinctive clinical and MRI features when compared to AQP4-neuromyelitis optica spectrum disorder and multiple sclerosis. A careful inspection of the morphology of brain and cord lesions together with clinical information can guide further analyses towards the diagnosis of MOG-antibody disease in clinical practice.

Comparative analysis of dimethyl fumarate and teriflunomide in relapsing-remitting multiple sclerosis.

BACKGROUND AND PURPOSE: In relapsing-remitting multiple sclerosis (RRMS), analyses from observational studies comparing dimethyl fumarate (DMF) and teriflunomide showed conflicting results. We aimed to compare the effectiveness of DMF and teriflunomide in a real-world setting, where both drugs are licensed as first-line therapies for RRMS. METHODS: We included all patients who initiated DMF or teriflunomide between 2013 and 2022, listed in the Swiss National Treatment Registry. Coarsened exact matching was applied using age, gender, disease duration, baseline Expanded Disability Status Scale (EDSS) score, time since last relapse, and relapse rate in the previous year as matching variables. Time to relapse and time to 12-month confirmed EDSS worsening were compared using Cox proportional hazard models. RESULTS: In total, 2028 patients were included in this study, of whom 1498 were matched (DMF: n = 1090, 69.6% female, mean age 45.1 years, median EDSS score 2.0; teriflunomide: n = 408, 68.9% female, mean age 45.1 years, median EDSS score 2.0). Time to relapse and time to EDSS worsening was longer in the DMF than the teriflunomide group (hazard ratio 0.734, p = 0.026 and hazard ratio 0.576, p = 0.003, respectively). CONCLUSION: Analysis of real-world data showed that DMF treatment was associated with more favorable outcomes than teriflunomide treatment.

Cortical abnormalities in episodic migraine: A multi-center 3T MRI study.

BACKGROUND: Several previous studies have investigated cortical abnormalities, specifically cortical thickness, in patients with migraine, with variable results. The relatively small sample sizes of most previous studies may partially explain these inconsistencies. OBJECTIVE: To investigate differences of cortical thickness between control subjects and migraineurs in a large cohort. METHODS: Three Tesla MRI data of 131 patients (38 with and 93 without aura) and 115 control subjects were analysed. A vertex-wise linear model was applied controlling for age, gender and MRI scanner to investigate differences between groups and determine the impact of clinical factors on cortical thickness measures. RESULTS: Migraineurs showed areas of thinned cortex compared with controls bilaterally in the central sulcus, in the left middle-frontal gyrus, in left visual cortices and the right occipito-temporal gyrus. Frequency of migraine attacks and the duration of the disorder had a significant impact on cortical thickness in the sensorimotor cortex and middle-frontal gyrus. Patients without aura showed thinner cortex than controls bilaterally in the central sulcus and in the middle frontal gyrus, in the left primary visual cortices, in the left supramarginal gyrus and in the right cuneus. Patients with aura showed clusters of thinner cortex bilaterally in the subparietal sulcus (between the precuneus and posterior cingulate cortex), in the left intraparietal sulcus and in the right anterior cingulate. CONCLUSION: These results indicate cortical abnormalities in specific brain regions in migraineurs. Some of the observed abnormalities may reflect a genetic susceptibility towards developing migraine attacks, while others are probably a consequence of repeated head pain attacks.

Morphological Abnormalities of Thalamic Subnuclei in Migraine: A Multicenter MRI Study at 3 Tesla.

The thalamus contains third-order relay neurons of the trigeminal system, and animal models as well as preliminary imaging studies in small cohorts of migraine patients have suggested a role of the thalamus in headache pathophysiology. However, larger studies using advanced imaging techniques in substantial patient populations are lacking. In the present study, we investigated changes of thalamic volume and shape in a large multicenter cohort of patients with migraine. High-resolution T1-weighted MRI data acquired at 3 tesla in 131 patients with migraine (38 with aura; 30.8 ± 9 years old; 109 women; monthly attack frequency: 3.2 ± 2.5; disease duration: 14 ± 8.4 years) and 115 matched healthy subjects (29 ± 7 years old; 81 women) from four international tertiary headache centers were analyzed. The thalamus and thalamic subnuclei, striatum, and globus pallidus were segmented using a fully automated multiatlas approach. Deformation-based shape analysis was performed to localize surface abnormalities. Differences between patients with migraine and healthy subjects were assessed using an ANCOVA model. After correction for multiple comparisons, performed using the false discovery rate approach (p < 0.05 corrected), significant volume reductions of the following thalamic nuclei were observed in migraineurs: central nuclear complex (F(1,233) = 6.79), anterior nucleus (F(1,237) = 7.38), and lateral dorsal nucleus (F(1,238) = 6.79). Moreover, reduced striatal volume (F(1,238) = 6.9) was observed in patients. This large-scale study indicates structural thalamic abnormalities in patients with migraine. The thalamic nuclei with abnormal volumes are densely connected to the limbic system. The data hence lend support to the view that higher-order integration systems are altered in migraine. SIGNIFICANCE STATEMENT: This multicenter imaging study shows morphological thalamic abnormalities in a large cohort of patients with episodic migraine compared with healthy subjects using state-of-the-art MRI and advanced, fully automated multiatlas segmentation techniques. The results stress that migraine is a disorder of the CNS in which not only is brain function abnormal, but also brain structure is undergoing significant remodeling.

Escalating to medium- versus high-efficacy disease modifying therapy after low-efficacy treatment in relapsing remitting multiple sclerosis.

BACKGROUND: In patients with relapsing remitting multiple sclerosis (RRMS) on low-efficacy disease modifying therapies (DMT), the optimal strategy on how to escalate treatment once needed, remains unknown. METHODS: We studied RRMS patients on low-efficacy DMTs listed in the Swiss National Treatment Registry, who underwent escalation to either medium- or high-efficacy DMTs. Propensity score-based matching was applied using 12 clinically relevant variables. Both groups were also separately matched with control subjects who did not escalate therapy. Time to relapse and to disability worsening were evaluated using Cox proportional hazard models. RESULTS: Of 1037 eligible patients, we 1:1 matched 450 MS patients who switched from low-efficacy to medium-efficacy (n = 225; 76.0% females, aged 42.4 ± 9.9 years [mean ± SD], median EDSS 3.0 [IQR 2-4]) or high-efficacy DMTs (n = 225; 72.4% females, aged 42.2 ± 10.6 years, median EDSS 3.0 [IQR 2-4]). Escalation to high-efficacy DMTs was associated with lower hazards of relapses than medium-efficacy DMTs (HR = 0.67, 95% CI 0.47-0.95, p = .027) or control subjects (HR = 0.61, 95% CI 0.44-0.84, p = .003). By contrast, escalation from low to medium-efficacy DMTs did not alter the hazard for relapses when compared to controls (i.e. patients on low-efficacy DMT who did not escalate DMT during follow-up) CONCLUSION: Our nationwide registry analysis suggests that, once escalation from a low-efficacy DMT is indicated, switching directly to a high-efficacy treatment is superior to a stepwise escalation starting with a moderate-efficacy treatment.

Harmonizing Definitions for Progression Independent of Relapse Activity in Multiple Sclerosis: A Systematic Review.

Importance: Emerging evidence suggests that progression independent of relapse activity (PIRA) is a substantial contributor to long-term disability accumulation in relapsing-remitting multiple sclerosis (RRMS). To date, there is no uniform agreed-upon definition of PIRA, limiting the comparability of published studies. Objective: To summarize the current evidence about PIRA based on a systematic review, to discuss the various terminologies used in the context of PIRA, and to propose a harmonized definition for PIRA for use in clinical practice and future trials. Evidence Review: A literature search was conducted using the search terms multiple sclerosis, PIRA, progression independent of relapse activity, silent progression, and progression unrelated to relapses in PubMed, Embase, Cochrane, and Web of Science, published between January 1990 and December 2022. Findings: Of 119 identified single records, 48 eligible studies were analyzed. PIRA was reported to occur in roughly 5% of all patients with RRMS per annum, causing at least 50% of all disability accrual events in typical RRMS. The proportion of PIRA vs relapse-associated worsening increased with age, longer disease duration, and, despite lower absolute event numbers, potent suppression of relapses by highly effective disease-modifying therapy. However, different studies used various definitions of PIRA, rendering the comparability of studies difficult. Conclusion and Relevance: PIRA is the most frequent manifestation of disability accumulation across the full spectrum of traditional MS phenotypes, including clinically isolated syndrome and early RRMS. The harmonized definition suggested here may improve the comparability of results in current and future cohorts and data sets.

Fluid and White Matter Suppression: New Sensitive 3 T Magnetic Resonance Imaging Contrasts for Cortical Lesion Detection in Multiple Sclerosis.

OBJECTIVE: Cortical lesions are common in multiple sclerosis (MS), but their visualization is challenging on conventional magnetic resonance imaging. The uniform image derived from magnetization prepared 2 rapid acquisition gradient echoes (MP2RAGE uni ) detects cortical lesions with a similar rate as the criterion standard sequence, double inversion recovery. Fluid and white matter suppression (FLAWS) provides multiple reconstructed contrasts acquired during a single acquisition. These contrasts include FLAWS minimum image (FLAWS min ), which provides an exquisite sensitivity to the gray matter signal and therefore may facilitate cortical lesion identification, as well as high contrast FLAWS (FLAWS hco ), which gives a contrast that is similar to one of MP2RAGE uni . In this study, we compared the manual detection rate of cortical lesions on MP2RAGE uni , FLAWS min , and FLAWS hco in MS patients. Furthermore, we assessed whether the combined detection rate on FLAWS min and FLAWS hco was superior to MP2RAGE uni for cortical lesions identification. Last, we compared quantitative T1 maps (qT1) provided by both MP2RAGE and FLAWS in MS lesions. MATERIALS AND METHODS: We included 30 relapsing-remitting MS patients who underwent MP2RAGE and FLAWS magnetic resonance imaging with isotropic spatial resolution of 1 mm at 3 T. Cortical lesions were manually segmented by consensus of 3 trained raters and classified as intracortical or leukocortical lesions on (1) MP2RAGE uniform/flat images, (2) FLAWS min , and (3) FLAWS hco . In addition, segmented lesions on FLAWS min and FLAWS hco were merged to produce a union lesion map (FLAWS min + hco ). Number and volume of all cortical, intracortical, and leukocortical lesions were compared among MP2RAGE uni , FLAWS min , and FLAWS hco using Friedman test and between MP2RAGE uni and FLAWS min + hco using Wilcoxon signed rank test. The FLAWS T1 maps were then compared with the reference MP2RAGE T1 maps using relative differences in percentage. In an exploratory analysis, individual cortical lesion counts of the 3 raters were compared, and interrater variability was quantified using Fleiss Ï°. RESULTS: In total, 633 segmentations were made on the 3 contrasts, corresponding to 355 cortical lesions. The median number and volume of single cortical, intracortical, and leukocortical lesions were comparable among MP2RAGE uni , FLAWS min , and FLAWS hco . In patients with cortical lesions (22/30), median cumulative lesion volume was larger on FLAWS min (587 µL; IQR, 1405 µL) than on MP2RAGE uni (490 µL; IQR, 990 µL; P = 0.04), whereas there was no difference between FLAWS min and FLAWS hco , or FLAWS hco and MP2RAGE uni . FLAWS min + hco showed significantly greater numbers of cortical (median, 4.5; IQR, 15) and leukocortical (median, 3.5; IQR, 12) lesions than MP2RAGE uni (median, 3; IQR, 10; median, 2.5; IQR, 7; both P < 0.001). Interrater agreement was moderate on MP2RAGE uni (Ï° = 0.582) and FLAWS hco (Ï° = 0.584), but substantial on FLAWS min (Ï° = 0.614). qT1 in lesions was similar between MP2RAGE and FLAWS. CONCLUSIONS: Cortical lesions identification in FLAWS min and FLAWS hco was comparable to MP2RAGE uni . The combination of FLAWS min and FLAWS hco allowed to identify a higher number of cortical lesions than MP2RAGE uni , whereas qT1 maps did not differ between the 2 acquisition schemes.

Brain atrophy measurement over a MRI scanner change in multiple sclerosis.

BACKGROUND: A change in MRI hardware impacts brain volume measurements. The aim of this study was to use MRI data from multiple sclerosis (MS) patients and healthy control subjects (HCs) to statistically model how to adjust brain atrophy measures in MS patients after a major scanner upgrade. METHODS: We scanned 20 MS patients and 26 HCs before and three months after a major scanner upgrade (1.5 T Siemens Healthineers Magnetom Avanto to 3 T Siemens Healthineers Skyra Fit). The patient group also underwent standardized serial MRIs before and after the scanner change. Percentage whole brain volume changes (PBVC) measured by Structural Image Evaluation using Normalization of Atrophy (SIENA) in the HCs was used to estimate a corrective term based on a linear model. The factor was internally validated in HCs, and then applied to the MS group. RESULTS: Mean PBVC during the scanner change was higher in MS than HCs (-4.1 ± 0.8 % versus -3.4 ± 0.6 %). A fixed corrective term of 3.4 (95% confidence interval: 3.13-3.67)% was estimated based on the observed average changes in HCs. Age and gender did not have a significant influence on this corrective term. After adjustment, a linear mixed effects model showed that the brain atrophy measures in MS during the scanner upgrade were not anymore associated with the scanner type (old vs new scanner; p = 0.29). CONCLUSION: A scanner change affects brain atrophy measures in longitudinal cohorts. The inclusion of a corrective term based on changes observed in HCs helps to adjust for the known and unknown factors associated with a scanner upgrade on a group level.

Choroid Plexus Volume in Multiple Sclerosis vs Neuromyelitis Optica Spectrum Disorder: A Retrospective, Cross-sectional Analysis.

BACKGROUND AND OBJECTIVES: The choroid plexus has been shown to play a crucial role in CNS inflammation. Previous studies found larger choroid plexus in multiple sclerosis (MS) compared with healthy controls. However, it is not clear whether the choroid plexus is similarly involved in MS and in neuromyelitis optica spectrum disorder (NMOSD). Thus, the aim of this study was to compare the choroid plexus volume in MS and NMOSD. METHODS: In this retrospective, cross-sectional study, patients were included by convenience sampling from 4 international MS centers. The choroid plexus of the lateral ventricles was segmented fully automatically on T1-weighted MRI sequences using a deep learning algorithm (Multi-Dimensional Gated Recurrent Units). Uni- and multivariable linear models were applied to investigate associations between the choroid plexus volume, clinically meaningful disease characteristics, and MRI parameters. RESULTS: We studied 180 patients with MS and 98 patients with NMOSD. In total, 94 healthy individuals and 47 patients with migraine served as controls. The choroid plexus volume was larger in MS (median 1,690 µL, interquartile range [IQR] 648 µL) than in NMOSD (median 1,403 µL, IQR 510 µL), healthy individuals (median 1,533 µL, IQR 570 µL), and patients with migraine (median 1,404 µL, IQR 524 µL; all p < 0.001), whereas there was no difference between NMOSD, migraine, and healthy controls. This was also true when adjusted for age, sex, and the intracranial volume. In contrast to NMOSD, the choroid plexus volume in MS was associated with the number of T2-weighted lesions in a linear model adjusted for age, sex, total intracranial volume, disease duration, relapses in the year before MRI, disease course, Expanded Disability Status Scale score, disease-modifying treatment, and treatment duration (beta 4.4; 95% CI 0.78-8.1; p = 0.018). DISCUSSION: This study supports an involvement of the choroid plexus in MS in contrast to NMOSD and provides clues to better understand the respective pathogenesis.

Severe Neuro-COVID is associated with peripheral immune signatures, autoimmunity and neurodegeneration: a prospective cross-sectional study.

Growing evidence links COVID-19 with acute and long-term neurological dysfunction. However, the pathophysiological mechanisms resulting in central nervous system involvement remain unclear, posing both diagnostic and therapeutic challenges. Here we show outcomes of a cross-sectional clinical study (NCT04472013) including clinical and imaging data and corresponding multidimensional characterization of immune mediators in the cerebrospinal fluid (CSF) and plasma of patients belonging to different Neuro-COVID severity classes. The most prominent signs of severe Neuro-COVID are blood-brain barrier (BBB) impairment, elevated microglia activation markers and a polyclonal B cell response targeting self-antigens and non-self-antigens. COVID-19 patients show decreased regional brain volumes associating with specific CSF parameters, however, COVID-19 patients characterized by plasma cytokine storm are presenting with a non-inflammatory CSF profile. Post-acute COVID-19 syndrome strongly associates with a distinctive set of CSF and plasma mediators. Collectively, we identify several potentially actionable targets to prevent or intervene with the neurological consequences of SARS-CoV-2 infection.

New and enlarging white matter lesions adjacent to the ventricle system and thalamic atrophy are independently associated with lateral ventricular enlargement in multiple sclerosis.

OBJECTIVE: To investigate the association between new or enlarging T2-weighted (w) white matter (WM) lesions adjacent to the ventricle wall, deep grey matter (DGM) atrophy and lateral ventricular enlargement in multiple sclerosis (MS). METHODS: Patients derived from the Genetic Multiple Sclerosis Associations study. Lateral ventricles and DGM were segmented fully automated at baseline and 5 years follow-up using Automatic Lateral Ventricle delineation (ALVIN) and Multiple Automatically Generated Templates brain segmentation algorithm (MAgeT), respectively. T2w and T1w lesions were manually segmented. To investigate the association between lesion distance to the ventricle wall and the lateral ventricle volume, we parcellated the WM into concentric periventricular bands using FMRIB Software Library. Associations between clinical and MRI parameters were assessed in generalized linear models using generalized estimating equations for repeated measures. RESULTS: We studied 127 MS patients. Lateral ventricles enlarged on average by 2.4%/year. Patients with new/enlarging T2w WM lesions between baseline and follow-up at 5 years had accelerated lateral ventricular enlargement compared with patients without (p = 0.004). This was true in a multivariable analysis adjusted for age, gender, and whole brain atrophy. When looking at the T2w lesions in different periventricular bands, we found the strongest association between new/enlarging T2w lesions and lateral ventricle enlargement for WM lesions adjacent to the ventricle system (p < 0.001). Moreover, and indepedent of new/enlarging WM lesions, DGM atrophy was associated with ventricular enlargement. In a multivariable analysis, this was driven by thalamic atrophy (p < 0.001). CONCLUSION: New/enlarging T2w lesions adjacent to the ventricle system and thalamic atrophy are independently associated with lateral ventricular enlargement in MS.