7 T imaging reveals a gradient in spinal cord lesion distribution in multiple sclerosis.

We used 7 T MRI to: (i) characterize the grey and white matter pathology in the cervical spinal cord of patients with early relapsing-remitting and secondary progressive multiple sclerosis; (ii) assess the spinal cord lesion spatial distribution and the hypothesis of an outside-in pathological process possibly driven by CSF-mediated immune cytotoxic factors; and (iii) evaluate the association of spinal cord pathology with brain burden and its contribution to neurological disability. We prospectively recruited 20 relapsing-remitting, 15 secondary progressive multiple sclerosis participants and 11 age-matched healthy control subjects to undergo 7 T imaging of the cervical spinal cord and brain as well as conventional 3 T brain acquisition. Cervical spinal cord imaging at 7 T was used to segment grey and white matter, including lesions therein. Brain imaging at 7 T was used to segment cortical and white matter lesions and 3 T imaging for cortical thickness estimation. Cervical spinal cord lesions were mapped voxel-wise as a function of distance from the inner central canal CSF pool to the outer subpial surface. Similarly, brain white matter lesions were mapped voxel-wise as a function of distance from the ventricular system. Subjects with relapsing-remitting multiple sclerosis showed a greater predominance of spinal cord lesions nearer the outer subpial surface compared to secondary progressive cases. Inversely, secondary progressive participants presented with more centrally located lesions. Within the brain, there was a strong gradient of lesion formation nearest the ventricular system that was most evident in participants with secondary progressive multiple sclerosis. Lesion fractions within the spinal cord grey and white matter were related to the lesion fraction in cerebral white matter. Cortical thinning was the primary determinant of the Expanded Disability Status Scale, white matter lesion fractions in the spinal cord and brain of the 9-Hole Peg Test and cortical thickness and spinal cord grey matter cross-sectional area of the Timed 25-Foot Walk. Spinal cord lesions were localized nearest the subpial surfaces for those with relapsing-remitting and the central canal CSF surface in progressive disease, possibly implying CSF-mediated pathogenic mechanisms in lesion development that may differ between multiple sclerosis subtypes. These findings show that spinal cord lesions involve both grey and white matter from the early multiple sclerosis stages and occur mostly independent from brain pathology. Despite the prevalence of cervical spinal cord lesions and atrophy, brain pathology seems more strongly related to physical disability as measured by the Expanded Disability Status Scale.

Radiologically isolated syndrome is antiquated amidst evolving McDonald criteria for multiple sclerosis.

The diagnosis of radiologically isolated syndrome (RIS) is untenable in the modern era as new diagnostic criteria for multiple sclerosis (MS) continue to evolve. Even without optic nerve involvement, the shift in the diagnostic criteria for MS forces clinicians to make a diagnosis at the earliest possible time and appropriate treatment initiated. In this analysis, we revisit the original RIS criteria as published and conclude that RIS as a diagnostic entity is obsolete.

Sample size requirements for one-year treatment effects using deep gray matter volume from 3T MRI in progressive forms of multiple sclerosis.

OBJECTIVE: The subcortical deep gray matter (DGM) develops selective, progressive, and clinically relevant atrophy in progressive forms of multiple sclerosis (PMS). This patient population is the target of active neurotherapeutic development, requiring the availability of outcome measures. We tested a fully automated MRI analysis pipeline to assess DGM atrophy in PMS. DESIGN/METHODS: Consistent 3D T1-weighted high-resolution 3T brain MRI was obtained over one year in 19 consecutive patients with PMS [15 secondary progressive, 4 primary progressive, 53% women, age (mean±SD) 50.8±8.0 years, Expanded Disability Status Scale (median, range) 5.0, 2.0-6.5)]. DGM segmentation applied the fully automated FSL-FIRST pipeline ( http://fsl.fmrib.ox.ac.uk ). Total DGM volume was the sum of the caudate, putamen, globus pallidus, and thalamus. On-study change was calculated using a random-effects linear regression model. RESULTS: We detected one-year decreases in raw [mean (95% confidence interval): -0.749 ml (-1.455, -0.043), p = 0.039] and annualized [-0.754 ml/year (-1.492, -0.016), p = 0.046] total DGM volumes. A treatment trial for an intervention that would show a 50% reduction in DGM brain atrophy would require a sample size of 123 patients for a single-arm study (one-year run-in followed by one-year on-treatment). For a two-arm placebo-controlled one-year study, 242 patients would be required per arm. The use of DGM fraction required more patients. The thalamus, putamen, and globus pallidus, showed smaller effect sizes in their on-study changes than the total DGM; however, for the caudate, the effect sizes were somewhat larger. CONCLUSIONS: DGM atrophy may prove efficient as a short-term outcome for proof-of-concept neurotherapeutic trials in PMS.

The Great Masquerader: Recurrent Ischemic Strokes Secondary to Meningovascular Syphilis in a Man With Cardiovascular Stroke Risk Factors.

A male in his 60s with stroke risk factors presented with confusion and word-finding difficulties. He was diagnosed with acute ischemic stroke in the right basal ganglia. He was started on secondary stroke prevention measures including dual antiplatelet therapy and a high-dose statin. A highly reactive rapid plasma reagin (RPR) was performed as part of the workup and found to be positive. Follow-up fluorescent treponemal antibody absorption (TPA) test was also positive, confirming a diagnosis of syphilis. He was discharged home with a scheduled course of antibiotic treatment for tertiary syphilis but returned due to a new episode of transient facial paralysis. Further workup and physical exam findings revealed the patient had neurosyphilis. He was started on the appropriate antibiotic therapy, which significantly improved his confusion and prevented new episodes of stroke.

Neurologic Sequela of COVID-19: Guillain-Barré Syndrome Following Johnson & Johnson COVID-19 Vaccination.

Guillain-Barré syndrome after Pfizer and Astra-Zeneca vaccinations against COVID-19 has been previously reported in the literature. The objective of this study was to report the first case of Guillain-Barré following the COVID-19 vaccination with the Johnson & Johnson COVID-19 vaccine. We report the case of a 53-year-old female who presented to the Emergency Department complaining of bilateral lower extremity weakness, paresthesias, and gait difficulties 14 days after having received the Johnson & Johnson COVID-19 vaccination. MRI of the lumbar spine with and without contrast revealed enhancement of the cauda equina nerve roots suggestive of acute inflammatory demyelinating polyradiculoneuropathy. Cerebrospinal fluid (CSF) analysis reported mildly elevated protein low white blood cells (WBCs). Ganglioside (GM1 and GQ1b) antibodies were reported as negative. After intravenous immunoglobulin (IVIg), the patient had significant improvement in her weakness and paresthesia and was discharged home. The case was reported to the Centers for Disease Control and Prevention (CDC) Vaccine Adverse Event Reporting System. Guillain-Barré syndrome after COVID-19 immunization remains a rare complication. A clear mechanism of disease has not been clarified; however, it is believed that there could be some type of molecular mimicry between the spike glycoprotein produced with the help of the vaccines and proteins in the myelin sheath.

Brain MRI Predicts Worsening Multiple Sclerosis Disability over 5 Years in the SUMMIT Study.

BACKGROUND AND PURPOSE: Brain MRI-derived lesions and atrophy are related to multiple sclerosis (MS) disability. In the Serially Unified Multicenter MS Investigation (SUMMIT), from Brigham and Women's Hospital (BWH) and University of California, San Francisco (UCSF), we assessed whether MRI methodologic heterogeneity may limit the ability to pool multisite data sets to assess 5-year clinical-MRI associations. METHODS: Patients with relapsing-remitting (RR) MS (n = 100 from each site) underwent baseline brain MRI and baseline and 5-year clinical evaluations. Patients were matched on sex (74 women each), age, disease duration, and Expanded Disability Status Scale (EDSS) score. MRI was performed with differences between sites in both acquisition (field strength, voxel size, pulse sequences), and postprocessing pipeline to assess brain parenchymal fraction (BPF) and T2 lesion volume (T2LV). RESULTS: The UCSF cohort showed higher correlation than the BWH cohort between T2LV and disease duration. UCSF showed a higher inverse correlation between BPF and age than BWH. UCSF showed a higher inverse correlation than BWH between BPF and 5-year EDSS score. Both cohorts showed inverse correlations between BPF and T2LV, with no between-site difference. The pooled but not individual cohort data showed a link between a lower baseline BPF and the subsequent 5-year worsening in disability in addition to other stronger relationships in the data. CONCLUSIONS: MRI acquisition and processing differences may result in some degree of heterogeneity in assessing brain lesion and atrophy measures in patients with MS. Pooling of data across sites is beneficial to correct for potential biases in individual data sets.

A two-year study using cerebral gray matter volume to assess the response to fingolimod therapy in multiple sclerosis.

BACKGROUND: Cerebral gray matter (GM) atrophy has clinical relevance in multiple sclerosis (MS). Fingolimod has known efficacy on clinical and conventional MRI findings in MS; the effect on GM is unknown. OBJECTIVE: To explore fingolimod's treatment effect on cerebral GM atrophy over two years in patients with relapsing forms of MS. DESIGN/METHODS: Patients starting fingolimod [n=24, age (mean±SD) 41.2±11.6years, Expanded Disability Status Scale (EDSS) score 1.1±1.4; 58% women] were compared to untreated patients [n=29, age 45.7±8.4years, EDSS 1.0±1.2; 93% women]. Baseline, one and two year MRI was applied to an SPM12 pipeline to assess brain parenchymal fraction (BPF) and cortical GM fraction (cGMF). T2 lesion volume (T2LV) and gadolinium-enhancing lesions were assessed. Change was modeled using a mixed effects linear regression with a random intercept and fixed effects for time, group, and the time-by-group interaction. The group slope difference was assessed using the interaction term. RESULTS: Over two years, cGMF remained stable in the fingolimod group (p>0.05), but decreased in the untreated group (p<0.001) (group difference p<0.001). BPF change did not differ between groups (all time-points p>0.05). T2LV increased over two years in the untreated group (p<0.001) but not in the fingolimod group (p≥0.44) (group difference p<0.001). CONCLUSION: These results suggest a treatment effect of fingolimod on cerebral GM atrophy in the first two years. GM atrophy is more sensitive to such effects than whole brain atrophy. However, due to the non-randomized, retrospective design, heterogeneous between-group characteristics, and small sample size, these results require confirmation in future studies.

The Effect of Dimethyl Fumarate on Cerebral Gray Matter Atrophy in Multiple Sclerosis.

INTRODUCTION: The objective of this pilot study was to compare cerebral gray matter (GM) atrophy over 1 year in patients starting dimethyl fumarate (DMF) for multiple sclerosis (MS) to that of patients on no disease-modifying treatment (noDMT). DMF is an established therapy for relapsing-remitting (RR) MS. METHODS: We retrospectively analyzed 20 patients with RRMS at the start of DMF [age (mean ± SD) 46.1 ± 10.2 years, Expanded Disability Status Scale (EDSS) score 1.1 ± 1.2, timed 25-foot walk (T25FW) 4.6 ± 0.8 s] and eight patients on noDMT (age 42.5 ± 6.6 years, EDSS 1.7 ± 1.1, T25FW 4.4 ± 0.6 s). Baseline and 1-year 3D T1-weighted 3T MRI was processed with automated pipelines (SIENA, FSL-FIRST) to assess percentage whole brain volume change (PBVC) and deep GM (DGM) atrophy. Group differences were assessed by analysis of covariance, with time between MRI scans as a covariate. RESULTS: Over 1 year, the DMF group showed a lower rate of whole brain atrophy than the noDMT group (PBVC: -0.37 ± 0.49% vs. -1.04 ± 0.67%, p = 0.005). The DMF group also had less change in putamen volume (-0.06 ± 0.22 vs. -0.32 ± 0.28 ml, p = 0.02). There were no significant on-study differences between groups in caudate, globus pallidus, thalamus, total DGM volume, T2 lesion volume, EDSS, or T25FW (all p > 0.20). CONCLUSIONS: These results suggest a treatment effect of DMF on GM atrophy appearing at 1 year after starting therapy. However, due to the retrospective study design and sample size, these findings should be considered preliminary, and require confirmation in future investigations. FUNDING: Biogen.

The Contribution of Cortical Lesions to a Composite MRI Scale of Disease Severity in Multiple Sclerosis.

OBJECTIVE: To test a new version of the Magnetic Resonance Disease Severity Scale (v.3 = MRDSS3) for multiple sclerosis (MS), incorporating cortical gray matter lesions (CLs) from 3T magnetic resonance imaging (MRI). BACKGROUND: MRDSS1 was a cerebral MRI-defined composite scale of MS disease severity combining T2 lesion volume (T2LV), the ratio of T1 to T2LV (T1/T2), and whole brain atrophy [brain parenchymal fraction (BPF)]. MRDSS2 expanded the scale to include cerebral gray matter fraction (GMF) and upper cervical spinal cord area (UCCA). We tested the contribution of CLs to the scale (MRDSS3) in modeling the MRI relationship to clinical status. METHODS: We studied 51 patients [3 clinically isolated syndrome, 43 relapsing-remitting, 5 progressive forms, age (mean ± SD) 40.7 ± 9.1 years, Expanded Disability Status Scale (EDSS) score 1.6 ± 1.7] and 20 normal controls by high-resolution cerebrospinal MRI. CLs required visibility on both fluid-attenuated inversion-recovery (FLAIR) and modified driven equilibrium Fourier transform sequences. The MACFIMS battery defined cognitively impaired (n = 18) vs. preserved (n = 33) MS subgroups. RESULTS: EDSS significantly correlated with only BPF, UCCA, MRDSS2, and MRDSS3 (all p < 0.05). After adjusting for depressive symptoms, the cognitively impaired group had higher severity of MRI metrics than the cognitively preserved group in regard to only BPF, GMF, T1/T2, MRDSS1, and MRDSS2 (all p < 0.05). CL number was not significantly related to EDSS score or cognition status. CONCLUSION: CLs from 3T MRI did not appear to improve the validity of the MRDSS. Further studies employing advanced sequences or higher field strengths may show more utility for the incorporation of CLs into composite scales.