Single Test to ARrive at Multiple Sclerosis (STAR-MS) diagnosis: A prospective pilot study assessing the accuracy of the central vein sign in predicting multiple sclerosis in cases of diagnostic uncertainty.

BACKGROUND: Misdiagnosis is common in multiple sclerosis (MS) as a proportion of patients present with atypical clinical/magnetic resonance imaging (MRI) findings. The central vein sign has the potential to be a non-invasive, MS-specific biomarker. OBJECTIVE: To test the accuracy of the central vein sign in predicting a diagnosis of MS in patients with diagnostic uncertainty at disease presentation using T2*-weighted, 3 T MRI. METHODS: In this prospective pilot study, we recruited individuals with symptoms unusual for MS but with brain MRI consistent with the disease, and those with a typical clinical presentation of MS whose MRI did not suggest MS. We calculated the proportion of lesions with central veins for each patient and compared the results to the eventual clinical diagnoses. The optimal central vein threshold for diagnosis was established. RESULTS: Thirty-eight patients were scanned, 35 of whom have received a clinical diagnosis. Median percentage of lesions with central veins was 51% in MS and 28% in non-MS. A threshold of 40.7% lesions with central veins resulted in 100% sensitivity and 73.9% specificity. CONCLUSION: The central vein sign assessed with a clinically available T2* scan can successfully diagnose MS in cases of diagnostic uncertainty. The central vein sign should be considered as a diagnostic biomarker in MS.

Ultra-high-field arterial spin labelling MRI for non-contrast assessment of cortical lesion perfusion in multiple sclerosis.

OBJECTIVES: To assess the feasibility of using an optimised ultra-high-field high-spatial-resolution low-distortion arterial spin labelling (ASL) MRI acquisition to measure focal haemodynamic pathology in cortical lesions (CLs) in multiple sclerosis (MS). METHODS: Twelve MS patients (eight female, mean age 50 years; range 35-64 years) gave informed consent and were scanned on a 7 Tesla Philips Achieva scanner. Perfusion data were collected at multiple post-labelling delay times using a single-slice flow-sensitive alternating inversion recovery ASL protocol with a balanced steady-state free precession readout scheme. CLs were identified using a high-resolution Phase-Sensitive Inversion Recovery (PSIR) scan. Significant differences in perfusion within CLs compared to immediately surrounding normal appearing grey matter (NAGMlocal) and total cortical normal appearing grey matter (NAGMcortical) were assessed using paired t-tests. RESULTS: Forty CLs were identified in PSIR scans that overlapped with the ASL acquisition coverage. After excluding lesions due to small size or intravascular contamination, 27 lesions were eligible for analysis. Mean perfusion was 40 ± 25 ml/100 g/min in CLs, 53 ± 12 ml/100 g/min in NAGMlocal, and 53 ± 8 ml/100 g/min in NAGMcortical. CL perfusion was significantly reduced by 23 ± 9% (mean ± SE, p = 0.013) and 26 ± 9% (p = 0.006) relative to NAGMlocal and NAGMcortical perfusion, respectively. CONCLUSION: This is the first ASL MRI study quantifying CL perfusion in MS at 7 Tesla, demonstrating that an optimised ASL acquisition is sensitive to focal haemodynamic pathology previously observed using dynamic susceptibility contrast MRI. ASL requires no exogenous contrast agent, making it a more appropriate tool to monitor longitudinal perfusion changes in MS, providing a new window to study lesion development. KEY POINTS: • Perfusion can be quantified within cortical lesions in multiple sclerosis using an optimised high spatial resolution arterial spin Labelling MRI acquisition at ultra-high-field. • The majority of cortical lesions assessed using arterial spin labelling are hypo-perfused compared to normal appearing grey matter, in agreement with dynamic susceptibility contrast MRI literature. • Arterial spin labelling MRI, which does not involve the injection of a contrast agent, is a safe and appropriate technique for repeat scanning of an individual patient.

Hookworm Treatment for Relapsing Multiple Sclerosis: A Randomized Double-Blinded Placebo-Controlled Trial.

Importance: Studies suggest gut worms induce immune responses that can protect against multiple sclerosis (MS). To our knowledge, there are no controlled treatment trials with helminth in MS. Objective: To determine whether hookworm treatment has effects on magnetic resonance imaging (MRI) activity and T regulatory cells in relapsing MS. Design, Setting, and Participants: This 9-month double-blind, randomized, placebo-controlled trial was conducted between September 2012 and March 2016 in a modified intention-to-treat population (the data were analyzed June 2018) at the University of Nottingham, Queen's Medical Centre, a single tertiary referral center. Patients aged 18 to 61 years with relapsing MS without disease-modifying treatment were recruited from the MS clinic. Seventy-three patients were screened; of these, 71 were recruited (2 ineligible/declined). Interventions: Patients were randomized (1:1) to receive either 25 Necator americanus larvae transcutaneously or placebo. The MRI scans were performed monthly during months 3 to 9 and 3 months posttreatment. Main Outcomes and Measures: The primary end point was the cumulative number of new/enlarging T2/new enhancing T1 lesions at month 9. The secondary end point was the percentage of cluster of differentiation (CD) 4+CD25highCD127negT regulatory cells in peripheral blood. Results: Patients (mean [SD] age, 45 [9.5] years; 50 women [71%]) were randomized to receive hookworm (35 [49.3%]) or placebo (36 [50.7%]). Sixty-six patients (93.0%) completed the trial. The median cumulative numbers of new/enlarging/enhancing lesions were not significantly different between the groups by preplanned Mann-Whitney U tests, which lose power with tied data (high number of zeroactivity MRIs in the hookworm group, 18/35 [51.4%] vs 10/36 [27.8%] in the placebo group). The percentage of CD4+CD25highCD127negT cells increased at month 9 in the hookworm group (hookworm, 32 [4.4%]; placebo, 34 [3.9%]; P = .01). No patients withdrew because of adverse effects. There were no differences in adverse events between groups except more application-site skin discomfort in the hookworm group (82% vs 28%). There were 5 relapses (14.3%) in the hookworm group vs 11 (30.6%) receiving placebo. Conclusions and Relevance: Treatment with hookworm was safe and well tolerated. The primary outcome did not reach significance, likely because of a low level of disease activity. Hookworm infection increased T regulatory cells, suggesting an immunobiological effect of hookworm. It appears that a living organism can precipitate immunoregulatory changes that may affect MS disease activity. Trial Registration: ClinicalTrials.gov Identifier: NCT01470521.

The MRI central vein marker; differentiating PPMS from RRMS and ischemic SVD.

OBJECTIVE: To determine whether the assessment of brain white matter lesion (WML) central veins differentiate patients with primary progressive MS (PPMS) from relapsing-remitting MS (RRMS) and ischemic small vessel disease (SVD) using 3T MRI. METHODS: In this cross-sectional study, 71 patients with PPMS, RRMS, and SVD were imaged using a T2*-weighted sequence. Two blinded raters identified the total number of WMLs, proportion of WMLs in periventricular, deep white matter (DWM) and juxtacortical regions, and proportion of WMLs with central veins in all patient groups. The proportions were compared between disease groups, including effect sizes. MS or SVD was categorized using a threshold of ≥40% WMLs with central veins as indicative of MS. Interrater and intrarater reproducibility was calculated. RESULTS: The mean proportion of WMLs with central veins was 68.4% in PPMS, 74.3% in RRMS, and 4.7% in SVD. The difference in proportions between PPMS and SVD groups was significant (p < 0.0005; effect size: 3.8) but not significant between MS subtypes (p = 0.3; effect size: 0.29). Distribution of WMLs was similar across both MS groups, but despite SVD patients having more DWM lesions than PPMS patients, proportions of WMLs with central veins remained low (2.75% in SVD; 62.5% in PPMS). Interrater and intrarater reproducibility comparing proportions of WMLs with central veins across all patients was 0.86 and 0.90, respectively. Level of agreement between the proportion of WML central veins and established diagnosis was 0.84 and 0.82 for each rater. CONCLUSIONS: WML central veins could be used to differentiate PPMS from SVD but not between MS subtypes.

The Central Vein Sign in Multiple Sclerosis Lesions Is Present Irrespective of the T2* Sequence at 3 T.

BACKGROUND AND PURPOSE: Previous T2*-weighted magnetic resonance imaging (MRI) studies have used white matter lesion (WML) central veins to distinguish multiple sclerosis (MS) from its mimics. To be clinically applicable, the "central vein sign" needs to be detectable across different T2* sequences. Our objective was to determine if the central vein sign is reliably present in MS and absent in patients with ischemic small vessel disease (SVD) across different T2* sequences at 3T MRI. METHODS: Ten patients with MS and 10 with SVD were each scanned on a 3 T Philips and GE scanner. The MRI protocol included 3-dimensional (3D) T2* GRE, T2* with high echo planar imaging (EPI) factor and susceptibility-weighted angiography (SWAN). Total WML numbers, central vein numbers, and proportion of WMLs with central veins were calculated using each sequence. Three blinded raters identified a subset of six WMLs with central veins to diagnose MS or SVD. RESULTS: Irrespective of the sequence, MS patients were identified based on a higher proportion of WMLs with central veins. This proportion was dependent on the T2* sequence used. T2* with high EPI allowed the highest median proportion (69.6%) in MS patients; 6.1% in SVD patients (P < .0004). Rater reproducibility varied depending on the T2* sequence used. T2* with high EPI produced good agreement with the clinical diagnosis (Cohen's kappa range; .78-.89), as did SWAN imaging with some raters; ĸ = .69. CONCLUSIONS: The central vein sign can diagnose MS in the clinical setting of modern 3T scanners. However, variations in the T2* sequences need to be considered when defining a threshold for diagnosis.