At present, the diagnosis of multiple sclerosis (MS) relies heavily on the use of MRI, which can demonstrate disease dissemination in space and time [1][2][3][4] . The current 2010 McDonald criteria have enabled earlier diagnosis 5,6 and initiation of disease-modifying treatment, with substantial benefits for disease outcome 7,8 , but they still have imperfect sensitivity and specificity 9,10 . The limited accuracy of the criteria results in challenging cases and misdiagnosis, which are prevalent problems in MS 11,12 . Therefore, more-accurate and pathologically specific MRI criteria are still needed to exclude other disorders that can mimic MS 13,14 .The MRI-detectable central vein inside white matter lesions has recently been proposed as a biomarker of inflammatory demyelination and, thus, may aid the diagnosis of MS 15 . The 'central vein sign' (CVS) has been investigated in various neurological conditions by several groups, and evidence has accumulated that the CVS may have the ability to accurately differentiate MS from its mimics [15][16][17][18][19][20][21] . As a consequence, recent guidelines from the Magnetic Resonance Imaging in MS (MAGNIMS) group 1,4 and the Consortium of MS Centers (CMSC) task force 22 have acknowledged the potential of the CVS and its dedicated MRI acquisitions for the differential diagnosis of MS, while calling for further research before considering a possible modification of the diagnostic criteria. However, the lack of standardization for the definition and imaging of the CVS, as well as a dearth of large-scale prospective studies evaluating the CVS for MS diagnosis, are currently preventing the clinical validation of this potential biomarker 1,23 .This Consensus Statement aims to provide recommendations for the definition, standardization and clinical evaluation of the CVS in the diagnosis of MS. These statements are based on a thorough review of the existing literature on the CVS and the consensus opinion of the members of the North American Imaging in Multiple Sclerosis (NAIMS) Cooperative. E X P E RT C O N S E N S U S D O C U M E N T on behalf of the NAIMS CooperativeAbstract | Over the past few years, MRI has become an indispensable tool for diagnosing multiple sclerosis (MS). However, the current MRI criteria for MS diagnosis have imperfect sensitivity and specificity. The central vein sign (CVS) has recently been proposed as a novel MRI biomarker to improve the accuracy and speed of MS diagnosis. Evidence indicates that the presence of the CVS in individual lesions can accurately differentiate MS from other diseases that mimic this condition. However, the predictive value of the CVS for the development of clinical MS in patients with suspected demyelinating disease is still unknown. Moreover, the lack of standardization for the definition and imaging of the CVS currently limits its clinical implementation and validation. On the basis of a thorough review of the existing literature on the CVS and the consensus opinion of the members of the North American Imaging in Mult...

Objective The aim of this work was to determine whether atrophy of specific retinal layers and brain substructures are associated over time, in order to further validate the utility of optical coherence tomography (OCT) as an indicator of neuronal tissue damage in patients with multiple sclerosis (MS). Methods Cirrus high-definition OCT (including automated macular segmentation) was performed in 107 MS patients biannually (median follow-up: 46 months). Three-Tesla magnetic resonance imaging brain scans (including brain-substructure volumetrics) were performed annually. Individual-specific rates of change in retinal and brain measures (estimated with linear regression) were correlated, adjusting for age, sex, disease duration, and optic neuritis (ON) history. Results Rates of ganglion cell + inner plexiform layer (GCIP) and whole-brain (r = 0.45; p<0.001), gray matter (GM; r = 0.37; p<0.001), white matter (WM; r = 0.28; p = 0.007), and thalamic (r = 0.38; p < 0.001) atrophy were associated. GCIP and whole-brain (as well as GM and WM) atrophy rates were more strongly associated in progressive MS (r = 0.67; p<0.001) than relapsing-remitting MS (RRMS; r = 0.33; p = 0.007). However, correlation between rates of GCIP and whole-brain (and additionally GM and WM) atrophy in RRMS increased incrementally with step-wise refinement to exclude ON effects; excluding eyes and then patients (to account for a phenotype effect), the correlation increased to 0.45 and 0.60, respectively, consistent with effect modification. In RRMS, lesion accumulation rate was associated with GCIP (r = −0.30; p = 0.02) and inner nuclear layer (r = −0.25; p = 0.04) atrophy rates. Interpretation Over time GCIP atrophy appears to mirror whole-brain, and particularly GM, atrophy, especially in progressive MS, thereby reflecting underlying disease progression. Our findings support OCT for clinical monitoring and as an outcome in investigative trials.

Background Microcystic macular edema (MME) of the retinal inner nuclear layer (INL) has recently been identified in multiple sclerosis (MS) patients with optical coherence tomography (OCT). We aimed to determine if MME of the INL, and/or higher thickness of the INL, are associated with disease activity, or disability progression. Methods This retrospective study was performed at Johns Hopkins Hospital (between 09/2008 and 03/2012). 164 MS patients and 60 healthy-controls underwent serial OCT scans and clinical evaluation (including visual function). OCT scanning, including automated intra-retinal layer segmentation, yielded thicknesses of the retinal nerve fiber layer, ganglion cell layer (plus inner plexiform layer), INL (plus outer plexiform layer), and outer nuclear layer. MS patients also underwent annual brain MRI scans. Disability scores were compared with the Wilcoxon rank-sum test. Mixed-effects linear regression was used to compare OCT measures and letter-acuity scores. Logistic regression was used to examine the relationships of baseline OCT thicknesses with clinico-radiological parameters. Findings Mean follow-up (standard deviation) for MS patients and healthy-controls was 25·8-months (9·1-months) and 22·4-months (11·4-months) respectively. 10 MS patients (6·1% of the cohort) demonstrated MME during at least one study visit, but MME was not visible at baseline in 6 of these patients. MS patients with vs. without MME (151 MS patients) at any time during the study had higher baseline multiple sclerosis severity scores (p=0·032), although expanded disability status scale (EDSS) scores were not significantly different (p=0·097). MS eyes with MME (12 eyes) vs. without MME (302 eyes) had lower letter-acuity scores (100%-contrast: p=0·017; 2·5%-contrast: p=0·031; 1·25%-contrast: p=0·014), and higher INL thicknesses (p=0·003) at baseline. Higher baseline INL thickness in MS predicted the development of contrast-enhancing lesions (p=0·007), new T2 lesions (p=0·015), EDSS progression (p=0·034), and relapses (in relapsing-remitting MS; p=0·008) during the study. MME was not associated with disease activity during follow-up. Healthy-controls did not demonstrate MME. Interpretation Increased INL thickness on OCT, potentially representing inflammation of the unmyelinated retina, is associated with disease activity in MS. If this finding is confirmed, INL thickness may be a useful predictor of disease progression in MS. Funding National Multiple Sclerosis Society (TR3760-A-3, RG4212-A-4), National Eye Institute (R01-EY014993, R01-EY019473), Braxton Debbie Angela Dillon and Skip Donor Fund.

SUMMARY An international group of neurologists and radiologists developed revised guidelines for standardized brain and spinal cord MR imaging for the diagnosis and follow-up of MS. A brain MR imaging with gadolinium is recommended for the diagnosis of MS. A spinal cord MR imaging is recommended if the brain MR imaging is nondiagnostic or if the presenting symptoms are at the level of the spinal cord. A follow-up brain MR imaging with gadolinium is recommended to demonstrate dissemination in time and ongoing clinically silent disease activity while on treatment, to evaluate unexpected clinical worsening, to re-assess the original diagnosis, and as a new baseline before starting or modifying therapy. A routine brain MR imaging should be considered every 6 months to 2 years for all patients with relapsing MS. The brain MR imaging protocol includes 3D T1-weighted, 3D T2-FLAIR, 3D T2-weighted, post-single-dose gadolinium-enhanced T1-weighted sequences, and a DWI sequence. The progressive multifocal leukoencephalopathy surveillance protocol includes FLAIR and DWI sequences only. The spinal cord MR imaging protocol includes sagittal T1-weighted and proton attenuation, STIR or phase-sensitive inversion recovery, axial T2- or T2*-weighted imaging through suspicious lesions, and, in some cases, postcontrast gadolinium-enhanced T1-weighted imaging. The clinical question being addressed should be provided in the requisition for the MR imaging. The radiology report should be descriptive, with results referenced to previous studies. MR imaging studies should be permanently retained and available. The current revision incorporates new clinical information and imaging techniques that have become more available.

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Purpose of review Multiple sclerosis is a chronic, predominantly immune-mediated disease of the central nervous system, and one of the most common causes of neurological disability in young adults globally. This review will discuss the epidemiology, diagnosis, disease course, and prognosis of multiple sclerosis and will focus on recent evidence and advances in these aspects of the disease. Recent findings Multiple sclerosis is increasing in incidence and prevalence globally, even in traditionally low-prevalence regions of the world. Recent revisions have been proposed to the existing multiple sclerosis diagnostic criteria, which will facilitate earlier diagnosis and treatment in appropriate patients. Classifying multiple sclerosis into distinct disease phenotypes can be challenging, and recent refinements have been proposed to clarify existing definitions. The prognosis of multiple sclerosis varies substantially across individual patients, and a combination of clinical, imaging, and laboratory markers can be useful in predicting clinical course and optimizing treatment in individual patients. Summary A number of recent advances have been made in the clinical diagnosis and prognostication of multiple sclerosis patients. Future research will enable the development of more accurate biomarkers of disease categorization and prognosis, which will enable timely personalized treatment in individual multiple sclerosis patients.

IMPORTANCE Cortical lesions (CLs) contribute to physical and cognitive disability in multiple sclerosis (MS). Accurate methods for visualization of CLs are necessary for future clinical studies and therapeutic trials in MS.OBJECTIVE To evaluate the clinical relevance of measures of CL burden derived from high-field magnetic resonance imaging (MRI) in MS. DESIGN, SETTING, AND PARTICIPANTSAn observational clinical imaging study was conducted at an academic MS center. Participants included 36 individuals with MS (30 relapsing-remitting, 6 secondary or primary progressive) and 15 healthy individuals serving as controls. The study was conducted from March 10, 2010, to November 23, 2012, and analysis was performed from June 1, 2011, to September 30, 2014. Seven-Tesla MRI of the brain was performed with 0.5-mm isotropic resolution magnetization-prepared rapid acquisition gradient echo (MPRAGE) and wholebrain, 3-dimensional, 1.0-mm isotropic resolution magnetization-prepared, fluid-attenuated inversion recovery (MPFLAIR). Cortical lesions, seen as hypointensities on MPRAGE, were manually segmented. Lesions were classified as leukocortical, intracortical, or subpial. Images were segmented using the Lesion-TOADS (Topology-Preserving Anatomical Segmentation) algorithm, and brain structure volumes and white matter (WM) lesion volume were reported. Volumes were normalized to intracranial volume. MAIN OUTCOMES AND MEASURESPhysical disability was measured by the Expanded Disability Status Scale (EDSS). Cognitive disability was measured with the Minimal Assessment of Cognitive Function in MS battery.RESULTS Cortical lesions were noted in 35 of 36 participants (97%), with a median of 16 lesions per participant (range, 0-99). Leukocortical lesion volume correlated with WM lesion volume (ρ = 0.50; P = .003) but not with cortical volume; subpial lesion volume inversely correlated with cortical volume (ρ = −0.36; P = .04) but not with WM lesion volume. Total CL count and volume, measured as median (range), were significantly increased in participants with EDSS scores of 5.0 or more vs those with scores less than 5.0 (count: 29 [11-99] vs 13 [0-51]; volume: 2.81 × 10 −4 [1.30 × 10 −4 to 7.90 × 10 −4 ] vs 1.50 × 10 −4 [0 to 1.01 × 10 −3 ]) and in cognitively impaired vs unimpaired individuals (count: 21 [0-99] vs 13 [1-54]; volume: 3.51 × 10 −4 [0 to 1.01 × 10 −4 ] vs 1.19 × 10 −4 [0 to 7.17 × 10 −4 ]). Cortical lesion volume correlated with EDSS scores more robustly than did WM lesion volume (ρ = 0.59 vs 0.36). Increasing log[CL volume] conferred a 3-fold increase in the odds of cognitive impairment (odds ratio [OR], 3.36; 95% CI, 1.07-10.59; P = .04) after adjustment for age and sex and a 14-fold increase in odds after adjustment for WM lesion volume and atrophy (OR, 14.26; 95% CI,; P = .045). Leukocortical lesions had the greatest effect on cognition (OR for log [leukocortical lesion volume], 9.65; 95% CI, 1.70-54.59, P = .01). CONCLUSIONS AND RELEVANCEThis study provides in vivo evidence that CLs are associated with cognitive and ...

Objective: To determine the effect of clinical and radiologic disease activity on the rate of thinning of the ganglion cell/inner plexiform (GCIP) layer and the retinal nerve fiber layer in patients with multiple sclerosis (MS) using optical coherence tomography (OCT).Methods: One hundred sixty-four patients with MS and 59 healthy controls underwent spectraldomain OCT scans every 6 months for a mean follow-up period of 21.1 months. Baseline and annual contrast-enhanced brain MRIs were performed. Patients who developed optic neuritis during follow-up were excluded from analysis.Results: Patients with the following features of disease activity during follow-up had faster rates of annualized GCIP thinning: relapses (42% faster, p 5 0.007), new gadolinium-enhancing lesions (54% faster, p , 0.001), and new T2 lesions (36% faster, p 5 0.02). Annual GCIP thinning was 37% faster in those with disability progression during follow-up, and 43% faster in those with disease duration ,5 years vs .5 years (p 5 0.003). Annual rates of GCIP thinning were highest in patients exhibiting combinations of new gadolinium-enhancing lesions, new T2 lesions, and disease duration ,5 years (70% faster in patients with vs without all 3 characteristics, p , 0.001).Conclusions: MS patients with clinical and/or radiologic nonocular disease activity, particularly early in the disease course, exhibit accelerated GCIP thinning. Our findings suggest that retinal changes in MS reflect global CNS processes, and that OCT-derived GCIP thickness measures may have utility as an outcome measure for assessing neuroprotective agents, particularly in early, active MS. The anterior visual pathway is frequently affected in multiple sclerosis (MS), with 94% to 99% of patients with MS demonstrating optic nerve lesions postmortem.