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We performed fast fluid-attenuated inversion recovery (fFLAIR) and conventional spin echo (CSE) brain MRI in 32 multiple sclerosis (MS) patients (eight each benign, relapsing-remitting, primary progressive, and secondary progressive). We compared number and site of lesions detected on each sequence. With initial separate assessment, we identified a total of 3,668 lesions-2,892 by CSE and 2,943 by fFLAIR. Following simultaneous review of the sequences, we identified an additional 217 lesions on fFLAIR and 229 on CSE. fFLAIR detected fewer lesions in the posterior fossa (66 versus 138, p = 0.001), fewer small (5 mm) discrete cerebral white matter lesions (671 versus 829, p = 0.0002), more subcortical lesions (542 versus 306, p0.0001), and more large discrete lesions (419 versus 385, p = 0.0006). Its relatively poor detection of posterior fossa lesions makes it premature for fFLAIR to replace CSE as the primary sequence for detecting MS lesions in clinical trials.

The quantitative analysis of MRI data is becoming increasingly important in the evaluation of therapies for the treatment of MS. This paper describes a processing environment for the automatic quantification of lesion load from large ensembles of MR volume data. The main components of this approach are stereotaxic transformation and multispectral classification, supported by pre- and postprocessing techniques to reduce noise and correct for intensity non-uniformities. The results of the automated approach are compared with those obtained by manual lesion delineation, showing a significant lesion volume correlation of 0.94.

The high resolution and excellent soft tissue contrast of Magnetic Resonance Imaging (MRI) have enabled direct, noninvasive visualization of Multiple Sclerosis (MS) lesions in vivo. This has allowed the quantification of changes in the appearance of lesions in MR exams to be used as a measure of disease state. Nevertheless, accurate quantification techniques are subject to inter- and intra-operator variability, which may hinder monitoring of disease progression. We have developed a computer program to assist an experienced operator in the quantification of MS lesions in standard spin-echo MR exams. The accuracy of assisted and manual quantification under known conditions was studied using exams of a test phantom, while inter- and intra-operator reliability and variability were studied using exams of a MS patient. Results from the phantom study show that accuracy is improved by assisted quantification. The patient exam results indicate that assisted quantification reduced inter-operator variability from 0.34 to 0.17 cm3, and reduced intra-operator variability from 0.23 to 0.15 cm3. In addition, the minimum significant change between two successive measurements of lesion volume by the same operator was 0.64 cm3 for manual quantification and 0.42 cm3 for assisted quantification. For two different operators making successive measurements, the minimum significant change was 0.94 cm3 for manual quantification, but only 0.47 cm3 for assisted quantification. Finally, the number of lesions to be monitored for an average change in volume at a given power and significance level was reduced by a factor of 2-4 by assisted quantification. These results suggest that assisted quantification may have practical applications in clinical trials, especially those that are large, multicenter, or extended over time, and therefore require lesion measurements by one or more operators.

In this study, we investigated the relationship between multiple sclerosis lesion volumes measured from magnetic resonance imaging scans and image-slice thickness. The lesion volume was computed using a semiautomated thresholding technique from axial scans of the brain of varying slice thickness. Ten patients were studied, and in all cases the computed lesion volume increased with decreasing slice thickness (p = 0.01). Linear extrapolation from our data allowed the lesion volume at very small slice thickness to be estimated; this was found to be on average 20% greater than that obtained using a slice thickness of 5 mm. Furthermore, there were considerable differences in the percentage of change in lesion volume from patient to patient, and it would appear that there is a larger variation with slice thickness for patients with smaller lesions and higher lesion loads.

Once it was thought that the mechanism for development of permanent neurological deficits in multiple sclerosis was understood. Demyelination, the pathological hallmark of the multiple sclerosis lesion, was the culprit. Elegant physiological studies demonstrated that demyelination results in conduction slowing and, in particular, conduction block (McDonald and Sears, 1969). These observations appeared sufficient to explain the majority of deficits in multiple sclerosis. However, clinical observations began to challenge this hypothesis. With the development of MRI, clinicians saw patients with extensive white matter lesion load with minimal or no neurological deficits. Pathological studies demonstrated that lesions observed by MRI were indeed demyelinated and frequently involved eloquent areas of CNS that should have resulted in neurological deficits. Autopsy series made it clear that substantial demyelination, sufficient to make the pathological diagnosis of multiple sclerosis, can be observed in individuals who during life remained normal in neurological function (Mews et al ., 1998). Patients with essentially normal vision have been documented in which the optic nerve and its tracts were completely demyelinated. The hypothesis that I favour is that demyelination is necessary, but not sufficient, for development of permanent deficits in multiple sclerosis. Demyelination predisposes axons to subsequent secondary injury. …

Objective: To assess whether quantitative susceptibility mapping (QSM) can function as a biomarker in patients with multiple sclerosis (MS) and provide an independent characterization of lesions commonly seen on T2-weighted images (T2WI). Background Although T2WI are used to support and confirm the clinical diagnosis of MS, T2 hyperintensity may indicate demyelination and/or edema. Previous studies have shown that iron deposition is associated with demyelination, but usually not appreciated on T2WI. Because QSM is sensitive to iron deposition, we hypothesize that QSM may provide a novel and independent biomarker in MS lesion characterization. Design/Methods: We retrospectively reviewed 181 white matter lesions in 16 consecutive confirmed MS patients (age=41±7, M/F=4/12) acquired with a protocol including T2W and QSM sequences. Lesions were identified on both T2W and QSM images with their sizes and signal intensities assessed. Differences were evaluated with a t-test. Results: A total of 181 lesions were detected on T2WI, 130(72%) of which presented on QSM. Lesion size on QSM was significantly smaller than that on T2WI(p 0.05ppm) compared to cortical gray matter. The size discrepancy was expected, since edema is hyperintense on T2WI but not on QSM. The increased signal on QSM lesions may be explained by the loss of myelin, whose susceptibility is usually negative. However, demyelination alone is unable to explain the strong paramagnetism seen in type (b) lesions, whose susceptibility is higher than cortical gray matter. In these lesions, iron may be responsible for the signal change. Further investigation may include correlation with clinical symptoms, spatial distribution of lesions, and global alternation in susceptibility value. Conclusions: MS lesions are smaller in size and demonstrate two distinct patterns on QSM when compared to routine T2WI. Disclosure: Dr. Chen has nothing to disclose. Dr. Comunale has nothing to disclose. Dr. Gauthier has received personal compensation for activities with Teva Neuroscience, Biogen Idec, Pfizer Inc, and Serono, Inc. as consultant. Dr. Gauthier has received research support from Biogen Idec, Pfizer Inc, and Serono, Inc. Dr. Heier has nothing to disclose. Dr. Liu has received personal compensation for activities with MedImageMetric LL as an employee. Dr. Tsiouris has nothing to disclose. Dr. Wang holds stock and/or stock options in MedImageMetric LLC.

There is a strong belief in the field of multiple sclerosis (MS) that central nervous system (CNS) demyelination is integrally related to the early selective depletion of the CNS myelinating cell, the oligodendrocyte. Subscribers to this theory are numerous and while still a hypothetical scenario, “oligodendrogliolysis” was first proposed by Lumsden1 in the 1950s. Thus far, however, investigators have been unable to provide evidence in situ for widespread lysis of oligodendrocytes in MS2, although from studies in vitro, it has been known for years that the oligodendrocyte is highly susceptible to damage by a number of soluble immune mediators. Included among the latter are anti-myelin immunoglobulins3, cytokines4 and complement5. The lack of compelling evidence for selective oligodendrocyte destruction notwithstanding, it is clear from the literature on the subject that their depletion in MS must occur sometime between the initial acute inflammatory, actively demyelinating phase when oligodendrocytes are abundant, and the chronic, silent fibrous astrogliotic MS plaque where few, if any, oligodendrocytes can be located2. Complicating the analysis of factors underlying the demise of the oligodendrocyte in MS, are reports documenting that during periods of disease activity, oligodendrocyte proliferation occurs at the margins of established lesions. These observations, together with subsequent confirmatory reports, have led to considerations of the possibility that immune-mediated destruction of myelin may actually exert a stimulatory effect upon the oligodendrocyte. This possibility is underscored by the presence of sometimes substantial amounts of CNS remyelination within and around acute and actively expanding MS lesions6,8,9.

Magnetization transfer imaging (MTI) was initially performed in normal guinea pigs and human volunteers. A magnetization transfer ratio (MTR) was calculated in the normal white matter and was found to be 42%-44%, with less than 2.5% variation, which indicates the high reproducibility of the measurement. MTI was then applied to an animal model of white matter disease, acute experimental allergic encephalomyelitis (EAE). In this model of EAE, pathologically proved lesions were edematous with essentially no demyelination. MTRs decreased slightly but significantly (5%-8%) compared with the MTRs of the same tissue region measured before the onset of the lesion [corrected]. Fifteen patients with multiple sclerosis (MS) also underwent MTI. In the 15 patients with MS, all lesions (209 plaques) had a significantly decreased MTR (average, 26%). The authors believe that demyelination produced the lower MTR, and, thus, lesions varied in transfer ratio on the basis of the extent of myelin loss. In patients with MS, particularly those with chronic and/or progressive MS, the MTR of the normal-appearing white matter was significantly decreased. The data suggest that calculated MTR obtained with in vivo MTI may enable differentiation of edema from demyelination, and that MTI can demonstrate white matter abnormalities that cannot be seen with standard spin-echo or gradient-echo magnetic resonance imaging.

Background The presence of antiphospholipid antibodies (APLA) in multiple sclerosis (MS) patients has been reported frequently but no clear relationship between APLA and the clinical and neuroimaging features of MS have heretofore been shown. We assessed the clinical and neuroimaging features of MS patients with plasma APLA. Methods A consecutive cohort of 24 subjects with relapsing-remitting (RR) MS were studied of whom 7 were in remission (Rem) and 17 in exacerbation (Exc). All subjects were examined and underwent MRI of brain. Patients' plasma was tested by standard ELISA for the presence of both IgM and IgG antibodies using a panel of 6 targets: cardiolipin (CL), β2 glycoprotein I (β2GPI), Factor VII/VIIa (FVIIa), phosphatidylcholine (PC), phosphatidylserine (PS) and phosphatidylethanolamine (PE). Results In exacerbation up to 80% of MS subjects had elevated titers of IgM antibodies directed against the above antigens. However, in remission, less than half of MS patients had elevated titers of IgM antibodies against one or more of the above antigens. This difference was significant, p < 0.01, for all 6 target antigens. Interestingly, none of the MS patients had elevated plasma titers of IgG against any of the target antigens tested. Correlation analysis between MRI enhancing lesions and plasma levels of APLA revealed high correlation for aPC, aPS and aFVIIa (p ≤ 0.0065), a trend for aPE and aCL (p = 0.056), and no correlation for aβ2GP1. The strongest correlation was for aFVIIa, p = 0.0002. Conclusion The findings of this preliminary study show that increased APLA IgM is associated with exacerbations of MS. Currently, the significance of this association in pathogenesis of MS remains unknown. However, systematic longitudinal studies to measure APLA in larger cohorts of patients with relapsing-remitting MS, particularly before and after treatment with immunomodulatory agents, are needed to confirm these preliminary findings.

A 54-year-old woman with a four-month history of progressive neurological illness was found at postmortem examination to have lesions of Balo's concentric sclerosis. Balo lesions were found in several areas scattered widely throughout the central nervous system, including the spinal cord, a previously unreported location, and were studied by histological and ultrastructural methods. Balo lesions consisted of bands of intact myelin alternating with zones of demyelination. These lesions were centered on a perivascular cuff of inflammatory cells. The center of the lesion was the oldest area with the concentric rings of demyelination decreasing in age with increasing distance from the center. The bands of intact myelin comprised mainly remyelinated fibers, were similar to those seen at the edges of chronic active multiple sclerosis plaques, and may have represented the repaired margins of preceding episodes. The occurrence of small foci of acute demyelination centered on perivascular cuffs and other changes typical of both acute and chronic active multiple sclerosis may indicate that the lesion of Balo's concentric sclerosis represents an intermediate stage in the development of an established multiple sclerosis lesion.

It seems to me that, celebrating the 25th anniversary of the Belgian Research Group for Multiple Sclerosis, we are at a critical point in the search for a treatment of multiple sclerosis, and may be also at a critical point in the understanding of the pathogenesis of this disease.

Multiple sclerosis is a relatively common disorder of the central nervous system characterized pathologically by focal areas of myelin destruction with preservation of the axons and clinically by a relapsing and remitting course with persistent disability developing ultimately in a majority of patients. The cause is unknown but both environmental and genetic factors appear to be important. The former is probably infective, possibly viral in nature and the latter is probably related to the control of immune regulation. There is evidence that the myelin breakdown is mediated immunologically, but the mode of interaction of the environmental and genetic factors which leads to the development of the disease, the mechanism of precipitation of the relapses, and the mechanisms of remission are obscure. There is no effective treatment.

The determination of T-helper and suppressor cells using monoclonal antibodies gives us information about the immunoregulatory subpopulation of T-cells in peripheral blood. The ratio T-helper: T-suppressor cells constitutes an immunoregulatory index. A disturbance of this ratio, which amounts to 2:1 in normal subjects, has been observed in various diseases of autoaggressive pathogenesis4.

Till now it is still unknown which initial factors are involved in the demyelination process in MS. Recent and established lesions have been extensively described by various authors using histological and enzyme-histological methods (Adams, 1975, 1977; Friede and Arbor, 1961; Friede and Knoller, 1964).

We present a study of multiple sclerosis segmentation algorithms conducted at the international MICCAI 2016 challenge. This challenge was operated using a new open-science computing infrastructure. This allowed for the automatic and independent evaluation of a large range of algorithms in a fair and completely automatic manner. This computing infrastructure was used to evaluate thirteen methods of MS lesions segmentation, exploring a broad range of state-of-theart algorithms, against a high-quality database of 53 MS cases coming from four centers following a common definition of the acquisition protocol. Each case was annotated manually by an unprecedented number of seven different experts. Results of the challenge highlighted that automatic algorithms, including the recent machine learning methods (random forests, deep learning, …), are still trailing human expertise on both detection and delineation criteria. In addition, we demonstrate that computing a statistically robust consensus of the algorithms performs closer to human expertise on one score (segmentation) although still trailing on detection scores.

Background: There are modest correlations between multiple sclerosis (MS) disability and white matter lesion (WML) volumes, as measured by T2-weighted (T2w) magnetic resonance imaging (MRI) scans (T2-WML). This may partly reflect pathological heterogeneity in WMLs, which is not apparent on T2w scans. Objective: To determine if ADvanced IMage Algebra (ADIMA), a novel MRI post-processing method, can reveal WML heterogeneity from proton-density weighted (PDw) and T2w images. Methods: We obtained conventional PDw and T2w images from 10 patients with relapsing–remitting MS (RRMS) and ADIMA images were calculated from these. We classified all WML into bright (ADIMA-b) and dark (ADIMA-d) sub-regions, which were segmented. We obtained conventional T2-WML and T1-WML volumes for comparison, as well as the following quantitative magnetic resonance parameters: magnetisation transfer ratio (MTR), T1 and T2. Also, we assessed the reproducibility of the segmentation for ADIMA-b, ADIMA-d and T2-WML. Results: Our study’s ADIMA-derived volumes correlated with conventional lesion volumes ( p < 0.05). ADIMA-b exhibited higher T1 and T2, and lower MTR than the T2-WML ( p < 0.001). Despite the similarity in T1 values between ADIMA-b and T1-WML, these regions were only partly overlapping with each other. ADIMA-d exhibited quantitative characteristics similar to T2-WML; however, they were only partly overlapping. Mean intra- and inter-observer coefficients of variation for ADIMA-b, ADIMA-d and T2-WML volumes were all < 6 % and < 10 %, respectively. Conclusion: ADIMA enabled the simple classification of WML into two groups having different quantitative magnetic resonance properties, which can be reproducibly distinguished.