Cortical Lesions In Multiple Sclerosis Research Articles

Heterogeneity of cortical lesions in multiple sclerosis

Autopsy cases show that cortical lesions (CLs) in multiple sclerosis (MS) lack lymphocyte/macrophage influx, blood-brain barrier breakdown, and complement activation. However, some CLs were demonstrated to harbor activated microglia. Here, we assessed the clinical significance of microglia activation in CLs in a large autopsy sample, and we investigated possible interrelationships with other pathologic characteristics. We cross-sectionally investigated the clinicopathologic characteristics of 22 patients with MS with extensive subpial demyelination (CL group) and 19 patients with MS with only little demyelination of the cerebral cortex (non-CL group). A subset of the patients in the CL group (12 patients) showed rims of activated microglia (RAM) at the border of the CLs (RAM-CL group), whereas the other 10 patients in this group did not show microglia activation (non-RAM-CL group). A subsequent comparison between groups showed that patients with MS harboring RAM-CLs were significantly younger at the time of their death (53.5 years) than patients harboring mainly non-RAM-CLs (68.7 years; p < 0.05) or patients without extensive numbers of CLs (66.9 years; p < 0.01). In addition, a significantly shorter disease duration was found for the RAM-CL group (mean 20.9 years) than for the non-CL group (mean 34.5 years; p < 0.05). We also found that the presence of RAM-CLs is associated with a higher number of chronic active white matter (WM) lesions (Spearman ρ = 0.74; p < 0.0001). RAM-CLs were found in a subset of patients with MS who also have more active WM inflammation and a less favorable disease course.

Microstructural magnetic resonance imaging of cortical lesions in multiple sclerosis

Background: Pathologic and magnetic resonance imaging (MRI) studies have shown that cortical lesions (CLs) are a frequent finding in multiple sclerosis (MS). Objective: To quantify microstructural damage in CLs and normal appearing (NA) cortex in relapse-onset MS patients at different stages of the disease. Methods: Brain double inversion recovery (DIR), diffusion tensor (DT) MRI and 3D T 1-weighted scans were acquired from 35 relapsing–remitting (RR) patients, 23 secondary progressive (SP) patients, 12 benign (B) MS patients and 41 healthy controls (HC). Diffusivity values in CLs, cortex, white matter (WM) lesions and normal-appearing white matter (NAWM) were assessed. Results: Compared to HC, MS patients had a significantly lower fractional anisotropy (FA) and higher mean diffusivity (MD) in the cortex and NAWM. CLs had higher FA vs HC cortex and vs patients’ cortex. Compared to RRMS patients, SPMS patients had higher WM lesion volume, higher MD in the cortex, and more severe damage to the NAWM and WM lesions. Compared to SPMS patients, BMS patients had lower MD and FA of CLs. Damage in other compartments was similar between SPMS and BMS patients. Damage in CLs had a high power to discriminate BMS from SPMS (area under the curve: 79–91%), with high specificity (85%), sensitivity (100%) and accuracy (90%). Conclusions: Microstructural imaging features of CLs differ from those of WM lesions and are likely to reflect neuronal damage and microglial activation. The nature and extent of CL damage can be used to help distinguish the different MS clinical phenotypes.

Improved detection of cortical MS lesions with phase-sensitive inversion recovery MRI

ObjectiveCortical grey matter lesions are common in multiple sclerosis (MS), but usually not seen on MRI. The authors compared the performance of double inversion recovery (DIR, currently considered the best...

Autoinflammatory grey matter lesions in humans

In recent years, evidence has accumulated that grey matter abnormalities are common in many inflammatory central nervous system (CNS) disorders, such as multiple sclerosis (MS), which is by far the most frequent autoimmune-mediated CNS disease. A recent study described comprehensively the pathology of grey matter lesions in early MS. In this study, cortical demyelination together with inflammation was frequently observed in early MS cases. This study and others serve as a basis for a model of the development of cortical MS lesions in which several consecutive events may be involved. After the activation of T cells, which may open the blood-brain barrier, the humoral immune system may mediate the inflammatory process. The inflammation may become chronic through the involvement of activated glial cells and the persistence of immune cells in the meninges.Apart from MS, other grey matter CNS disorders exist in which antibodies against neuronal structures contribute to pathophysiological events such as in limbic encephalitis. Humoral and adaptive immunity mediates the pathophysiology of Rasmussen encephalitis. This review focuses on the difference between inflammatory grey matter and white matter lesions. New insights into inflammatory grey matter lesions in MS and other CNS inflammatory processes such as limbic encephalitis are discussed.

Detecting cortical lesions in multiple sclerosis at 7 T using white matter signal attenuation

Cortical lesions have recently been a focus of multiple sclerosis (MS) MR research. In this study, we present a white matter signal attenuating sequence optimized for cortical lesion detection at 7 T. The feasibility of white matter attenuation (WHAT) for cortical lesion detection was determined by scanning eight patients (four relapsing/remitting MS, four secondary progressive MS) at 7 T. WHAT showed excellent gray matter–white matter contrast, and cortical lesions were hyperintense to the surrounding cortical gray matter, The sequence was then optimized for cortical lesion detection by determining the set of sequence parameters that produced the best gray matter–cortical lesion contrast in a 10-min scan. Despite the B1 inhomogeneities common at ultra-high field strengths, WHAT with an adiabatic inversion pulse showed good cortical lesion detection and would be a valuable component of clinical MS imaging protocols.

Advances in understanding gray matter pathology in multiple sclerosis: Are we ready to redefine disease pathogenesis?

The purpose of this special issue in BMC Neurology is to summarize advances in our understanding of the pathological, immunological, imaging and clinical concepts of gray matter (GM) pathology in patients with multiple sclerosis (MS). Review articles by Lucchinetti and Popescu, Walker and colleagues, Hulst and colleagues and Horakova and colleagues summarize important recent advances in understanding GM damage and its implications to MS pathogenesis. They also raise a number of important new questions and outline comprehensive approaches to addressing those questions in years to come. In the last decade, the use of immunohistochemistry staining methods and more advanced imaging techniques to detect GM lesions, like double inversion recovery, contributed to a surge of studies related to cortical and subcortical GM pathology in MS. It is becoming more apparent from recent biopsy studies that subpial cortical lesions in early MS are highly inflammatory. The mechanisms responsible for triggering meningeal inflammation in MS patients are not yet elucidated, and they should be further investigated in relation to their role in initiating and perpetuating the disease process. Determining the role of antigens, environmental and genetic factors in the pathogenesis of GM involvement in MS is critical. The early involvement of cortical and subcortical GM damage in MS is very intriguing and needs to be further studied. As established in numerous cross-sectional and longitudinal studies, GM damage is a better predictor of physical disability and cognitive impairment than WM damage. Monitoring the evolution of GM damage is becoming an important marker in predicting future disease course and response to therapy in MS patients.

Spotlight on the January 31 Issue

Single-slab 3D DIR (double inversion recovery) and 3D FLAIR images of 56 matched fresh brain samples from 14 patients with chronic multiple sclerosis (MS) were acquired at 1.5 T. DIR is a useful technique to visualize cortical lesions in MS; many lesions are still missed, but those that are detected are likely actual lesions in terms of histopathology. See p. 302 From editorialists Ciccarelli & Chen: “Although DIR MRI is a recent innovation, it has provided important insights into the occurrence of cortical pathology in all subtypes of MS and the association …

Postmortem verification of MS cortical lesion detection with 3D DIR

To assess the sensitivity and specificity of 3D double inversion recovery (DIR) MRI for detecting multiple sclerosis (MS) cortical lesions (CLs) using a direct postmortem MRI to histopathology comparison. Single-slab 3D DIR and 3D fluid-attenuated inversion recovery (FLAIR) images of 56 matched fresh brain samples from 14 patients with chronic MS were acquired at 1.5 T. The images of both sequences were prospectively scored for CLs in consensus by 3 experienced raters who were blinded to histopathology and clinical data. Next, CLs were identified histopathologically and were scored again on 3D DIR and 3D FLAIR (retrospective scoring). CLs were classified as intracortical or mixed gray matter (GM)-white matter lesions. Deep GM lesions were also scored. False-positive scores were noted and, from this, specificity was calculated. We found a sensitivity for 3D DIR to detect MS CLs of 18%, which is 1.6-fold higher than 3D FLAIR (improves to 37% with retrospective scoring; 2.0-fold higher than 3D FLAIR). We detected mixed GM-white matter lesions with a sensitivity of 83% using 3D DIR (65% sensitivity for 3D FLAIR), which improved to 96% upon retrospective scoring (91% for 3D FLAIR). For purely intracortical lesions, 3D DIR detected more than 2-fold more than 3D FLAIR (improved to >3-fold upon retrospective scoring). The specificity of 3D DIR to MS CLs was found to be 90%. In this postmortem verification study, we have shown that 3D DIR is highly pathologically specific, and more sensitive to CLs than 3D FLAIR in MS.

MS cortical lesions on double inversion recovery MRI

Double inversion recovery (DIR) MRI is a relatively novel imaging technique in which both white matter (WM) and CSF signals are suppressed; cortical lesions are thereby identified as focal areas of hyperintensity relative to surrounding gray matter (GM).1 Three dimensional DIR increases intracortical lesion detection by 500% compared to lesion identification on T2-weighted spin-echo, and by more than 150% when compared to 3D fluid-attenuated inversion recovery (FLAIR).1 Despite these improvements, DIR-detected lesions are fewer than expected based on postmortem studies2: less than 7 (on average) per patient in relapsing-remitting (RR), primary progressive (PP), and secondary progressive (SP) multiple sclerosis (MS).3,–,5 This low rate of detection could be due to technical factors, such as low signal-to-noise ratio, poor definition of lesion boundaries, and the high likelihood of artifacts (e.g., flow, signal intensity differences between slabs, and vessel hyperintensities). It is not easy to see cortical lesions on DIR images, and even when following the conservative international recommendations on lesion scoring (subpial lesions are excluded), experts reached complete agreement in only 19% of the lesions scored.6 Why have these challenges and limitations not discouraged the use of DIR in clinical studies? The short answer is that there is a …

Imaging the tip of the iceberg: visualization of cortical lesions in multiple sclerosis

Background: Cortical lesions (CLs) occur frequently in multiple sclerosis (MS), but only few CLs are observed on conventional magnetic resonance imaging (MRI). Why some CLs are visible and others are not is currently unknown. Here, we investigated whether CLs that are visible on conventional MRI differ from MRI-invisible CLs in terms of underlying histopathology and quantitative MRI (qMRI) measures. Methods: A total of 16 brain slices from 10 patients with chronic MS were analysed histopathologically and with conventional and qMRI. A region-of-interest approach was used to compare MRI-visible CLs with MRI-invisible CLs. Results: Although under-powering cannot be completely excluded in this study, MRI-visible CLs did not seem to differ from MRI-invisible CLs in terms of histopathology or qMRI measures. They were, however, significantly larger than their invisible counterparts (mean 13.3 ± 1.7 mm2 versus 6.9 ± 1.3 mm2; p = 0.001). Furthermore, the number of MRI-visible lesions correlated with the overall number of CLs in the brain slice (r = 0.96, p < 0.01) and with the overall percentage of demyelination (r = 0.78, p < 0.01) per hemispheric brain slice. Conclusion: MRI visibility of CLs is determined by lesion size, and not by any distinctive underlying pathology. Visible CLs are associated with a higher total cortical lesion load, which suggests that when CLs in patients with MS become detectable on MRI, they merely represent ‘the tip of the pathological iceberg’.

Modelling the distribution of cortical lesions in multiple sclerosis

Recent studies have shown the relevance of the cerebral grey matter involvement in multiple sclerosis (MS). Cortical lesions (CLs), detected by specific MRI sequences, are likely to become a new research outcome in MS studies. The aim of this study was to infer the optimal statistical model describing the distribution of CLs in patients with relapsing–remitting (RR)MS. The negative binomial model gave the best fit to the observed distribution of CLs in a group of 44 RRMS patients with one MRI scan of the brain. This observation has important implications for the statistical analysis of CLs in MS studies.

In vivo evidence of disseminated subpial T2* signal changes in multiple sclerosis at 7 T: A surface-based analysis

Cortical subpial demyelination is frequent in multiple sclerosis (MS) and is closely associated with disease progression and poor neurological outcome. Although cortical lesions have been difficult to detect using conventional MRI, preliminary data using T2*-weighted imaging at ultra-high field 7T MRI showed improved sensitivity for detecting and categorizing different histological types of cortical MS lesions. In this study we combined high-resolution 7T MRI with a surface-based analysis technique to quantify and map subpial T2*-weighted signal changes in seventeen patients with MS. We applied a robust method to register 7T data with the reconstructed cortical surface of each individual and used a general linear model to assess in vivo an increase in subpial T2*-weighted signal in patients versus age-matched controls, and to investigate the spatial distribution of cortical subpial changes across the cortical ribbon. We also assessed the relationship between subpial T2* signal changes at 7T, Expanded Disability Status Scale (EDSS) score and white matter lesion load (WMLL). Patients with MS showed significant T2*-weighted signal increase in the frontal lobes (parsopercularis, precentral gyrus, middle and superior frontal gyrus, orbitofrontal cortex), anterior cingulate, temporal (superior, middle and inferior temporal gyri), and parietal cortices (superior and inferior parietal cortex, precuneus), but also in occipital regions of the left hemisphere. We found significant correlations between subpial T2*-weighted signal and EDSS score in the precentral gyrus (ρ=0.56, P=0.02) and between T2*-weighted signal and WMLL in the lateral orbitofrontal, superior parietal, cuneus, precentral and superior frontal regions. Our data support the presence of disseminated subpial increases in T2* signal in subjects with MS, which may reflect the diffuse subpial pathology described in neuropathology.

Cortical Lesions in Multiple Sclerosis

The presence and frequency of cortical lesions (CLs) in 24 pediatric patients with relapsing-remitting multiple sclerosis (RRMS) were compared to 15 adult patients with RRMS and 10 pediatric healthy controls, in a study at University Ospedale San Raffaele, Milan and other centers in Italy.

MS cortical lesion or not?

Histopathologic analyses of postmortem brains from patients with multiple sclerosis (MS) have revealed that demyelinated cortical lesions are a common occurrence1 and may account for a larger proportion of brain demyelination than white matter (WM) lesions.2,–,4 Unlike WM lesions, cortical lesions are typically not revealed in vivo by conventional MRI (only 16% detected using fluid-attenuated inversion recovery [FLAIR] MRI3). As a result, our overall understanding of the incidence and role of cortical lesions in MS remains relatively poor. Double inversion recovery (DIR) is an advanced MRI technique that improves visualization of the cortex by selectively suppressing both the CSF signal (as in FLAIR) and the normal WM signal, resulting in an image with hyperintense gray matter (GM) that is relatively noisy. In MS, DIR has revealed cortical foci that are hyperintense relative to surrounding normal-appearing GM, which are believed to be associated with demyelinated cortical lesions. Unfortunately, DIR is not reliably sensitive to subpial demyelination,5,6 which represents the most common type of cortical demyelination in MS.2,5 Despite this weakness, significant associations have been reported between DIR hyperintense cortical foci and disability in MS.7,–,9 In practice, DIR is not standardized across imaging …

Consensus recommendations for MS cortical lesion scoring using double inversion recovery MRI

Different double inversion recovery (DIR) sequences are currently used in multiple sclerosis (MS) research centers to visualize cortical lesions, making it difficult to compare published data. This study aimed to formulate consensus recommendations for scoring cortical lesions in patients with MS, using DIR images acquired in 6 European centers according to local protocols. Consensus recommendations were formulated and tested in a multinational meeting. Cortical lesions were defined as focal abnormalities on DIR, hyperintense compared to adjacent normal-appearing gray matter, and were not scored unless ≥ 3 pixels in size, based on at least 1.0 mm(2) in-plane resolution. Besides these 2 obligatory criteria, additional, supportive recommendations concerned a priori artifact definition on DIR, use of additional MRI contrasts to verify suspected lesions, and a constant level of displayed image contrast. Robustness of the recommendations was tested in a small dataset of available, heterogeneous DIR images, provided by the different participating centers. An overall moderate agreement was reached when using the proposed recommendations: more than half of the readers agreed on slightly more than half (54%) of the cortical lesions scored, whereas complete agreement was reached in 19.4% of the lesions (usually larger, mixed white matter/gray matter lesions). Although not designed as a formal interobserver study, the current study suggests that comparing available literature data on cortical lesions may be problematic, and increased consistency in acquisition protocols may improve scoring agreement. Sensitivity and specificity of the proposed recommendations should now be studied in a more formal, prospective, multicenter setting using similar DIR protocols.

Toward understanding cortical lesions in multiple sclerosis

Multiple sclerosis (MS) is insidious, with a complex pathology and unknown pathogenesis. MS researchers have realized that the condition is not a typical “white matter disease,” but that damage to the cerebral gray matter (GM), both cortical and in deep gray nuclei, may be as extensive, or more so, as WM pathology.1 Histopathology2 and MRI studies3,4 show that GM damage becomes increasingly prominent with progression of disease. In the chronic disease phase, total brain atrophy as measured with MRI is determined predominantly by GM atrophy.3 While cortical demyelinated MS lesions were investigated and classified histopathologically,5,6 their in vivo visualization remains challenging.7 On conventional imaging techniques such as T2-weighted MRI, cortical lesions are missed in up to 95% of the cases,7 and a need for advanced MRI techniques that could fill this gap became apparent. One of these newly developed MRI techniques, double inversion recovery (DIR), uses 2 inversion pulses to suppress signals from WM and from CSF, leaving only the cerebral GM visible,8 though also slightly suppressed. The resulting GM signal, with better contrast between normal-appearing GM …

Cortical lesions in multiple sclerosis

Multiple sclerosis (MS) is typically considered to be a chronic inflammatory-demyelinating disease of CNS white matter. In the past decade, however, pathological and MRI studies have shown that lesions are often located in the gray matter, especially in the cerebral cortex. The histopathological characteristics of these cortical lesions differ substantially from lesions located in the white matter, which suggests location-dependent expression of the MS immunopathological process. Double inversion recovery imaging--an MRI technique that selectively images gray matter and lesions--has enabled researchers to image cortical lesions in vivo. Double inversion recovery studies have shown that cortical lesions can be detected at the earliest clinical stages of MS, and cortical lesion burden positively correlates with the severity of physical and cognitive impairments. These gray matter lesions are also independent predictors of subsequent disease evolution. This Review provides a summary of the main histopathological and MRI findings with regard to cortical lesions in MS, and indicates that increasing our understanding of cortical lesions has increased our knowledge of MS pathobiology.

Imaging Cortical Lesions in Multiple Sclerosis With Ultra–High-Field Magnetic Resonance Imaging

To determine the sensitivity of T2*-weighted gradient-echo (T2*GRE) and inversion recovery turbo-field-echo (TFE) sequences for cortical multiple sclerosis lesions at 7 T. Autopsied brain tissue from individuals with multiple sclerosis was scanned with 3-dimensional T2*GRE and 3-dimensional inversion recovery white matter-attenuated TFE sequences at 7 T. Cortical lesions visible with either sequence were scored for each anatomical lesion type. Imaged brain tissue was then processed for immunohistochemical analysis, and cortical lesions were identified by labeling with antibody against myelin basic protein and CD68 for microglia. Magnetic resonance images were matched with corresponding histological sections and scored retrospectively to determine the sensitivity for each cortical lesion type. Main Outcome Measure Cortical lesion detection by 3-dimensional T2*GRE and white matter-attenuated TFE sequences. The 3-dimensional T2*GRE and white matter-attenuated TFE sequences retrospectively detected 93% and 82% of all cortical lesions, respectively (with varying sensitivities for different lesion types). Lesion visibility was primarily determined by size as all undetected lesions were smaller than 1.1 mm at their smallest diameter. The T2*GRE images showed hypointense rings in some cortical lesions that corresponded with increased density of activated microglia. Three-dimensional T2*GRE and white matter-attenuated TFE sequences at a 7-T field strength detect most cortical lesions in postmortem multiple sclerosis tissue. This study indicates the potential of T2*GRE and white matter-attenuated TFE sequences in ultra-high-field magnetic resonance imaging for cortical lesion detection in patients with multiple sclerosis.

Improved in vivo detection of cortical lesions in multiple sclerosis using double inversion recovery MR imaging at 3 Tesla

ObjectiveTo investigate the impact of a higher magnetic field strength of 3 Tesla (T) on the detection rate of cortical lesions in multiple sclerosis (MS) patients, in particular using a dedicated double inversion recovery (DIR) pulse sequence.MethodsThirty-four patients with clinically isolated syndromes or definite MS were included. All patients underwent magnetic resonance imaging (MRI) at 1.5 T and 3 T, including T2-weighted turbo spin echo (TSE), fluid-attenuated inversion recovery (FLAIR) and DIR sequences. All images were analysed for focal lesions categorised according to their anatomical location.ResultsThe total number of detected lesions was higher at 3 T across all pulse sequences. We observed significantly higher numbers of lesions involving the cortex at 3 T using a DIR sequence. DIR at 3 T showed 192% more pure intracortical (p < 0.001) and 30% more mixed grey matter-white matter lesions (p = 0.008). No significant increase in cortical lesions could be detected on the FLAIR and T2-weighted images. Using the T2-weighted and FLAIR sequences, significantly more lesions could be detected at 3 T in the infratentorial, periventricular and juxtacortical white matter.ConclusionDIR brain MR imaging at 3 T substantially improves the sensitivity of the detection of cortical lesions compared with the standard magnetic field strength of 1.5 T.

Accumulation of cortical lesions in MS: relation with cognitive impairment

Background Gray matter (GM) lesions are frequently found in multiple sclerosis (MS) and their in-vivo detection has been improved using new magnetic resonance imaging sequences, such as double inversion recovery (DIR). However, little is known about progression of GM lesions over time. Objective To study the longitudinal behavior of GM lesions and to explore their relation to cognitive impairment in MS. Methods DIR images were acquired from 13 MS patients and seven healthy controls at two time points with a median interval of 3 years. At follow-up, all subjects underwent cognitive testing. Lesions were classified as white matter, cortical or hippocampal lesions. Results In patients, median cortical lesion number had increased from 18 to 26 at follow-up (P = 0.01), median white matter (WM) lesion number had increased from 56 to 65 (P = 0.02), and no significant increase over time was found for hippocampal lesions. Cortical lesion number at follow-up was significantly higher in secondary progressive (SP) than in relapsing-remitting patients. Significant relations were found between cortical and WM lesion number at follow-up on the one hand and visuospatial memory and processing speed on the other hand. Hippocampal lesion number was related to visuospatial memory. Conclusion Cortical lesions increase significantly over a 3-year time period, are most frequent in SP patients, and are associated with cognitive impairment.