Cortical pathology in multiple sclerosis patients with epilepsy: A 3 year longitudinal study
The cause of epilepsy in multiple sclerosis (MS) has not yet been elucidated. The relevance of cortical pathology (cortical lesions and thickness) in MS patients with and without epilepsy was evaluated in a longitudinal study.
32 relapsing-remitting MS patients with epilepsy (RRMS/E) and 60 matched RRMS patients without epilepsy were included in a 3 year longitudinal study. The following clinical and MR parameters were analysed: Expanded Disability Status Scale (EDSS), cognitive score (CS), cortical lesion (CL) number and volume, grey matter fraction (GMf), global cortical thickness (CTh), T2 white matter lesion volume (T2WMLV), new CLs and new WM lesions.
At baseline (T0), CLs were observed in 27/32 (84.4%) RRMS/E and in 26/60 (43.3%) RRMS (p<0.001) patients, and the RRMS/E group had a higher number (10.2 ± 8.9 vs 4.5 ± 2.4; p<0.001) and total volume (2.0 ± 1.3 vs 0.7 ± 0.8 cm(3); p<0.001) of CLs compared with the RRMS group. No significant difference in T2WMLV was observed. Global CTh was lower in RRMS/E (2.12 ± 0.19 vs 2.35 ± 0.14 mm; p<0.001), and this group also showed a decline in cognition (CS 10.9 ± 6.3 vs 6.2 ± 3.5; p<0.001). After 3 years (T1), the RRMS/E group had a higher accumulation of new CLs (3.4 ± 3.2 vs 1.2 ± 1.1; p<0.001) and faster reduction of GMf (p=0.022) while the two groups did not differ in the number of new WM and new Gad+ lesions.
RRMS/E had a more severe and rapidly evolving cortical pathology (CLs and atrophy) compared with RRMS without epilepsy. The RRMS/E group was also characterised by more pronounced cognitive decline, higher EDSS and higher prevalence of men.
Available from: Christiane Wegner
- "Despite early description of neocortical lesions in MS , these lesions have mostly been overlooked until recently since they are difficult to detect with traditional staining techniques  or conventional magnetic resonance imaging (MRI) [17, 27]. The use of new MRI sequences has shown that cortical lesions in MS are more common than previously thought [8, 17, 26] and are supposed to contribute to cognitive impairment [7, 44] and epilepsy  in MS. Therefore, cortical involvement may represent an important pathophysiological substrate for disease manifestation, progression and therapy in MS [12, 18, 30]. "
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ABSTRACT: Cerebral cortex shows a high endogenous propensity for remyelination. Yet, widespread subpial cortical demyelination (SCD) is a common feature in progressive multiple sclerosis (MS) and can already be found in early MS. In the present study, we compared oligodendroglial loss in SCD in early and chronic MS. Furthermore, we addressed in an experimental model whether repeated episodes of inflammatory SCD could alter oligodendroglial repopulation and subsequently lead to persistently demyelinated cortical lesions. NogoA+ mature oligodendrocytes and Olig2+ oligodendrocyte precursor cells were examined in SCD in patients with early and chronic MS, normal-appearing MS cortex, and control cortex as well as in the rat model of repeated targeted cortical experimental autoimmune encephalomyelitis (EAE). NogoA+ and Olig2+ cells were significantly reduced in SCD in patients with chronic, but not early MS. Repeated induction of SCD in rats resulted only in a transient loss of NogoA+, but not Olig2+ cells during the demyelination phase. This phase was followed by complete oligodendroglial repopulation and remyelination, even after four episodes of demyelination. Our data indicate efficient oligodendroglial repopulation in subpial cortical lesions in rats after repeated SCD that was similar to early, but not chronic MS cases. Accordingly, four cycles of experimental de- and remyelination were not sufficient to induce sustained remyelination failure as found in chronic cortical MS lesions. This suggests that alternative mechanisms contribute to oligodendrocyte depletion in chronic cortical demyelination in MS.
Electronic supplementary material
The online version of this article (doi:10.1007/s00401-014-1260-8) contains supplementary material, which is available to authorized users.
Available from: Koushik Govindarajan
- "Cortical thinning on magnetic resonance imaging (MRI) is a consistent and early feature in multiple sclerosis (MS) brains (Sailer et al., 2003). Reduced mean cortical thickness, particularly in the frontal and temporal regions may be a predictor of epilepsy in relapsing remitting MS (RRMS) patients (Calabrese et al., 2012). In one of the earliest studies, Sailer et al. (2003) reported smaller average cortical thickness in MS patients compared to healthy controls and demonstrated that cortical thinning correlated with clinical disability and T1 hypointense (T1 lesions), and T2 hyperintense (T2 lesions) white matter (WM) lesion volumes. "
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ABSTRACT: A comprehensive analysis of the global and regional values of cortical thickness based on 3D magnetic resonance images was performed on 250 relapsing remitting multiple sclerosis (MS) patients who participated in a multi-center, randomized, phase III clinical trial (the CombiRx Trial) and 125 normal controls. The MS cohort was characterized by relatively low clinical disability and short disease duration. An automatic pipeline was developed for identifying images with poor quality and artifacts. The global and regional cortical thicknesses were determined using FreeSurfer software. Our results indicate significant cortical thinning in multiple regions in the MS patient cohort relative to the controls. Both global cortical thinning and regional cortical thinning were more prominent in the left hemisphere relative to the right hemisphere. Modest correlation was observed between cortical thickness and clinical measures that included the extended disability status scale and disease duration. Modest correlation was also observed between cortical thickness and T1-hypointense and T2-hyperintense lesions. These correlations were very similar at 1.5 T and 3 T field strengths. A much weaker inverse correlation between cortical thickness and age was observed among the MS subjects compared to normal controls. This age-dependent correlation was also stronger in males than in females. The values of cortical thickness were very similar at 1.5 T and 3 T field strengths. However, the age-dependent changes in both global and regional cortical thicknesses were observed to be stronger at 3 T relative to 1.5 T.
Available from: Bogdan F Gh Popescu
- "Although very prominent in chronic progressive MS [4,15,16,18], pathological and MRI evidence show that cortical demyelinated lesions are also present and common in early MS, and may be driven by meningeal inflammation [18,21,27,41,43-45]. Their inflammatory character suggests that neurodegeneration in MS runs on a background of inflammation [21,27]. "
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ABSTRACT: Although historically considered a disease primarily affecting the white matter of the central nervous system, recent pathological and imaging studies have established that cortical demyelination is common in multiple sclerosis and more extensive than previously appreciated. Subpial, intracortical and leukocortical lesions are the three cortical lesion types described in the cerebral and cerebellar cortices of patients with multiple sclerosis. Cortical demyelination may be the pathological substrate of progression, and an important pathologic correlate of irreversible disability, epilepsy and cognitive impairment. Cortical lesions of chronic progressive multiple sclerosis patients are characterized by a dominant effector cell population of microglia, by the absence of macrophagic and leukocytic inflammatory infiltrates, and may be driven in part by organized meningeal inflammatory infiltrates. Cortical demyelination is also present and common in early MS, is topographically associated with prominent meningeal inflammation and may even precede the appearance of classic white matter plaques in some MS patients. However, the pathology of early cortical lesions is different than that of chronic MS in the sense that early cortical lesions are highly inflammatory, suggesting that neurodegeneration in MS occurs on an inflammatory background and raising interesting questions regarding the role of cortical demyelination and meningeal inflammation in initiating and perpetuating the disease process in early MS.
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