Cortical Lesions are an Important Component of Multiple Sclerosis
Abstract & Commentary
By Timothy Vartanian, MD, PhD, Professor of Neurology and Neuroscience, Weill Cornell Medical College, Director, Judith Jaffe Multiple Sclerosis Center. Dr. Vartanian reports that he is on the speakers bureau for UCB Pharma and Cyberonics..
Synopsis: In a carefully studied group of patients who underwent brain biopsies for atypical presentations of multiple sclerosis, cortical demyelination or cortical inflammatory lesions were demonstrated in about half.
Source: Lucchinetti CF, et. al. Inflammatory cortical demyelination in early multiple sclerosis. N Engl J Med 2011;365:2188-2197.
Cortical lesions in multiple sclerosis (ms) have been largely overlooked until recently for two major reasons: 1) histology protocols for myelin stains generally require de-staining the tissue until the cortex is unstained, and 2) conventional MRI protocols are surprisingly insensitive in detecting cortical lesions.1 Initial efforts to define the cellular composition of cortical lesions in multiple sclerosis (MS) enigmatically revealed a paucity of inflammatory cells in these lesions.2-4 This presented a dichotomy: white matter lesions contained perivenular lymphocytes and abundant tissue macrophages, whereas grey matter lesions showed little in adaptive and innate immune response. An ensuing hypothesis suggested cortical demyelination occurred independent of cellular immunity. Lucchinetti et al's report challenges this concept of "bland" demyelination in cortex by showing that a significant percentage of cortical lesions contain inflammatory infiltrates characteristic of white matter lesions.5
Biopsies were performed at the time of clinical presentation for patients in whom neoplasms or other neurologic disease were considered. Typically, the target lesion was in the white matter, and cortex was collected en route. Within this larger cohort of biopsied patients, sufficient cortex for histologic examination was available in 138 patients. Of those patients, 53 (38%) showed evidence of cortical demyelination, 12 (9%) showed cortical inflammation without demyelination, and 73 (53%) showed normal cortex. More than half (56%) of the 138 patients studied had comprehensive clinical follow up (median time to follow-up: 3.5 years); of these 77 patients, three-fourths were found to fulfill criteria for clinically definite MS and 25% for a clinically isolated syndrome. Since biopsies were performed early after clinical presentation, it follows that cortical lesions occur early in the course of MS.
In a sub-analysis of 41 patients with cortical demyelination, 27 (66%) showed the presence of foamy macrophages in cortical lesions consistent with active demyelination. Activated microglia were identified in all demyelinating lesions studied in this sub-analysis. Sufficient tissue was available for an analysis of lymphocytic infiltrates in 38 patients. Perivascular CD3+ and CD8+ T-cells were present in 82% and 77% of lesions respectively. Furthermore, patients with cortical lesions were more likely to have overlying meningeal inflammation. Taken together, these data support the concept that inflammatory demyelination is relatively common in early cortical lesions.
This study provides evidence supporting three important concepts in MS: 1) that cortical lesions occur early in the clinical course of MS; 2) that early cortical lesions contain a repertoire of inflammatory cells identified in established active white matter lesions; and 3) that resolution of inflammation in cortical lesions is more rapid.
Commentary
It seems most likely that the pathophysiologic mechanisms leading to demyelination in cortical and white matter lesions of MS share a common initial pathway. If so, then why is the cellular phenotype of cortical lesions so different from that of white matter lesions? A clue comes from examination of the leukocortical lesions those lesions that span white matter and grey matter from a single center of origin. Established leukocortical lesions show consistent demyelination in both the white and grey matter portions of the lesion. However, these established leukocortical lesions display abundant activated innate immune cells in the white but not the grey matter portions of the lesions.
Thus, reconciling Luccinetti's serendipitous findings with those of studies that find a paucity of inflammatory cells in cortical lesions may be a simple matter related to time of sampling in the lesion's evolution. The cellular context in which demyelination occurs may dictate the rapidity of the inflammatory response's resolution. It is well known that neurons, and particularly grey matter, suppress inflammation when compared to white matter or non-neuronal tissues. Thus, inflammatory demyelination in the cortex may resolve rapidly, whereas inflammatory demyelination in the white matter may be prolonged.
Criticism of Luccinetti's approach has been repeatedly made: MS that requires biopsy for diagnosis is atypical, thus the pathological findings do not apply to typical MS. Although this criticism holds some validity, it should be remembered that the spectrum of clinical presentations for MS is broad. What we learn from one edge of the spectrum undoubtedly bears relevance to the entire disease. Biopsies, along with the rare mortalities that occur early after onset of symptoms, provide glimpses into the histopathologic features of the early lesion.5,6 In this study, while atypical lesions were the biopsy target, the tissue under study here was obtained en passant. As a consequence, this study cannot be meaningfully criticized for analysis of atypical lesions. Since cortical lesions were not identified by MRI and were not the biopsy target, there is some randomness in the cortex sampled thus making the findings even more impressive. The insights gained from this innovative work are numerous and open important new avenues of investigation. This novel approach has yielded heretofore-unrecognized findings that further our understanding of MS pathophysiology.
References
1. Kidd D, et al. Cortical lesions in multiple sclerosis. Brain 1999; 122:17-26.
2. Peterson JW, et al. Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann Neurol 2001;50:389-400.
3. Bø L, et al. Intracortical multiple sclerosis lesions are not associated with increased lymphocyte infiltration. Mult Scler 2003;9:323-331.
4. Bø L, et al. Subpial demyelination in the cerebral cortex of multiple sclerosis patients. J Neuropathol Exp Neurol 2003;62:723-732.
5. Lucchinetti CF, et al. Inflammatory cortical demyelination in early multiple sclerosis. N Engl J Med 2011;365:2188-2197.
6. Barnett MH, Prineas JW. Relapsing and remitting multiple sclerosis: Pathology of the newly forming lesion. Ann Neurol 2004;55:458-468.
7. Kutzelnigg A, et. al. Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain 2005;128:2705-2712.
In a carefully studied group of patients who underwent brain biopsies for atypical presentations of multiple sclerosis, cortical demyelination or cortical inflammatory lesions were demonstrated in about half.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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