Inflammatory Demyelination of Cortex Starts Early in MS

Susan Jeffrey

December 09, 2011

December 9, 2011 — A new study suggests that, rather than being a late feature of the disease, cortical demyelinating lesions are common in patients in the early stages of multiple sclerosis (MS).

Using cortical tissue obtained during brain biopsy for other reasons, researchers found that cortical lesions were "frequent, inflammatory, and strongly associated with meningeal inflammation."

"Our study shows the cortex is involved early in MS," Claudia F. Lucchinetti, MD, co-lead author of the study and a neurologist at the Mayo Clinic College of Medicine, Rochester, Minnesota, told Medscape Medical News. "The cortex in some cases may even be the initial target."

"We found that lesions in the cortex that we identified looked exactly like the lesions that had been reported previously at autopsy, but with one important difference: that they were highly inflammatory," co-lead author Richard M. Ransohoff, MD, from the Cleveland Clinic, Ohio, said in an interview.

The finding is reassuring, he said, because it "suggests that the fundamental inflammatory process that drives MS in the white matter is also driving it in the gray matter, the cortex."

Their work appears in the December 8 issue of the New England Journal of Medicine.

Gray vs White Matter

Most efforts in the area of MS research have focused on white matter, the researchers write. Imaging and histopathology have suggested that cortical damage, on the other hand, is a process that occurs later, that it correlates with cognitive dysfunction and disease progression, and that it reflects demyelination or secondary neurodegeneration, they note.

Cortical lesions studied at autopsy after a lengthy disease process of 30 to 50 years were "clearly described by neuropathologists as being demyelinating but noninflammatory," Dr. Ransohoff said. On the other hand, although conventional magnetic resonance imaging can't yet image cortical lesions, double inversion-recovery imaging, a technique not routinely used in practice, has suggested there may be abnormalities in the cortex even early in the disease process.

"So our study was a chance to use pathology to understand what's going on early in the cortex, and bring together these 2 disparate pieces of information," he said.

Dr. Lucchinetti was in a unique position at Mayo, she said, having led the MS Lesion Project funded by the National Multiple Sclerosis Society over the past decade, "where I had been focused on collecting and phenotyping a unique resource of tissue from patients in very early stages of multiple sclerosis."

The brain biopsy specimens were obtained during stereotactic sampling of white matter lesions because a tumor was suspected; white matter lesions can look like a tumor on imaging. Most of these biopsies were done off-site and the samples sent to Mayo to confirm a diagnosis.

Of 563 samples, they selected 138 that had a fragment of cortex attached; the biopsies targeted white matter lesions but the needle passed through the cortex, providing some random samples.

"We identified that cortical demyelination MS occurs quite early, given that these patients presented within days to weeks of their symptoms," Dr. Lucchinetti said. "Secondly, we were able to show that all 3 cortical plaque types that had been observed in chronic established MS, were also present in early MS, namely, intracortical lesions, subpial lesions and leukocortical plaques."

Cortical demyelination was present in 53 patients (38%; 104 lesions and 222 tissue blocks) and absent in 85 patients (121 tissue blocks). Twenty-five patients with cortical demyelination had definite MS, representing 81% of 33 patients who underwent long-term follow-up; 33 patients without cortical demyelination also were found to have definite MS over time, or 72% of 46 such patients with long-term follow-up.

The team found 58 of 71 lesions (82%) showed CD3+ T-cell infiltrates, and 32 of 78 lesions (41%) showed macrophage-associated demyelination.

Interestingly, they also found that inflammation in the meninges, which enclose the subarachnoid space within which the spinal fluid circulates, was topographically associated with cortical demyelination in patients for whom enough meningeal tissue was available for study.

"The presence of meningeal inflammation was strongly associated with increased odds of demyelination, almost 45-fold increased odds, that you would have demyelination immediately below these meningeal infiltrates," she said.

"We got sort of an additional bonus, an unexpected finding when we began to think about the implications of these data," Dr. Ransohoff said. "The traditional view of MS has been that the earliest lesions occur in the white matter, and that's because you can see them with the MRI scanner, and that cortical damage comes along later. Our data suggest a completely different approach to understanding how the disease works at least in some cases, in some patients."

The topographic association they saw suggests that inflammation may start in the subarachnoid space enclosed by the meninges and may initiate the process of demyelination in any adjacent tissue: in the brain, that would be the cortex; in the spinal cord, the white matter, and then the process works deeper into the surrounding tissue, so that white matter lesions may follow cortical lesions, not the other way around.

"And this has some implications for treating and understanding the inflammatory process in MS, because you would like to be able to do something about the very early meningeal-based inflammation," Dr. Ransohoff said.

"It suggests that the events that occur in the meninges are key to understanding how the process gets started," he said.

"At the same time, I think it tends to restructure, reorder, research priorities to say that we need a ramped-up effort to try to see cortical lesions using the MRI scanner, because we think that if it remains impossible, or unachieved to see cortical lesions in life during clinical trials, then we’re going to have an incomplete understanding of the potential of our various medications to help," he added.

Dr. Lucchinetti agrees. "Given that imaging and pathological studies in chronic MS indicated that cortical demyelination was associated with disease progression, coupled with recent imaging studies that demonstrated cortical involvement in early MS was a predictor of whether a patient ultimately progressed, it becomes absolutely critical that we better understand the nature and sequence of these early pathogenic events in hopes of identifying novel therapies that selectively target these inflammatory and destructive processes. We still do not really know to what extent our current therapies are impacting cortical demyelination, especially with respect to the subpial cortical plaque type, which is the most difficult to visualize using currently available imaging techniques."

An animation illustrating their hypothesis can be found on the Mayo Clinic Web site.

Definitive Evidence

In an editorial accompanying the article, Peter A. Calabresi, MD, from the Department of Neurology, Johns Hopkins Hospital in Baltimore, Maryland, says these new findings, "are provocative, and provide definitive evidence that inflammatory disease of the gray matter commences early in the pathogenesis of some cases of multiple sclerosis."

The new results suggest that cortical neuronal loss is directly associated with inflammatory demyelination, "and therefore early therapeutic efforts to suppress inflammation may be neuroprotective in both gray-matter and white-matter compartments," Dr. Calabresi writes.

Future research should look at whether the mechanisms underlying cortical inflammation are different from those of white matter inflammation, he adds, including whether the immune response is directed at nonmyelin antigens in the central nervous system.

"As has frequently been the case in medicine, much can be learned from rare, outlier presentations of a disease that may exaggerate the pathologic changes to an extent that allows an understanding of a critical aspect of its pathogenesis," he concludes. "Such has been the case in the study of lesions in tumefactive multiple sclerosis, in which there is more than just a touch of gray-matter disease."

"What's unique about the study is, and the reason the National MS Society funded this international team of researchers, is that it offers a rare view of MS early in the disease," Timothy Coetzee, PhD, chief research officer at the National Multiple Sclerosis Society, said in a statement.

"Collaborative studies like this, that deepen our understanding of the sequence of nervous system-damaging events, should offer new opportunities for stopping MS disease progression and improving quality of life for people with MS."

The study was funded by the National Multiple Sclerosis Society and the National Institutes of Health. Disclosures for coauthors and the editorialist are available on the journal's Web site

N Engl J Med. 2011;365:2188-2197. Abstract, Editorial

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