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A Game-Changer in MS Pathogenesis: New Evidence for Early Cortical Inflammation as Primary Target for Therapy

Robinson, Richard

doi: 10.1097/01.NT.0000411141.73994.c0
REPRESENTATIVE TYPES OF cortical demyelinated plaques in early MS on immunohistochemical staining for proteolipid protein

REPRESENTATIVE TYPES OF cortical demyelinated plaques in early MS on immunohistochemical staining for proteolipid protein

The cortex is a principal early target of inflammatory changes in many multiple sclerosis (MS) patients, according to a unique new study. The findings may have significant implications for understanding pathogenesis of the disease, and for tracking the effects of treatment, experts told Neurology Today.

Much of what is known about cortical involvement in MS comes from autopsy studies of patients with longstanding disease, said Claudia Lucchinetti, MD, professor of neurology at the Mayo Clinic College of Medicine in Rochester, MN, and one of two lead authors of the Dec. 8 New England Journal of Medicine study, along with Richard Ransohoff, MD, of the Neuroinflammation Research Center at the Cleveland Clinic in Cleveland, OH.

Autopsy “gives you a snapshot very late in the disease, but doesn't give you a sense of some of the dynamic processes that might be occurring earlier on,” she said, and standard MRI imaging techniques don't resolve gray matter lesions. A technique called double inversion recovery MRI can do so, but it is not widely used and fails to delineate the largest lesions.

Evidence that the cortex may be involved very early has accumulated, including recent reports of patients with initial cortical involvement who went on to develop typical MS. Understanding the scope and frequency of cortical demyelination, however, “really wasn't possible until this study,” Dr. Lucchinetti said.



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The study took advantage of a unique repository of tissue from over 500 patients who underwent brain biopsy as part of a diagnostic work-up, usually for an atypical deep white matter lesion suspected to be a tumor. Grey matter was sampled “en passant,” as the needle passed through the cortex to reach the lesion. One hundred thirty-eight patients had sufficient cortex captured in the sample to analyze.

Of the 138 patients, 53 (38 percent) had evidence of cortical demyelination; an additional 12 patients (14 percent) had cortical inflammation without demyelination. Importantly, Dr. Lucchinetti said, this is almost certain to be a significant underestimate of the true prevalence, because the sample was not meant to target the cortex. Just a millimeter to the left or right, she noted, and another lesion might have been captured or lesions might have been missed altogether.

Among patients with demyelination, three types of lesions were seen: leukocortical, intracortical, and subpial — consistent with results from previous autopsy studies of chronic MS. Some specimens in the current study contained more than one cortical plaque type.

The majority of early cortical lesions displayed evidence of mild or moderate inflammation, and the limited neurodegeneration observed “occurred on a background of inflammation,” Dr. Lucchinetti said. This finding is in fundamental contrast to late-disease autopsy specimens. That is important, she said, because some studies have suggested that the disease may be a primary degenerative one, with secondary inflammation. “Our observations based on early MS reinforce the notion that MS is a primary inflammatory demyelinating disease, and the focus should be on limiting those processes.”

COMPONENTS OF PARENCHYMAL INFLAMMATORY infiltrates in cortical lesions

COMPONENTS OF PARENCHYMAL INFLAMMATORY infiltrates in cortical lesions

Meningeal inflammation was a strong risk factor for cortical demyelination. Patients with diffuse meningeal inflammation had a 45-fold increased likelihood of having cortical demyelination, especially subpial demyelination just below the meningeal inflammation.

“This really suggests there are processes occurring in the subarachnoid space, and meningeal infiltration that may be driving or contributing to the changes we observed in the underlying cortex,” Dr. Lucchinetti said.

That led her and Dr. Ransohoff to propose a hypothesis that “rather than beginning in the deep white matter, and extending to the cortex, perhaps the disease begins in the outer compartments in the subarachnoid space and progresses into the cortex, and this drives the changes in the deeper white matter.”

Support for this hypothesis comes from animal models, in which meningeal inflammation is an early event that precedes white matter lesions and neurological symptoms. Furthermore recent clinical and imaging studies have demonstrated that cortical damage occurs early in MS and may even precede dissemination of classic MS white matter lesions.

As brain biopsies are not routinely done to diagnose MS, it was important to ensure that the findings of their study were representative of non-biopsied MS. Dr. Lucchinetti said previous studies that followed the clinical course and radiographic profile of biopsied MS and compared it to non-biopsied MS have revealed that, despite an atypical presentation that may have led to biopsy, the majority of patients go on and develop typical MS with a clinical course and disability profile similar to a non-biopsied MS population-based cohort.

Furthermore, among biopsied patients with cortical demyelination in the current study, in whom clinical follow-up was available, Dr. Lucchinetti and colleagues confirmed the majority had developed MS by last follow-up. “Overall, there are pretty strong data to indicate we are not looking at the fringes of disease,” she said. “We are convinced that these findings can be extrapolated to prototypic MS.”

“At the end of the day, we ultimately show that the cortex is involved very early in the disease, that it's highly inflammatory supporting a primary immune process, and that meningeal inflammation is highly associated with cortical damage. Finally, the cortex could even be an initial target,” Dr. Lucchinetti added.

Patients with cortical involvement may have a worse prognosis, Dr. Lucchinetti said, including greater risk of cognitive losses, seizures, and more rapid progression.

The findings highlight the need to develop and disseminate imaging techniques that can capture this early and ongoing cortical demyelination, both to better understand the disease, and to determine whether disease-modifying therapies are having an impact on the cortex.

“Our findings regarding cortical demyelination early in the disease should help rearrange the MS research agenda to heighten the priority for identifying these lesions using the MRI scanner,” Dr. Ransohoff noted. “Once this technology has been developed, using double-inversion recovery or other imaging protocols, the techniques should rapidly be made available at MS centers. Only in this way can we be more confident that current treatments and future clinical trials will evaluate as much as possible the ongoing MS pathology, to help us choose the best medications for the patients.”

“These results highlight that MS is a global brain disease,” concluded Dr. Lucchinetti. “If we aren't looking at what happens in the cortex, we may miss some very important things about initiation, perpetuation, and progression. We need to understand this both etiologically and radiologically, and we need to know whether our therapies are targeting this effectively or not. If we aren't measuring cortical involvement, we can't know.”

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Timothy L. Vollmer, MD, professor of neurology at the University of Colorado Health Sciences Center in Denver and medical director of the Rocky Mountain MS Center at Anschutz Medical Center, concurs. In an interview with Neurology Today, he noted that the “highlight of the paper,” that cortical lesions are inflammatory early in the disease, has several important implications. First, he said, “this begins to change our thinking about the disease. It's really not a disease of the white matter. It's a disease of the central nervous system,” involving all its components. Second, based on these results and others, “the assumption should be that the patient has cortical involvement until proven otherwise.” Third, the early involvement of the cortex, even at a time when patients are not declining clinically, indicates that adaptation is going on, probably through cortical remodeling.

“The patient is using cognitive reserve to mask the disease,” Dr. Vollmer continued. “Once we recognize that, the onset of progressive disease is no longer about a change in immunology, but has to represent loss of that cognitive reserve.” The implication, he said, is that to minimize disability, “we are going to have to treat early and aggressively.”



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Standard magnetic resonance imaging techniques provide relatively low contrast between white matter and grey matter, making it difficult to resolve cortical lesions. Double inversion recovery MRI, developed in 1998, overcomes this by simultaneously suppressing signals from both white matter and CSF, increasing the delineation of grey matter. Nonetheless, the number of grey matter lesions detected with double inversion recovery is less than the true number as determined histologically, indicating the need for better techniques to image grey matter in MS.

—Richard Robinson

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Lucchinetti CF, Bogdan FG, Popescu FG, et al. Inflammatory cortical demyelination in early multiple sclerosis. N Engl J Med 2011;365:2188-2197.
©2012 American Academy of Neurology