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Disease Mechanisms-Multiple Sclerosis
Post-Mortem Tissue Reveals a New Subtype of MS



DEMYELINATION IN MYELOCORTICAL MS and typical MS: (A) A centimeter-thick slice from a typical MS brain that contains a large white-matter lesion (arrow). (B) A centimeter-thick slice from a myelocortical MS brain without white-matter lesions. (C) A normally myelinated spinal cord section labelled with antiPLP antibodies. (D and E) Spinal cord demyelination was detected in tissue sections from individuals with typical multiple sclerosis (D) and myelocortical multiple sclerosis (E). (F) Normally myelinated cortex labelled with an antiPLP antibody. (G and H) Subpial cortical lesions in typical multiple sclerosis (G) and myelocortical multiple sclerosis (H). Black lines separate spinal cord grey and white matter (C–E) and cortical and subcortical white matter (F–H). PLP=myelin proteolipid protein.

Researchers identified for the first time in post-mortem tissue a subtype of multiple sclerosis — myelocortical MS — that shows neuronal loss but no demyelination of the brain's white matter. The findings suggest that that neurodegeneration and demyelination can occur independently in MS.

Examining autopsied brains from patients with multiple sclerosis (MS), scientists at the Cleveland Clinic have identified a new subtype of the disease — myelocortical MS — that does not have the classic cerebral white matter demyelination. The importance of the study, published online on August 21 in Lancet Neurology, is that it shows that neuronal degeneration can occur independent of cerebral white matter demyelination.

The lead scientist on the paper, Bruce D. Trapp, PhD, chair of the department of neurosciences at the Lerner Research Institute of the Cleveland Clinic, said that it has long been thought that demyelination in the brain white matter drives neuronal degeneration and neurological disability.

“Our study provides the first pathological evidence that neurodegeneration can occur independent of white matter demyelination,” said Dr. Trapp. “The concept isn't new. We have known that cortical gray matter atrophy proceeds white matter load on magnetic resonance imaging (MRI). What we didn't know is that there is a subset of patients without cerebral white matter demyelination. It may explain some of the heterogeneity we encounter in MS. It also means that our MRI scans might not be picking up demyelination of the white matter but some other pathology.”


Dr. Trapp drew upon a large collection at the Cleveland Clinic of brain and spinal cord tissues from patients who have died with MS. In 2010, Dr. Trapp was slicing a brain on autopsy and found no white matter demyelination and wondered if it was MS. There was demyelination in the cerebral cortex and spinal cord, so he concluded that it was the right diagnosis. He wanted to know whether this was a common pathological event.

For this study, he and his colleagues analyzed tissue from 100 MS patients, examining centimeter-thick slices from both hemispheres to look for evidence of demyelinated lesions. White matter turns brown or gray and it is generally quite visible with the naked eye. They reported that 12 of the 100 patients had no cerebral white-matter discolorations or demyelinating lesions. Then, they collected records for each patient's medical history and matched the myelocortical MS patients by age, sex, disease subtype, duration, disability scores, and MRI protocol to those patients with white matter demyelination, the typical MS pathological presentation. They looked at tissue sections from five cortical regions, the cerebral white matter, spinal cord, and cerebral cortex. They chose cortical regions that were not directly connected to spinal cord — cortical layers III, V, and VI in the cingulate gyrus and inferior frontal cortex, the superior temporal cortex, and the superior insular cortex and the inferior insular cortex. They compared these two groups plus post-mortem brains from age-matched people without any pathological evidence of a brain disease.

Those with myelocortical MS had demyelinating lesions in the spinal cord and cerebral cortex but not in the cerebral white matter. The cortical demyelinated lesions were similar in both patient groups, and the spinal demyelination was more severe in the typical MS patients than in those with myelocortical MS: median 3.81 percent in myelocortical MS versus 13.81 percent in typical MS (p=0.0083).

There were specific cortical neuronal density differences. Compared to control brains, neuronal densities in the myelocortical cortex were decreased in 11 of the 15 areas analyzed. In contrast, neuronal densities in typical MS patient issue were decreased in five of the 15 cortical areas analyzed. Compared to control tissue, myelocortical MS had more neuronal loss than typical MS.

The researchers are now trying to understand the molecular mechanisms that differ in the myelocortical patients compared to typical MS patients.

Cleveland Clinic neurologist Daniel Ontaneda, MD, turned to the medical records to see whether there were other differences between patients with the newly-identified subtype and those with typical MS. They also interviewed family members.

“We looked at these patients quite carefully and could not find any differences outside of the missing cerebral white matter demyelination,” he said. Characterization of clinical features and MRI findings were different than they are today, he added. Still, he said, “they were indistinguishable from typical MS patients.”

The researchers found 31 MRI lesions (abnormal by T1-T2-MTR analyses) and characterized their pathology. There was decreased axonal density and gliosis — but the myelin was intact. They stained for immune cells in the lesion and found no immune system infiltrates. “There was something wrong,” said Dr. Trapp. “The myelinated axons were swollen. This axonal pathology is one of the major observations of our study.”

It is still not clear whether the immune system plays a role in myelocortical MS. “If the immune system is involved it is not working like it does in typical MS,” added Dr. Trapp.

The researchers said that the findings raise important issues about the interpretation of MRI scans. “MRI doesn't provide good contrast to differentiate between myelocortical and typical MS,” said Dr. Ontaneda. “The specificity for demyelinated axons in white matter is low.”

He added that myelocortical patients could reduce the power in clinical trials that target the immune system or test remyelinating therapies.

For now, there is no way to differentiate the subtypes in living patients. “But we need to understand what is driving this process,” said Dr. Trapp. “What is causing these lesions to look abnormal on MRI?”

The investigators are now working to characterize the axonal swelling. “It's possible it is a primary axonal degeneration without demyelination,” Dr. Trapp added. “Careful examination of axonal pathology will be important going forward.”


“The field has assumed for generations that MS is primarily a white matter disorder,” said Jeroen Geurts, PhD, professor of translational neuroscience in the department of anatomy & neurosciences at the VU University Medical Center in Amsterdam, the Netherlands. “My own work has focused on demonstrating that the gray matter is heavily affected as well, but never with the idea that gray matter damage could go entirely without white matter lesions. It leaves an important shadow of a doubt on our current assumptions of the origin of the disease, too. At least in some cases.

“I was worried when I first read the study that we're missing something on MRI or there's a mismatch between MRI and pathology, but the study seems very sturdy. This looks to be real,” Dr. Geurts added. “We need to continue working on more pathology-specific imaging techniques. Both in Cleveland and in Amsterdam, there are post mortem protocols which can show directly which pathological correlate is responsible for which MRI abnormality. Now that we know what to look for, we can try and adapt the imaging so we can start recognizing the new pattern in vivo.” “This new pathologic subtype of MS is very interesting. It dissociates neuron cell loss in cortex from subcortical white matter demyelination. These patients had brain MRI findings typical of MS, but the cerebral white matter lesions seen on MRI were not demyelinated,” said Anne H. Cross, MD, head of the neuroimmunology (MS) section in adult neurology and the Manny and Rosalyn Rosenthal-Dr. John Trotter MS Center chair in neuroimmunology at Washington University in St. Louis. “We don't have a way now to detect these patients when they are alive. The clinicians looking back on the MR scans and medical records could not differentiate between the patients with typical MS and with the new subtype.

“The first step to better understanding is recognizing this subtype, especially while people with it are alive,” she added. “The study raises many questions. Is there a genetic predisposition to more neuronal loss and less cerebral white matter demyelination? Does this type of MS have a different autoimmune target within the central nervous system compared to typical MS?”

Jerry S. Wolinsky, MD, emeritus professor in neurology at the University of Texas Health Science Center at Houston (UTHealth) McGovern Medical School, said that he is “currently reluctant to split the MS phenotypes any further. How can we in practice consider this as a new phenotype when there is no way yet to distinguish these two groups of patients clinically or by current MR imaging?

“We have a lot of work to do to figure out this mismatch in the MRI and what pathologists at several centers now tell us are patterns seen at the end of a person's life,” he added.


• Trapp BD, Vignos M, Dudman J, et al. Cortical neuronal densities and cerebral white matter demyelination in multiple sclerosis: A retrospective study Lancet Neurol 2018; Epub 2018 Aug 21.