Scientists at the Cleveland Clinic report the discovery of a new subtype of multiple sclerosis (MS) that they say will provide a better understanding of the individualized nature of the disease.

MS has long been characterized as a disease of the brain's white matter, where immune cells destroy myelin. The demyelination was believed to be responsible for neuronal death that leads to irreversible disability in patients with MS.

However, in the new findings, a team led by Bruce Trapp, Ph.D., the Morris R. and Ruth V. Graham endowed chair in biomedical research, and professor, molecular medicine, Cleveland Clinic, identified for the first time a subtype of the disease that features neuronal loss but no demyelination of the brain's white matter. The study (“Cortical neuronal densities and cerebral white matter demyelination in multiple sclerosis: a retrospective study”), published in Lancet Neurology, could potentially lead to more personalized diagnosis and treatments, according to the researchers.

“We propose that myelocortical multiple sclerosis is a subtype of MS that is characterized by demyelination of spinal cord and cerebral cortex but not of cerebral white matter. Cortical neuronal loss is not accompanied by cerebral white-matter demyelination and can be an independent pathological event in myelocortical MS. Compared with control brains, cortical neuronal loss was greater in myelocortical MS cortex than in typical multiple sclerosis cortex. The molecular mechanisms of primary neuronal degeneration and axonal pathology in myelocortical MS should be investigated in future studies,” write the investigators.

This new subtype, called myelocortical MS (MCMS), was indistinguishable from traditional MS on MRI. The researchers observed that in MCMS, part of the neurons become swollen and look like typical MS lesions indicative of white matter myelin loss on MRI. The disease was only diagnosed in post-mortem tissues.

The team's findings support the concept that neurodegeneration and demyelination can occur independently in MS and underscore the need for more sensitive MRI imaging techniques for evaluating brain pathology in real time and monitoring treatment response in patients with the disease, note the scientists.

“This study opens up a new arena in MS research. It is the first to provide pathological evidence that neuronal degeneration can occur without white matter myelin loss in the brains of patients with the disease,” says Dr. Trapp, chair of Cleveland Clinic's Lerner Research Institute Department of Neurosciences. “This information highlights the need for combination therapies to stop disability progression in MS.” 

In the study of brain tissue from 100 MS patients who donated their brains after death, the researchers observed that 12 brains did not have white matter demyelination. They compared microscopic tissue characteristics from the brains and spinal cords of 12 MCMS patients, 12 traditional MS patients and also individuals without neurological disease. Although both MCMS and traditional MS patients had typical MS lesions in the spinal cord and cerebral cortex, only the latter group had MS lesions in the brain white matter.

Despite having no typical MS lesions in the white matter, MCMS brains did have reduced neuronal density and cortical thickness, which are hallmarks of brain degeneration also observed in traditional MS. Contrary to previous belief, these observations show that neuronal loss can occur independently of white matter demyelination. 

“The importance of this research is two-fold. The identification of this new MS subtype highlights the need to develop more sensitive strategies for properly diagnosing and understanding the pathology of MCMS,” says Daniel Ontaneda, M.D., clinical director of the brain donation program at Cleveland Clinic's Mellen Center for Treatment and Research in MS. “We are hopeful these findings will lead to new tailored treatment strategies for patients living with different forms of MS.”

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