Myelocortical multiple sclerosis is a novel subtype of multiple sclerosis (MS) which exhibits demyelination of the spinal cord and cerebral cortex but not the cerebral white matter, according to a recent study published in the Lancet Neurology.
Demyelination of the cerebral white matter is pathognomonic for MS, and thought to mediate neuronal degeneration and permanent neurologic disability in this illness. Nevertheless, MRI findings have suggested that demyelination and neurodegeneration occur independently.
“Identification of a new subtype of MS supports the concept that MS is a complex disease with multiple underlying disease mechanisms,” wrote authors, led by Bruce D Trapp, PhD, Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH. “Our findings are consistent with a neurodegenerative process in MS that is independent of demyelination.”
In the current study, the researchers harvested brains and spinal cords from 100 patients who lived with disability and died of MS. Before autopsy, the brains were scanned using MRI.
By means of gross visual inspection of cerebral hemisphere slices, 12 subjects were identified as having typical MS (with white-matter demyelination) and 12 subjects were identified as having myelocortical MS (without white-matter cerebral demyelination). These two sets of patients were matched according to sex, age, MS disease subtype, MRI protocol, disease duration, and Expanded Disability Status Scale.
The team compared cortical neuronal loss, cortical atrophy, cortical demyelination, spinal cord demyelination, and cerebral white-matter MRI abnormalities in patients with typical MS vs those with myelocortical MS.
Dr. Trapp and colleagues found that many spinal cord demyelinated lesions met MS diagnosis criteria (spatial separation of demyelinated lesions). They suggested that these lesions resulted in severe problems with walking. More specifically, the spinal cord demyelinated area was significantly higher in typical MS (median value of 13.81%) than it was in myelocortical MS (median value of 3.81%; P=0.0083).
The team also found that patients with typical MS and those with myelocortical MS both evidenced similar cerebral white-matter abnormalities. In myelocortical MS, these changes were associated with—and likely secondary to—swelling of myelinated axons.
When compared with control brains, the researchers found that cortical neuronal loss was larger in myelocortical MS than it was in typical MS. In myelocortical MS, neuronal densities were lower in layers III, V, and VI as compared with corresponding values in control brains. In typical MS, however, mean cortical neuronal densities were lower in only layer V as compared with the corresponding value in control brains.
“We propose that myelocortical MS is characterized by spinal cord demyelination, subpial cortical demyelination, and an absence of cerebral white-matter demyelination,” the authors wrote. “Our findings indicate that abnormal cerebral white-matter T2-T1-MTR regions of interest are not always demyelinated, and this pathological evidence suggests that cerebral white-matter demyelination and cortical neuronal degeneration can be independent events in myelocortical MS.”
The findings of this study stressed the nonspecific nature of MRI abnormalities in MS patients, as well as the absence of specificity for demyelination. The inclusion of patients with myelocortical MS in immunomodulatory clinical trials could help elucidate different treatment responses as monitored with MRI.
In total, 12% of the autopsied patients evidenced myelocortical MS. According to the authors, this frequency may not reflect prevalence in the entire population because MS patients in the current study were late stage and died of the disease. In other words, the observed prevalence may not recapitulate the prevalence of myelocortical MS in patients with early-stage disease.
"This study opens up a new arena in MS research,” reflected Dr. Trapp. “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. This information highlights the need for combination therapies to stop disability progression in MS.”
Daniel Ontaneda, MD, clinical director of the brain donation program, Cleveland Clinic Mellen Center for Treatment and Research in MS, agreed:
"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 [myelocortical MS]. We are hopeful these findings will lead to new tailored treatment strategies for patients living with different forms of MS."
This study was funded by the National Institutes of Health and National Multiple Sclerosis Society.