Investigators have identified a new subtype of MS in postmortem tissue, characterized by a lack of cerebral white matter demyelination.
Bruce Trapp, PhD
Researchers from Cleveland Clinic have identified myelocortical multiple sclerosis (MS) as a new subtype of the condition, characterized by the demyelination of the spinal cord and cerebral cortex, but not cerebral white matter.
While the condition is currently indistinguishable in vivo from the typical form of MS, the implications of the findings are tremendous for the field. Co-author Daniel Ontaneda, MD, told NeurologyLive that the data shows that, possibly, “one of the explanations—one of the layers—of this heterogeneity is that some MS patients will not have white matter demyelination in the brain, therefore, they probably will be quite different.”
Led by Bruce Trapp, PhD, the group of researchers had collected brains and spinal cords from 100 deceased patients with MS from May 1998 and November 2012. In total, 12 of these individuals were identified as lacking cerebral white matter demyelination, thus having myelocortical MS, and were compared to a matching cohort of 12 typical patients with MS.
“What these patients gave us was a platform to investigate the effects of cerebral white matter demyelination on neuronal viability,” Trapp told NeurologyLive. “In general, it’s assumed that neurodegeneration in MS is a consequence of demyelination, but now we have this cohort of MS patients that did not have cerebral white matter demyelination.”
The analysis revealed that cortical demyelinated lesion areas were similar between the 2 groups, with a median of 4.45% (interquartile range [IQR], 2.54 to 10.81) with the myelocortial patients compared to 9.74% (IQR, 1.35 to 19.50) in the typical patients (P = .5512). The spinal cord demyelinated areas were significantly greater in the patients with myelocortical MS (median, 3.81%; IQR, 1.72 to 7.42) compared to the typical group (median, 13.81%; IQR, 6.51 to 29.01; P = .0083).
Despite a lack of cerebral white matter demyelination in patients with myelocortical MS, the mean cortical neuronal densities were significantly decreased in comparison. There were 349.8 neurons per mm2 (standard deviation [SD], 51.9) compared to 419.0 (SD, 43.6) in the controls in layer III (P = .0104). The results were similar in layer V (355.6 [SD, 46.5] for myelocortical compared to 454.2 [SD, 48.3]; P = .0006) and layer VI (366.6 [SD, 50.9] compared to 458.3 [SD, 48.4]; P = .0049), as well.
Conversely, the mean cortical neuronal densities in typical MS brains were decreased in layer V compared to controls (392.5 [SD, 59] compared to 454.2 [SD, 48.3]; P = .0182). This was not the case in layers III and VI.
“If cerebral white matter demyelination was causing neurodegeneration, we should see a greater neuronal loss in typical MS than in myelocortical, but in fact, what we found was the opposite,” Trapp said. “Compared to control brains, there was more neuronal loss in myelocortical MS. We looked at 5 cortical regions and looked at 3 layers in these 5 regions—these are the layers that project axons to the white matter projection neurons—and in myelocortical MS, 11 of 15 of those layers had decreased densities compared to control, whereas in typical MS only 5 out of the 15 had a decrease.”
Historically, Trapp noted, it was thought that most of the degeneration in MS was caused by demyelination. The concept that demyelination and degeneration are not connected is not novel—the MRI community has presented data in several instances that supports the concept that brain atrophy precedes significant amounts of cerebral white matter demyelination as measured by MRI. Until now, though, there has been no pathological evidence that provides support for that data.
“Our analysis—if we look at the MRIs, the region that are most severely affected are altered on T2, T1, and by magnetization transfer ratio (MTR). Historically, those regions are thought to be chronically demyelinated regions—black holes,” Trapp said. “Yet, here they are present in white matter that’s myelinated. We found 31 of these regions in the paper and we analyzed them histologically, they were all myelinated, but what we found is that their axons, their myelinated axons, were swollen. If you look at the sensitivity of the T1 and the MTR, they’re much more sensitive than T2. Those values are affected by free water. If you swell an axon, there’s an increase in free water, so our hypothesis right now is that the MRI changes are caused by axonal pathology.”
Trapp BT, Vignos M, Dudman J, et al. Cortical neuronal densities and cerebral white matter demyelination in multiple sclerosis: a retrospective study. Lancet Neurol. Epub August 21, 2018. doi:10.1016/ S1474-4422(18)30245-X.