Specialty Area

Multiple Sclerosis: State of the Field in 2017

Target Audience

Neuroradiologists and Neurologists interested in multiple sclerosis (MS).

Outcomes/Objectives

To provide a detailed description of cortical neuronal loss, cortical atrophy, spinal cord demyelination, cortical demyelination, and cerebral white matter MRI abnormalities in a subpopulation of postmortem brains from severely disabled MS patients that do not contain demyelination of cerebral white matter.

Purpose

Postmortem macroscopic examination of cerebral hemispheres from 97 individual with MS identified 12 brains without cerebral white matter lesions. The purpose of this study was to perform a detailed pathological study of these brains and to establish pathological correlates of cerebral white matter MRI abnormalities that were prominent in these brains.

Methods

Demyelination was quantified in cerebral white matter, cerebral cortex, and spinal cord and compared with demyelination in 12 MS brains with cerebral white matter lesions. Postmortem MRI compared brain atrophy, cortical thickness, T1-weighted and T2-weighted intensities, and magnetization transfer ratio (MTR) volumes in the two cohorts. Cortical neuronal densities and pathological correlates of brain white matter MRI abnormalities were also investigated.

Results

Twelve of 97 postmortem brains (12%) from individuals with MS were characterized by spinal cord and subpial cortical demyelination and a paucity of cerebral white matter demyelination. Despite the lack of cerebral white matter demyelination, cortical neuronal loss, cortical thinning, and cerebral white matter MRI abnormalities were significantly increased compared to control brains and were similar to those in MS brains with cerebral white matter demyelination. In the 12 brains without cerebral white matter demyelination, swollen myelinated axons were the pathological correlate of cerebral white matter regions with increased T1-weighted hyperintensities, T2-weighted hypointensities, and reduced MTRs.

Discussion

We coined the term “myelocortical multiple sclerosis” to describe individuals with spinal cord demyelination, subpial cortical demyelination, and an absence of cerebral white matter demyelination. Myelocortical MS cases represent 12% of our postmortem MS cohort, an incidence similar to primary-progressive MS. Despite the paucity of cerebral white matter demyelination, cortical neuronal loss, cortical thinning, and cerebral white matter MRI abnormalities were similar to those found in MS brains with abundant white matter demyelination. Our studies extend the concept that cerebral white matter MRI abnormalities in individuals with MS do not always reflect demyelination. In individuals with classical MS, 45% of white matter regions of interest (ROIs) with increased T2-weighted hyperintensities (De Groot et al., 2001; Fisher et al., 2007) and 17% of white matter ROIs with abnormal T1-weighted, T2-weighted, and MTR intensities (Fisher et al., 2007) were normally myelinated. Cerebral white matter ROIs with altered T1, T2, and MTR appear as “black holes” that often reflect chronically demyelinated lesions with demyelinated axonal swelling and axonal degeneration (Fisher et al., 2008, Young et al., 2008). In chronic demyelinated lesions, the severity of decreased T1 contrast and MTRs correlate with demyelinated axonal swelling and loss of axonal Na+/K+ ATPase (Young et al., 2008). Myelocortical cerebral white matter regions with abnormal T1-weighted, T2-weighted, and MTR signals contain swollen myelinated axons. Increased water content in swollen myelinated axons is the likely correlate for increased T1-weighted hyperintensities and reduced MTR in cerebral white matter from individuals with myelocortical MS. Myelocortical MS should be considered as a distinct subtype of MS. Identification of individuals with myelocortical MS has implications for clinical trial inclusion criteria. Individuals with myelocortical MS should be excluded from remyelination clinical trials and considered as a separate cohort in anti-inflammatory clinical trials. It would be informative to know whether anti-inflammatory therapies reduced cortical atrophy or new T2 lesion load in individuals with myelocortical MS, as the lack of traditional immune cell-mediated cerebral white matter demyelination does not exclude the possibility that the peripheral immune system is responsible for the MRI and pathological changes in myelocortical cerebral white matter and cerebral cortex. Development of brain imaging modalities that distinguish between myelinated and demyelinated cerebral white matter will be essential for identifying living myelocortical patients and addressing the role of the immune system in myelocortical MS.

Conclusion

We have identified a new cohort of MS patients, termed myelocortical MS, which is characterized by demyelination of spinal cord and cerebral cortex, but not of cerebral white matter. Cortical neuronal loss and cerebral white matter demyelination are independent events in individuals with myelocortical MS. Swollen myelinated axons are the pathological correlate of the cerebral white matter regions with increased T2 hypointensities, increased T1 hyperintensities, and reduced MTR.

Acknowledgements

No acknowledgement found.