Early in the disease course, Multiple Sclerosis involves recurrent bouts of Central Nervous System inflammation that results in damage to both the myelin sheath surrounding axons as well as the axons themselves. Histologic examination reveals foci of severe demyelination, decreased axonal and oligodendrocyte numbers, and glial scarring. The exact cause of inflammation remains unclear, but an autoimmune response directed against Central Nervous System antigens is suspected.In progressive Multiple Sclerosis, inflammation is a less defining pathological hallmark. Instead, progressive Multiple Sclerosis is characterized by neurodegeneration of the white and grey matter resulting in brain and spinal cord atrophy on a background of mild-moderate inflammation. Predominant factors driving neurodegeneration include mitochondrial dysfunction due to defective oxidative phosphorylation and nitric oxide production, resulting in a chronic state of virtual hypoxia due to unmet energy demands, and age-dependent iron accumulation in myelin and oligodendrocytes leading to oxidative tissue damage. Further research is needed to understand how these different pathologic subtypes affect prognosis and response to treatments. Currently, brain biopsy is the only method to definitively determine pathologic subtypes, but studies are underway to find blood, cerebrospinal fluid, and Magnetic Resonance Imaging Biomarkers.Historically, Multiple Sclerosis was classified as an inflammatory disease targeting white matter, with diagnostics and therapeutics focused on this mechanism of pathology. However, more recent imaging and histopathological studies suggest that cortical demyelination plays a crucial role in Multiple Sclerosis pathogenesis and cognitive dysfunction. Cortical demyelination is now recognized in early Multiple Sclerosis. Although some investigative Magnetic Resonance Imaging modalities capture some cortical involvement, including double inversion recovery sequences at 3 Tesla and Ultra-high field Magnetic Resonance Imaging, conventional Magnetic Resonance Imaging metrics used in clinical practice do not show these changes well. Likewise, extensive cortical demyelination that is seen in histopathological studies is not clearly demonstrated on any current Magnetic Resonance Imaging Modality. This pathology/imaging discordance demonstrates that we are still technologically disadvantaged in accurately assessing cortical lesion pathology in the live patient.In the past, inflammation was thought to involve only demyelination, but pathologic studies have found significant axonal pathology as well. In actively demyelinating Multiple Sclerosis lesions, an average of more than 11,000 transected axons/mm3 was observed, while control brain tissue had less than one transected axon/mm. Significant axonal injury is also observed in cortical demyelinating lesions. Clearly, axonal injury is significant in the early stages of the disease.Later in the disease course, the gradual progression of disability is observed. However, there is significantly less active inflammation during this period, so clinical progression may arise instead from degenerative changes. Nonetheless, oligodendrocyte progenitor cells capable of remyelinating axons have been observed even in white matter plaques from patients with chronic Multiple Sclerosis. This observation suggests that the potential for remyelination persists even very late in the disease course, which is an encouraging indicator for possible therapeutic targets at this late stage of the disease.
