The Future of Multiple Sclerosis – Time for a Change in Classification?

Current Classification of MS and Its Basis

The most widely used classification of multiple sclerosis (MS) dates back to 1996. It divides MS into 4 basic phenotypes:

• relapsing-remitting (RRMS)
• secondary progressive (SPMS)
• primary progressive (PPMS)
• progressive-relapsing

However, since the late 20th century, our understanding of MS has advanced significantly. This led to an update of the phenotype classification in 2013. However, the newer version of the classification also only partially reflects current insights into pathogenesis. It categorizes MS as either relapsing or progressive and further subdivides both types into active or inactive (based on MRI results or the presence of relapses). It acknowledges the presence of inflammatory activity and neurodegenerative processes in all patients from the onset of the disease.

However, even this division does not fully account for all the pathological processes, whose quantitative differences determine the final clinical phenotype:

• acute inflammatory activity
• chronic smoldering inflammation
• demyelination of both white and gray matter
• axonal degeneration
• neuron loss

Change in Character of Inflammation Over Time

In the initial stages of the disease, acute inflammation is predominantly present. It is caused by T and B lymphocytes and monocytes migrating into the central nervous system (CNS) from the periphery through the still-open blood-brain barrier (BBB). In later years, the BBB closes. This does not mean the inflammation disappears; instead, its character changes. The proportion of chronic parenchymal and interstitial inflammatory activity increases, manifesting as diffuse microglia activation at the edges of existing lesions (chronic active/smoldering lesions). An extensive post-mortem study analyzing 182 patients (with an average disease duration of 29 years) found the presence of active or smoldering lesions in 78% of them. The occurrence rate of active or smoldering lesions was comparable in patients with both primary and secondary progressive MS.

Processes Leading to Neurodegeneration

Inflammation primarily targets the myelin sheaths of nerve fibers – hence the term demyelinating disease. The basis for permanent damage and progression is the loss of neurons and nerve fibers, which is present from the disease's onset and gradually begins to dominate. It is attributed to the following processes:

• inflammation and lesion accumulation leading to retro- and anterograde neuronal degeneration
• mitochondrial damage and oxidative stress
• iron accumulation in myelin sheaths and oligodendrocytes
• ectopic lymphoid follicles
• age-related neurodegeneration and loss of functional reserves

Conclusion

The gradual unraveling of the immunopathogenesis of MS increasingly highlights the insufficiency of the current clinical division of the disease. Identifying the contributions of individual processes and developing new targeted therapeutic modalities could enable truly personalized medicine in the future. The division into classic phenotypes thus gradually loses clinical significance in this light.

(dos)

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