[Multiple sclerosis: a degenerative disease?]

Multiple sclerosis (MS) is an organ-specific autoimmune disease targeting central nervous system myelin. The clinical course results from an interplay between relapses and progression. Relapses are the clinical counterpart of acute focal inflammation of the central nervous system, whereas progression is due to chronic diffuse neurodegeneration. According to the autoimmune theory, successive clinical and especially subclinical relapses eventually lead to irreversible disability, while the accumulation of focal lesions explains the diffuse neurodegeneration. Things are not that simple, however. Relapses are not the main contributor to irreversible disability, as shown both in individual patients and at the population level. Likewise, MRI studies show that focal lesions are not entirely responsible for the diffuse neurodegeneration. Relapse prevention with disease-modifying drugs does not markedly influence the onset of irreversible disability or the progression of cerebral atrophy. In fact, acute inflammatory focal lesions and relapses may be the "tree that hides the forest". Indeed, clinical progression and chronic diffuse neurodegeneration both play a key role, developing independently of relapses and focal lesions. Should MS therefore be considered a primary degenerative disorder rather than a primary autoimmune disease? Not yet: recent pathological studies clearly demonstrate the presence of disseminated activated microglial-like inflammatory cells in the central nervous system. These could lead to a deleterious inflammatory process, even if not specifically autoimmune, unlike the inflammation occurring in acute lesions. If this pathogenetic picture of the disease is correct, then it has implications for therapeutic strategies. Indeed, treating the acute focal inflammation, as we successfully do nowadays, will not be enough. It will also be necessary to extinguish the slow-burning diffuse inflammation nested in the central nervous system behind the blood-brain barrier. This is the new therapeutic challenge in MS.