Cortical lesions in MS: a correlate of disease progression?

Multiple sclerosis is generally considered a disease of the white matter of the CNS. This, however, is not true and demyelination may also be prominent in the grey matter of deep cerebral nuclei and the cerebral cortex. The results of recent neuropathological and fMRI studies suggest that cortical plaques are of importance for the understanding of the disease process in multiple sclerosis. Cortical plaques have been studied only incompletly in multiple sclerosis patients. Due to their structural features (very mild inflammatory reaction and only minor changes in global tissue texture) they so far escape detection with MRI. Thus, little is known regarding their distribution within the CNS, their relation to different clinical manifestations of the disease and their mechanisms of formation. These questions will be addressed in our current project. We have started to systematically analyze cortical demyelinated plaques in a large sample of multiple sclerosis patients from different stages of the disease and with different clinical disease manifestations. Our results, obtained so far, indicate the following: cortical demyelinated plaques are abundant in patients with primary or secondary progressive MS, but are virtually absent in patients with acute or relapsing-remitting MS. The extent of the white matter plaques was almost the same in the four groups. Aim of the present project is to determine the incidence and topographical distribution of cortical plaques in different clinical forms of multiple sclerosis (acute MS, RRMS, SPMS, PPMS) and to define the dominant pathogenetic pathway, leading to demyelination and tissue injury in cortical MS lesions. To address these questions and to define the type of tissue injury within cortical lesions, detailed investigation of all grey matter plaques within the CNS, including cerebral cortex, cerebellar cortex and brain stem is warranted. Additional aims of the present project are to find new MRI/MRS parameters, which allow the identification of cortical plaques and to search for clinical manifestations of cortical plaques in MS patients. Incidence and distribution of cortical lesions in multiple sclerosis may be a pathological correlate of disease progression and suggest that fundamently different pathological mechanisms may play a role in different stages of the disease.

Multiple sclerosis (MS) is the most common neurological disease of young adults in the Western world. It is a chronic inflammatory disease of the central nervous system, which leads to randomly distributed focal demyelinating lesions within the brain and spinal cord. Recent clinical and radiological studies, however, revealed that focal demyelinated plaques in the white matter only incompletely explain the progressive neurological deterioration of the patients. The aim of our project was to define the pathological substrate of disease progression in MS. We found that in the early relapsing / remitting stage of the disease focal demyelinated lesions in the white matter of the central nervous system dominate, while in the progressive stage of the disease the brain is affected in a global sense. This is reflected by the appearance of extensive demyelination in the cerebral cortex and a diffuse axonal damage in the global white matter. Similar as in early relapsing MS also the chronic diffuse brain damage in the progressive stage is associated with inflammation. The nature of the inflammatory reaction, however, differs. While in acute and relapsing MS new waves of inflammation enter the nervous tissue from the circulation, inflammation in the chronic stages becomes trapped within the nervous system and is no longer controlled by the peripheral immune system. Our findings have major implications for diagnosis and therapy of MS. They for the first time define pathological alterations in progressive MS, which so far are undetectable with clinical and paraclinical tools. They further explain, why current anti-inflammatory and immunomodulatory therapies are only effective in relapsing MS, but fail in the progressive stage of the disease.