Cortical lesions and brain atrophy in MS
Introduction
The transition from the relapsing–remitting phase to the secondary progressive phase of the disease is a pivotal event in the lives of MS patients. This change in the disease course leads to dramatic changes in clinical presentation and response to treatment [1], [2]. In the majority of patients the disease starts with acute episodes of neurological deficit, followed by complete recovery. This initial phase of the disease usually leads, after a disease course of 10–20 years, to a phase of steady progression of irreversible neurological deficit [1], [3], [4]. According to epidemological studies 90% of patients with RRMS eventually develop SPMS when followed up long enough [4]. In 15–20% of the patients, clinical progression with or without superimposed relapses is seen from the onset of the disease (primary progressive MS [5], [6]).
The phenomenon of progressive MS is a challenge in terms of clinical management of the patients as well as for MRI and neuropathological research. The identification of inter-relapse progression as a diagnostic criterion of the progressive phase can only be performed in a retrospective way and treatment of progressive MS patients is up to now principally restricted to symptomatic options as the efficacy of disease-modifying drugs is still controversial and may be limited to the early stages of the progressive phase [7], [8]. The diagnosis of primary progressive MS is even more challenging as distinguishing retrospectively between primary and secondary progressive MS can be difficult and, additionally, other progressive neurological conditions have to be excluded [9].
While in the relapsing–remitting phase of the disease inflammatory activity is quite pronounced in serial MRI scans, appearance of new lesions with inflammatory mediated blood brain barrier damage is much less prominent in the progressive phase [10], [11], [12], [13]. Although slowly expanding demyelinating lesions are a feature of SPMS [14], it seems plausible that in the progressive phase of the disease neurodegenerative events predominate [15], [16], while inflammation and demyelination are the dominant processes in patients with acute or relapsing remitting disease. However, so far no pathological feature of the disease has been described which clearly distinguishes relapsing–remitting from progressive disease in multiple sclerosis patients.
Pathologically, multiple sclerosis is an inflammatory demyelinating disease of the central nervous system. The hallmark of multiple sclerosis pathology is the demyelinated plaque in the white matter of the brain and spinal cord [17]. Demyelinated lesions occur on the background of a chronic inflammatory process and it is generally believed that this inflammatory response is the driving force for demyelination and tissue injury. Demyelination in the plaques is associated with axonal injury and destruction [18], [19] and the extent of axonal injury correlates with infiltration and activation of macrophages and cytotoxic T-cells in the lesions [18], [20], [21], [22].
The mechanisms of lesion formation and the pathogenesis of white matter lesions in multiple sclerosis have been extensively studied during the last decades, but these descriptions do not cover the whole spectrum of MS pathology. Systematic neuropathological analyses of typical chronic MS brains reveal the following: huge plaques in the periventricular and deep white matter of the hemispheres, extensive demyelination in the cerebral cortex and severe atrophy of both white and grey matter (Fig. 1).
Section snippets
Brain atrophy
Brain atrophy in MS is a very well known phenomenon–especially in later stages of the disease–and has been already described by Jellinger in 1969 [23]. Half of the seventy cases with chronic multiple sclerosis included in this analysis showed severe atrophy of the cerebrum, with severe cognitive impairment and dementia as clinical correlates. In many of these cases MS-encephalopathy, affecting especially the deep white matter of the cerebral hemispheres, was found and defined as a result of
Cortical lesions
Multiple sclerosis is considered to predominantly affect the white matter of the human central nervous system [17]. However, cortical MS lesions have been identified early on by neuropathologists [33], [34], [35], [36], [37] and are well described in neuropathological literature [38], [39]. Similar to plaques in the white matter, grey matter lesions are defined as sharply demarcated areas of demyelination located within the cerebral cortex [34], [38], [39], the basal ganglia and the grey matter
Clinical consequences
Although multiple sclerosis lesions are frequently sited in the cerebral cortex, they are still difficult to visualize in MRI, even in new sequences [61]. Underestimation of cortical lesions may–in addition to other confounders–may lead to the poor association of clinical and MRI findings in MS [62]. Recent fMRI studies [46], [51] suggest that cortical adaption may be important for MS patients in order to limit functional impairment, particularly in the early stages of the disease. Therefore,
Acknowledgements
This study was supported by the Fonds zur Förderung der wissen schaftlichen Forschung, Austria (grant P16848-B02).
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