Neuroradiological aspects of multiple sclerosis : from early signs to late disease stages

Background: Multiple sclerosis (MS) is a chronic inflammatory and degenerative disease of the central nervous system and a leading cause of neurological disability in young adults. Magnetic resonance imaging (MRI) has improved the diagnostic process in MS, but has also led to incidental MS-like findings. The growing therapeutic arsenal and the variable clinical expression of MS makes MRI important for evaluating treatment response and advanced volumetric measurements are common endpoints in MS treatment trials. More feasible MRI measurements are, however, needed in order to implement quantitative MRI biomarkers in clinical practice, where they may aid in individualizing treatment and care for MS patients.

Purpose: The aim of this thesis is to describe neuroradiological aspects of MS, from its earliest signs to late stages, by describing the frequency and significance of incidental MRI findings suggestive of MS, and by studying corpus callosum atrophy as a biomarker for cognitive and physical disability in MS over a wide range of disease duration.

Study I, a systematic review, showed that incidental brain MRI findings suggestive of MS without typical MS symptoms, and with no better explanation of the findings, are of clinical importance. This entity is preferably called radiologically isolated syndrome (RIS) and persons with RIS often have subclinical cognitive impairment and radiological measurements similar to those seen in MS. RIS progresses radiologically in a majority of cases and about one third of the patients are diagnosed with MS over a mean follow-up time of five years.

Study II, a retrospective cohort study, showed that RIS is an uncommon finding. In a yearly sample of the brain MRI examinations of 2105 patients at Karolinska University Hospital, only one case of RIS was found (0.05%). The patient later developed clinically active MS.

Study III compared the performance and feasibility of the two leading radiological methods for assessing corpus callosum atrophy, corpus callosum area (CCA) and corpus callosum index in a cross-sectional evaluation of the participants in Study IV. Both measurements could be obtained in less than a minute with excellent repeatability. CCA had the strongest correlations with cognitive and physical disability, and was most accurate in differentiating patients from controls and relapse-remitting MS from progressive forms of MS.

Study IV was a 17-year longitudinal cohort study of 37 MS patients that were evaluated clinically, neuropsychologically and radiologically, and a matched healthy control group. The disease durations spanned over five decades, reflecting a panorama of early to late stages of the disease. The corpus callosal atrophy rate decreased with increasing disease duration. The normalized corpus callosum area was correlated with cognitive (r = 0.79, p < 0.001) and physical (r = -0.55, p < 0.001) disability, outperforming commonly used volumetric methods.

Conclusions: RIS is a rare but clinically important condition that in many cases constitutes preclinical MS. CCA is a feasible measurement of corpus callosum atrophy for MS research and clinical practice, and outperforms classical volumetric measurements as a biomarker for cognitive and physical disability in MS.

List of scientific papers

I. Radiologically isolated syndrome – incidental magnetic resonance imaging findings suggestive of multiple sclerosis, a systematic review. Granberg T, Martola J, Kristoffersen-Wiberg M, Aspelin P and Fredrikson S. Multiple Sclerosis Journal. 2013 Mar;19(3):271–80.
https://doi.org/10.1177/1352458512451943

II. Radiologically isolated syndrome: an uncommon finding at a university clinic in a high-prevalence region for multiple sclerosis. Granberg T, Martola J, Aspelin P, Kristoffersen-Wiberg M and Fredrikson S. BMJ Open. 2013 Nov;3(11):e003531.
https://doi.org/10.1136/bmjopen-2013-003531

III. MRI-defined corpus callosal atrophy in multiple sclerosis: a comparison of volumetric measurements, corpus callosum area and index. Granberg T, Bergendal G, Shams S, Aspelin P, Kristoffersen-Wiberg M, Fredrikson S, Martola, J. Journal of Neuroimaging. E-published ahead of print 2015 Mar 19.
https://doi.org/10.1111/jon.12237

IV. Corpus callosum atrophy is strongly associated with cognitive impairment in multiple sclerosis: results of a 17-year longitudinal study. Granberg T, Martola J, Bergendal G, Shams S, Damangir S, Aspelin P, Fredrikson S and Kristoffersen-Wiberg M. Multiple Sclerosis Journal. E-published ahead of print 2014 Dec 4.
https://doi.org/10.1177/1352458514560928