Objective
To prospectively investigate potential signs of pre-clinical multiple sclerosis (MS) activity and when they are present prior to first symptom using data from a historical cohort.
Methods
We linked the cognitive performance of all Norwegian men born in 1950-95 that underwent conscription examination at ages 18-19 to the Norwegian MS registry to identify those later developing MS, and randomly selected controls frequency-matched on year of birth from the Norwegian Conscript Service database. In this nested case-control study cognitive test-scores were available for 924/19530 male cases/controls. We estimated mean score differences among cases and controls (Student's t-test) and the risk of developing MS comparing lower to higher scores (Cox regression) in strata of years to clinical onset.
Results
Men developing first clinical MS symptoms up to 2 years after the examination scored significantly lower than controls (Δ=0.80, p=0.0095), corresponding to a 6 intelligence quotient (IQ)-points difference. Those scoring lowest, i.e. over 1 standard deviation below the controls' mean, had an increased MS risk during the two following years (relative risk=2.81, 95% confidence interval: 1.52-5.20). While results were similar for relapsing-remitting MS cases (RRMS), those developing primary-progressive MS (PPMS) scored 4.6-6.9 IQ-points significantly lower than controls up to 20 years prior to first progressive symptoms.
Interpretation
RRMS may start years prior to clinical presentation and disease processes in PPMS could start decades prior to first apparent progressive symptoms. Cognitive problems could be present in both MS forms before apparent symptoms. Apart from potential implications for clinical practice and research, these findings challenge our thinking about the disease.
Reference
Cortese, M., Riise, T.,Bjørnevik, K., Bhan, A., Farbu, E., Grytten, N., Hogenesch, I., Midgard, R.,Smith Simonsen, C., Telstad, W., Ascherio, A. and Myhr, K.-M. (2016),Pre-clinical disease activity in multiple sclerosis- a prospective study oncognitive performance prior to first symptom. Ann Neurol. 2016 Aug 23. doi: 10.1002/ana.24769. [Epub ahead of print]