A cohort of 25,234 Danish patients testing positive (at titers of 1/32) for Epstein-Barr virus related mononucleosis (MONO), during the period 1940-1988, was followed for more than 550,000 person-years. The cohort was linked to the Multiple Sclerosis (MS) Registry for determination of risk of developing MS, in a study at Statens Serum Institut, Copenhagen. A total of 104 cases of MS observed vs 46 expected in the cohort testing positive for MONO corresponded to a standardized incidence ratio (SIR) of 2.27. In a cohort with negative MONO test, 68 observed cases corresponded to a SIR of 1.23, and similar to that prevailing in the general population. Elevated SIRs for MS were observed for MONO patients at all ages, except those 30 years or older. SIR for MS diagnosis was inversely correlated with age at MONO infection (P for trend =0.03). Increased risk of MS appeared 10 years or more after MONO occurred and remained increased for more than 3 decades. The risk was uniformly distributed for sex and age; it was not correlated with severity of MONO infection. 
COMMENT. After recovery from infectious mononucleosis, a patient has a greater than 2-fold increased risk of developing multiple sclerosis. The risk of MS is increased soon after mononucleosis and extends for up to 30 years; it is independent of sex, age, and time from infection or severity of infection.
The association of 3-methylcrotonyl-CoA carboxylase deficiency and severe multiple sclerosis is reported in a 13-year-old female . She presented with a mild Reye-like syndrome following influenza A infection at age 5 years. Alopecia areata, psychomotor retardation and ADHD followed, and the diagnosis of MCC deficiency was made at the onset of multiple sclerosis. Urinary organic acids showed an increased excretion of 3-MCG and 3-HIVA, carnitine was decreased, and enzyme measurements in cultured fibroblasts confirmed the 3-MCC deficiency. Response to interferon was poor, but a good response followed treatment with mitoxantrone.