To review the treatment and mechanisms underlying the increased prevalence of seizures associated with multiple sclerosis (MS). We carried out an extensive review of the literature pertaining to seizures in MS. We propose that an increase in interleukin-18, and its associated induction of indoleamine 2, 3-dioxygenase and quinolinic acid, mediates seizure activity in MS at least in part via an increase in interferon-gamma (IFNg). Increased kynurenine pathway activity decreases the availability of serotonin and melatonin. Increases in blood–brain barrier and circumventricular organ permeability are linked to these changes. Antiepileptic drugs modulate wider MS symptomatology, interacting with melatonin and vitamin D3. This manuscript provides a framework for the wider understanding and treatment of seizures in MS and wider MS symptomatology.