A clinically isolated syndrome indicating a pathological process involving the cranial nerves or the posterior fossa may constitute a hard diagnostic challenge for the clinician. Whereas internuclear ophthalmoplegia, for example, is almost pathognomonic of multiple sclerosis (MS), other clinical presentations are often puzzling. The main alternative causes of symptoms that may suggest a clinical onset of MS are reviewed here, grouped in principal clinical syndromes, with particular attention to some rare, recently recognised conditions.