The relationship between headache and multiple sclerosis (MS) has been a matter of controversy for over 60 years. Headaches are still rated as a "red flag", indicating alternative diagnoses to MS, although in the last few years numerous studies have shown a frequent association between headache and MS. In recent studies on MS patients, a link was found between lower age/shorter disease duration of MS and frequent headaches. A study of 50 patients manifesting MS for the first time showed the highest headache prevalence in MS of 78% reported so far.Headaches can also be a possible side effect of most disease-modifying MS drugs. In many cases, however, the headache appears to be a symptom of MS in terms of secondary headache. This is also supported by pathophysiological implications, for example, by detecting B cell follicles in the meninges of MS patients.Migraine is the most common type of headache in MS. In some cases, this is a comorbidity of two diseases with many similarities, but headaches caused by inflammatory MS lesions also appear to be phenomenologically very similar to classic migraines; thus, distinguishing between them is often only successful with the help of thorough differential diagnostics (cerebrospinal fluid, MRI etc.).The task of future studies must be to specify the phenomenology of headache in MS even more precisely, in order to, to gain knowledge in, among others, patients with radiologically isolated syndrome, who often suffer from headache, because in these patients a considerable differential diagnostic and therapeutic uncertainty exists.
Keywords: Calcitonin gene-related peptide; Clinically isolated syndrome; Migraine; Radiologically isolated syndrome; Secondary Headaches.