Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved. C URRENT O PINION Vaccine-associated inflammatory diseases of the central nervous system: from signals to causation Xuan-Hung Nguyen a,b,c , Abdelhadi Saoudi a,b,c , and Roland S. Liblau a,b,c,d Purpose of review As the most cost-effective intervention in preventive medicine and as a crucial element of any public health program, vaccination is used extensively with over 90% coverage in many countries. As approximately 5–8% of the population in developed countries suffer from an autoimmune disorder, people with an autoimmune disease are most likely to be exposed to some vaccines before or after the disease onset. In fact, a number of inflammatory disorders of the central nervous system have been associated with the administration of various vaccines. These adverse events, be they spurious associations or genuine reactions to the vaccine, may lead to difficulties in obtaining public trust in mass vaccination programs. There is, thus, an urgent need to understand whether vaccination triggers or enhances autoimmune responses. Recent findings By reviewing vaccine-associated inflammatory diseases of the central nervous system, this study describes the current knowledge on whether the safety signal was coincidental, as in the case of multiple sclerosis with several vaccines, or truly reflected a causal link, as in narcolepsy with cataplexy following pandemic H1N1 influenza virus vaccination. Summary The lessons learnt emphasize a central role of thorough, ideally prospective, epidemiological studies followed, if the signal is deemed plausible or real, by immunological investigations. Keywords autoimmunity, central nervous system, multiple sclerosis, narcolepsy, vaccination INTRODUCTION Vaccination may be followed by central neurologi- cal manifestations, giving rise to safety signals. Regardless of whether these signals reflect a causal link or are coincidental associations, they have the potential to undermine the public confidence in vaccines as a whole. It is, therefore, crucial to understand whether an association between a given vaccine and a given central nervous system (CNS) autoimmune disease is a ‘chance’ observation or reveals a causal link, which needs to be further explored. Here, based on the basic principles of vaccination, we analyze two very distinct situations. In the first one, the claimed associations of two vaccines with onset of multiple sclerosis (MS) were not confirmed by large-scale epidemiological stud- ies. In the second one, a vaccine, namely Pandemrix, was convincingly associated with onset of narco- lepsy with cataplexy, providing a unique window into the immunopathogenesis of this rare disease. Further immunological studies should therefore be performed to understand the mechanisms under- lying such an association and, thereby, hopefully increase vaccine safety. IMMUNOLOGICAL PRINCIPLES OF VACCINATION Human beings are exposed to a great variety of infectious agents, which can cause disease or be lethal if they multiply in uncontrolled manner. Thanks to the immune system, most infections in healthy individuals are short-lived leaving little a INSERM, U1043, b CNRS, U5282, c Centre de Physiopathologie Tou- louse-Purpan (CPTP), Universite ´ de Toulouse and d De ´ partement d’Immu- nologie, Ho ˆpital Purpan, CHU Toulouse, Toulouse, France Correspondence to Professor Roland S. Liblau, MD, PhD, INSERM UMR1043-CNRS U5282, Ho ˆ pital Purpan, BP 3028, 31024 Toulouse, France. E-mail: roland.liblau@inserm.fr Curr Opin Neurol 2016, 29:362–371 DOI:10.1097/WCO.0000000000000318 www.co-neurology.com Volume 29  Number 3  June 2016 REVIEW