Illuminating neuromyelitis optica pathogenesis.

W hat is the most important moment in the history of a disease? Let us consider neuromyelitis optica (NMO), which was coined by French neurologist Eugene Devic in 1894 for a disease believed until recently to be a subtype of multiple sclerosis (MS). The discovery (in 2004) of a disease-specific biomarker for NMO revolutionized our understanding of both NMO and MS (1). In PNAS, Hinson et al. (2), including Lennon, who discovered the biomarker, address mechanisms of pathogenesis mediated by that same biomarker. NMO and MS, clinically characterized by the French neurologist Jean-Martin Charcot in 1868, have long been intertwined (3). NMO and MS are both inflammatory diseases of the CNS. MS, the prototypic demyelinating disease, causes selective destruction of CNS myelin, a fatty membrane that nourishes and insulates nerve fibers. Early symptoms of MS arise because demyelinated nerve fibers conduct impulses poorly, and later symptoms may involve degeneration of nerve fibers deprived of myelin’s metabolic support. NMO seemed to be more destructive than MS, and it remained unclear whether selective demyelination could be seen. However, clinical similarities were striking: both MS and NMO showed onset around 30–40 y, and women were more proportionally affected than men. Both exhibited years of clinical quiescence punctuated by abrupt attacks of neurological symptoms that variably receded after weeks to months. Both typically impaired vision and walking among other functions. NMO, 10-fold less common than MS in North America and Western Europe, was, therefore, considered a subtype of MS. There were differences: the eponymic effects of NMO seemed focused specifically on optic nerves and spinal cord, whereas MS was less commonly fatal and showed more widely distributed symptoms. Among susceptible, largely Caucasian populations, MS cases are concentrated in temperate zones of both hemispheres. Worldwide, about 2 million people are affected by MS. Western NMO research has lagged behind MS studies, whereas Asian research on NMO, previously termed opticospinal MS, was vigorous but suffered from the relatively low disease prevalence. With recognition that NMO, unlike MS, occurs equally in all ethnic groups and climates, it seems likely that the global case burden of NMO may approach one-quarter to one-half the case burden of MS, albeit much more widely dispersed (4). NMO, previously thought a rare disease, is now considered a legitimate target for drug development.