The definition of multiple sclerosis (MS) is based on a single principle: lesions in the central nervous system disseminated in time and space, subject to the caveat that the syndromes used to define the lesions are typical of MS as recognized by a health care professional familiar with that diagnosis. Although a series of iterations of these diagnostic criteria have succeeded one another, there has been no fundamental change in that overriding principle. Many neurological conditions, including metabolic, inflammatory, and vascular diseases, lead to multifocal and relapsing manifestations. Accordingly, and considering the nonspecific symptoms that may occur in MS, many diseases masquerade as and are misdiagnosed as MS. Even when “lesions” are restricted to syndromes characteristic of MS, such as optic neuritis and myelitis, their associated disease states may be more appropriately classified as idiopathic inflammatory demyelinating diseases distinct from MS.1 Such disorders include acute disseminated encephalomyelitis and the controversial entity of recurrent acute disseminated encephalomyelitis; tumefactive forms of MS, including Balo syndrome; Marburg variant of MS; and recurring disorders of restricted distribution, the prototype of which is neuromyelitis optica (NMO) but includes recurrent myelitis and recurrent optic neuritis. Although many health care professionals regard such disorders as distinct from MS, these disorders are not yet convincingly distinguished from MS based on either clinical criteria or biomarkers. Recently, a combination of clinical and radiological observations2,3 and a highly specific biomarker4 demonstrated that NMO is distinct from MS. Multiple sclerosis and NMO have overlapping manifestations but are distinguishable clinically, radiologically, prognostically,5- 7 pathologically,8 therapeutically,9 and by an IgG serum biomarker, NMO-IgG.4,10 Just as rheumatoid arthritis and lupus share clinical manifestations but are distinct, NMO and MS are distinct.