Neuromyelitis optica (NMO) is an inflammatory demyelinating disease (IDD) of the central nervous system (CNS) and probably the most common non-multiple sclerosis (MS) CNS IDD. Serum immunoglobulin G autoantibodies have been identified in the majority of NMO patients with the water channel aquaporin-4 (AQP4) as their main target autoantigen. Previous studies have suggested ethnicity-based prevalence differences of NMO. The genetic background for these putative differences is not known. An HLA-association with NMO has been identified, but the association is not very pronounced. Human and experimental studies support that anti-AQP4 antibodies/NMO-IgG are involved in the pathogenesis of NMO. Previous experimental animal models have reported induction of NMO-like histopathology in animals by transfer of human anti-AQP4 antibodies/NMO-IgG. A main goal of this PhD thesis was to perform a population-based study in a predominantly Caucasian population (in the Region of Southern Denmark) to estimate the incidence and prevalence of NMO and describe the clinical phenotypes in this population. Furthermore the aims were to investigate whether autoimmunity underlies or contributes to the pathogenesis of NMO with specific clinical, immunogenetic and experimental perspectives. The yearly incidence rate of NMO in the population was estimated to be 0.4 per 105 person-years (95% CI 0.30-0.54) and the prevalence was 4.4 per 105 (95% CI 3.1-5.7). The results indicated that NMO is more common in a Caucasian population than earlier believed. Clinical, radiologic and serological data were reviewed in order to establish the diagnostic accuracy of anti-AQP4 antibodies/NMO-IgG for specific syndromes in NMO. We observed assay characteristics with a sensitivity of 62% and a specificity of 100%. The diagnosis of NMO based on either the Wingerchuk 2006 criteria or the United States National Multiple Sclerosis Society 2008 criteria could be made purely on clinical grounds in a high proportion (64%) of cases. Heterogeneity of clinical NMO manifestations including optic neuritis, longitudinal extensive transverse myelitis (LETM) and brain lesions were observed. In the clinical immunogenetic study we observed that NMO patients had frequent co-existence of autoimmune disease and family occurrence of NMO and MS. The frequency of HLA-DQB1*0402 allele was increased in NMO and a significantly increased frequency of the PD-1.3A allele in the NMO patients was observed. The data suggest a possible genetic autoimmune dependency of NMO. In the experimental part a novel animal model for NMO was established, utilizing the minimally invasive intrathecal route for antibody administration that does not involve blood brain barrier disruption or pre-existing CNS inflammation. Human IgG from AQP-4 antibody-positive NMO patients (from the clinical study) were injected together with human complement to study the effects on CNS. NMO-like histological lesions were observed at topographically restricted sites at the ependyma and in the parenchyma of the brainstem, cerebellum and periventricular areas. The lesions were characterized by deposition of immunoglobulin and complement, loss of AQP-4 expression and loss of reactive astrocytes co-localizing with inflammatory cell infiltration. This pattern is similar to the characteristic histological and radiologic features of human NMO lesions. Taken together this PhD combined clinical, epidemiological, neuroimaging, genetic and immunological data, which contribute to the characterization of the natural course of the disease and understanding of the pathogenesis of NMO. Practical consequences may be earlier diagnosis of NMO and better distinction of NMO from MS and other IDDs, important due to differences in prognosis and therapy.