Thus, it can be assumed that the rate of misdiagnoses may have dropped and that more patients are diagnosed and treated earlier. Moreover, treatment options have improved. Nevertheless, NMO remains a potentially life-threatening and severely disabling condition that usually requires prompt and consequent immunosuppressive treatment. Clinical decision-making see more with respect to diagnosis and treatment initiation remains challenging when a patient presents with ON or myelitis only, or with other clinical symptoms, such as brainstem encephalitis with intractable

hiccups and vomiting or a syndrome of inappropriate anti-diuretic hormone secretion [1, 46-50]. In such cases, testing

for AQP4-antibody by means of a both highly sensitive and highly specific assay can be essential [51]. Other symptoms and syndromes that have occasionally been reported in association with AQP4 autoimmunity include seizures [52], posterior reversible encephalopathy syndrome [53], myeloradiculitis [54], meningoencephalitis [55], findings related to brainstem involvement, Protein Tyrosine Kinase inhibitor such as hearing loss, diplopia, olfactory dysfunction and other cranial nerve palsies, or endocrinological abnormalities due to diencephalic lesions [1, 56-58]. Moreover, pain syndromes [1, 59, 60] and cognitive dysfunction [61-63] seem to develop more

frequently than appreciated previously. In contrast to MS, a higher filipin proportion of NMO patients (30–50%) exhibit laboratory findings or clinical signs of other systemic or organ-specific autoimmunity, such as systemic lupus erythematosus, Sjögren’s syndrome, autoimmune thyroid disease, myasthenia gravis or, possibly, autoimmune-mediated vitamin B12 deficiency [64-74]. The invariable association with myelitis and/or ON suggests that AQP4 antibodies in patients with rheumatic diseases do not represent an unspecific epiphenomenon, but rather points to the existence of two concomitant autoimmune conditions. Two studies found an increase in relapse rate in the first or the first and second trimenon, respectively, after delivery [75, 76]. Preliminary data suggest that AQP4-antibodies might also be capable of causing damage in AQP4-expressing organs and tissues outside the CNS (e.g. placentitis with the risk of miscarriage [77-79], myositis [80-83], internal otitis [56] or gastritis [74]). In 2006, the diagnostic criteria for NMO were revised after NMO-IgG were detected. In addition to including this novel and highly specific marker, the absolute restriction of CNS involvement beyond the optic nerves and spinal cord was removed and the specificity of longitudinally extensive spinal cord lesions emphasized [84, 85].