AQP4 and neuromyelitis optica: However, the lack of AQP4-IgG-seropositivity in a subset of patients even in the most up-to-date, recombinant assays, and in particular the demonstration of such a lack in some patients with NMO and conditions that may cause myelitis and optic neuritis by other mechanisms, e.g. connective tissue disorders [72], paraneoplastic disorders [88,89], or infectious diseases [90], has provided strong evidence in favour of the hypothesis of NMO being aetiopathogenetically heterogeneous.