Aquaporin-4 IgG: Overview and future perspectives

ABSTRACT

The discovery of aquaporin-4 IgG in patients with demyelination is an exciting development. Initially associated with the Devic’s phenotype, aquaporin-4 IgG has also been consistently found albeit less frequently in tumefactive disease, encephalopathies, classical MS and by one group in GBS. Curiously the cerebellum has the highest concentration of the target antigen, but remains the only part of the nervous system yet to demonstrate “characteristic lesions” with aquaporin-4 IgG. Moreover there is tantalising evidence that seropositivity is influenced by age, sex, and ancestral immunogenetic haplotypes. There is no exclusive clinical or radiological feature of seropositivity, and prospective cohorts universally find transitional cases. The use of teleological definitions is unhelpful and unscientific. Older detailed pathological studies have documented changes of both neuromyelitis optica and multiple sclerosis in the same individual, with both necrotising and classical lesions. Any hypothesis must accommodate the above observations, amongst other problematic findings. A logical initial conclusion is that demyelinating disease is a complex and extraordinarily heterogeneous process, and that aquaporin-4 IgG provides a new window into the disease. Crucially, the diagnostic and therapeutic implications of aquaporin-4 IgG can only be ascertained with evidence from rigorous prospective clinical study in different immunogenetic populations, and further pathological investigations are necessary.