A clinical/immunological neuromyelitis optica association study

Neuromyelitis optica (NMO) and NMO spectrum disorders (NMOSD) are associated with the disease-specific autoantibody aquaporin-4 (AQP4-Ab), which is thought to be pathogenic. Some NMO/NMOSD patients do not have this antibody and may have different clinical and immuno-pathological disease characteristics, but previous clinical NMO/NMOSD studies have been confounded by inclusion of such patients. To define better the characteristics of AQP4-Ab disease, disease course, outcomes and predictors of disability were investigated in 106 AQP4-Ab positive NMO/NMOSD patients from the UK and Japan. AQP4-Ab positivity conferred a high risk of relapsing disease and substantial disability; age at disease onset and ethnicity were important predictors of disability type. Visual disability was more common in younger patients and those of Afro-Caribbean ethnicity whilst older patients and Caucasian patients were more at risk of motor disability. To determine whether disease characteristics were influenced by AQP4-Ab binding specificities, the differential binding of patient AQP4-Ab against the two main AQP4 isoforms was investigated. Although the relative binding to the two isoforms differed between patients, there was no association between these differences and clinical features such as relapse type, severity, onset age and ethnicity. The clinical and in vitro characteristics of AQP4-Ab negative NMO/NMOSD patients were studied. It was shown that these patients represent an aetiologically heterogeneous group. Some have other inflammatory and infectious disorders, some have low levels of AQP4-Ab and a significant proportion have antibodies to myelin oligodendrocyte glycoprotein (MOG-Ab). Others have antibodies that bind to neurons or oligodendrocytes in primary cultures. Attempts to identify novel antigens by immunocapture techniques were made, but were not successful. Patients with MOG-Ab showed differences when compared to those with AQP4-Ab including higher proportion of males, younger age at disease onset and greater likelihood of conus involvement on imaging. Additionally, patients with MOG-Ab appear to have more favourable outcomes, with better improvement from the onset attack and a lower probability of subsequent relapses. In conclusion, the work in this thesis has shown that AQP4-Ab disease is not synonymous with the term NMO and that seronegative NMO/NMOSD patients represent a clinically and aetiologically heterogeneous group and should therefore be classed separately from those with AQP4-Ab.This thesis is not currently available in ORA