Frequency and prognostic impact of antibodies to aquaporin-4 in patients with optic neuritis

Abstract

Background

Antibodies to aquaporin-4 (AQP4-Ab) are found in 60–80% of patients with neuromyelitis optica (NMO), a severely disabling inflammatory CNS disorder of putative autoimmune aetiology, which predominantly affects the optic nerves and spinal cord.

Objective

To assess the frequency of AQP4-Ab in patients with optic neuritis (ON), and to investigate the prognostic implications of AQP4-Ab seropositivity in such patients.

Patients and methods

AQP4-Ab serum levels were determined in 224 individuals from Austria, Denmark, France, Germany, Italy, and Turkey using a newly developed fluorescence immunoprecipitation assay employing recombinant human AQP4.

Results

AQP4-Ab were detectable in 8/139 (5.8%) patients with acute monosymptomatic optic neuritis (AMON) and in 10/17 (58.8%) patients with established NMO and a last relapse of acute ON (NMO/ON), but not in 32 patients with multiple sclerosis or in 36 healthy controls. At last examination, 4/8 (50%) seropositive AMON patients had met the criteria for NMO but 0/128 seronegative AMON patients. Disease severity differed significantly between seropositive and seronegative AMON. Complete bilateral or unilateral blindness occurred in six AQP4-Ab positive patients, but only in one AQP4-Ab negative patient. AQP4-Ab levels did not vary between seropositive AMON and NMO/ON and did not correlate with disease severity. Female gender, a relapsing course, and concomitant autoimmunity were associated with AQP4-Ab seropositive status and risk of developing NMO.

Conclusion

AQP4-Ab is relatively rare among patients with AMON, but if present it predicts a high rate of conversion to NMO within one year.

Introduction

Optic neuritis (ON) in the absence of other signs of CNS inflammation poses substantial diagnostic challenges to neurologists and ophthalmologists. In some cases, the condition has to be considered as a first manifestation of MS [1], but numerous other autoimmune, rheumatologic, and infectious diseases have to be ruled out. However, despite broad differential diagnostic considerations, the aetiology of ON remains elusive in many cases at first presentation [1]. Recently, however, a new serum reactivity staining structure adjacent to CNS microvessels and pia mater (called NMO-IgG) was detected in some patients with ON [2], [3]. Subsequently, the antibody was shown to bind to aquaporin-4, the most abundant water channel in the CNS [4], [5]. Aquaporin-4 antibody (AQP4-Ab) positive ON is now thought to belong to the broadening spectrum of Devic's disease, which also includes AQP4-Ab positive cases of neuromyelitis optica (NMO), Asian optico-spinal MS (OSMS), longitudinally extensive transverse myelitis (LETM), and brain stem encephalitis [6]. There is increasing evidence from immunological and histopathological studies that AQP4-Ab is directly involved in the pathogenesis of these conditions [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17]. Detection of AQP4-Ab could therefore help to identify patients who are eligible for antibody-targeted immunotherapies such as B cell depletion or plasma exchange.

Previous studies used immunohistochemical assays (IHC) to assess the frequency of NMO-IgG antibodies in patients with ON [18], [19]. However, IHC assays may not be sufficiently sensitive and specific when compared to recombinant, AQP4-specific tests [9], [20], [21]. Moreover, results from IHC assays are observer-dependent and non-quantitative. We recently developed a fluorescence based immunoprecipitation assay (FIPA), which employs both isoforms of human AQP4 as substrate [9]. Using this semi-quantitative assay, we assessed for the first time the frequency of AQP4-Ab in a large series of unselected patients with ON from various European countries, and investigated whether AQP4-Ab positivity in patients with ON predicts visual outcome and subsequent conversion to NMO.