Neuromyelitis optica spectrum disorders with and without aquaporin 4 antibody: Characterization, differential diagnosis, and recent advances

Abstract

Importance: The term neuromyelitis optica spectrum disorders (NMOSD) currently includes neuromyelitis optica (NMO) and rare neurological disorders characterized by specific IgG autoantibodies directed against aquaporin 4 (AQP4); from a clinical perspective, optic nerves and spinal cord are the usual target tissues. The discovery and characterization of AQP4-IgG has revolutionized the diagnosis of NMOSD and can be used to predict relapses. Similarities with multiple sclerosis (MS) include immune-mediated demyelination and axonal damage but unlike MS, identification of AQP4 Ab positive and seronegative NMOSD (also called anti-MOG-Ab positive) have revolutionized the diagnosis of NMOSD leading to early diagnosis and therapeutic options. Similar to MS, the clinical presentation in NMOSD can have a relapsing-remitting disease course but some patients with NMOSD tend to run a more aggressive disease course. It is important to recognize that, despite the development of tests to identify specific autoantibodies, the diagnosis of NMOSD can be challenging and often missed, leading to delay in treatment options, particularly in the cohort of patients who do not have AQP4-IgG antibodies in serum (seronegative NMOSD). One cardinal difference in therapeutic options between NMOSD and MS is that there are no FDA-approved therapeutic interventions for NMOSD. Objectives: The aim of this study is to review recent changes in diagnostic criteria of NMOSD and outline challenges in characterizing patients with seronegative NMOSD. Findings: Depending on the assays used and the cohorts studied, 10% to 50% of NMOSD patients are AQP4-negative which can be challenging for the clinician treating the disease. Furthermore, identification of seronegative NMOSD or anti-MOG antibody positive patient cohorts can be difficult since antibody testing is available only in Japan and UK. Conclusions: The diagnostic criteria for NMOSD continue to evolve in this rapidly developing field. Concurrent diagnosis of systemic lupus erythematosus, Sjögren’s syndrome or myasthenia gravis increase the likelihood of diagnosis of NMOSD. As compared to the AQP4-IgG positive group, MOG-Ab positive patients with NMOSD or seronegative NMOSD have distinguishing characteristics that be exploited for early treatment. Recent breakthroughs, including the discovery of Fc receptor polymorphism, will likely aid in the medical management of NMOSD patients. Patients with clinical presentation with at least one core ‘syndrome’ should be evaluated for possible NMOSD. Some of these are seen in MS, such as optic neuritis and acute myelitis. Others include area postrema syndrome (APS) which presents with intractable nausea and vomiting, or hiccups, acute brainstem syndrome or symptomatic narcolepsy. As always, alternate diagnoses such as MS, sarcoidosis, malignancy, paraneoplasia, and infective etiologies affecting the brain should be sought and excluded.