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Neuromyelitis optica (NMO) is an inflammatory disorder of the central nervous system (CNS) that predominantly affects the optic nerves and spinal cord.
Although it has been initially considered to be a severe variant of multiple sclerosis (MS), the finding that most NMO patients have autoantibodies against aquaporin-4 (AQP4) has improved our knowledge of its pathogenesis and led to the concept that NMO is a disease distinct from MS. The antibody is pathogenic and its seropositivity allows for early and accurate diagnosis even in the absence of cardinal findings of optic neuritis and myelitis. NMO is now considered as an anti-AQP4 antibody-mediated astrocytopathy, and different from a demyelinating disorder as is MS.
The identification of this specific biomarker was a breakthrough in NMO research and prompted a revision of the NMO diagnostic criteria in 2006 (Wingerchuk et al., 2006). The specificity of AQP4-IgG facilitated observations that the clinical and neuroimaging spectrum of NMO was even broader than previously recognized. In 2007, the term NMO spectrum disorders (NMOSD) (Wingerchuk et al., 2007) was introduced to include AQP4-IgG seropositive patients with single or recurrent events of longitudinally extensive myelitis and recurrent or simultaneous bilateral optic neuritis. It also included patients with concomitant systemic autoimmunity, such as systemic lupus erythematosus or Sjögren syndrome.
It is important to note that brain lesions in NMO and NMOSD are not uncommon, do not rule out the diagnosis, and show characteristic patterns. Although 2006 NMO diagnostic criteria required optic nerve and spinal cord involvement, more restricted or more extensive CNS involvement may occur. Recent studies have demonstrated that a significant proportion of AQP4 antibody–positive patients did not meet 2006 NMO/NMOSD criteria (Sato et al., 2013), including: short-segment transverse myelitis, monophasic unilateral optic neuritis with severe visual impairment, and brainstem syndromes with persisting hiccups, nausea or vomiting episodes. Accordingly, an International Panel for NMO Diagnosis (IPND) has been working to develop revised diagnostic criteria using systematic literature reviews.
Approximately 90% of adult patients with NMO are positive for autoantibodies against AQP4. Therefore, a proportion of patients with a clinical NMO or NMOSD phenotype remains AQP4 antibody-seronegative, despite the use of the best assays available on serum samples collected during an acute attack before any treatment.
Recently, autoantibodies against myelin oligodendrocyte glycoprotein (MOG) were reported in patients who were clinically diagnosed with NMOSD and negative for AQP4 antibodies. Compared with patients with AQP4 antibodies, adult individuals with MOG antibodies were more frequently male, had a more restricted phenotype, more frequently had bilateral simultaneous optic neuritis, more often had a single attack, had lesions involving the lower portion of the spinal cord, and usually demonstrated better recovery after an attack. MOG-autoantibodies are relatively more common in pediatric inflammatory and demyelinating syndromes compared to adults, especially in children with ADEM, MS, and the NMOSD phenotype. (Sato et al., 2014; Weinshenker & Wingerchuk, 2014; Miyauchi et al., 2014; Kitley et al., 2014; Rostasy et al., 2013)
Although the brain is widely recognized to be relatively spared in NMOSD, most studies using advanced neuroimaging techniques have found abnormalities in normal-appearing gray matter (NAGM) as well as normal findings or minimal changes in normal-appearing white matter. These findings suggest selective or more severe damage of gray matter, which is a site of high AQP4 expression. Cognitive impairment in patients with NMOSD has been recently reported even in the limited forms of the disease. Published data also describe the pathological processes consisting of inflammatory events with a pattern-specific loss of AQP4 immunoreactivity, cortical neurodegeneration, with no evidence of cortical demyelination (Saji et al., 2013; Lucchinetti et al., 2014).
Treatment of NMO/NMOSD includes both the management of acute attacks and the prevention of future exacerbations. The goal of acute therapy is to minimize irreversible damage and accelerate recovery. Plasmapheresis following IV methyl-prednisolone effectively removed anti-AQP4 anti¬bodies and was accompanied by a substantial improvement in the neurological disability of patients with NMOSD according to recently published studies. (Kimbrough et al., 2012; Kim et al., 2013; Tenembaum et al., 2013; Kowarik et al., 2014; Morgan et al., 2014)
Preventative therapy should lower the frequency and severity of future relapses, and has focused on a range of immunosuppressive medications, none of which have been validated in a rigorous randomized trial. However, multiple retrospective and a few recent prospective studies have provided evidence for the use of six medications for the prevention of NMO relapses: azathioprine, rituximab, mycophenolate mofetil, prednisone, methotrexate, and mitoxantrone.
In general it is recommended to start with one of the following four first-line options: azathioprine, mycophenolate mofetil, rituximab, or prednisone. Cost, availability, patient choice, route of administration, side effects, and the prescribing physician's familiarity with the specific agent will also influence the treatment decision.
