Spectrum Library

1. Introduction

Neuromyelitis optica (NMO), also known as Devic’s disease, is a chronic inflammatory disease of the central nervous system (CNS) that preferentially targets the optic nerves and spinal cord [1]. The overall disease incidence has been estimated at 1:100,000 and that it has a predilection for middle-aged, non-Caucasian females [2]. NMO spectrum disorders (NMOSD) encompass a variation of this classical picture in that patients may have brain involvement or a more limited presentation such as isolated transverse myelitis or an optic neuritis [3]. Historically, many thought of NMO as a rare variant of multiple sclerosis (MS). Given the identification of unique clinical and radiological differences and the discovery of the NMO-IgG, an autoantibody against aquaporin-4 (aqp4), it is now understood to be its own entity with distinct pathogenesis, diagnostic criteria, prognosis, and treatment [1–5].

Until recently, NMO was considered a disease of limited therapeutic options and poor prognosis. Research over the last decade brought new understanding of the disease pathogenesis that translated into immunotherapy directed against this disease. Moreover, there is a growing body of evidence that NMO can be controlled by immunotherapeutics targeting its cellular and humoral immune mechanisms. We review the immunotherapy of NMO, the various treatment options, and the clinical strategies that are typically encountered in practice.

2. Neuromyelitis Optica: An Overview

NMO is a neurological disorder that classically presents as a case of severe bilateral optic neuritis associated with a transverse myelitis [1–5]. The typical disease onset is either acute or subacute, and the symptoms are likely to persist without treatment. Optic neuritis results in decreased or a complete loss of vision. Transverse myelitis is usually extensive and spans more than 3 consecutive vertebral segments. Deficits related to myelitis include paralysis and sensory loss below the lesion level along with gait impairment. Additional complications may include phrenic nerve paralysis, loss of sphincter control, dysautonomia, and painful tonic spasms. Brainstem (medulla oblongata and area postrema) can be involved at times with resultant persistent nausea and hiccups [6].

Magnetic resonance imaging (MRI) is used for diagnosis and monitoring of the disease [1, 4]. Optic nerve and spinal cord lesions appear as hyperintense on T2- and hypointense on T1-weighted images and enhance with gadolinium when they are inflamed. In the acute phase, the inflamed lesions also enlarge in size secondary to tissue edema. Inflammation may persist for months and result in tissue atrophy [7]. MRI lesions involving the brainstem, hypothalamus, and periventricular white matter may be seen in typical NMOSD and sometimes late in the disease course of NMO [1–3]. Independent of imaging, visual evoked potentials and CSF studies can be helpful in establishing the diagnosis [4, 8]. Optic coherence tomography (OCT) may also be used to monitor the extent and the degree of progression of optic neuropathy [9].

NMO follows a relapsing-remitting clinical course in 70–90% of all patients [2]. Such a clinical course is correlated with female gender, older age of disease onset, longer (>3 months) optic neuritis-myelitis interval, and presence of systemic autoimmunity [2, 3]. Seropositivity for anti-aqp4 antibody is also a strong predictor for future disease relapses [10]. A monophasic clinical course tends to occur in young males. Neurological disability in relapsing-remitting disease appears to be a cumulative result of disease relapses [2]. After five years, approximately 50% of affected individuals have significant visual or motor impairment and require assistive devices for ambulation [2]. This time frame of five years is also notable for a mortality rate of 32% with the relapsing-remitting disease and 10% with the monophasic disease. Most patients expire from disease complications such as respiratory failure, urosepsis, and pulmonary embolism [2–4].

The etiology of NMO is unknown but it is believed to be an autoimmune disorder triggered by an environmental factor, possibly an infection, in genetically susceptible individuals [11–13]. The principal effector in NMO is the self-reactive, complement-activating anti-aqp4 antibody [14]. Aqp4 is a transmembrane protein that regulates the flow of water in cells. It is expressed by CNS astrocytes and astrocytic processes surrounding small blood vessels at the glia limitans [15]. The autoantibody has the capacity to bind to aqp4 on the astrocytic foot processes and then recruit and activate complement. This leads to the mobilization of polymorphonuclear cells (neutrophils and eosinophils), inflammation, and tissue swelling [16, 17].

Recent studies indicate that Th17 cells (a T cell subset producing interleukin 17) specific to aqp4 may also be involved in the disease pathogenesis [18]. They are implicated in the breakdown of the blood-brain barrier allowing extravasation of anti-aqp4 antibody and complement, along with recruitment of polymorphonuclear cells to the lesion sites. Pathologically, NMO lesions involve both the white and gray matter. They contain perivascular deposits of immune complexes, activated complement, and inflammatory cellular infiltrates [19]. The cellular infiltrates are composed of mononuclear and polymorphonuclear cells. Astrocytes targeted by the autoimmune response display cytopathic changes and downregulate the expression of aqp4 in a vasculocentric pattern [20]. Vascular hyalinization, tissue necrosis, demyelination, and gliosis commonly accompany the inflammatory process [18–22].

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