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Copyright ? 2012 Jiwon Oh and Michael Levy. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Neuromyelitis optica (NMO) is a recurrent inflammatory disease that preferentially targets the optic nerves and spinal cord leading to blindness and paralysis. The hallmarks of NMO include bilateral optic neuritis and longitudinally extensive transverse myelitis. Woman and African Americans are overrepresented in the US patient population. NMO is associated with the NMO-IgG biomarker, which targets the aquaporin-4 water channel on astrocytes. The humoral pathology of NMO lesions include IgG and IgM deposits and infiltration by granulocytes suggesting that the NMO-IgG may be involved in the pathogenesis of disease. This review of the recent NMO literature covers the clinical features, epidemiology, radiology and pathology of disease and includes discussion of the important basic science research work in the field.

1. Introduction

Neuromyelitis optica (NMO) is an autoimmune inflammatory disorder of the central nervous system that predominately affects the optic nerves and spinal cord.

In 1870, Allbutt was the first to report a case of NMO [1], but it was Devic who described the disorder in detail, and summarized 16 cases in the existing literature in 1894 [2]. Based on this initial description, historically, NMO has been regarded as a severe, generally monophasic disorder of the optic nerves and spinal cord and was thought to be a variant of multiple sclerosis (MS). A convincing body of evidence in the past decade has established NMO as a distinct disease entity from MS. NMO is now recognized as a recurrent disease that largely targets the spinal cord and optic nerves but can also affect the brain as well. NMO occupies a unique position in the spectrum of inflammatory central nervous system demyelinating disorders in that it is the only such disorder that has an associated disease-specific antibody, aquaporin-4 antibody (AQP4 Ab), or NMO-IgG. Recognition of this antibody has been instrumental in elucidating the underlying pathobiology and in guiding treatment options for NMO.

2. Clinical Features

The clinical hallmarks of NMO are acute optic neuritis that is often bilateral and transverse myelitis that is often longitudinally extensive. Commonly reported symptoms include unilateral and bilateral loss of visual acuity, ocular pain, severe paraplegia, a symmetric sensory level, bladder dysfunction, paroxysmal tonic spasms of the trunk and limbs, and Lhermitte’s phenomenon [3, 4]. Rostral extension of cervical cord lesions into the cervicomedullary junction can cause symptoms such as acute respiratory decompensation, nausea, intractable vomiting, and hiccups. These symptoms can precede or occur in association with the more typical features of optic neuritis or transverse myelitis [3, 5–7].

Clinical features attributable to locations outside of the optic nerves and spinal cord can also occur in patients with NMO. Hypothalamic-pituitary axis dysfunction can manifest as hypersomnolence, hyponatremia, hypothermia, hypothyroidism, and hyperprolactinemia [8]. In addition, confusion, abrupt changes in level of consciousness, cortical blindness, and imaging findings suggestive of posterior reversible encephalopathy syndrome (PRES) have also been reported [9].

The clinical course of NMO historically took one of two forms: monophasic or relapsing, with relapsing forms comprising approximately 80–90% of cases. However, after an index event, the distinction between monophasic and relapsing NMO is often difficult to make since relapses can occur many years after an event. In the vast majority of cases (~80%), a relapse occurs by 2-3 years after the index event [3, 10]. Clinical features that may predict a relapsing course of disease include older age, female gender, less severe motor impairment with the initial myelitis event, and evidence of systemic autoimmunity [3].

Clinical attacks typically progress over days, with varying degrees of recovery seen in the ensuing weeks to months. Recovery is usually incomplete, and most patients sustain residual disability, which increases with subsequent attacks [3]. Factors predictive of mortality in patients with relapsing NMO include the presence of other systemic autoimmune disorders, higher attack frequency in the first two years, and poor motor recovery following the index myelitis event [10, 11]. Longitudinal case series of NMO patents with follow-up ranging from 5 to 10 years have demonstrated that the majority of patients (47–100%) have significant ambulatory difficulties at follow-up. Residual visual deficits are also common, with >60% of patients reporting significant vision loss in at least one eye. Mortality due to respiratory failure has been reported to take place in up to 32% of patients [12, 13]. Of note, this mortality figure was derived from the original Mayo Clinic study [3], which took place prior to the widespread recognition of NMO and NMOSDs, and the patient population may have been biased with respect to clinical disease severity. Therefore, the prognosis of NMO may not be as grave as was reported in these earlier studies.

In 1999, Wingerchuk et al. proposed diagnostic criteria for NMO which were based on clinical and radiographic features [3]. With the discovery of AQP4-Ab, these criteria were revised in 2006 to include the testing of this disease-specific antibody. In addition, the necessary clinical features included were modified and simplified in an attempt to improve the diagnostic properties of the criteria. At present, the 2006 proposed diagnostic criteria for NMO consist of the presence of optic neuritis and transverse myelitis as well as 2 out of 3 of a contiguous spinal cord MRI lesion extending over more than 3 vertebral segments (i.e., longitudinally extensive), brain MRI not meeting diagnostic criteria for MS, and NMO-IgG seropositive status [14]. These criteria are 99% sensitive and 90% specific for the diagnosis of NMO and have been independently validated in different patient populations [15].

The recent literature suggests that in addition to its utility in the diagnosis of NMO, the presence of NMO-IgG may have a role in disease prognosis. In a prospective study of patients with longitudinally extensive transverse myelitis (LETM), 55% of those positive for NMO-IgG relapsed with recurrent LETM or optic neuritis, while none of the seronegative patients relapsed [4]. Similarly, in a series of patients with recurrent optic neuritis, the presence of NMO-IgG heralded a 50% chance of developing transverse myelitis [16], while only 6.6% of seronegative patients developed transverse myelitis. More recently, Jarius et al. found that in acute monosymptomatic optic neuritis, 50% of NMO-IgG seropositive patients progressed to NMO within 12 months, while none of the seronegative patients progressed after a median follow-up of 26 months [17].

In light of the fact that NMO is a disorder that has the potential to cause significant disability, the ability to recognize and differentiate NMO and related disorders from other demyelinating disorders is important from a clinical perspective. The term “NMO spectrum disorders” has been coined to reflect a variety of disorders thought to be related to NMO but do not quite meet the clinical diagnostic criteria for definite NMO. Disorders that are typically included in this classification are NMO-IgG seropositive limited forms of NMO (single or recurrent LETM, recurrent or simultaneous bilateral ON), Asian opticospinal MS (OSMS), optic neuritis or LETM associated with systemic autoimmune disease, and optic neuritis or myelitis associated with brain lesions typical of NMO (e.g., hypothalamic or brainstem lesions) [12]. Whether the NMO-IgG seronegative forms of these disorders are a forme fruste of classic NMO or whether they are variants of other autoimmune diseases is, at present, unclear. Until we are able to better identify with certainty that these are distinct disorders, the designation of NMO spectrum disorders is useful, as it has specific prognostic and therapeutic implications for these potentially related disorders.

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