Chapter 26 - Neuromyelitis optica (Devic’s syndrome)

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Abstract

Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system that selectively targets the optic nerve and spinal cord, although it may also target certain areas of the brain. The majority of cases are associated with relapses. A specific biomarker, an autoantibody that targets aquaporin-4, is present in the majority of patients and facilitates the diagnosis. Detection of this biomarker in serum has enabled recognition of an expanded spectrum of clinical disorders that previously would not have met diagnostic criteria for NMO. Aquaporin-4 IgG1 autoantibodies are pathogenic and produce lesions of the brain when injected intracerebrally or systemically. The clinical course of NMO is dominated by acute attacks. Progressive worsening of disability, as occurs in prototypic multiple sclerosis, is distinctly unusual. Corticosteroids and plasma exchange are useful for management of acute attacks. Several treatments used to prevent attacks of multiple sclerosis are ineffective in this condition; effective immunotherapies include azathioprine, mycophenolate mofetil and rituximab.

Introduction

Neuromyelitis optica (NMO), also known as Devic’s syndrome or Devic’s disease, after the French physician who is most credited with bringing this entity to clinical attention, was first reported in the 19th century (Cree et al., 2002, de Seze, 2003, Wingerchuk and Weinshenker, 2003a). For the next hundred years, standard neurology references contained the oft-repeated definition of NMO as a severe, monophasic disorder simultaneously affecting the spinal cord and both optic nerves but sparing the remainder of the central nervous system (CNS). The position of NMO within the nosologic schema of CNS demyelinating diseases has been long debated (Cree et al., 2002, de Seze et al., 2003). Many investigators have considered it simply a severe variant of multiple sclerosis (MS), with a disproportionate burden of white-matter lesions affecting optic nerve and spinal cord; others have maintained that it represents a distinct disease (Wingerchuk and Weinshenker, 2003a). Some clinicians espouse an intermediate position, suggesting that NMO is a form of acute disseminated encephalomyelitis peculiarly restricted to expression in optic nerve and spinal cord (Modi et al., 2001). In this chapter, we review the features of NMO that distinguish it from typical forms of MS, and recent advances in immunology and immunopathology that further support the distinctness of NMO. These advances support the importance of antibodies in the pathogenesis of NMO and current beliefs that optimal treatment of NMO differs from that for MS.

Section snippets

History and nomenclature

Although Albutt’s (1870) account of a patient with a “sympathetic disorder of the eye” that came on “twelve or thirteen weeks at least” after an acute myelitis was often credited as the first description of a syndrome compatible with NMO, recent reports suggest case descriptions from the 19th century as early as 1804 (Albutt, 1870, Jarius and Wildemann, 2011, Jarius and Wildemann, 2012a, Jarius and Wildemann, 2012b). Erb, however, provided the first detailed description of NMO in 1880. He

Prevalence and incidence relative to MS

Studies of prevalence and incidence of NMO are difficult to interpret because of the evolving nature of diagnostic criteria, and the indistinct separation between “optic spinal” presentations of MS and NMO in published literature. Some patients with ON and myelitis episodes, even those without clinical or radiologic evidence for brain involvement, follow a typical course of MS in follow-up. Such patients usually have attacks of myelitis that are not accompanied by the relatively specific

Current diagnostic criteria

A variety of NMO definitions or diagnostic criteria have been put forth but the criteria that we proposed in 1999 based on a large retrospective case series were widely used until the discovery of NMO-IgG (Table 26.1). These criteria require both ON and myelitis and absence of clinical symptoms or signs implicating other CNS structures. Attainment of certain major or minor supportive criteria, including characteristics of the attacks (bilateral ON, attack severity and recovery), brain and

Natural history and prognosis

Once the “index events” of ON and myelitis have occurred, establishing a diagnosis of NMO, the disease may seemingly remit permanently (monophasic course) or additional relapses of ON or myelitis may occur (relapsing course) (Wingerchuk et al., 1999, Wingerchuk and Weinshenker, 2003b). It is difficult to be completely certain that the course is monophasic because NMO, like MS, can remit clinically for years, and occasionally decades, before attacks re-emerge. Over 80% of patients have relapsing

Pathology

Recent studies have reported a consistent set of distinctive findings that may permit a specific pathologic diagnosis when an adequate sample of active inflammatory tissue is examined, although the results are based on limited data. Several groups had described necrotic central spinal cord lesions, affecting gray and white matter with macrophage infiltration that ultimately result in atrophic, gliotic, and cavitary lesions in some cases (Cloys and Netsky, 1970, Mandler et al., 1993, Prineas and

Immunology

One or more organ-specific and nonspecific immunoglobulins are encountered in approximately 50% of patients with NMO, often in high titer; about 25% have clinical evidence of nonneurologic autoimmunity (Wingerchuk et al., 1999). However, the only autoantibody specific for NMO is one detected by Lennon and colleagues (2004), which has been called NMO-IgG. NMO-IgG was originally detected by immunofluorescence on a substrate of mouse tissues with a protocol used to test for organ-specific

Therapy

Interest in NMO is increasing but the relative rarity of the disorder in most developed world regions has hindered the development of concerted efforts to perform large-scale treatment trials. Recommendations for treatment of attacks and long-term therapy to prevent them rely entirely on case series and individual clinical experience (Wingerchuk and Weinshenker, 2008).

Future research directions

Future research will clarify the boundaries of NMO. NMO-IgG and its antigen target, AQP4, undoubtedly will be major clues to the pathogenesis of this condition. However, it remains to be established whether NMO-IgG is a marker of the disease or a pathogen. Preliminary evidence, outlined above, is compatible with its pathogenicity, but active immunization and passive transfer experiments, among other studies, will be required to confirm this hypothesis. If pathogenic, it will be necessary to

Conclusion

A growing body of clinical, neuroimaging, immunologic, and immunopathologic evidence demonstrates that NMO is a distinct disease. The NMO disease spectrum has widened to encompass as many as half of patients previously diagnosed with “idiopathic recurrent transverse myelitis,” most patients with Japanese opticospinal MS, and some patients with silent or clinically manifest brain and brainstem lesions. The combination of a longitudinally extensive spinal cord lesion and normal or nonspecific

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