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Neuromyelitis Optica: Immunopathogenesis, Clinical Manifestations, and Treatments

Shin C. Beh, Teresa C. Frohman, and Elliot M. Frohman

Neuromyelitis optica (NMO) is an autoimmune inflammatory disease of the central nervous system (CNS), typically characterized by severe recurrent attacks of acute optic neuritis (AON) and transverse myelitis (TM). The initial description of the disease we recognize today as NMO was attributed to Eugene Devic (hence the eponymous term Devic’s disease) and Ferdinand Gault in the nineteenth century, although numerous antecedent case reports that underscore highly reminiscent facets of this disorder strongly suggest that Devic and colleagues were not in fact the first to have codified the highly conspicuous and typically catastrophically disabling syndrome that characterizes this disorder [1].


Although initially thought to be a severe variant of multiple sclerosis (MS), the discovery of complement-fixing antibodies directed against aquaporin-4 (AQP4), also referred to as NMO-IgG, proved that NMO was a distinct disease entity [2-6].

S. C. Beh, MD (*)

Department of Neurology and Neurotherapeutics, Multiple Sclerosis & Neuroimmunology Program, University of Texas Southwestern School of Medicine,

5323 Harry Hines Blvd, Dallas, TX 75390, USA e-mail: This email address is being protected from spam bots, you need Javascript enabled to view it

T. C. Frohman, PA-C

Department of Neurology and Neurotherapeutics, University of Texas Southwestern School of Medicine, Dallas, TX, USA

E.M. Frohman, MD, PhD

Department of Neurology and Neurotherapeutics, University of Texas Southwestern School of Medicine, Dallas, TX, USA

Department of Ophthalmology, University of Texas Southwestern School of Medicine,

Dallas, TX, USA

© Springer International Publishing AG 2017 187

A. Minagar, J.S. Alexander (eds.), Inflammatory Disorders of the Nervous System, Current Clinical Neurology, DOI 10.1007/978-3-319-51220-4_9

AQP4 is the most abundant water channel in the CNS and is predominantly located on astrocytic foot processes that form the glia limitans of the blood-brain barrier (BBB), ependyma, and around the synapses at the nodes of Ranvier [7]. Corresponding with the usual distribution of lesions in NMO, AQP4 is concentrated in the hypothalamus, diencephalon, brainstem (particularly within the floor of the IV ventricular tegmentum), optic nerves, and spinal cord [8].

The binding of NMO-IgG to the AQP4 epitope results in astrocytic damage via activation of the classical complement pathway and antibody-dependent, cell- mediated cytotoxicity [9-11]. As such, NMO can be considered as an autoimmune astrocytopathy, as opposed to MS, which is now widely recognized as a highly complex autoimmune disorder of the CNS, and characterized by histopathological and pathophysiologic heterogeneity, affecting both white and gray matter, and now considered both a demyelinating and neurodegenerative disorder [12].

Two pathologic subtypes of NMO lesions have been described. The classic NMO lesion is characterized by confluent and/or focal demyelination, infiltration of myelin-laden macrophages, severe axonal loss, necrosis of both gray and white matter in the cord, and pronounced astrocytic loss. The second NMO lesion is characterized by vacuolated myelin in the relative absence of frank demyelination, reactive astrocytes, microglial activation, limited axonal injury, and variable, typically granulocytic inflammation [11]. Remyelination is sometimes present at the edge of NMO lesions. Interestingly, peripheral Schwann cells have been observed to enter the spinal cord to drive remyelination; this observation provides further evidence of astrocytic dysfunction in NMO, since astrocytes normally prevent Schwann cells from entering the CNS [11].

B-cell dysregulation lies at the immunoetiopathological center of NMO, as evidenced by increased levels of circulating plasmablasts and intrathecal B-cells expressing NMO-IgG antibodies during NMO attacks [13, 14], as well as the efficacy of rituximab in treating the disease (further discussed later). Plasmablasts, the likely precursor of NMO-IgG producing plasma cells, rely on interleukin-6 (IL-6) for survival [13]. Other B-cell cytokines that play an important role in NMO include IL-5, IL-17, nitric oxide, tumor necrosis factor-alpha (TNF-alpha), a proliferation- inducing ligand (APRIL), and B-cell-activating factor (BAFF) [15]. Interestingly, suppressive B-cell activity may also be impaired in NMO, as evidenced by lower IL-10 and IL-35 levels [15].

There is also evidence that T-cell dysfunction contributes to the immunopatho- genesis of the disease. Peripheral AQP4-specific T-cells are needed to drive the production of NMO-IgG from B-cells [16]. Increased circulating Th1 and Th17 subsets have also been observed in NMO [16]. While T-cells most likely play an important pathogenic role in NMO, their precise significance in initiating and accelerating the disease is unclear.

Eosinophils have also been implicated in NMO immunopathogenesis. In the bone marrow, eosinophils are the main source of APRIL and IL-6. Eosinophil infiltration of the CNS may help support plasma cell survival and NMO-IgG production within NMO lesions. The role of eosinophils in NMO may also explain why two MS disease-modifying agents have been observed to exacerbate NMO disease activity - fingolimod (which promotes retention of eosinophils in the bone marrow) and natalizumab (which increases the levels of circulating eosinophils) [15].

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