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Mechanisms of Disease: aquaporin-4 antibodies in neuromyelitis optica Sven Jarius, Friedemann Paul, Diego Franciotta, Patrick Waters, Frauke Zipp, Reinhard Hohlfeld, Angela Vincent* and Brigitte Wildemann S U M M A RY Neuromyelitis optica (NMO) is a rare CNS inflammatory disorder that predominantly affects the optic nerves and spinal cord. Recent serological findings strongly suggest that NMO is a distinct disease rather than a subtype of multiple sclerosis. In NMO, serum antibodies, collectively known as NMO-IgG, characteristically bind to cerebral microvessels, pia mater and Virchow–Robin spaces. The main target antigen for this immunoreactivity has been identified as aquaporin-4 (AQP4). The antibodies are highly specific for NMO, and they are also found in patients with longitudinally extensive transverse myelitis without optic neuritis, which is thought to be a precursor to NMO in some cases. An antibody-mediated pathogenesis for NMO is supported by several observations, including the characteristics of the AQP4 antibodies, the distinct NMO pathology—which includes IgG and complement deposition and loss of AQP4 from spinal cord lesions—and emerging evidence of the beneficial effects of B-cell depletion and plasma exchange. Many aspects of the pathogenesis, however, remain unclear. KEYWORDS aquaporin-4 antibodies, Devic syndrome, multiple sclerosis, neuromyelitis optica, pathogenesis
REVIEW CRITERIA References for this review were identified by searches of PubMed for articles published from 1966 to March 2007, with the terms “neuromyelitis”, “(Devic’s OR Devic) AND (syndrome OR disease)”, “opticospinal OR optico-spinal”, “multiple sclerosis AND Japan”, “longitudinal extensive transverse myelitis”, “myelitis AND optic neuritis” and “aquaporin-4”. Articles were also identified through searches of the authors’ own files. With a few exceptions (publications from the 19th century), only papers published in English were reviewed.
CME S Jarius is a Neurologist and Neuroimmunologist and P Waters is a Postdoctoral Scientist in the Neurosciences Group, Weatherall Institute of Molecular Medicine, University of Oxford, UK. F Paul is a Neurologist and Senior Physician, and F Zipp is Professor of Neurology at the Cecilie Vogt Clinic for Neurology, Charité–Universitaetsmedizin Berlin, Germany. D Franciotta is Head of the Laboratory of Neuroimmunology at the Neurological Institute “C. Mondino”, Pavia, Italy. R Hohlfeld is Professor of Neurology and Clinical Neurosciences at the Ludwig Maximilian University, Munich, Germany. A Vincent is Professor of Neuroimmunology and Head of the Neurosciences Group, University of Oxford. B Wildemann is Professor of Neurology and Head of the Division of Molecular Neuroimmunology, Department of Neurology, University of Heidelberg, Germany. Correspondence *Neurosciences Group, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, UK
[email protected] Received 27 August 2007 Accepted 9 January 2008 Published online 11 March 2008 www.nature.com/clinicalpractice doi:10.1038/ncpneuro0764
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Vanderbilt Continuing Medical Education online This article offers the opportunity to earn one Category 1 credit toward the AMA Physician’s Recognition Award. Competing interests A Vincent declared associations with the following companies: Athena Diagnostics and RSR Ltd. See the article online for full details of the relationships. The other authors declared no competing interests.
INTRODUCTION
Neuromyelitis optica (NMO or Devic syndrome) was first described in the late 19th century by Eugène Devic and others.1–4 In Japan and other Asian countries, NMO is often called opticospinal multiple sclerosis (OSMS), and is more prevalent than typical multiple sclerosis (MS). Although NMO has been classified as a subtype of MS for many years, the disease is classically restricted to the optic nerves and spinal cord, and it is now clear that it has distinct clinical and pathological features. In particular, new histopathological and serological findings strongly suggest the involvement of the humoral immune system, and the detection of NMOspecific serum autoantibodies, collectively known as NMO-IgG, helps to distinguish NMO from MS.5,6 The discovery of NMO-IgG, and the subsequent identification of aquaporin-4 (AQP4)—the most abundant water channel in the CNS—as its target antigen,6–9 makes NMO the first inflammatory demyelinating disorder of the CNS to have a defined autoantigen, which enables diagnosis of the disease by use of a serological test. Moreover, the possibility that NMO is an autoantibody-mediated disease, analogous to myasthenia gravis and other autoimmune channelopathies, raises the likelihood of establishing therapeutic strategies aimed at the humoral arm of the immune system. In this article, we will first review the clinical, serological and pathological characteristics of NMO. We will then discuss the evidence for an antibodymediated mechanism in the pathogenesis of this disease.
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CLINICAL FEATURES OF NEUROMYELITIS OPTICA
NMO predominantly affects the optic nerves and spinal cord.1,10,11 Brain lesions can occur during the course of the disease, but they mostly remain clinically silent.12 NMO usually begins with either myelitis or optic neuritis—Devic’s classical syndrome of simultaneous bilateral optic neuritis and myelitis occurs in only 10% of cases.11 Spinal cord symptoms in NMO range from mild sensory disturbances to complete transverse myelitis with tetraplegia or paraplegia, sensory impairments and bladder–bowel dysfunction. NMO usually follows a relapsing course without marked progression of disability between relapses, but in a minority of cases the disease course can be monophasic (15–23%)10,13 or secondary chronic progressive (2%). 14 Spontaneous remission of neurological dysfunction is rare in NMO in comparison with MS, and accumulation of irreversible deficits and rapid progression of disability are frequent. Studies on the natural course of NMO report progression to severe motor dysfunction (muscle strength ≤2 on the Medical Research Council scale) or substantial loss of visual function (
