New Insights, Promises and Challenges

Introduction

In the late 19th century, physicians in Europe and other parts of the world started to pay attention to a unique disease involving optic nerves and the spinal cord. Among them, Eugine Devic's case report of a 45‐year‐old woman in 1894 deserves special consideration because he not only described two cardinal features of the disease, acute bilateral severe optic neuritis (ON) and transverse myelitis (TM) 1, but also the characteristic neuropathological findings consisting of severe demyelination and necrosis in the optic nerves and spinal cord, in the absence of obvious brain lesions. In the same year, Gault, a student of Devic, described in his thesis the clinical findings of 17 cases with similar clinical features, including the original Devic case 3. Interestingly, this series included both monophasic and relapsing disease, and several had brain symptoms. Based on these early reports, they first proposed the term “neuromyelitis optica (NMO),” and thereafter neurologists started to use “NMO” and/or “Devic's disease” to refer to this syndrome.

However, their report also generated some confusion regarding the clinical definition of NMO. Should only monophasic cases be defined as NMO? Is bilateral ON a requirement of NMO or can unilateral ON, non‐TM and/or brain symptoms be included as part of the clinical spectrum of the disease? Moreover, because both ON and myelitis are common manifestations of multiple sclerosis (MS), cases with NMO had often been labeled as severe MS in various parts of the world, including in Asian countries where the prevalence of MS was much lower than in Western countries. Here the term “opticospinal MS (OSMS)” was coined for the disease and OSMS was recognized as a unique feature of “Asian MS” 2.

In 2004, Lennon and her colleagues reported a new serum autoantibody, NMO‐immunoglobulin G (IgG), exclusively detected in patients with NMO and its high‐risk syndromes (TM longitudinally extending over three or more vertebral segments and/or recurrent ON [simultaneous or sequential] ) 5. In the following year, aquaporin‐4 (AQP4) was identified as the target antigen. AQP4 is the dominant water channel protein in the central nervous system where it is richly expressed in the endfeet of astrocytes 6. Just before the discovery of AQP4 as the NMO target antigen, Peter Agre had been awarded the 2003 Nobel Prize in Chemistry for his discovery of aquaporins [Karl Grandin, ed (2003). “Peter Agre Biography.” Les Prix Nobel. The Nobel Foundation. Retrieved 2008‐07‐29].

The discovery of NMO‐IgG/AQP4 antibody truly revolutionized our understanding of NMO, and led to a major increase in clinical and basic research focused on NMO and AQP4. Studies on NMO‐IgG/AQP4 seropositive patients helped to further define the clinical, magnetic resonance imaging (MRI), and laboratory features, as well as treatment responses that distinguished NMO from MS. Neuropathological analyses revealed the crucial role of humoral immunity and astrocytopathic changes, while experimental studies (both in vitro and in vivo) provided evidence supporting the pathogenicity of AQP4 antibody. These findings further confirmed that NMO and MS are different diseases. A simple indicator of the impact of NMO‐IgG/AQP4 antibody on NMO research is reflected by the trend of annual number of publications related to NMO. Figure 1 is a PubMed search using “neuromyelitis optica” as the search term. Before the original report of NMO‐IgG by Lennon et al in 2004, there had been less than 20 papers on NMO each year. In contrast, after Lennon et al's paper was published, the number of NMO‐related publications increased steadily each subsequent year, and exceeded 300 in 2012. As of mid‐August, 2013, 215 papers on NMO have already been indexed in PubMed, therefore it is likely the annual number of NMO‐related publications in 2013 will again surpass the previous year.

Figure 1.

Recent explosion of neuromyelitis optica (NMO)‐related publications. The bars represent annual number of publications related to NMO as a result of a PubMed search using “neuromyelitis optica” as a search term. The publication numbers have drastically increased after the original report of NMO‐IgG in 2004 and are increasing steadily every year.

In this context, it is very timely for Brain Pathology to cover NMO as a hot topic in the journal's mini‐symposium. We were asked to serve as guest editors in this project, and we invited several experts in this field to provide cutting‐edge information about NMO to readers. This mini‐symposium is divided into two parts. Part 1 in this issue includes three papers: (i) Clinical Spectrum and Treament of Neuromyelitis Optica Spectrum Disorders: Evolution and Current State, by D. Sato, M Lana‐Peixoto, K Fujihara, and J De Seze; (ii) Aquaporin‐4 Antibodies (NMO‐IgG) as a Serological Marker of Neuromyelitis Optica: A Critical Review of the Exisiting Literature, by S Jarius and B Wildemann; and (iii) Biology of AQP4 and anti‐AQP4 antibody: Therapeutic Implications, by AS Verkman, P Phuan, N Asavapanumas and L Tradtrantip Part 2, which will be published in the next volume, will include three additional manuscripts: (i) Cytokines and Chemokines in Neuromyelitis Optica: Pathogenic and Therapeutic Implications by A Uzawa, M Mori, and S Kuwabara; (ii) Experimental Models of Neuromyelitis Optica by M Bradl and H Lassmann; and (iii) The Pathology of an Autoimmune Astrocytopathy: Lessons Learned from Neuromyelitis Optica by C Lucchinetti, Y Guo, B Popescu and T Misu.

In the contribution by Sato and colleagues 7, the clinical, MRI, neuro‐ophthalmological and laboratory findings of NMO are described in detail. A historical perspective is provided regarding the evolving and expanding clinical spectrum and definition of NMO (i.e. NMO spectrum disorders) following the discovery of AQP4‐IgG. Established as well as future treatment options are discussed, including recent promising results observed with several monoclonal antibody trials. However, because NMO carries a poor prognosis if untreated, it is still debated whether the use of placebo‐controlled trials is acceptable in the design of future clinical trials aimed at testing potential novel candidate drugs in NMO patients.

Jarius and Wildemann 4 provide a thorough and extensive review of the various NMO‐IgG/AQP4 antibody assays currently available, including methodological differences associated with assay sensitivity and specificity, pitfalls in antibody detection, and the clinical implications. The clinical characteristics of “seronegative NMO” are also discussed. Although various methodological details to increase assay sensitivity and specificity have been clarified, a highly sensitive and easy to use AQP4 antibody assay has yet to be standardized. There are also variations in reported data from different institutions, which make interpreting results difficult. In an attempt to overcome these challenges, the authors emphasize the importance of conducting large‐scale, multicenter studies in unselected cohorts.

In the chapter by Verkman and colleagues 8, the molecular and cellular biology of AQP4 are discussed in detail, including evidence for AQP4 pathogenicity. Moreover, based on their own extensive experimental data, they propose new therapeutic strategies to block the binding of pathogenic AQP4 antibody to AQP4 by aquaporumab, a genetically manipulated, nonpathogenic monoclonal antibody to AQP4, and by small molecules, as well as strategies to enzymatically neutralize pathogenic AQP4 antibody. These approaches hold promise of translating experimental therapeutics into the clinical practice and management of NMO, and will require active collaborations between academia, and industry in order to be successful.