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Ther Adv Neurol Disord. 2008 July; 1(1): 5–12.
PMCID: PMC3002541

Treatment of Neuromyelitis Optica: Current Debate

Abstract

Neuromyelitis optica (NMO) is an inflammatory demyelinating disease that largely affects optic nerves and spinal cord. Recent studies have identified an elevation of serum anti-aquaporin 4 antibody as a hallmark of NMO. Typical cases of NMO significantly differ from multiple sclerosis (MS) in immunological markers, histopathology, and responses to therapy. In fact, plasma exchange may be more efficacious for NMO than MS, whereas interferon-ß is recommended for MS but not for NMO. An emerging idea that pathogenesis of NMO may involve an interaction of the newly identified helper T cell subset, Th17, with B cells offers potential targets of therapy.

Keywords: neuromyelitis optica, multiple sclerosis, Th17 cells, anti-aquaporin-4 antibody, interferon-β

Introduction

Neuromyelitis optica (NMO; Devic syndrome) is an inflammatory disease of the central nervous system (CNS) that affects optic nerves and spinal cord [Jacob et al. 2007; Matiello et al. 2007; Wingerchuk et al. 2007]. In older literature, NMO was defined as a disorder that is characterized by development of a single episode of bilateral optic neuritis and transverse myelitis Table 1. However, recent studies have indicated that presence of serum antibodies against aquaporin 4 (AQP4), a water channel protein, is a hallmark of NMO and could be essential for making the diagnosis. Since anti-AQP4 antibody became recognised as a serological marker of NMO, the clinical picture of NMO has been significantly broadened. Indeed, when the latest criteria [Wingerchuk et al. 2006] are used for diagnosis of NMO, a large majority of the NMO patients follow a relapsing clinical course and sometimes develop brain lesions.

Table 1.
Brief history on NMO research.

Of interest, NMO has been traditionally separated from multiple sclerosis (MS) in western countries, whereas they have been integrated into the category of MS in Japan, by giving a term ‘opticospinal MS (OSMS)’. Because not all OSMS exhibit an elevation of anti-AQP4 antibody titer in the sera, and because OSMS may develop brain lesions characteristic of MS [Barkhof et al. 1997], it is still debatable as to whether OSMS and NMO may cover an entirely identical disease spectrum or not.

Nowadays, a large proportion of patients with MS are being treated with standard drugs such as interferon-/? and glatiramer acetate. It has been reported that interferon-ß may also be efficacious for NMO/OSMS based on analysis of a small number of patients [Saida et al. 2005]. However, more recent works have emphasized the differences in immunological and pathological features between NMO and conventional MS, which indicates the relevance of distinctive therapeutic strategies for NMO and MS. The aim of this review is to provide up-dated information on the diagnosis and treatment of NMO and also discuss the immunological pathogenesis of NMO with special reference to a critical interaction between B cells and Th17 cells, a newly identified helper T cell subset [Hsu et al. 2008].

Diagnosis of NMO: discovery of anti-aquaporin 4 (AQP4) antibody and its impact

In general, the clinical picture of typical NMO is very different from that of conventional MS. Important points for differential diagnosis are as follows: (1) Optic neuritis in NMO could be much more serious than in MS, and often leads to blindness, (2) MRI scan of NMO often reveals presence of an extensive lesion extending over three vertebral segments (Figure 1, referred to as ‘Longitudinally extensive spinal cord lesion’ (LESL), (3) Oligoclonal bands (OBs) commonly found in the cerebrospinal fluid of MS is only rarely seen in NMO, (4) NMO may show brain lesions, although they are different from characteristic MS lesions. However, the patients during an early stage of NMO or those who have been actively treated may not show the characteristic clinical profile of NMO, and could be misdiag-nosed. In this regard, a recent discovery of the specific serological marker of NMO (NMO-IgG or anti-AQP4 antibody) [Lennon et al. 2004; Lennon et al. 2005] has opened a new gate for diagnosis of NMO. The NMO-specific autoanti-body was first identified in the sera from NMO as ‘NMO-IgG’ based on the ability to stain mouse CNS tissue. The target antigen of NMO-IgG was subsequently identified to be AQP4 [Lennon et al. 2005], which has led to establishment of assays that are more feasible and more sensitive than the original NMO-IgG assay [Paul et al. 2007; Tanaka et al. 2007; Takahashi et al. 2006].

Figure 1.
Longitudinally extensive spinal cord lesion (LESL) in a case of NMO T2-weighted cervical MRI demonstrates an extension of T2 high density involving central gray matter, which is characteristic of LESL associated ...

Recent studies have shown that anti-AQP4 antibody or NMO-IgG can be detected in a large majority of NMO/OSMS patients, whereas most patients with conventional MS are anti-AQP4 negative [Paul et al. 2007; Tanaka et al. 2007; Nakashima et al. 2006]. Although, it has been argued whether NMO and MS represent distinct entities or not [Weinshenker et al. 2006; Kikuchi and Fukazaw, 2005], discovery of anti-AQP4 antibody has obviously strengthened the idea that typical NMO cases are distinct from MS in the pathogenesis. Furthermore, pathological analysis has recently demonstrated a remarkable loss of AQP4 [Misu et al. 2007; Roemer et al. 2007] along with concomitant absence of glial fibrillary acidic protein, a marker of astrocytes [Misu et al. 2007] in the lesions of NMO but not of MS. Although primary targets in MS are thought to be myelin and myelin-forming oligodendrocytes, the results of pathological studies suggest that astrocytes could be attacked by antibodies against AQP4 in NMO, further highlighting the differences between NMO and MS.

As mentioned above, patients predominantly manifesting optic nerve and spinal cord signs have been traditionally diagnosed as OSMS in Japan. A recent analysis showed that a majority of the OSMS patients are anti-AQP4 antibody positive and accompany the LESL, implying that most cases of OSMS could be diagnosed as NMO. However, some of the patients exhibited neither aniti-AQP4 nor LESL [Tanaka et al. 2007]. It is possible that these patients may belong to the category of MS, although the distribution of lesions resembles that of NMO.

Previously, presence of brain lesions and symptoms was an exclusion criterion for NMO. However, the revised diagnostic criteria allow diagnosis of NMO for patients who have brain lesions, provided that the MRI findings do not meet the diagnostic criteria for MS [Wingerchuk et al. 2006]. However, Matsuoka et al. reported on the presence of NMO patients, who have multiple juxtacortical or periventricular ovoid lesions in the brain, which is characteristic of MS, but not of NMO [Matsuoka et al. 2007]. Although this information may be used to argue against the distinction between MS and NMO, we would rather interpret that the patients might have both MS and NMO simultaneously. This possibility needs to be verified rigorously in future studies.

As such, discovery of anti-AQP4 antibody has greatly influenced on the understanding the pathogenesis of NMO. However, it remains unclear whether anti-AQP4 truly plays a role in the formation of destructive lesions in the optic nerve and spinal cord, although the selective loss of AQP4 in the NMO lesions indicate the pathogenic role of anti-AQP4 antibody. A number of investigators are trying to reproduce the pathology of NMO in rodents by passively transferring anti-AQP4 antibody. However, the results have not been published yet. Currently, it remains possible that pathogenic autoantibody in NMO may target CNS antigens other than AQP4.

Cerebrospinal fluid findings in NMO

Cerebrospinal fluid (CSF) examination could also be useful for distinguishing NMO from MS. For instance, presence of prominent CSF pleocy-tosis (> 50 × 106WBC/L) during acute phase could be regarded as supporting diagnosis of NMO but not of MS [Wingerchuk et al. 1999]. It is also of note that OBs could be detected more frequently in MS than in NMO [Bergamaschi et al. 2004; Misu et al. 2002]. Misu et al. previously reported that OBs are negative in the Japanese OSMS patients who have no brain lesions on MRI [Misu et al. 2002]. However, Bergamaschi et al. have recently reported that presence of OBs could be demonstrated in 27% of NMO, when CSF samples were examined repeatedly [Bergamaschi et al. 2004]. Notably, the authors pointed out that OBs could be continuously detected during the course of MS, whereas appearance of OBs appears to be temporary in NMO, indicating the importance of repeated CSF examination to distinguish NMO from MS. Very recently, Jarius et al. have reported that a polyspecific humoral response against measles, rubella, and varicella zoster virus (MRZ) was positive in 37 out of 42 CSF samples from MS, but was detected only in one out of 20 samples from NMO. They suggest that assessment of the MRZ reaction in the CSF could also help in distinguishing MS and NMO [Jarius et al. 2008]. Taken together, these results indicate that a combination of CSF and serum studies may further improve diagnostic certainty.

Activation of IL-17/IL-8 axis in NMO

Besides an elevation of anti-AQP4, recent work has shown that IL-17 and IL-8 are specifically increased in the CSF from NMO [Ishizu et al. 2005]. IL-17 is a proinflammatory cytokine mainly produced by activated T cells, whose role in allergy and autoimmune inflammation has been highlighted lately. IL-8 is a chemokine whose major role is to recruit neutrophils. Of note, IL-8 production from macrophages and epithelial cells is promoted by IL-17. Because neutrophil infiltration is dominant in the necrotic lesions of NMO [Ishizu et al. 2005], the authors have argued that intrathecal activation of IL-17/IL-8 axis may uniquely contribute to the formation of destructive lesions found in NMO. If this is the case, an important question should be directed to the relationship between the IL-17/IL-8 axis and B cell immunity associated with an elevation of anti-AQP4 antibody. Though very little was known about the relationship between IL-17 and B cells, it has recently been reported that IL-17-producing T cells, namely Th17 cells [Bettelli et al. 2007; Steinman, 2007], would promote spontaneous formation of a germinal center and augment production of pathogenic autoantibodies in a model of systemic autoimmune disease [Hsu et al. 2008]. In the next section, we discuss on our hypothetical model in which the Th17 cell/B cell interaction plays a role in the patho-genesis of NMO.

Th17 cell biology and pathogenesis of NMO

Th17 cells are a novel helper T cell subset distinct from Th1 or Th2. Because it has been shown that Th17 cells play a decisive role in a variety of inflammatory processes, the biology of Th17 cells is currently the subject of broad interest [Bettelli et al. 2007; Steinman 2007]. Before Th17 cells were identified, studies had emphasized the role of Th1 cells that produce interferon-? in the pathogenesis of MS and its animal model experimental autoimmune encephalomyelitis (EAE). However, it now becomes clear that Th17 cells are crucial in the induction of EAE, and lymphocytes infiltrating the brain of MS would contain Th17 cells [Tzartos et al. 2008]. Although the pathogenic role of Th17 cells is sometimes being overemphasized, involvement of Th1 cells has been confirmed in various inflammatory pathologies. Interestingly, Th1 cells and Th17 cells express different sets of chemokine receptors [Sato et al. 2007], indicating that they might be recruited to different types of inflammatory lesions or to different anatomical sites.

Differentiation of rodent Th17 cells depends on IL-6 and transforming growth factor (TGF)-yô [Bettelli et al. 2007] whereas human Th17 cells appear to be induced in the presence of IL-6 and IL-1ß [Acosta-Rodriguez et al. 2007]. IL-23 is required for the expansion and maintenance of Th17 cells. As such IL-6 and IL-23 are now thought to be key cytokines in the generation of pathogenic Th17 cells.

The relation between Th17 cells and production of anti-AQP4 antibody is still not clear but could be speculated on the results of animal experiments. It is noteworthy that IL-17 produced by Th17 cells has recently been found to promote the germinal center formation in a spontaneous autoimmune disease model by altering the B cell chemotactic response, which leads to a massive production of pathogenic autoantibody [Hsu et al. 2008]. In contrast, blocking IL-17 signaling was inhibitory to the production of autoantibody and prevented the development of the autoimmune disease. These results indicate that Th17 cells would contribute to augmenting B cell auto-immunity through a mechanism distinct from its proinflammatory action. Notably, presence of a germinal center-like structure was demonstrated in the subarachnoid space of a rodent NMO model, which has been created by introducing genes for both T cell receptor (TCR) and B cell receptor for myelin oligodendrocytes glycoprotein (MOG) [Bettelli et al. 2006; Krishnamoorthy et al. 2006]. The mice spontaneously develop optic neuritis and myelitis. Furthermore, it is thought that collaboration of T cells (Th17) and B cells play a critical role in shaping the unique lesion distribution in this mouse model. If human NMO also involves a Th17 cell/B cell interaction, cytokines, chemo-kines and their receptors that play a role in Th17 cell-dependent production of pathogenic autoantibody could be potential therapeutic targets in NMO. The hypothetical model will be verified in a future study.

Interferon-/β and NMO

Although a small preliminary report suggests the efficacy of interferon-/? on OSMS [Saida et al. 2005], another study does not recommend its use for NMO in comparison with immunosup-pressive agents [Papeix et al. 2007]. The most prominent and common side effects of interferon are a flu-like syndrome of fever, headache, myalgia, arthralgia, and general malaise. Furthermore, there are several case reports in Japan documenting a worsening of NMO [Warabi et al. 2007] or development of large brain lesions in NMO patients after starting interferon-yß [Shimizu et al. 2008].

Although the clinical reports need to be carefully analyzed before making a conclusion, some cautions should be made upon the fact that type I interferon (including interferon-a and –ß) would worsen or trigger the development of some antibody-mediated autoimmune diseases. For example, therapeutic use of type I interferon for cancer and hepatitis has been shown to cause exacerbation of SLE, thyroiditis, diabetes, psoriasis, rheumatoid arthritis, autoimmune hemolytic anemia, and myasthenia gravis [Baccala, et al. 2005; Theofilopoulos et al. 2005; Gota and Calabrise 2003; Stewart, 2003]. Among these, SLE and type I interferon has been causally linked following intensive analysis [Banchereau and Pascual, 2006; Pascual et al. 2006]. Early studies reported increased serum levels of IFN-a in lupus patients, which correlate with disease activity [Kim et al. 1987l; Ytterberg and Schnitzer, 1982]. More recently, microarray studies have identified increased expression of interferon-a- and interferon-y-induced genes in peripheral blood lymphocytes of SLE patients in correlation with disease severity [Bennett et al. 2003; Baechler et al. 2003; Crow et al. 2003; Han et al. 2003]. Consistently, interferon-a was recently identified as the serum factor in SLE that could induce differentiation of dendritic cells with efficacious antigen-presenting ability [Blanco et al. 2001]. Type I interferon might also contribute to immune complex formation in SLE by directly activating B cells [Le bon et al. 2001]. These results highlight the augmenting effect of type I interferon on antibody-mediated autoimmunity, which differs greatly from that of MS.

It is also of note that interferon-yß shows a potential to induce IL-6 in vitro [Satoh et al. 2006] and in vivo [Nakatsuji et al. 2006]. IL-6 is a key cyto-kine involved in the induction of Th17 cells as well as growth and differentiation of B cells. Satoh et al. examined the gene expression profile of peripheral blood lymphocytes after culture with interferon-yß and found a number of inflammatory cytokines including IL-6 are up-regulated. Nakatsuji et al. has shown that the level of serum IL-6 after injection of interferon-yß would correlate with side effects such as headache in the patients with MS, but ironically also predict the efficacy of interferon-yß treatment in MS. Taken these together, injection of interferon-yß could lead to induction of IL-6 at least transiently. From a theoretical point of view, one may argue that the IL-6-stimulatory property of interferon-yß is not beneficial for treating NMO involving B cells and Th17 cells, both of which are responsive to IL-6. A systematic retrospective survey for interferon-yß treated NMO patients will clarify if this concern is appropriate or not.

According to recent studies, abnormalities found in the brain MRI of NMO ranged from 10 to 50%. Asymptomatic brain lesions are now thought to be common in NMO, and symptomatic brain lesions do not exclude the diagnosis of NMO. Cabrera-Gómez et al. has reported that none of the brain MRI abnormalities in NMO were compatible with the criteria of MS brain lesions proposed by Barkhof et al. (1997) [Cabrera-Gómez et al. 2007]. As an extreme example, we show a patient with NMO, who developed a few large lesions in the brain white matter two months after starting interferon-yô (Figure 2. A recent report by Shimizu et al. has also described the presence of similar NMO patients who developed large brain lesions after starting interferon-yß [Shimizu et al. 2008]. The initial clinical and radiological features of our patient were consistent with NMO, and anti-AQP4 antibody was positive. This case suggests to us that a unique pattern of NMO lesion distribution could be transformed into another pattern of disease after undergoing imunomodulation. We also speculate that interferon-yß treatment might have triggered the unusual relapse in NMO.

Figure 2.
Development of large white matter lesions in a case of neuromyelitis optica (NMO) 2 months after starting interferon-/? This young female patient was aquaporin 4 antibody-positive and showed a clinical and ...

Therapy of NMO in practice

At present, very little information is available that helps physicians and patients choose the best treatment for NMO. In general, treatment of acute exacerbation of NMO may start with intravenous corticosteroids (typically 1,000 mg of methylprednisolone for 3-5 consecutive days). Because the efficacy of plasma exchange was reported in NMO-IgG-positive patients with NMO [Watanabe et al. 2007a], plasmapher-esis could be considered if clinical improvement is not satisfactory. However, effects of plasma-pheresis are not consistent, and anti-AQP4 antibody could rise rapidly after plasmapheresis (Figure 3. To prevent the rebound of pathogenic antibody titers after plasma exchange, a combination therapy with immunosuppressive agents may be needed in some cases. Figure 3 demonstrates the clinical course of representative patients who were treated with plasmapheresis (plasma exchange or immunoadsorption (IA)). In the first case (Figure 3(a)), intravenous methylprednisolone (IVMP) treatment was found to reduce anti-AQP4 antibody titers in the serum, which was accompanied with some clinical improvement. However, as residual symptoms were not tolerable, plasma exchange was subsequently applied, which led to further recovery and disappearance of anti-AQP4 antibody. In the second case (Figure 3(b)), IVMP treatment was followed by plasmapheresis by using IA. We found that the first course of the IVMP plus IA tended to increase the titers of anti-AQP4 antibody eleven weeks after starting the treatment. Subsequently, we measured the antibody titers and amount of serum IgG before and after each successive IA treatment. On each occasion, IA effectively removed the antibody and reduced the IgG amount. However, anti-AQP4 as well as total immunoglobulins recovered very quickly and returned to the pre-treatment level one month after the last IA. We attempted to add an immunosuppressive drug, but the patient could not tolerate the side effects. The unsatisfactory result indicates that the primary target of therapy should be plasma cells producing pathogenic autoantibody.

Figure 3.
Treatment of NMO with plasmapheresis: representative cases (a) This 36-year-old female developed dysesthesia of the right leg and a constrictive band sensation in the chest region. A few days later, she ...

To control the production of antibody, azathio-prine could be used during the remission phase of NMO, often in combination with oral predni-sone. Mandler et al. treated seven patients with newly diagnosed NMO with prednisone and azathioprine for 18 months. They found that relapses were prevented completely for more than 18 months and the patients improved significantly in the Expanded Disability Status Scale score [Mandler et al. 1998]. Figure 4 shows the clinical course of an anti-AQP4 antibody positive NMO patient being treated in our clinic. This NMO patient was in a state of remission for almost four years after two clinical attacks. However, she suddenly developed optic neuritis and myelitis at 57 years of age, and then interferon-/? 1b therapy was introduced. The patient did not respond to the therapy, and clinical activity seemed to be even exacerbated. Because of frequent relapses, azathioprine (100mg/day) was prescribed in addition. The patient then entered a state of remission, which was maintained even after stopping interferon-yß. This interesting case indicates the efficacy of azathioprine in NMO.

Recently, a retrospective investigation revealed that low-dose corticosteroids might reduce the rate of relapses in NMO [Watanabe et al. 2007b]. In some NMO patients, monthly intravenous infusion of immunoglobulin was reported to be effective [Bakker and Metz 2004]. Intravenous infusions of mitoxantrone hydro-chloride (12mg/m2, monthly for six months followed by three additional treatments every three months) appeared to reduce relapses [Weinstock-Guttman et al. 2006]. As mitoxantrone would very potently suppress B-cell immunity directly or through a macrophage-mediated mechanism [Fidler et al. 1986], its efficacy in NMO is not unexpected. An open-label study of rituximab (a monoclonal antibody specific for CD20+ B cells) showed an effective outcome for NMO [Cree et al. 2005]. Rituximab is an attractive treatment option for NMO because of its selective action against B cells. However, the potential risk and side effects should be taken into consideration. As an alternative therapeutic option, a single case report showed the efficacy of mycophenolate mofetil (2g/day), which controls T cell-dependent antibody responses through purine synthesis inhibition [Falcini et al. 2006]. There is also a case report suggesting efficacy of glatiramer acetate on NMO [Bergamaschi et al. 2003].

Figure 4.
A patient with NMO who did not respond to interferon-/? (IFN-/3) but to azathioprine. Interferon-/? was introduced to this female patient with NMO, as the patient's condition became active. However, there ...

Concluding remark

NMO is an autoimmune CNS disease characterized by the presence of anti-AQP4 antibody. According to the latest criteria for diagnosis, typical cases of NMO could be easily differentiated from MS by measuring anti-AQP4 antibody and examining the presence of LESL by spinal MRI. However, patients who have been treated with interferon-yß or immunosuppressive drugs may show an atypical presentation, such as association of large brain lesions or clinical presentation of NMO without accompanying detectable anti-AQP4 antibody titers. Moreover, if the available anti-AQP4 assay is not sensitive enough, it might be hard to make a conclusive diagnosis of NMO. Interestingly, transgenic mice bearing MOG-specific T cell and B cell receptor are reported to exhibit NMO-like pathology, in which collaboration between T cells and B cells is critical [Bettelli et al. 2006; Krishnamoorthy et al. 2006]. By contrast, it remains unclear whether anti-AQP4 antibody may be truly pathogenic. It is rather promising to target B cells by a monoclonal antibody like rituximab or block the T cell-B cell interaction by available drugs. An increase of IL-17 in the CSF also tempts us to consider therapy that modulates IL-6 or IL-23 signaling, which is involved in the generation and maintenance of Th17 cells. Because of recent advances in research, it may not take so long to establish a reasonable and more efficacious protocol for treatment of NMO.

Acknowledgment

We thank Dr Toshiyuki Takahashi at Tohoku University for measuring anti-AQP4 antibody levels.

Conflict of interest statement

None declared.

Contributor Information

Tomoko Okamoto, Department of Neurology, Musashi Hospital, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.

Masafumi Ogawa, Department of Neurology, Musashi Hospital, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.

Youwei Lin, Department of Neurology, Musashi Hospital, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan. Department of Immunology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.

Miho Murata, Department of Neurology, Musashi Hospital, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.

Sachiko Miyake, Department of Immunology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.

Takashi Yamamura, Department of Immunology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan ; pj.og.pncn@arumamay.

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