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Neuromyelitis optica: Concepts in evolution
Journal of Neuroimmunology 231 (2011) 100–104
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Journal of Neuroimmunology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j n e u r o i m
Neuromyelitis optica: Concepts in evolution Raffaella Fazio, Marta Radaelli, Roberto Furlan ⁎ Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy Department of Neurology, San Raffaele Scientific Institute, Milan, Italy
a r t i c l e Keywords: Neuromyelitis optica Devic's disease Aquaporin-4 Myelitis Optic neuritis Multiple sclerosis
i n f o
a b s t r a c t Neuromyelitis optica (NMO) is a rare demyelinating disease, affecting selectively the optic nerve and the spinal cord. It was previously considered to be a severe variant of multiple sclerosis (MS) due to the similar pathological features and its resemblance to optico-spinal, or Japanese, MS, typical of Asian populations. The finding that most NMO patients have auto-antibodies against aquaporin-4, a water channel particularly abundant on the astrocytes of the glia limitans, has allowed early diagnosis and specific treatment of these patients, and has greatly improved our knowledge of its pathogenesis. When laboratories worldwide can detect anti-aquaporin-4 auto-antibodies with comparable sensitivity and specificity, we will be able to have large multi-centric studies to define better the epidemiological, clinical and pathological features of patients and their responses to treatment. © 2010 Elsevier B.V. All rights reserved.
1. Introduction Sir Thomas Clifford Allbutt, stated in 1870 for the first time that “it is tolerably certain that disturbances of the optic disc and its neighborhood is seen to follow disturbances of the spine with sufficient frequency and uniformity to establish the probability of a causal relation between the two events” (Allbutt, 1870). Ten years later Dr. Wilhelm Erb, in 1880 published a paper entitled “On the concurrence of optic neuritis and myelitis subacuta” (Erb, 1880). Fourteen years later, Eugéne Devic supervised a medical student, Fernand Gault, in his PhD thesis work describing 17 cases of optic neuromyelitis (Gault, 1894), then reported by Devic himself (Devic, 1894a,b). These cases were first cited as Devic's disease (DV) by a further case report in 1907 (Acchiote, 1907). The finding, more than one hundred years later of anti-AQP4 antibodies in a high percentage of patients affected by DV (Lennon et al., 2005, 2004), or neuromyelitis optica (NMO), dramatically increased the interest of neurologists (basic scientists and clinicians) to this rare disease, which was until then considered a manifestation of multiple sclerosis (MS) and treated accordingly. The availability of a specific biomarker, for this distinct disease has had several clinical implications, first of all allowing the clinicians to make an earlier and more certain diagnosis, and consequently to use a more specific therapeutic approach. Moreover, NMO is now considered an autoimmune channelopathy rather than a generic inflammatory CNS disease.
⁎ Corresponding author. Clinical Neuroimmunology Unit-Dibit, San Raffaele Scientific Institute, Via Olgettina, 58, 20132 Milano, Italy. Tel.: +39 0226432791; fax: +39 0226434855. 0165-5728/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.jneuroim.2010.10.012
In the past, neurologists considered NMO as a particular subtype of MS, clinically characterized by the selective involvement of the optic nerve and the spinal cord, with the absence of the typical brain MRI lesions and relative absence of oligoclonal bands (OCB), and by the presence of pleocytosis in the CSF. Until 2004, NMO diagnosis was made according to major and minor supportive, clinical and paraclinical, criteria (Wingerchuk et al., 1999) with an accent on the presence of pleocytosis (more than 50 leucocytes/mm3) and the absence of complete recovery after the attack. In the early phases of the disease it is clinically very difficult to distinguish between classical MS and NMO. Typically, patients with optic neuritis and myelitis were treated for MS for years before the diagnosis of NMO was finally reached. In 2004, Lennon and co-workers identified in sera of patients with Devic's disease the presence of IgG antibodies directed against brain vessel walls, Virkow-Robin spaces, glia limitans and the ependyma, and called them NMO-IgG (Lennon et al., 2004). A year later, the aquaporin-4 (AQP4) water channel, the most abundantly expressed water channel in the brain, was identified as the target antigen of these auto-antibodies (Lennon et al., 2005). This finding had several effects in clinical neuroimmunology: the first is that NMO was at last (and not by all) considered a different disease from MS, its pathogenesis related to humoral responses. NMO-IgG positive status became a supportive criterion for the diagnosis of NMO and, consequently, diagnosis of NMO can now be made more easily during the early phases of the disease (Wingerchuk et al., 2006). Secondly, clinicians noticed a broadening of the NMO clinical spectrum including not only clinically definite NMO, but also partial forms such as longitudinally extending transverse myelitis (LETM), or recurrent optic neuritis (ON), with the practical consequence that patients were treated with a more appropriate therapy earlier than in the past.
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2. Epidemiology and clinical features From an epidemiological point of view, NMO is a rare disease, more frequent in non-Caucasians, while classic MS is more frequent in Caucasian populations. In a recent Italian study the prevalence of NMO among CNS demyelinating diseases was found to be 1.5% with a MS/NMO ratio of 42.7 (Bizzoco et al., 2009). In Asian countries, on the other hand, NMO, often called optico-spinal MS (OSMS) represents 15–40% of all MS forms (Kira, 2003). NMO is an inflammatory demyelinating disease of the CNS mainly involving the optic nerve and the spinal cord. Eugéne Devic described it as a monophasic illness with the concomitance of blindness and spinal cord signs. In the following years, however, several patients with a relapsing–remitting course have been described. The relapses can occur within months from the onset of clinical symptoms (Wingerchuk et al., 1999). In particular Wingerchuk underlined that, in the relapsing–remitting forms, the second attack appeared within the first year in 60% of patients and within 3 years in 95% of patients (Wingerchuk et al., 1999). In a more recent French study on 125 patients affected by NMO, the median interval between the first and second attacks was 12 months and the median optical–spinal interval (i.e. the time between the occurrence of optic neuritis and myelitis) was 15 months (Collongues et al., 2010). Now we know that the relapsing–remitting form is more frequent than the monophasic one, representing approximately 80–90% of cases (O'Riordan et al., 1996; Wingerchuk et al., 1999; Wingerchuk and Weinshenker, 2003). A longer interval between the first two episodes (more than six months), an older age at onset, the female gender, and a benign first myelitis attack are all prognostic factors for a relapsing course (Wingerchuk and Weinshenker, 2003). Monophasic NMO is less biased towards females, has a less severe respiratory involvement and has a lower mortality rate than the relapsing form (Hazin et al., 2009). Relapsing–remitting NMO has been considered for years as an aggressive form of MS. Even if the clinical appearance of the two diseases may be similar, in particular at onset when patient may have optic neuritis or myelitis, the neuroradiologic and pathological features are very different (Wingerchuk et al., 2007). Furthermore, a progressive course is a rare event in NMO, while it is the natural evolution in most MS patients, indicating a different pathogenic mechanism in determining the CNS damage (Wingerchuk et al., 2007). The presence of antibodies directed against AQP4 in sera of patients affected by NMO disease greatly contributed to differentiate NMO from MS, confirming the hypothesis that NMO may be a humoral-mediated disease, while, up to now, no disease-specific antibodies of likely pathogenic significance have been detected in MS despite much effort. Since 2005, several studies revealed anti-AQP4 antibodies in between 33 and almost 100% of NMO patient ranges (Adoni et al., 2010; Cabrera-Gomez et al., 2009; Collongues et al., 2010; Jarius et al., 2007; Saiz et al., 2007; Waters and Vincent, 2008) and also in patients with LEMT (50–80%) (Saiz et al., 2007; Takahashi et al., 2007; Waters et al., 2008) and in relapsing ON (14–20%) (Matiello et al., 2008; Saiz et al., 2007). Thus, we now consider NMO as a syndrome with a wide spectrum of clinical manifestations, from classical defined NMO to isolated LETM, isolated recurrent ON, or ON and LETM-associated with systemic autoimmune diseases such as Systemic Lupus Erythematosus (Wingerchuk et al., 2007). As a result, the classical diagnostic criteria (Wingerchuk et al., 1999) were revised and replaced in 2006 by new criteria and antiAQP4 antibodies (or NMO-IgG) have a crucial role in the diagnosis of NMO, more than the MRI criteria (Wingerchuk et al., 2006). 3. Japanese form of MS In Japan, classical MS is very rare and typically involves the optic nerve and the spinal cord, clinically resembling relapsing–remitting
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NMO described in Western countries (Kira, 2003). Also MRI studies reveal striking similarities between Asian (OSMS) and classic NMO with transverse myelitis lesions extending for three or more vertebral segments, principally involving the thoracic spinal cord. Compared to classical MS, OSMS in Asian people demonstrates older age, female gender preponderance, higher relapse rate, and greater disability due to severe optic nerve and spinal cord involvement—similar characteristics to those in Western NMO patients. NMO-IgG or AQP4 antibodies are present in Asian OSMS, but less frequently than in Western NMO, indicating that the anti-AQP4 antibodies positive status does not completely overlap OSMS in the Asian populations (Kira, 2008). 4. Clinical signs NMO is a very disabling disease: about 50% of patients have severe visual deficits, or motor impairment within 5 years from the onset (Ghezzi et al., 2004; Wingerchuk and Weinshenker, 2003). In a recent French study, (Collongues et al., 2010) it was reported that 55.8% of NMO patients need support to walk. Mortality rate ranges from 2.9 to 25% within five years (Collongues et al., 2010; Ghezzi et al., 2004; Papais-Alvarenga et al., 2002; Rivera et al., 2008; Wingerchuk and Weinshenker, 2003). Negative prognostic factors are a high relapse rate in the first year of the disease, the severity of the first attack, a poor recovery after the first attack and a high number of brain lesions (Cabrera-Gomez et al., 2009; Collongues et al., 2010; Ghezzi et al., 2004; Wingerchuk and Weinshenker, 2003). Other clinical features distinguishing NMO from classic MS, are the absence of full recovery from optic neuritis and the more frequent relapses in NMO. Furthermore, myelitis in NMO is characterized by symmetric and bilateral signs associated with sphincter symptoms related to the complete transverse spinal lesion. Respiratory impairment is also present resulted from bulbar lesions. MRI brain lesions are often found in patients with NMO, but these lesions are mainly located where AQP4 is mostly expressed in the brain, i.e. the brainstem, the hypothalamus and the diencephalus (Pittock et al., 2006b). However, many NMO patients during the illness (around 60%) display nonspecific cerebral lesions in the white matter and 10% of these lesions are consistent with the Barkhof's criteria for MS (Pittock et al., 2006a). 5. Prognostic value The prognostic role of these antibodies is still debated. In a prospective study on 29 patients with a first LETM event, NMO-IgG positive status was predictive for the occurrence of a subsequent relapse (56% patients) as compared with NMO-IgG negative patients, experiencing no relapses (Weinshenker et al., 2006). In a one year follow-up study, 40% of patients with NMO-IgG positive status had a relapse, versus no relapses in the seronegative group (Lennon et al., 2004). In a study of patients with recurrent LETM, AQP4 positivity was associated with lesions located in upper to middle thoracic cord, involving the gray matter, to female predominance, to higher relapse rate, to more brain lesions, and to less frequent response to interferon beta therapy (Matsuoka et al., 2007). The titres of anti-AQP4 antibodies may be relevant too: in a longitudinal study involving 8 patients with NMO, sera were serially evaluated and a 3 fold elevation of the anti-AQP4 antibody titre was observed at clinical relapse, suggesting a pathogenic role of these antibodies (Jarius et al., 2008b). Indeed, immunosuppressive drugs, such as azathioprin, cyclophosphamide and rituximab induce a marked reduction of antibody titres and of clinical NMO episodes/relapses (Jarius et al., 2008b). Using an in vitro approach, it was also shown that there is a statistically significant association between attack severity in NMO patients, and measures of complement mediated injury to AQP4expressing cells (Hinson et al., 2009). On the contrary, in a series of 28 Brazilian patients affected by NMO, the NMO-IgG status did not correlate with the extension of spinal cord lesions (Adoni et al., 2010).
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6. Pathogenic role of anti-AQP4 antibodies The pathological hallmark of NMO lesions is a very selective and characteristic deposition of immunoglobulins and complement on astrocytes at the glia limitans, which is associated with destruction and loss of glial fibrillary acidic protein and AQP4 positive astrocytes in fresh lesions, associated with demyelination and global tissue destruction (Lucchinetti et al., 2002). NMO lesions demonstrate a striking loss of AQP4 regardless of the stage of demyelinating activity suggesting that indeed AQP4 is the target of the immune response (Roemer et al., 2007). As in other antibody-mediated diseases, granulocytes, and in particular eosinophils, are major components of the inflammatory infiltrates (Lucchinetti et al., 2002). Strikingly, the regional AQP4 expression in the brain corresponds to the distribution of the lesions in the brain and spinal cord of NMO patients (Pittock and Lennon, 2008). Ex juvantibus, we should also note, that therapies targeting antibodies (IVIg or plasma exchange) (Watanabe et al., 2007), or targeting B lymphocytes (Rituximab) (Cree et al., 2005), have been reported to be partially effective in NMO. Based on this evidence, NMO is now largely considered an antibody-mediated autoimmune disease. However, direct proof of the pathogenic potential of AQP4 antibodies has started to emerge only recently. The definitive piece of evidence needed, is clearly the possibility to passively transfer the disease to rodents with anti-AQP4 antibodies. It has now been shown that anti-AQP4 antibodies from NMO patients administered to rats or guinea pigs with experimental autoimmune encephalomyelitis, or at least immunized with CFA, were able to increase the severity of the disease (Bennett et al., 2009; Bradl et al., 2009; Kinoshita et al., 2010) or, with additional human complement, directly induce lesions (Saadoun and Papadopoulos, 2010). Most convincing, the immunopathological features resembled those already described for NMO patients: with extensive immunoglobulin and complement deposition on astrocyte processes of the perivascular and superficial glia limitans, and granulocytic infiltrates, T cells and activated macrophages/microglia cells, with AQP4 and astrocyte loss (Bradl et al., 2009). The attempt to transfer disease in naïve animals, however, failed. Possible effector function of anti-AQP4 antibodies binding to their target could be alteration of the blood brain barrier, and the infiltration of granulocytes (Vincent et al., 2008). Importantly, the loss of the excitatory amino acid transporter 2 (EAAT2), which is complexed with AQP4, and the consequent increase of glutamatergic excitotoxicity (Hinson et al., 2008) are also likely to be pathogenic mechanisms. Since it has been reported that anti-AQP4 antibodies preferentially bind AQP4 when it is organized in orthogonal arrays (Nicchia et al., 2009) there may also be specific functional alterations of water balance that have not been reported yet. 7. Detection of anti-AQP4 antibodies The measurement of NMO-IgG or anti-AQP4 antibodies has undoubtedly become a valuable tool in the differential diagnosis between NMO, MS and the different forms of transverse myelitis. This will clearly impact on the treatment strategies and thus to long term prognosis of such patients. It may also lead, however, to the identification of a spectrum of new nosological entities, associated with anti-AQP4 antibodies. Identification of sensitive and specific assays to measure the antibodies, as well as their specificities in the different groups of patients, is necessary. In the recent history of neuroimmunology, the technological issues related to the detection of auto-antibodies has been overlooked several times, leading to the report of certain auto-antibodies as promising diagnostic or prognostic tools, not confirmed by subsequent follow-up studies, as, for example, in the case of anti-MOG and anti-MBP antibodies in MS patients (Kuhle et al., 2007). Several different techniques have been proposed to measure antiAQP4 antibody. The gold-standard proposed in the new diagnostic
criteria is the detection of NMO-IgG by indirect immunofluorescence on brain tissue, in particular that performed on monkey cerebellum (Wingerchuk et al., 2006). However, several reliable techniques measure the more specific anti-AQP4 antibodies (Waters and Vincent, 2008). Immunofluorescence performed on AQP4-transfected cell lines is generally the most sensitive (Fazio et al., 2009; Lennon et al., 2005), and potentially highly specific (Fig. 1). Although different techniques measure two different entities, NMO-IgGG and anti-AQP4 antibodies (Fazio et al., 2009), there is no evidence that NMO-IgG includes reactivities against proteins other than AQP4, and the results should be similar, as shown in other studies (Waters and Vincent, 2008). Nevertheless, parallel comparisons of different techniques can demonstrate incoherence between assays, possibly due to differences in the features of the antigen (Fazio et al., 2009). More quantitative techniques, such as FACS analysis, radioimmunoprecipitation assays (RIPA), and fluorescence based immunoprecipitation assays (FIPA) are more specific but less sensitive when compared to immunofluorescence (Fazio et al., 2009; Hinson et al., 2007; Jarius et al., 2008a; Paul et al., 2007). There are comparable rates of incoherence in multicentric workshops as, for example, those for ICA in diabetes (Bingley et al., 2003; Torn et al., 2008). More problems may emerge when techniques hampered by non-specific binding of human serum IgG, like ELISA, are more widely used (Hayakawa et al., 2008). 8. Conclusions After over a hundred year from its first description, Devic's disease has regained attention because of the possible lessons that can be learned from the discovery of its association with anti-AQP4 antibodies, information that may shed light on the possible mechanisms leading to site-specific neuroinflammation. Typically brain MRI is normal or, especially in late stages, displays T2 weighted lesions in atypical sites such as the brainstem or peri-aqueductal areas. The spinal cord MRI discloses extended lesions longer than three segments. CSF shows a mild pleocytosis and is mostly without oligoclonal bands, which is remarkable for an antibody-mediated CNS disorder. The detection of NMO-IgG has changed also the therapeutic approach. In fact the antibody-mediated pathogenesis suggests the use of drugs targeting humoral immunity such as plasmapheresis, cyclophosphamide, rituximab, that are now the most widely used treatments in this disease. Their use in the early stages of NMO may induce better control of the evolution of the neurological signs. The correlation between anti-NMO positive status and aggressive course, underlined in several papers, is a clear indication to use aggressive immunosuppressive drugs in NMO patients with anti-AQP4 antibodies, even in the early stage of the disease in the hope of preventing further relapses and irreversible disability. With identification of AQP4 as the target of NMO-IgG, however, not all the pathogenesis of NMO has been clarified, and effector mechanisms may be diverse and complex in nature. Anti-AQP4 antibodies were able to transfer disease only in rodents with an ongoing, T cell mediated and CNS-specific, autoimmune process, or when injected into the brain with human complement. This may be due to a particular resistance of the rodent strains to this disease, but it may also indicate the need for predisposing conditions, since in humans with NMO there are often signs of a concomitant autoimmune process affecting the brain. This has been explained with the coincidence of most frequently affected areas with the areas of highest AQP4 expression in the brain, however, it is suggestive to think that anti-AQP4 antibodies, as in rodents, act as add-on to an underlying, often sub-clinical, encephalitic process. This would explain also the great variety of clinical manifestation of NMO, due to reciprocal balance of the two, humoral and T cell mediated, components. European and North-American neurologists are consistent with the hypothesis that NMO is a different disease from classical MS, supported by the evidence of anti-AQP4 antibodies, but Asian
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Fig. 1. EGFP-AQP4 transfected cells bind human NMO-Ig. 293T cells were transfected with an EGFP-AQP4 fusion protein. The fluorescence from GFP, demonstrating its correct subcellular localization, is shown in A, its ability to bind antibodies from an NMO serum in B, and the degree of co-localization of the two fluorescent stainings in the merge in C.
neurologists sometimes report NMO-IgG positivity in MS and support the idea of a continuum between OSMS, MS and NMO. All these aspects will be better clarified when we will be able to merge the data from different studies around the world, and this requires shared and standardized tools for the diagnosis. Thus it is essential to standardize and optimize assays across laboratories worldwide with independent quality control. To achieve this goal an international effort, similar to what has been done for the detection of ICA in the field of diabetes, is, in our opinion, definitively needed.
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Contents lists available at ScienceDirect
Journal of Neuroimmunology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j n e u r o i m
Neuromyelitis optica: Concepts in evolution Raffaella Fazio, Marta Radaelli, Roberto Furlan ⁎ Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy Department of Neurology, San Raffaele Scientific Institute, Milan, Italy
a r t i c l e Keywords: Neuromyelitis optica Devic's disease Aquaporin-4 Myelitis Optic neuritis Multiple sclerosis
i n f o
a b s t r a c t Neuromyelitis optica (NMO) is a rare demyelinating disease, affecting selectively the optic nerve and the spinal cord. It was previously considered to be a severe variant of multiple sclerosis (MS) due to the similar pathological features and its resemblance to optico-spinal, or Japanese, MS, typical of Asian populations. The finding that most NMO patients have auto-antibodies against aquaporin-4, a water channel particularly abundant on the astrocytes of the glia limitans, has allowed early diagnosis and specific treatment of these patients, and has greatly improved our knowledge of its pathogenesis. When laboratories worldwide can detect anti-aquaporin-4 auto-antibodies with comparable sensitivity and specificity, we will be able to have large multi-centric studies to define better the epidemiological, clinical and pathological features of patients and their responses to treatment. © 2010 Elsevier B.V. All rights reserved.
1. Introduction Sir Thomas Clifford Allbutt, stated in 1870 for the first time that “it is tolerably certain that disturbances of the optic disc and its neighborhood is seen to follow disturbances of the spine with sufficient frequency and uniformity to establish the probability of a causal relation between the two events” (Allbutt, 1870). Ten years later Dr. Wilhelm Erb, in 1880 published a paper entitled “On the concurrence of optic neuritis and myelitis subacuta” (Erb, 1880). Fourteen years later, Eugéne Devic supervised a medical student, Fernand Gault, in his PhD thesis work describing 17 cases of optic neuromyelitis (Gault, 1894), then reported by Devic himself (Devic, 1894a,b). These cases were first cited as Devic's disease (DV) by a further case report in 1907 (Acchiote, 1907). The finding, more than one hundred years later of anti-AQP4 antibodies in a high percentage of patients affected by DV (Lennon et al., 2005, 2004), or neuromyelitis optica (NMO), dramatically increased the interest of neurologists (basic scientists and clinicians) to this rare disease, which was until then considered a manifestation of multiple sclerosis (MS) and treated accordingly. The availability of a specific biomarker, for this distinct disease has had several clinical implications, first of all allowing the clinicians to make an earlier and more certain diagnosis, and consequently to use a more specific therapeutic approach. Moreover, NMO is now considered an autoimmune channelopathy rather than a generic inflammatory CNS disease.
⁎ Corresponding author. Clinical Neuroimmunology Unit-Dibit, San Raffaele Scientific Institute, Via Olgettina, 58, 20132 Milano, Italy. Tel.: +39 0226432791; fax: +39 0226434855. 0165-5728/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.jneuroim.2010.10.012
In the past, neurologists considered NMO as a particular subtype of MS, clinically characterized by the selective involvement of the optic nerve and the spinal cord, with the absence of the typical brain MRI lesions and relative absence of oligoclonal bands (OCB), and by the presence of pleocytosis in the CSF. Until 2004, NMO diagnosis was made according to major and minor supportive, clinical and paraclinical, criteria (Wingerchuk et al., 1999) with an accent on the presence of pleocytosis (more than 50 leucocytes/mm3) and the absence of complete recovery after the attack. In the early phases of the disease it is clinically very difficult to distinguish between classical MS and NMO. Typically, patients with optic neuritis and myelitis were treated for MS for years before the diagnosis of NMO was finally reached. In 2004, Lennon and co-workers identified in sera of patients with Devic's disease the presence of IgG antibodies directed against brain vessel walls, Virkow-Robin spaces, glia limitans and the ependyma, and called them NMO-IgG (Lennon et al., 2004). A year later, the aquaporin-4 (AQP4) water channel, the most abundantly expressed water channel in the brain, was identified as the target antigen of these auto-antibodies (Lennon et al., 2005). This finding had several effects in clinical neuroimmunology: the first is that NMO was at last (and not by all) considered a different disease from MS, its pathogenesis related to humoral responses. NMO-IgG positive status became a supportive criterion for the diagnosis of NMO and, consequently, diagnosis of NMO can now be made more easily during the early phases of the disease (Wingerchuk et al., 2006). Secondly, clinicians noticed a broadening of the NMO clinical spectrum including not only clinically definite NMO, but also partial forms such as longitudinally extending transverse myelitis (LETM), or recurrent optic neuritis (ON), with the practical consequence that patients were treated with a more appropriate therapy earlier than in the past.
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2. Epidemiology and clinical features From an epidemiological point of view, NMO is a rare disease, more frequent in non-Caucasians, while classic MS is more frequent in Caucasian populations. In a recent Italian study the prevalence of NMO among CNS demyelinating diseases was found to be 1.5% with a MS/NMO ratio of 42.7 (Bizzoco et al., 2009). In Asian countries, on the other hand, NMO, often called optico-spinal MS (OSMS) represents 15–40% of all MS forms (Kira, 2003). NMO is an inflammatory demyelinating disease of the CNS mainly involving the optic nerve and the spinal cord. Eugéne Devic described it as a monophasic illness with the concomitance of blindness and spinal cord signs. In the following years, however, several patients with a relapsing–remitting course have been described. The relapses can occur within months from the onset of clinical symptoms (Wingerchuk et al., 1999). In particular Wingerchuk underlined that, in the relapsing–remitting forms, the second attack appeared within the first year in 60% of patients and within 3 years in 95% of patients (Wingerchuk et al., 1999). In a more recent French study on 125 patients affected by NMO, the median interval between the first and second attacks was 12 months and the median optical–spinal interval (i.e. the time between the occurrence of optic neuritis and myelitis) was 15 months (Collongues et al., 2010). Now we know that the relapsing–remitting form is more frequent than the monophasic one, representing approximately 80–90% of cases (O'Riordan et al., 1996; Wingerchuk et al., 1999; Wingerchuk and Weinshenker, 2003). A longer interval between the first two episodes (more than six months), an older age at onset, the female gender, and a benign first myelitis attack are all prognostic factors for a relapsing course (Wingerchuk and Weinshenker, 2003). Monophasic NMO is less biased towards females, has a less severe respiratory involvement and has a lower mortality rate than the relapsing form (Hazin et al., 2009). Relapsing–remitting NMO has been considered for years as an aggressive form of MS. Even if the clinical appearance of the two diseases may be similar, in particular at onset when patient may have optic neuritis or myelitis, the neuroradiologic and pathological features are very different (Wingerchuk et al., 2007). Furthermore, a progressive course is a rare event in NMO, while it is the natural evolution in most MS patients, indicating a different pathogenic mechanism in determining the CNS damage (Wingerchuk et al., 2007). The presence of antibodies directed against AQP4 in sera of patients affected by NMO disease greatly contributed to differentiate NMO from MS, confirming the hypothesis that NMO may be a humoral-mediated disease, while, up to now, no disease-specific antibodies of likely pathogenic significance have been detected in MS despite much effort. Since 2005, several studies revealed anti-AQP4 antibodies in between 33 and almost 100% of NMO patient ranges (Adoni et al., 2010; Cabrera-Gomez et al., 2009; Collongues et al., 2010; Jarius et al., 2007; Saiz et al., 2007; Waters and Vincent, 2008) and also in patients with LEMT (50–80%) (Saiz et al., 2007; Takahashi et al., 2007; Waters et al., 2008) and in relapsing ON (14–20%) (Matiello et al., 2008; Saiz et al., 2007). Thus, we now consider NMO as a syndrome with a wide spectrum of clinical manifestations, from classical defined NMO to isolated LETM, isolated recurrent ON, or ON and LETM-associated with systemic autoimmune diseases such as Systemic Lupus Erythematosus (Wingerchuk et al., 2007). As a result, the classical diagnostic criteria (Wingerchuk et al., 1999) were revised and replaced in 2006 by new criteria and antiAQP4 antibodies (or NMO-IgG) have a crucial role in the diagnosis of NMO, more than the MRI criteria (Wingerchuk et al., 2006). 3. Japanese form of MS In Japan, classical MS is very rare and typically involves the optic nerve and the spinal cord, clinically resembling relapsing–remitting
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NMO described in Western countries (Kira, 2003). Also MRI studies reveal striking similarities between Asian (OSMS) and classic NMO with transverse myelitis lesions extending for three or more vertebral segments, principally involving the thoracic spinal cord. Compared to classical MS, OSMS in Asian people demonstrates older age, female gender preponderance, higher relapse rate, and greater disability due to severe optic nerve and spinal cord involvement—similar characteristics to those in Western NMO patients. NMO-IgG or AQP4 antibodies are present in Asian OSMS, but less frequently than in Western NMO, indicating that the anti-AQP4 antibodies positive status does not completely overlap OSMS in the Asian populations (Kira, 2008). 4. Clinical signs NMO is a very disabling disease: about 50% of patients have severe visual deficits, or motor impairment within 5 years from the onset (Ghezzi et al., 2004; Wingerchuk and Weinshenker, 2003). In a recent French study, (Collongues et al., 2010) it was reported that 55.8% of NMO patients need support to walk. Mortality rate ranges from 2.9 to 25% within five years (Collongues et al., 2010; Ghezzi et al., 2004; Papais-Alvarenga et al., 2002; Rivera et al., 2008; Wingerchuk and Weinshenker, 2003). Negative prognostic factors are a high relapse rate in the first year of the disease, the severity of the first attack, a poor recovery after the first attack and a high number of brain lesions (Cabrera-Gomez et al., 2009; Collongues et al., 2010; Ghezzi et al., 2004; Wingerchuk and Weinshenker, 2003). Other clinical features distinguishing NMO from classic MS, are the absence of full recovery from optic neuritis and the more frequent relapses in NMO. Furthermore, myelitis in NMO is characterized by symmetric and bilateral signs associated with sphincter symptoms related to the complete transverse spinal lesion. Respiratory impairment is also present resulted from bulbar lesions. MRI brain lesions are often found in patients with NMO, but these lesions are mainly located where AQP4 is mostly expressed in the brain, i.e. the brainstem, the hypothalamus and the diencephalus (Pittock et al., 2006b). However, many NMO patients during the illness (around 60%) display nonspecific cerebral lesions in the white matter and 10% of these lesions are consistent with the Barkhof's criteria for MS (Pittock et al., 2006a). 5. Prognostic value The prognostic role of these antibodies is still debated. In a prospective study on 29 patients with a first LETM event, NMO-IgG positive status was predictive for the occurrence of a subsequent relapse (56% patients) as compared with NMO-IgG negative patients, experiencing no relapses (Weinshenker et al., 2006). In a one year follow-up study, 40% of patients with NMO-IgG positive status had a relapse, versus no relapses in the seronegative group (Lennon et al., 2004). In a study of patients with recurrent LETM, AQP4 positivity was associated with lesions located in upper to middle thoracic cord, involving the gray matter, to female predominance, to higher relapse rate, to more brain lesions, and to less frequent response to interferon beta therapy (Matsuoka et al., 2007). The titres of anti-AQP4 antibodies may be relevant too: in a longitudinal study involving 8 patients with NMO, sera were serially evaluated and a 3 fold elevation of the anti-AQP4 antibody titre was observed at clinical relapse, suggesting a pathogenic role of these antibodies (Jarius et al., 2008b). Indeed, immunosuppressive drugs, such as azathioprin, cyclophosphamide and rituximab induce a marked reduction of antibody titres and of clinical NMO episodes/relapses (Jarius et al., 2008b). Using an in vitro approach, it was also shown that there is a statistically significant association between attack severity in NMO patients, and measures of complement mediated injury to AQP4expressing cells (Hinson et al., 2009). On the contrary, in a series of 28 Brazilian patients affected by NMO, the NMO-IgG status did not correlate with the extension of spinal cord lesions (Adoni et al., 2010).
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6. Pathogenic role of anti-AQP4 antibodies The pathological hallmark of NMO lesions is a very selective and characteristic deposition of immunoglobulins and complement on astrocytes at the glia limitans, which is associated with destruction and loss of glial fibrillary acidic protein and AQP4 positive astrocytes in fresh lesions, associated with demyelination and global tissue destruction (Lucchinetti et al., 2002). NMO lesions demonstrate a striking loss of AQP4 regardless of the stage of demyelinating activity suggesting that indeed AQP4 is the target of the immune response (Roemer et al., 2007). As in other antibody-mediated diseases, granulocytes, and in particular eosinophils, are major components of the inflammatory infiltrates (Lucchinetti et al., 2002). Strikingly, the regional AQP4 expression in the brain corresponds to the distribution of the lesions in the brain and spinal cord of NMO patients (Pittock and Lennon, 2008). Ex juvantibus, we should also note, that therapies targeting antibodies (IVIg or plasma exchange) (Watanabe et al., 2007), or targeting B lymphocytes (Rituximab) (Cree et al., 2005), have been reported to be partially effective in NMO. Based on this evidence, NMO is now largely considered an antibody-mediated autoimmune disease. However, direct proof of the pathogenic potential of AQP4 antibodies has started to emerge only recently. The definitive piece of evidence needed, is clearly the possibility to passively transfer the disease to rodents with anti-AQP4 antibodies. It has now been shown that anti-AQP4 antibodies from NMO patients administered to rats or guinea pigs with experimental autoimmune encephalomyelitis, or at least immunized with CFA, were able to increase the severity of the disease (Bennett et al., 2009; Bradl et al., 2009; Kinoshita et al., 2010) or, with additional human complement, directly induce lesions (Saadoun and Papadopoulos, 2010). Most convincing, the immunopathological features resembled those already described for NMO patients: with extensive immunoglobulin and complement deposition on astrocyte processes of the perivascular and superficial glia limitans, and granulocytic infiltrates, T cells and activated macrophages/microglia cells, with AQP4 and astrocyte loss (Bradl et al., 2009). The attempt to transfer disease in naïve animals, however, failed. Possible effector function of anti-AQP4 antibodies binding to their target could be alteration of the blood brain barrier, and the infiltration of granulocytes (Vincent et al., 2008). Importantly, the loss of the excitatory amino acid transporter 2 (EAAT2), which is complexed with AQP4, and the consequent increase of glutamatergic excitotoxicity (Hinson et al., 2008) are also likely to be pathogenic mechanisms. Since it has been reported that anti-AQP4 antibodies preferentially bind AQP4 when it is organized in orthogonal arrays (Nicchia et al., 2009) there may also be specific functional alterations of water balance that have not been reported yet. 7. Detection of anti-AQP4 antibodies The measurement of NMO-IgG or anti-AQP4 antibodies has undoubtedly become a valuable tool in the differential diagnosis between NMO, MS and the different forms of transverse myelitis. This will clearly impact on the treatment strategies and thus to long term prognosis of such patients. It may also lead, however, to the identification of a spectrum of new nosological entities, associated with anti-AQP4 antibodies. Identification of sensitive and specific assays to measure the antibodies, as well as their specificities in the different groups of patients, is necessary. In the recent history of neuroimmunology, the technological issues related to the detection of auto-antibodies has been overlooked several times, leading to the report of certain auto-antibodies as promising diagnostic or prognostic tools, not confirmed by subsequent follow-up studies, as, for example, in the case of anti-MOG and anti-MBP antibodies in MS patients (Kuhle et al., 2007). Several different techniques have been proposed to measure antiAQP4 antibody. The gold-standard proposed in the new diagnostic
criteria is the detection of NMO-IgG by indirect immunofluorescence on brain tissue, in particular that performed on monkey cerebellum (Wingerchuk et al., 2006). However, several reliable techniques measure the more specific anti-AQP4 antibodies (Waters and Vincent, 2008). Immunofluorescence performed on AQP4-transfected cell lines is generally the most sensitive (Fazio et al., 2009; Lennon et al., 2005), and potentially highly specific (Fig. 1). Although different techniques measure two different entities, NMO-IgGG and anti-AQP4 antibodies (Fazio et al., 2009), there is no evidence that NMO-IgG includes reactivities against proteins other than AQP4, and the results should be similar, as shown in other studies (Waters and Vincent, 2008). Nevertheless, parallel comparisons of different techniques can demonstrate incoherence between assays, possibly due to differences in the features of the antigen (Fazio et al., 2009). More quantitative techniques, such as FACS analysis, radioimmunoprecipitation assays (RIPA), and fluorescence based immunoprecipitation assays (FIPA) are more specific but less sensitive when compared to immunofluorescence (Fazio et al., 2009; Hinson et al., 2007; Jarius et al., 2008a; Paul et al., 2007). There are comparable rates of incoherence in multicentric workshops as, for example, those for ICA in diabetes (Bingley et al., 2003; Torn et al., 2008). More problems may emerge when techniques hampered by non-specific binding of human serum IgG, like ELISA, are more widely used (Hayakawa et al., 2008). 8. Conclusions After over a hundred year from its first description, Devic's disease has regained attention because of the possible lessons that can be learned from the discovery of its association with anti-AQP4 antibodies, information that may shed light on the possible mechanisms leading to site-specific neuroinflammation. Typically brain MRI is normal or, especially in late stages, displays T2 weighted lesions in atypical sites such as the brainstem or peri-aqueductal areas. The spinal cord MRI discloses extended lesions longer than three segments. CSF shows a mild pleocytosis and is mostly without oligoclonal bands, which is remarkable for an antibody-mediated CNS disorder. The detection of NMO-IgG has changed also the therapeutic approach. In fact the antibody-mediated pathogenesis suggests the use of drugs targeting humoral immunity such as plasmapheresis, cyclophosphamide, rituximab, that are now the most widely used treatments in this disease. Their use in the early stages of NMO may induce better control of the evolution of the neurological signs. The correlation between anti-NMO positive status and aggressive course, underlined in several papers, is a clear indication to use aggressive immunosuppressive drugs in NMO patients with anti-AQP4 antibodies, even in the early stage of the disease in the hope of preventing further relapses and irreversible disability. With identification of AQP4 as the target of NMO-IgG, however, not all the pathogenesis of NMO has been clarified, and effector mechanisms may be diverse and complex in nature. Anti-AQP4 antibodies were able to transfer disease only in rodents with an ongoing, T cell mediated and CNS-specific, autoimmune process, or when injected into the brain with human complement. This may be due to a particular resistance of the rodent strains to this disease, but it may also indicate the need for predisposing conditions, since in humans with NMO there are often signs of a concomitant autoimmune process affecting the brain. This has been explained with the coincidence of most frequently affected areas with the areas of highest AQP4 expression in the brain, however, it is suggestive to think that anti-AQP4 antibodies, as in rodents, act as add-on to an underlying, often sub-clinical, encephalitic process. This would explain also the great variety of clinical manifestation of NMO, due to reciprocal balance of the two, humoral and T cell mediated, components. European and North-American neurologists are consistent with the hypothesis that NMO is a different disease from classical MS, supported by the evidence of anti-AQP4 antibodies, but Asian
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Fig. 1. EGFP-AQP4 transfected cells bind human NMO-Ig. 293T cells were transfected with an EGFP-AQP4 fusion protein. The fluorescence from GFP, demonstrating its correct subcellular localization, is shown in A, its ability to bind antibodies from an NMO serum in B, and the degree of co-localization of the two fluorescent stainings in the merge in C.
neurologists sometimes report NMO-IgG positivity in MS and support the idea of a continuum between OSMS, MS and NMO. All these aspects will be better clarified when we will be able to merge the data from different studies around the world, and this requires shared and standardized tools for the diagnosis. Thus it is essential to standardize and optimize assays across laboratories worldwide with independent quality control. To achieve this goal an international effort, similar to what has been done for the detection of ICA in the field of diabetes, is, in our opinion, definitively needed.
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