Diagnosis and management of neuromyelitis optica spectrum disorders - An update

Autoimmunity Reviews 17 (2018) 195–200

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Autoimmunity Reviews journal homepage: www.elsevier.com/locate/autrev

Diagnosis and management of neuromyelitis optica spectrum disorders - An update Alice Bruscolini a, Marta Sacchetti a, Maurizio La Cava a, Magda Gharbiya a, Massimo Ralli b, Alessandro Lambiase a,⁎, Armando De Virgilio c, Antonio Greco a a b c

Department of Sense Organs, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy Department of Oral and Maxillofacial Sciences, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy Otorhinolaryngology Unit, Humanitas Clinical and Research Center, Via Alessandro Manzoni, 56, 20089 Rozzano (MI), Italy

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Article history: Received 3 October 2017 Accepted 8 October 2017 Available online 13 January 2018 Keywords: Neuromyelitis optica Neuromyelitis optica spectrum disorders Aquaporin-4 immunoglobulin G Diagnostic criteria Management

a b s t r a c t Neuromyelitis optica (NMO) and Neuromyelitis optica spectrum disorders (NMOSD) are a group of autoimmune conditions characterized by inflammatory involvement of the optic nerve, spinal cord and central nervous system. Novel evidence showed a key role of autoantibodies against aquaporin-4 immunoglobulin G (AQP4 IgG) in the pathogenesis of NMOSD and, recently, new classification and diagnostic criteria have been adopted to facilitate an earlier identification and improve the management of these conditions. Diagnosis of NMOSD is currently based on clinical, neuroimaging and laboratory features. Standard treatment is based on the use of steroids and immunosuppressive drugs and aims to control the severity of acute attacks and to prevent relapses of the disease. This review gives an update of latest knowledge of NMOSD and NMO, emphasizing the novel diagnostic criteria and both current and future therapeutic approaches. © 2018 Elsevier B.V. All rights reserved.

Contents 1. 2. 3. 4.

Introduction . . . . . . . . . . . . . . . . . Immunopathogenesis . . . . . . . . . . . . . Clinical manifestation and diagnostic criteria . . Standard management . . . . . . . . . . . . 4.1. Acute attack (first episode and/or relapse) 4.2. Maintenance treatment. . . . . . . . . 5. Novel therapeutic approaches . . . . . . . . . 6. Conclusions . . . . . . . . . . . . . . . . . Take home message . . . . . . . . . . . . . . . . Conflict of interest all authors . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . .

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Abbreviations: AQP4, aquaporin-4; AQP4 IgG, immunoglobulin G against aquaporin-4; ARR, Annualized Relapse Rates; AZT, azathioprine; BBB, blood-brain barrier; CNS, central nervous system; EDSS, Expanded Disability Status Scale; GFAP, glial fibrillary acid protein; ICAM1, intercellular adhesion molecule-1; LETM, longitudinally extensive transverse myelitis; MM, mycophenolate mofetil; MOG, myelin oligodendrocytes glycoprotein; MS, multiple sclerosis; NMO, neuromyelitis optica; NMOSD, neuromyelitis optica spectrum disorders; OCT, ocular coherence tomography; ON, optic neuritis; PLEX, plasma exchange; PNS, peripheral nervous system; VEP, visual evoked potential; VCAM1, vascular adhesion molecule-1; VEGF A, endothelial growth factor-A. ⁎ Corresponding author at: Department of Sense Organs, University Sapienza of Rome, Viale del Policlinico, 155, 00161 Rome, Italy. E-mail addresses: [email protected] (A. Bruscolini), [email protected] (M. Sacchetti), [email protected] (M. La Cava), [email protected] (M. Gharbiya), [email protected] (M. Ralli), [email protected] (A. Lambiase), [email protected] (A. De Virgilio), [email protected] (A. Greco).

https://doi.org/10.1016/j.autrev.2018.01.001 1568-9972/© 2018 Elsevier B.V. All rights reserved.

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A. Bruscolini et al. / Autoimmunity Reviews 17 (2018) 195–200

1. Introduction Neuromyelitis optica spectrum disorders (NMOSD), that include the neuromyelitis optica (NMO), previously known as Devic's syndrome, are a group of inflammatory disorders of the central nervous system (CNS) characterized by episodes of immune-mediated demyelination and axonal damage mainly involving optic nerves and spinal cord. The term “NMO spectrum disorders” (NMOSD) has been recently introduced to expand the definition of NMO and to include a wider spectrum of clinical manifestations [1,2]. In fact, the increasing understanding of the pathogenesis of these disorders, the identification of disease-specific serum NMO-IgG antibodies, that selectively bind aquaporin-4 (AQP4), and the definition of specific neuroimaging features of NMO resulted in the revision of the previous classification of NMO, redefined as NMOSD, with more specific diagnostic criteria and an update in the guidelines for disease management [3–6]. These clinical, immunological and radiological features allow a proper differential diagnosis between NMO and multiple sclerosis (MS), or autoimmune diseases [7–9]. Beside NMOSD with AQP4-IgG (NMOSD-AQP4), the novel classification has defined a group of NMOSD without AQP4-IgG or with unknown AQP4-IgG status that includes patients with atypical manifestations such as unilateral optic neuritis (ON), isolated or recurrent transverse myelitis, or isolated brain lesions with or without detectable anti AQP4-IgG autoantibody [10]. NMO is usually sporadic but a few familial cases have been described [11]. NMO is a rare disease (ORPHA:71211) that affects all ethnicities in different socio-economic environments, with a prevalence in ranging from 0.52 to 4.4/100000 in different studies [12–16]. Overall, the wide range of prevalence reported for NMO is due to variability in the source data, as well as to the different diagnostic criteria and assay used to test the AQP4-IgG. The aim of the present review is to describe clinical features of NMO and NMOSD and to provide an update on the novel classification, diagnostic criteria, and the current therapeutic approach. 2. Immunopathogenesis The causes of NMO and NMODS are still unknown, but it is widely recognized that these conditions are primarily antibody-mediated disorders with the main role played by the humoral immune system that targets astrocytes [17,18]. Several immune pathogenic targets have been described in NMOSD, including aquaporin (AQP), myelin oligodendrocytes glycoprotein (MOG), glial fibrillary acid protein (GFAP), S100 protein, metalloprotease-9, VEGF A, ICAM1 and VCAM1 [10,19,20]. Of note, the recent discovery of the aquaporin involvement in NMO increased the understanding of its pathogenic mechanisms, allowing a novel classification and opening novel perspectives in terms of therapeutic approach [2]. Aquaporins constitute a family of water channels that regulate the transport of water in many organs including the nervous system, eye, kidney, gastrointestinal tract, secretory glands, inner ear and muscles [21–25]. Aquaporin-4 (AQP4), the main target in NMO pathogenesis, is an integral protein of astrocytes and ependymal in the nervous system, of Müller cells in the retina and of Hensen's and inner sulcus cells in the ear [24,26]. In the mammalian brain, aquaporins are concentrated at the blood-brain barrier (BBB), anchored in the astrocytic foot process membrane by the dystroglycan complex [27]. Immunopathological studies have shown that AQP4 immunoreactivity is localized in a perivascular rim and rosette pattern, which matches the pattern of IgG and activated complement components deposition in NMO lesions [25]. Changes of the perivascular region with macrophage infiltration, complement and immunoglobulin deposition, and vascular hyalinization suggest that the perivascular space is the primary target site of the NMO inflammatory process [25]. The selective IgGs binding to aquaporin-4 down-regulates the AQP4 surface expression, causing

the increased BBB permeability in NMO. Moreover, the IgG-AQP4 complex binding to astrocytes activates the complement, with subsequent tissue infiltration of leucocytes (eosinophils and neutrophils), T lymphocytes (CD3+ and CD8+) and NK cells [18,26,28,29]. The resulting inflammatory process leads to astrocyte damage and death, and secondary oligodendrocyte and neuron involvement [25]. Two types of inflammatory demyelinating or non-demyelinating lesions have been described in NMO. The classic acute NMO lesion is characterized by confluent and/or focal perivascular demyelination, infiltration of inflammatory cells, severe axonal loss, necrosis of both the gray and white matter of the spinal cord, loss of astrocytes and oligodendrocytes [30]. The second type of NMO lesion, that is not characterized by demyelination, typically presents granulocytic inflammation, astrocyte and microglial activation, axonal damage and apoptosis of oligodendrocytes [31]. This last type of lesion can potentially be reversible. In the late and chronic stages, NMO lesions present gliosis, cavitation, cystic and atrophic degeneration of the optic nerves and spinal cord. An increasing number of blood vessels – with the walls thickening – within the necrotic lesion are a common histopathological feature [18]. In light of the wide spectrum of both demyelinating and nondemyelinating components in NMO, it is difficult to stage the disease based on lesions and according to classification schemes similar to those used to stage the demyelinating activity of multiple sclerosis (MS) plaques. 3. Clinical manifestation and diagnostic criteria NMO generally affects young adults (mean age 32.6–45.7 years) with a predominance in females (ranges from 68% to 88% of the affected population) [13,32]. However, cases of disease onset in the elderly and during childhood have been described [17]. The most typical clinical presentation of NMO is with acute optic neuritis (bilateral or rapidly sequential) or longitudinally extensive transverse myelitis (LETM) [33]. Optic neuritis (ON) is an inflammation of the optic nerve with a severe impairment of visual acuity that can lead to blindness associated to ocular pain. Transverse myelitis is an inflammatory disease involving three or more contiguous vertebral segments, also called longitudinally extensive transverse myelitis (LETM), that typically presents with several symptoms including paraplegia, bladder dysfunction and sensory loss [1–4,34]. The relapsing course of the disease is the most typical presentation, representing approximately 90% of NMOSD [33]. On the other hand, the monophasic course (representing the remaining 10% of cases) is uncommon and characterized by simultaneous ON and LETM severe attack with acute impairment and poorer prognosis of recovery if untreated [4]. The monophasic course does generally affects a younger population and does not appear to have gender differences in terms of prevalence; it has a less frequent association with other autoimmune diseases and a lower prevalence of AQP4IgG-serum antibodies [33]. The consensus panel who set up the new diagnostic criteria for NMOSD recommends that 5 years or longer of relapse-free time is necessary before making a monophasic course diagnosis. In patients with a relapsing course, after the first occurrence of NMO, the relapses may occur within one year (60% of patients) or up to three (90% patients) or more years, and presents a typically progressive course that leads to the development of persistent disabilities [4,8]. These typical and common clinical features are observed in most NMO patients, and great efforts have been made to identify diagnostic criteria that can allow a prompt and timely diagnosis of all cases, including those with partial or uncommon manifestations. These criteria are based on medical history, clinical manifestations, laboratory tests and MRI features, and have significantly evolved over the years in parallel to the increased understanding of NMO pathogenic mechanisms [34]. The basis for a consensus over NMO diagnostic criteria was set back in 1999 and revised in 2006, and the first actual international consensus

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was reached in 2015 when the current criteria were enunciated [1,2,33]. These new and updated criteria have adopted the broader term of NMO Spectrum Disorders (NMOSD) to include patients with limited or uncommon manifestations (Table 1). More importantly, they have classified NMOSD into two subtypes based on the role of AQP4-IgG in the disease pathogenesis: NMOSD with AQP4-IgG (NMOSD-AQP4); and NMOSD without AQP4-IgG or with unknown AQP4-IgG status. According to the new diagnostic criteria, NMOSD-AQP4 refers to patients with: (i) at least one of the six core clinical characteristics of NMOSD that confirm the involvement of either the optic nerve, spinal cord, dorsal medullar, brainstem, diencephalon, or cerebrum; (ii) positive AQP4-IgG; (iii) an exclusion of alternative diagnoses.

NMOSD without AQP4-IgG or with unknown AQP4-IgG are diagnosed, according to the same international criteria, based on: (i) at least two of the six core clinical characteristics of NMOSD, of which:

A) at least one has to be Optic Neuritis, Acute Myelitis, or Area postrema syndrome; B) dissemination in space of the lesions with related clinical characteristics; C) typical MRI characteristics;

(i) negative or unavailable AQP4-IgG test; (iii) an exclusion of alternative diagnoses.

This novel classification aims to include patients with clinical manifestation not limited to optic nerve or spinal cord, giving a major diagnostic role to the detection of AQP4 antibodies and MRI specific features. In fact, it has been shown that 15% of NMO patients present neurologic symptoms indicating encephalopathy, brainstem alteration, hypothalamic dysfunction and, rarely, muscle involvement [8,35–37]. Nausea and vomiting or intractable hiccups, associated with brainstem dysfunction, have been described, and acute neurogenic respiratory failure may occur, leading to death [33,35,38]. Brainstem involvement may be associated with visual dysfunction, including diplopia and nystagmus, and hearing and balance disorders [39]. Other symptoms in patients with NMOSD are facial weakness, narcolepsy, obesity, Table 1 Core clinical characteristics of NMOSD and additional MRI findings. Core clinical characteristics

MRI findings

Optic neuritis

Normal brain imaging or non-specific white matter lesions, OR optic nerve T2-hyperintense lesion or T1-weighted gadolinium enhancing lesion extending over half of optic nerve or involving the chiasm Associated intramedullary lesion extending over ≥3 contiguous segments (LETM) OR ≥3 contiguous segments of focal spinal cord atrophy in patients with history compatible with acute myelitis Associated dorsal medulla/area postrema lesions Associated periependymal brainstem lesions Typical diencephalic MRI lesions

Acute myelitis

Area postrema syndrome Acute brainstem syndrome Symptomatic narcolepsy or acute diencephalic clinical syndrome with NMOSD Symptomatic cerebral syndrome with NMOSD

Typical diencephalic MRI lesions

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hypotension, bradycardia, hypothermia and peripheral neuralgia [40]. Brainstem and hypothalamic involvement has been frequently associated with positivity for IG-AQP4 antibodies and typical MRI lesions in the brain [23]. MRI shows typically nonspecific white matter alterations, such as patches and dots, in the area with major expression of AQP4, such as the subcortical and deep white matter in NMOSD patients (Table 2) [37,41]. Interestingly, brain lesions are detected by MRI in approximately 89% of AQP4-NMOSD patients [42,43]. In particular, MRI techniques play a crucial role in the differential diagnosis of AQP4negative NMOSD from other autoimmune diseases and MS [8,41,44]. In addition, children with NMO frequently present with clinical features of encephalopathy and/or seizures and usually have lesions on brain MRI resembling those typically seen with multiple sclerosis or acute disseminated encephalomyelitis, often causing a significant delay in diagnosis and treatment, with a consequently worse shortterm disease outcome [45–48]. With the technological improvements in MRI definition and with the support of serum and CSF biomarkers, the differential diagnosis of NMOSD based on cerebral and spinal cord lesions has become increasingly accurate in the last years (Table 2), however, the added value of the MRI in case of patients with isolated ON remains lower [2]. In fact, MRI frequently shows nonspecific optic nerve sheath thickening, similar to the changes described in MS patients, and only a more posterior involvement of the optic nerve including the chiasm, and simultaneous bilateral disease, allow making a differential diagnosis of NMO [49]. In addition, acute optic neuritis in MMOSD patients may also show normal MRI features [36]. In this case, to perform an accurate differential diagnosis with other optic neuritis, such as that of MS, a multimodal comprehensive evaluation including multifocal visual evoked potential, visual field, visual acuity and ocular coherence tomography (OCT) should be performed [50]. Several studies support the clinical utility of OCT (a simple, non-invasive and repeatable exam) to evaluate the optic nerve tissue damage, and suggest that OCT can be useful to monitor disease progression and response to treatments. Moreover, OCT may be useful for the differential diagnosis of NMO whit MS. In fact, patients with NMO show a more severe thinning of retinal nerve fiber layer and ganglion cells layer, frequently associated with macular edema [50,51]. Particularly in the cases of poor diagnostic value of the MRI, laboratory findings play a key role. In fact, while for NMOSD patients the clinical and radiological differential diagnoses remains of primary importance, according to the 2015 revised criteria the presence of AQP4-Ab in serum is central in diagnosing NMOSD-AQP4 [2]. Indeed, AQP4-IgGs are highly sensitive (73%) and specific (91%) for typical and atypical NMOSD and can be detected in sera of most patients (68%–91%), also in uncommon or recurrent ON and LETM associated to autoimmune diseases (organ and non-organ specific) [47,48,52]. Interestingly, AQP4-IgG serum levels are a useful biomarker to monitor disease activity and treatment response [10,53,54]. Additional diagnostic biomarkers have been suggested in AQP4-IgGs seronegative patients, such as AQP1-IgG and myelin oligodendrocyte glycoprotein (MOGIgGs), that have been detected in 10–25% of cases [55–58].

Table 2 Characteristic MRI findings in NMOSD. Lesion location

MRI feature

Spinal cord

Longitudinally extensive (≥3 vertebral segments) Central/gray matter involvement T1 hypointensity (acute lesions) Posterior involvement/chiasmal involvement Periependymal lesions surrounding the ventricles Hemispheric tumefactive lesions Involvement of corticospinal tracts “Cloud-like” enhancement

Optic nerve Brain

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The role of CSF examination is currently limited, since pleocytosis (N50 leukocytes per microliter), high level of neutrophils or eosinophils (N5 per microliter), protein loss and loss of oligoclonal IgG bands may be considered only supportive criteria. CSF glial fibrillary acidic protein (GFAP) evaluation has been suggested as additional diagnostic biomarker in NMODS; in fact it is higher during relapses and correlates with disability damage, rated with Expanded Disability Status Scale (EDSS) at 6 months of follow-up, suggesting that it is a specific marker of oligodendrocyte injury [59,60]. Advanced magnetic resonance imaging techniques, such as proton MR spectroscopy, diffusion tensor imaging, magnetization transfer imaging, quantitative MRI volumetry, and ultrahigh-field strength MRI, are currently under investigation and might induce an improvement in early diagnosis and monitoring of NMODS, allowing a quantitative evaluation of the central and peripheral nervous system lesions [61]. 4. Standard management In patients with NMOSD, the correct therapeutic approach has to recognize two distinct clinical situations: treatment of the acute attacks and prevention of the relapses, or maintenance treatment. Several studies report that a prompt diagnosis and treatment of the monophasic cases allow a better long-term outcome and a five years survival rate higher than that of patients with recurrences. 4.1. Acute attack (first episode and/or relapse) Acute NMO attacks are usually severe, lead to severe morbidity (disability due to cumulative sequelae) and may also be fatal. Therefore, not only it is relevant to decrease the number of relapses to prevent the cumulative sequelae and consequent disabilities, but it is of primary importance to reduce the severity of an acute attack. In this perspective, the mainstay of acute treatment for NMOSD is high-dose corticosteroids, typically intravenous methyl prednisolone 1 g/day for 3-to-5 days, followed by a slowly tapering course of oral steroids to avoid an early relapse. In particular, patients AQP4IgG-serum positive should be assumed to be at risk for relapse indefinitely and, therefore, treatment should be considered over a long term following clinical remission. For those patients who do not respond appropriately to the steroid approach, plasmapheresis is the treatment of choice. Specifically, plasma exchange (PLEX) is performed for five treatments, typically every other day. Some recent publications also suggest performing PLEX from the very beginning, together with corticosteroids, especially in patients who present with a relapse and history of positive response to PLEX [62]. Bonnan and colleagues retrospectively demonstrated that patients receiving steroids plus PLEX have a significant decrease of EDSS scores when compared to patients receiving steroids alone [63]. Recently, Abboud and colleagues showed that 65% of patients receiving steroids plus PLEX have a stable or improved EDSS post-relapse, compared to only 35% of patients treated with steroids alone [62]. 4.2. Maintenance treatment As mentioned above, it is crucial to reduce the acute attack severity in NMOSD. However, it is also fundamental to reduce the frequency of relapses in order to reduce morbidity and mortality. Unfortunately, unlike MS, NMO does not respond to immunomodulatory therapies, which may even be detrimental in this disease [64]. Instead, maintenance therapy in NMO should be aggressively pursued through a number of immunosuppressive therapies (Table 3), most commonly Rituximab, Mycophenolate Mofetil (MM), and Azathioprine (AZT), but also Mitoxantrone, Methotrexate and Cyclophosphamide [64]. However, to date all these treatments remain “empiric” as no randomized clinical trials have been performed to compare efficacy and safety of the different immunosuppressive agents, and most of the available data are limited to retrospective case series. Among them, two recent studies by Mealy

et al. and Torres et al. suggest that rituximab might induce a greater reduction in annual relapse rates and that up to 50% of patients receiving this treatment can become remission free [65,66]. However, both studies are limited by the retrospective design, the small sample size, and the presence of several confounding factors, such as concomitant treatments (i.e. steroids). Therefore, head-to-head randomized trials to compare the efficacy of the different immunosuppressive agents are highly needed to set up a standardized treatment algorithm and optimize the management of NMOSD. 5. Novel therapeutic approaches In addition to the above immunosuppressive drugs, novel therapeutic agents targeting humoral markers are currently under investigation in patients with severe clinical manifestation and not responding to standard therapy (Table 4). Tocilizumab is a human monoclonal antibody directed against the IL-6 receptor, used in rheumatoid arthritis and juvenile idiopathic arthritis [67]. Tocilizumab reduces plasmablasts survival and AQP4-Ab production and seems to ameliorate the disease course of AQP4-Ab positive NMOSD [68]. Two retrospective studies with a small sample size, and one prospective pilot trial, report promising results showing an improvement of annualized relapse rates (ARRs) in all treated patients [69,70]. The safety and efficacy of tocilizumab in NMOSD patients is currently under investigation in two phase III trials (Table 4). Eculizumab is a humanized monoclonal antibody, that neutralizes the complement protein C5 and prevents the complement cascade activation in the CNS [71,72]. Complement deposition is involved in the pathogenesis of NMOSD with product deposition co-localizing in the areas where AQP4 is normally distributed [10,18]. The results of an open prospective clinical study show that eculizumab reduces relapse frequency and improves the disabilities evaluated by EDSS [71]. A phase III open-label, and a randomized, double-blinded clinical trial are currently ongoing (Table 4). Aquaporumab is a recombinant human monoclonal antibody that is comprised of a Fc portion that tightly binds AQP4 and a mutated Fc portion that blocks the activation of the complement cascade, reducing cellular damage [73]. It has been demonstrated that treatment with

Table 3 Characteristics of the most common maintenance treatments for NMOSD. Molecule

Start dose

Main side effects

Rituximab

1000 mg weekly for 2 weeks

Mycophenolate mofetil

1000–2000 mg daily associated with oral steroid

Azathioprine

2–3 mg/kg/daily associated with oral steroid For 6–12 months 12 mg/m2 for 3–6 months

Sepsis, infections, leukopenia, transaminase elevation, Progressive Multifocal Leukoencephalopathy (PML) (rare) Photosensitivity, recurrent infections, headache, constipation, abdominal pain leukopenia, PML (rare) Nausea, diarrhea, rash, recurrent infections, leucopoenia, transaminase elevation, increased risk of lymphoma Nausea, transaminase elevation, leukopenia, hair loss, amenorrhea, minor infections, heart failure and acute leukemia (rare) Pneumonitis, gastrointestinal upset, cytopenia, hepatotoxicity

Mitoxantrone

Methotrexate

Cyclophosphamide (contradictory findings in NMO)

Start with 7.5 mg weekly associated with oral steroid 1000 mg every 2 months associated steroids

Leukopenia, neutropenia, thrombocytopenia, arrhythmias, heart block, nausea/vomiting, hepatic sinusoidal obstruction syndrome, hyponatremia, pneumonitis, haematuria, opportunistic infections

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Table 4 Currently ongoing clinical trials evaluating novel therapeutic approach in NMOSD. Clinical trial Treatment registration number NCT02073279 NCT02028884 NCT00904826

NCT01892345

NCT02865018

Study design

Geographic area

N. patients

Primary outcome

SA237 (TOCILIZUMAB) Multicenter, randomized, double-blind, Europe, Asia, USA 70adult and child Time to first relapse placebo-controlled, phase 3 study SA237 (TOCILIZUMAB) Multicenter, randomized, double-blind, Worldwide 90 Time to first relapse placebo-controlled, phase 3 study ECULIZUMAB Open study, phase 1–2 USA 14 Median number of NMO attacks/year -T0 -After treatment (1 year) Worldwide 132 Time to first relapse ECULIZUMAB Randomized, double-blind, placebo-controlled, multi-center study CETIRIZINE Open label USA 16 ARR before cetirizine (T0) ARR after cetirizine (1 year)

aquaporumab inhibits the development of brain lesions in a mouse model of NMO [72]. This drug would be a very interesting novel therapeutic agent, due to the specific mechanism of action in NMOSD and the reported absence of side effects. Other therapeutic strategies to target cellular inflammation in NMOSD are currently in the preclinical development phase. Among them it is worth mentioning Silvestat, which is already used in Japan to treat acute respiratory distress syndrome, is a molecule involved in neutrophil migration and phagocytosis [74]. In fact, neutrophil elastase has been shown, along with other Th17 cytokines, to be elevated in patients with NMOSD. Treatment with Silvestat reduced the inflammatory reaction in both spinal cord and optic nerves in animal model of EAE and in mouse exposed to human AQP4-Ig [75,76]. In mice treated with intracerebral injection of AQP4 Ab, treatment with antihistamines, such as cetirizine, also reduced lesion burden mediated by AQP4 Ab and eosinophils infiltration [77]. Despite these promising experimental results, clinical trials are required to confirm the efficacy of antihistamines or other drugs targeting eosinophils to improve NMOSD's outcome. Finally, an intriguing potential therapeutic strategy in NMOSD is to restore immune-tolerance by DNA vaccination, T cell vaccination, tolerogenic dendritic cells and peptide-coupling strategies, but in spite of the strong rationale, to date no clinical evidence are reported [78,79]. 6. Conclusions Neuromyelitis optica spectrum disorders (NMOSD) are a group of autoimmune inflammatory diseases of the central nervous systems mainly affecting the optic nerves and spinal cord. NMOSD are associated with IgG antibody binding to aquaporins that trigger astrocyte and axon loss. The discovery of the pathogenic role of AQP4-Ig allowed a novel classification of NMOSD (published in the 2015), that facilitates an early and accurate differential diagnosis of these disorders. MRI evaluation shows limited diagnostic value in isolated ON, suggesting to perform serum autoantibody evaluation and ophthalmic exams, such as multifocal VEP and OCT. Indeed, AQP4-IgG and other potential biomarkers may represent useful tools for monitoring and predict the disease outcome. Current treatments are based on steroids to reduce the severity of acute attacks, and on other immunosuppressive drugs to decrease the frequency of relapses, since both increased frequency and severity of the acute attacks are associated with increasing neurological disabilities and mortality. The results of ongoing clinical trials will allow to evaluate the safety and efficacy of novel biological agents, targeting humoral and cellular markers, in order to improve management and outcome of NMOSD cases that still shows a poor prognosis. Take home message • The novel diagnostic criteria published in 2015 are based on clinical features, MRI imaging and AQP4-IgG serum detection.

Expected end of date September 2017 December 2017 December 2011

December 2017

February 2016

• These criteria allow an early diagnosis of typical forms and aim to include the spectrum disease with uncommon clinical manifestations. • Differential diagnosis with other autoimmune diseases, such as MS, is based on MRI findings and AQP4 testing. • Differential diagnosis of isolated ON may benefit from visual evoked potential and OCT exams. • Disabilities and mortality are associated with the severity of acute attacks and frequency of relapses. • Current treatment is based on steroids for the acute phase and other immunosuppressive drugs as maintenance treatment, but do not completely achieve the therapeutic goal. • Novel biological agents, targeting humoral and cellular markers, are under development to improve management and outcome of the disease and to decrease side effects.

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