Multiplehttp://msj.sagepub.com/ Sclerosis Journal 6th Pactrims Invited Lecture Mult Scler 2014 20: 901 DOI: 10.1177/1352458514531864 The online version of this article can be found at: http://msj.sagepub.com/content/20/7/901

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On behalf of: European Committee for Treatment and Research in Multiple Sclerosis

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Latin American Committee on Treatment and Research of Multiple Sclerosis

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Multiple Sclerosis Journal 2014; 20: (7) 901–960

Abstracts

6th PACTRIMS INVITED LECTURE

Opening Lecture L-1 International Progressive Multiple Sclerosis Alliance Alan Thompson Dean of the UCL Faculty of Brain Sciences, UK Progressive multiple sclerosis (MS), whether it is primary or secondary, has been much neglected over the recent decades and despite significant progress in the development of therapies for relapsing/remitting multiple sclerosis (MS), treatment of progressive MS remains disappointing. Progression is the key determinant of disability and therefore needs to be more effectively addressed. However there are a number of major challenges in developing therapies for progressive MS, not least of which is our limited understanding of the mechanisms underlying progression. If we are to accelerate the development of treatment for progression we need to target specific blocks to treatment and overcome them. It is this realisation that stimulated the establishment of an international initiative by volunteer and staff leaders from several MS societies with the explicit mission to expedite the development of effective disease-modifying and symptom management therapies for progressive forms of multiple sclerosis. This has been entitled the Progressive MS Alliance (PMSA) Through a series of scientific and strategic planning meetings, the PMSA has identified and developed new perspectives on five key priority areas for research: (1) experimental models, (2) identification and validation of targets and repurposing opportunities, (3) proof-of-concept clinical trial strategies, (4) clinical outcome measures, (5) symptom management and rehabilitation. Five working groups developed these areas and presented their outcomes at an international scientific meeting in Milan in 2013. Flowing from this an international call for challenge and infrastructure awards has been made and it is anticipated that this will be the forerunner of a major collaborative call, provided there has been a successful international fund-raising initiative. This integrated, multi-disciplinary approach will enable effective translation of research into therapies for progressive MS.

Special Lecture L-2 Epidemiology and Genetics of MS; what have we missed? George Ebers Professor at the Department of Clinical Neurology, University of Oxford, UK For many years research into the epidemiology and genetics of MS have run parallel tracks with dispute over the relevant

importance of each. It has become increasingly clear now that susceptibility represents an interaction between these factors and they themselves can be subdivided into a variety of different entities. Efforts spent at identifying genes with small effect have turned up many but collectively they add up to very little of the overall risk. Claims that these are “immunological” fail to take into account that the SNPs are mostly in regulatory regions and only give hints as to the area of a genetic effect only occasionally implicating specific genes. Although the environment has proven to be relatively inscrutable with many possible environmental agents having been proposed, it should be clear now that it will be the environment not the genes that hold the key to preventing the disease. A simple move from regions of highest to lowest risk is highly protective for Northern Europeans and focus on this age-related factor is important. Recent evidence indicates that the major histocompatility complex is the site of many of the interactions involved in MS risk. There is evidence now that epigenetic modification is important although specific molecular mechanisms have not yet been identified. We will review the evidence pointing to this interpretation of the genetic epidemiology.

Main Symposium-1 Genetics of MS and NMO: what’s next? L-3 Genetic Study of MS/NMO in Iran Masoud Etemadifar Professor of Neurology, Director of Isfahan MS Clinic, Isfahan University of Medical Sciences, Iran Multiple sclerosis (MS) is an inflammatory disease of the central nervous system. Genetic and environmental factors especially interactions between them are very important in the pathogenesis of MS. The HLA region is the strongest susceptibility locus linked to MS, but it does not explain the whole heritability of the disease. The HLA class II alleles (DRB1*1501, DQA1*0102, DQB1*0602) may have the strongest genetic effect in MS, but in Iranian MS patients there is no association of these HLA haplotypes with clinical presentation, disease duration, and disability which is in line with other previous studies in different ethnic groups. In another study s HLA-DRB1*1501 allele and TNF-α -308 G/A polymorphism were associated with the risk of multiple sclerosis in Iranian population. Interaction between these two loci that support the role of HLA alleles and cytokine genes and gene-gene interaction in the development and pathogenesis of MS.

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To find other non-HLA loci associated with MS, several highthroughput genotyping, sequencing, and gene-expression studies have been performed, producing a valuable quantity of information. Analysis of DNA samples from MS patients in Iran revealed a significant lower frequencies of tumor necrosis factor-alpha GA and TGF beta C/C G/G genotypes and higher frequency of TGF beta T/C G/C genotype in patients (P < 0.05). This findings suggest that these polymorphisms play a role in susceptibility to MS, which is possibly mediated by dysregulated production of these cytokines. IL2 polymorphisms as functional promoter position may be involved in IL2 expression and regulation .Both -475 and -631 IL2 polymorphisms were higher in Iranian MS patients as compared to controls, but the frequency differences were not significant. Data from other study in Iran suggested that the genetic variation in IL-12 A/C (-1188) and IFN-gamma A/T (+874) cytokine genes could be risk factors for MS patients. One study in Iran showed no association between -94 ins/del ATTG polymorphism and risk of multiple sclerosis in Iranian .In NMO syndrome the role of genetic factors is unclear. However some study showed Polymorphism at position -1003bp (A-G) of AQP4-promoter 0 is associated with the presence of anti-AQP4 antibody. Interleukin 17 gene polymorphism is also associated with anti-aquaporin 4 antibody-positive neuromyelitis in chinese patients.it seems that Caucasian patients with NMO and MS have a different HLA-DRB1 allelic distribution. DRB1*03 allele seems to contribute to NMO seropositivity. L-4 Genetic Study of MS/NMO in India Lehka Pandit Director of Center for Advanced Neurological Research at Nitte University, India Prevalence of Multiple sclerosis (MS) has increased more than 8 times in the past decade in India. This has enabled dedicated registries in India to obtain data for genetic analysis. The association between multiple sclerosis (MS) and class II alleles of the major histocompatability complex (MHC) particularly DRB1, DQAI and DQB1 have now been studied in the Indian population. The preliminary results obtained from evaluation of single neuclotide polymorphisms (SNP) related to the non MHC regions of the genome have been replicated in a larger data set. A limited study of association of MS with MHC related SNP’s was completed recently. Genotyping results in 400 patients and 450 controls suggest that the strongest association is with HLADRB1*03 allele though a trend for association was also seen with DRB1*15. The DRB1*03 - DQB1*0201haplotype was significantly associated with MS. This effect stemmed primarily from DRB1*03 and not DQB1*0201. Evaluation of SNP’s in the MHC and non MHC regions showed similarity in risk allele frequencies between Indian and white populations. In particular the association with SNP’s related to CLEC 16A, CD226, IL2RA and CD6 showed promising results with improved power in the replicated data set. Environmental agents related to MS namely Epstein – Barr (EBV) infection and Vitamin D deficiency have not shown a strong association in Indian patients. But high EBV –EBNA1 titres were strongly associated with the presence of HLA DRB1* 15:01 in our patients. While it appears that genetic susceptibility for MS among Indians is similar to white populations, epigenetic influences are clearly different. Future studies involving larger data sets are planned which will address these issues.

L-5 Genetic Study of MS/NMO in Japan Shinya Sato Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan Remarkable advances in genome technology, such as high-density DNA microarrays, have permitted effective screening for single nucleotide polymorphisms (SNPs) and copy number variations (CNVs), which are associated with disease susceptibility. CNVs are gains or losses of genomic segments ranging from 1 kb to 1 Mb. Similar to SNPs, CNVs contribute to human genetic and phenotypic diversity. Although susceptible CNVs in several diseases have been reported, the effect of CNVs on susceptibility to multiple sclerosis (MS) and neuromyelitis optica (NMO) still remains to be elucidated. In a genome-wide analysis of CNVs in Japanese patients with MS and NMO/NMO spectrum disorder (NMOSD) using high-density SNP microarrays, we recently identified a deletion of approximately 40 kb at 7p14.1. This deletion encompassed the T cell receptor (TCR) gamma genes and was found in 9.03% of 277 MS patients, but was only found in 0.35% of 288 healthy individuals (p=8.6E-7) and in 15.56% of 135 NMO/ NMOSD patients (p=5.2E-11). Additionally, a deletion of at least 40 kb at 14q11.2, which contains the TCR alpha genes, occurred more frequently in MS patients (9.75% vs. 0.35%, p=2.7E-7) and NMO/NMOSD patients (12.59% vs. 0.00%, p=7.9E-10) than in healthy individuals. Although further validation studies are required, our results support the importance of T cell-mediated mechanisms linked to CNVs at the TCR genes in MS and NMO. We are performing ongoing studies, with a genome-wide association study in MS and NMO/NMOSD, and genomic analysis of monozygotic twins discordant for MS in Japan. L-6 Genetic Study in Australia: What’s next Helmut Butzkueven Joint Director, Royal Melbourne Hospital and Box Hill Hospital MS Services, Melbourne Australia Numerous Genome-wide association studies (GWAS) have now successfully identified and replicated common genetic variants associated with Multiple Sclerosis, including a contribution from Australia identifying two loci. By November 2013, the MS Immunochip project from the IMSGC will be published and will have confirmed and added more loci, with an estimated total of over 100 common variations identified. This should effectively end the search for genetics of MS causation, but all loci identified subsequent to HLADR15 (OR 2 to 2.5) have odds ratios for causation of between 1.05 and 1.3. What are the next steps? In some circumstances, detailed fine mapping or locus sequencing will probably identify rare variants that are “hiding” behind the common risk SNPs and that have a greater effect, but evidence to date suggests this will be rare. Linking of SNP genotypes with expression or splice changes of expressed genes nearby might identify SNP candidates with possible biologic effect, and performing these experiment in an immune cell specific manner can add better resolution to these experiments. This so-called eQTL (expression-quantitative trait locus) approach might also yield candidates for SNP combination analysis. The identification of SNP combinations from genomic data alone so

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6th PACTRIMS 20 (7) far has been defeated by the multiple testing problem, for any SNP combinations greater than 2, but new approaches are being tested. Additional “inputs” into SNP combination testing might include CPG methylation data and data derived from pathway analyses. Finally, future efforts will be directed to predictors of MS severity and drug efficacy and safety.

PACTRIMS Basic Science Lecture L-7 Glial cell biology in demyelinating and dysmyelinating disorders Kazuhiro Ikenaka National Institute for Physiological Sciences, Okazaki, Japan Myelin is a membrane structure enabling saltatory conduction of action potential and is formed by oligodendrocytes in the CNS. In chronic demyelinating lesions in the multiple sclerosis (MS) patient brain, oligodendrocyte precursor cells are found abundantly, and moreover pre-myelinating oligodendrocytes are also found, but they somehow fail to achieve terminal differentiation into myelin-forming oligodendrocytes. We have been searching for molecules that inhibit maturation/survival of oligodendrocytes in chronic demyelinated lesions. We found that cystatin F (CysF), a cysteine protease inhibitor, is expressed in microglia during remyelinating stage and the expression level decreased when chronic demyelinated lesions appeared. CysF mRNA expression was induced when microglia phagocytosed myelin debris. Interestingly, CysF mRNA expression was not induced during normal developmental stages, dysmyelination or hypoglossal nerve injury, which results in the Wallerian degeneration. CysF is expressed in some immune cells but not in infiltrating T cells in the demyelinating lesions of MOG induced EAE model. In addition, the expression pattern of cathepsin C (CatC) which is the target of CysF was similar to that of CysF in remyelinating regions but we found CatC+/CysF- regions in chronic demyelinated lesions. Additionally, we found that CatC is expressed in microglia and CatC co-localized with that of CysF in primary cultured microglia. It is reported that CatC is involved in the production of pro-inflammatory cytokines. Together, we propose that CysF, which is expressed in microglia, dominates the activity of CatC that directs the production of pro-inflammatory cytokines in the re-myelinating phase of demyelinating lesions.

Main Symposium-2 Progressive MS L-8 Keynote lecture-1: Clinical and Imaging characteristics of progressive MS David H Miller Queen Square MS Centre, Department of Neuroinflammation, UCL Institute of Neurology Progressive MS may occur from symptom onset (primary progressive [PP] MS; 15% of all cases), or following a relapsing remitting [RR] phase (secondary progressive [SP] MS, which

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more than half of those with RRMS will eventually develop). It has a poor prognosis compared to RRMS although the rate of progression varies considerably between and within patients over time. Progressive MS is determined primarily on clinical evidence of a gradual increase in neurological deficit for more than a year: it is a by nature retrospective and imperfect classification but it is clearly important because of its poorer prognosis and the current absence of effective disease modifying treatment for this phase of disease. PPMS affects males and females equally and has an average age of onset around 40 years. 80% of PPMS cases present with progressive myelopathy. This is also common in SPMS. Other common progressive syndromes involve brain stem and cerebellar function: progressive dementia and optic neuropathy are very uncommon. MRI shows a larger brain lesion load in SPMS than PPMS, with similar and sometimes extensive spinal cord lesions. Disease modifying treatments that prevent new MRI lesion formation such as beta interferon and glatiramer acetate are ineffective in progressive MS. Imaging measures that reflect neurodegeneration are better associated with disability measures in progressive MS: there is an especially robust association between upper cervical cord atrophy and EDSS; and in the brain, grey matter atrophy and other imaging measures that reflect intrinsic cortical pathology are also correlated with functional deficits. Whole brain atrophy, measured using registration-based methods, is being used to assess potential neuroprotective treatments in proofof-concept trials. A recent phase 2 trial of high dose simvastatin in SPMS showed a 42% decrease in rate of brain volume loss over two years. In the UK, a phase 2 trial will shortly begin in SPMS that will compare three putative neuroprotective agents versus placebo: ibudilast, riluzole and amiloride. L-9 Keynote lecture-2: Pathology of progressive multiple sclerosis Wolfgang Brück Department of Neuropathology, University Medical Center, Georg-August University, Göttingen, Germany Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system with involvement of focal white matter lesions, grey matter demyelination and pathological changes in the normal-appearing white matter. Clinically, the majority of patients starts with a relapsing-remitting disease course. Secondary or primary progressive MS is characterized by slowly and steadily increasing disability in the absence of relapses. The pathological correlate of progressive MS has not yet been defined exactly. Potential pathological mechanisms relevant in progressive MS are discussed in the present lecture. These include:  Slowly expanding pre-existing lesions  Persistent microglial activation  Compartmentalized inflammation  B cell/antibody involvement  Remyelination failure  Axonal/neuronal loss  Cortical/gray matter involvement  Changes in the NAWM These features of progressive MS pathology are discussed in context of clinical and radiological findings as well as the therapy response.

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L-10 Molecular mechanism of oligodendrogliopathy and axonal damage in MS Trevor Kilpatrick Director, Melbourne Neuroscience Institute, University of Melbourne; Head, MS Division, Florey Institute of Neuroscience and Mental Health; Head, MS Unit, Royal Melbourne Hospital Oligodendrogliopathy is a potential contributor to the pathogenesis of MS although its influence remains controversial, with some studies identifying significant oligodendrocyte death in acute disease whilst others have failed to identify evidence of oligodendrocyte apoptosis. Independent of this controversy, there is an emerging view that the disruption of interactions between neurons and glial cells, including astrocytes, oligodendrocytes and oligodendrocite progenitors, is likely to be a key determinant of outcome in multiple sclerosis. Experimental models of oligodendrogliopathy that we and others have generated indicate that these interactions can be critically disrupted well before frank demyelination ensues. Molecular mechanisms that have been posited to be involved include inhibition of metabolite transport and loss of cytokine support by either direct or indirect mechanisms. Other events that could contribute to axonal pathology have also been identified. Such events include immune cell mediated injury, glutamate-induced excitotoxicity, oxidative stress, conduction defects due to either sodium or potassium channel dysfunction and the toxic effects of raised intracellular calcium, recognising that these mechanisms are not necessarily mutually exclusive. Understanding of these processes will be crucial in developing strategies to reduce the impact of progressive MS. L-11 Rapidly Progressive Multiple Sclerosis and Gliopathy Katsuhisa Masaki Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan Multiple sclerosis (MS) and neuromyelitis optica (NMO) occasionally have extremely aggressive disease courses. However, their molecular mechanisms are unknown. We aimed to determine a relationship between connexin (Cx) pathology and disease aggressiveness in Asian patients with MS and NMO. Samples included 11 autopsied cases with NMO and NMO spectrum disorder (NMOSD), and 6 cases with MS. Measurements included immuno-histochemical localization of astrocytic Cx43/Cx30, oligodendrocytic Cx47/ Cx32 levels relative to AQP4 and other astrocytic and oligodendrocytic proteins, extent of demyelination, vasculocentric deposition of complement and immunoglobulin, and lesion staging by CD68 staining for macrophages/activated microglia. Six NMO/NMOSD and 3 MS cases showed preferential loss of astrocytic Cx43 beyond the demyelinated areas in actively demyelinating and chronically active lesions, where heterotypic Cx43/Cx47 astrocyte-oligodendrocyte gap junctions were extensively lost. Cx43 loss was significantly associated with a rapidly progressive disease course, because 6 of 9 cases with Cx43 loss, but none of the 8 cases without Cx43 loss, regardless of disease phenotype, died within 2 years after disease onset (66.7% vs. 0%, P=0.0090). Overall, 5 of 9 cases with Cx43 loss, and 0 of 8 cases without Cx43 loss had distal oligodendrogliopathy characterized by selective myelin associated glycoprotein loss (55.6% vs. 0.0%, P=0.0296). Loss of oligodendrocytic Cx32 and Cx47 expression was observed in most active and chronic lesions

from MS and NMO/NMOSD cases. Given that we reported extensive loss of Cx43 in Baló’s disease, a most grave variant of MS, the present findings suggest that astrocytic Cx43 loss may be related to disease aggressiveness and distal oligodendrogliopathy in both MS and NMO. L-12 Primary microgliopathy mimics primary progressive MS Kunihiro Yoshida, Ryo Yamasaki Department of Brain Disease Research, Shinshu University School of Medicine; Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University Both hereditary diffuse leukoencephalopathy with neuroaxonal spheroids (HDLS) and Nasu-Hakola disease (NHD) are characterized by progressive white matter degeneration with neuroaxonal spheroids. The causative genes for HDLS (CSF1R) and NHD (TYROBP and TREM2) are mainly expressed on microglia/macrophage in the brain, suggesting that they are indispensable for the differentiation, proliferation, survival, and functions of microglia/ macrophage. Therefore, microglial dysfunction may be closely linked to degeneration and destruction of axons and myelin sheaths in HDLS and NHD, exhibiting the concept of microgliopathy for these diseases. Since pre-mortem diagnosis of HDLS became feasible by CSF1R testing at the end of 2011, reports on HDLS patients have been increasing in number. HDLS presents clinically with pre-senile dementia which mainly includes executive dysfunction, lack of spontaneity, emotional blunting, indifference, and irresponsibility. Some patients show predominantly motor symptoms such as speech disturbance, hemiplegia, parkinsonism, and ataxia. With the wide variety of neurological features, HDLS, especially in the early stage of disease, mimics several neurological diseases; they are frontotemporal dementia, Alzheimer’s disease, vascular dementia (including CADASIL and CARASIL), and multiple sclerosis (MS). Even taken the MR images into consideration, it is sometimes very difficult to differentiate HDLS from primary progressive MS. Thus, HDLS patients have often undergone immunosuppressive therapy under the misdiagnosis of primary progressive MS, but no significant improvement has been reported so far. In this paper, we will focus on the difference between HDLS and primary progressive MS clinically, neuroradiologically and neuropathologically. We will also discuss the involvement of microglial dysfunction in both diseases.

PACTRIMS Educational Course Diagnosis and Treatment of MS and NMO in Asians L-13 How to diagnose MS as early as possible based on the new McDonald criteria in Asians: tips and pitfalls Ho Jin Kim Research Institute and Hospital of National Cancer Center, Korea The diagnostic criteria for multiple sclerosis (MS) have evolved over time from being solely clinical symptom-based (Schumacher and Poser) to integrating MRI assessments (McDonald). This

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6th PACTRIMS 20 (7) salient advance allows for a more timely diagnosis and earlier treatment, which are critical to prevent irreversible disability in patients with MS. The new 2010 McDonald criteria simplified the MRI requirements for demonstration of dissemination in space and time and improved the diagnostic sensitivity while preserving their specificity. The new criteria enable to make a diagnosis of MS on the basis of the single MRI scan performed with a typical initial clinical manifestation. Previous studies have demonstrated the applicability of McDonald criteria across populations. Recently, we showed that once the alternative diagnosis, particularly neuromyelitis optica (NMO) and its spectrum disorder (NMOSD), have been carefully excluded, MS in Korea did not fundamentally differ from typical MS in the Caucasian population and the McDonald criteria were applicable to Korean patients with clinically isolated syndromes (CIS) suggestive of MS. This finding highlights that exclusion of NMO/NMOSD is an imperative element before applying McDonald criteria in Asia. However, there have been no definite guidelines to systematically exclude alternative diagnoses in the McDonald criteria. Detection of anti-aquaprorin-4 antibody is helpful on this matter. However the assays measured by a validated laboratory are not widely available in Asia and seronegative NMO despite repetitive test is still present. Therefore, the diagnosis of MS requires special consideration in Asia where the relative prevalence of NMO/ NMOSD is high among inflammatory demyelinating diseases of CNS. Additionally, physicians should carefully monitor their patients, being particularly alert to the development of additional characteristics that are atypical of MS even after initial diagnosis of MS was made and to poor treatment response to disease-modifying therapy for MS. L-14 Fingolimod in MS: special reference to Asian patients Makoto Matsui Department of Neurology, Kanazawa Medical University Fingolimod, isolated from Isaria sinclairii, functions as a modulator of sphingosine-1-phosphate (S1P) receptors expressed on the surface of T and B lymphocytes, leading to their internalization. These lymphocytes typically egress from secondary lymphoid organs to systemic circulation using differences in S1P levels, thus loss of S1P receptors results in their sequestration in lymph nodes. Following successful treatment of an animal model of multiple sclerosis (MS), clinical trials of oral fingolimod for patients with relapsing-remitting MS showed a 50-60% reduction in the annualized rate of relapse. The Food and Drug Administration (FDA) approved fingolimod as a first-line drug for MS treatment in 2010 and data have been accumulated. However, MS experts have recommended that this drug should remain as a secondline option because of unforeseen long-term risks for infection and malignancy. Also, because of different genetic backgrounds, Asian MS patients may require special attention regarding other infectious agents and secondary cancer than those reported in Caucasian patients. Furthermore, some Japanese patients who developed severe symptoms were later positive for the anti-aquaporin-4 antibody. In addition, reports of some western MS patients have noted worsening after initiation as well as discontinuation of fingolimod treatment. Opticospinal type of MS and neuromyelitis optica spectrum disorders are more prevalent in Asian than western countries, thus establishment of criteria for determining which Asian MS patients would benefit from fingolimod treatment is mandatory.

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L-15 How to diagnose NMOSD patients as early as possible in Asians Sasithorn Sirito Neurologist, MS Clinic, Siriraj Hospital, Mahidol University, Thailand Neuromyelitis optica (NMO) is an idiopathic inflammatory demyelinating CNS disease (IIDCD) that typically develops severe optic neuritis and longitudinally extensive, transverse myelitis. Since aquaporin4 (AQP4) antibody was discovered, clinical and laboratory features distinguishing NMO from MS have been clarified, and treatment strategies are also different in these two diseases. AQP4 antibody studies showed that besides ‘definite’ NMO defined by Wingerchuk 2006 Criteria, there are cases with other NMO spectrum disorders (NMOSD). Detection of serum AQP4-antibody does not only serve as a disease marker but also plays a crucial role in the pathogenesis of NMO. Several methods available for AQP4-antibody detection has been described including the original indirect immunofluorescence tissue-based assay (IIF-TBA), enzyme-linked immunosorbent assay (ELISA), indirect immunofluorescence cellbased assay (IIF-CBA) with differences in sensitivity and specificity. The prevalence of seropositive NMO/NMOSD varies depending on the assays used in each country. Although the ratio of NMO to MS in Asian countries is much higher than in Western countries, there are problems when diagnosing based on clinical manifestations alone or if the patients come at the beginning with the clinical manifestation not yet fulfill the criteria or with negative test for AQP4-antibody. The differences in the clinical manifestations of the seronegative and seropositive NMO/NMOSD have not been clarified. Figuring out the key for early detection of the patients with NMO and its spectrum disorder is clinically important. L-16 Long term treatment strategy of NMO/NMOSD: How we can reduce the side effects of corticosteroid therapy Ichiro Nakashima Department of Neurology, Tohoku University School of Medicine Neuromyelitis optica (NMO) is an autoimmune demyelinating disease of the central nervous system preferentially affects the optic nerves and spinal cord. Although it had been recognized as a variant of multiple sclerosis (MS) and had been called as opticspinal form of MS especially in Asia, NMO is now recognized to be a unique disease associated with anti-aquaporin-4 antibody. It has a unique pathology and immunological pathomechanism, so the patients do not respond to disease modifying treatments for classic MS including interferons, natalizumab, and fingolimod. Although preventive therapy in NMO has focused on a range of immunosuppressive medications, none of them have been validated in a controlled randomized trial. However, our retrospective studies implicate the effectiveness of using low dose prednisolone for the prevention of NMO exacerbations. The annual relapse rate during the prednisolone treatment was found to be significantly lower than that during without prednisolone treatment. As for the dose of prednisolone, relapses occurred significantly more frequently with ‘10mg/day or less’ than with ‘over 10mg/day’. We also found that most of the patients who had been relapsefree for more than 18 months remained relapse-free for many years after even they reduced the dose of prednisolone to 5mg/ day. Therefore, we strongly recommend using more than 10mg/

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day of prednisolone for at least one year and taper it gradually to 5mg/day. Although prednisolone has many side effects, 5 mg/day is relatively safe for most of the patients.

Tatsuro Misu Department of Multiple Sclerosis Therapeutics, Tohoku University Graduate School of Medicine, Sendai, Japan

Main Symposium-3

Neuromyelitis optica (NMO) is an autoimmune disease targeting against aquaporin 4 (AQP4), localized mainly at the astrocytic foot processes. Here we show that active lesions in NMO display at least 6 different types in the spectrum of astrocytopathy even within a single tissue block of an individual patient. Type 1 reflect complement deposition at the surface of astrocytes, associated with granulocyte infiltration and astrocyte necrosis, which is followed by demyelination, global tissue destruction and the formation of cystic, necrotic lesions (Type 2). Such destructive lesions lead to Wallerian degeneration in lesion related tracts (Type 3). Around active NMO lesions AQP4 may selectively be lost in the absence of loss of aquaporin 1 (AQP1) or other structural damage (Type 4). Another pattern is characterized by clasmatodendrosis of astrocytes, defined by cytoplasmic swelling and vacuolation, beading and dissolution of their processes, which was associated with internalization of AQP and astrocyte apoptosis in the absence of complement, which may occur in part in the absence of any other tissue injury (Type 5). Finally, lesions with a variable degree of astrocyte clasmatodendrosis are found, which show plaque like primary demyelination, that is associated with oligodendrocyte apoptosis, but with preservation of axons (Type 6). In contrast, loss of AQP4 is observed only in the initial stage of aggressive multiple sclerosis, which is associated with retraction of astrocyte processes in the absence of complement deposition and loss of astrocytes. Understanding the diversity of NMO lesions may shed light on the pathomechanisms of other demyelinationg diseases.

Advanced NMO Research updates L-17 Novel biomarker for NMO Kai-Chen Wang Cheng Hsin General Hospital, Taipei, Taiwan School of Medicine, National Yang-Ming University, Taipei, Taiwan Many patients with NMO are initially diagnosed with MS, owing to similar initial neurologic presentations in the early stage, especially in Asia. However, the clinical course of NMO is usually more severe than that of classical MS after years follow up. Interferon treatment for MS may exacerbate the severity of NMO. The likelihood that NMO may be mistaken for MS underscores the importance of early detection. The diagnosis of NMO has currently depended on the presence of Aquaporin 4 (AQP4) antibody. However, its sensitivity varies between studies, being particularly low for Asian patients. The potential use of proinflammatory cytokines as markers for NMO is also not optimal, given their association with many diseases. Until recently, there are some potential biomarkers that can aid to detect NMO, and might also be the therapeutic targets for NMO. L-18 Blood-brain barrier disruption in NMO Takashi Kanda Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine Since large molecules like IgG cannot pass through the intact blood-brain barrier (BBB), the destruction of the BBB is the initial and crucial step of the disease process in neuromyelitis optica (NMO). So far, it is unclear whether sera from patients with NMO can open the BBB, and which component of patient sera is responsible for this disruption. We evaluated the effects of sera from antiaquaporin 4 (AQP4) antibody positive NMO patients against the BBB in vitro, utilizing the parameters including the expression of tight junction proteins and transendothelial electrical resistance (TEER) in human brain microvascular endothelial cells (BMECs). Tight junction proteins such as claudin-5 and TEER in BMECs were significantly decreased after exposure to acute phase NMO sera, and this effect was reversed after application of an anti-vascular endothelial growth factor (VEGF) neutralizing antibody or MMP-2/9 inhibitor. Purified IgG obtained from patients’ sera did not influence these two BBB properties, but increased the amount of VCAM-1 in BMECs. Conclusions: 1. Undetermined substance other than IgG in NMO sera at acute stage disrupt the BBB via autocrine secretion of VEGF and MMP-2/9. 2. Autoantibodies against BMECs other than anti-AQP4 antibody in NMO sera upregulate VCAM-1 and also contribute to the destruction of BBB. L-19 Pathology of Neuromyelitis Optica: The Diversity of Astrocyte Lesions

Closing Lecture L-20 IL-6 signaling in the pathogenesis and treatment of NMO Takashi Yamamura Department of Immunology, National Institute of Neuroscience & Multiple Sclerosis Center, NCNP Hospital, NCNP Neuromyelitis optica (NMO) is an inflammatory neurological disease, characterized by elevation of antibodies against aquaporin-4 (AQP4) water channel protein. Although corticosteroid and immunosuppressive drugs show some efficacy, we often encounter NMO patients who are resistant against available drugs. Therefore, it is important to seek for a reasonable therapeutic option, which may suppress the pathological autoimmune responses, underlying the pathogenesis of NMO. We have recently found that IL-6 dependent plasmablasts are increased in the peripheral blood of NMO, and that these plasmablasts are able to produce anti-AQP4 antibodies. Furthermore, in vitro analysis has revealed that blocking IL-6 signaling would inhibit survival of these potentially pathogenic plasmablasts (Chihara et al. 2011). Based on these laboratory findings, we initiated clinical investigation to explore the effect of humanized anti-IL6 antibody tocilizumab for NMO. Tocilizumab is a drug approved for rheumatoid arthritis in Japan. We are now witnessing the remarkable efficacy of the drug targeting IL-6 in patients with intractable NMO. In this lecture, I will present our experience after starting the study on plasmablasts and also discuss on the value of immunology-driven translational approach in NMO and MS.

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ORDINARY SUBMISSION

Hospital of Guiyang Medical College, PR China; 4Department of Neurology, VU University Medical Center, Amsterdam, The Netherlands; 5Institute of Immunology and Infectious Diseases, Murdoch University, Western Australia

Oral Presentation 1 O-1 Association of Geography and Clinical Phenotype in Asians With MS And Related Disorders A. Dessa Sadovnick1,2, Joshua D. Lee1, Carles Vilariño-Güell1, Zhi-Ying Wu3, & Anthony L. Traboulsee3 1 Department of Medical Genetics, University of British Columbia, Vancouver, Canada; 2 Faculty of Medicine, Division of Neurology, University of British Columbia, Vancouver, Canada; 3 Department of Neurology and Institute of Neurology, Huashan Hospital, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Shanghai Medical College, Fudan University, Shanghai, China Background: Two major clinical phenotypes are commonly observed in Asians with multiple sclerosis (MS) and related disorders: conventional MS and neuromyelitis optica (NMO), including NMO spectrum disorders (together referred to as NMO(SD)). MS and NMO(SD) now appear to have distinct aetiologies. We investigated a Canadian Asian population to determine the relationship between place of residence prior to disease onset and clinical phenotype. Methods: We investigated 92 eligible patients with full East or Southeast Asian ancestry attending the University of British Columbia (BC) Hospital MS Clinic with a diagnosis of MS or NMO(SD). Clinical data were extracted by retrospective chart review. Final diagnosis was reviewed by an MS/NMO specialist (ALT). Patients were administered a questionnaire to determine ethnicity and migration history. Results: MS cases showed a tendency to have been born in Canada (42.4% vs. 24.2%, p=0.064) or to have resided in Canada for a longer period prior to disease onset (17.8 vs. 14.2 years, p=0.133) compared to NMO(SD) cases. When considering only foreignborn cases, duration of residence in Canada before disease onset was significantly longer in MS than NMO(SD) patients (12.6 vs. 7.6 years, p=0.031). Moreover, among foreign-born cases, those who resided in Canada at the onset of disease were more likely to be diagnosed with MS than NMO(SD) compared to those with disease onset in their country of origin (66.0% vs. 25.0%, p=0.013). Conclusions: Our data suggest that length of Canadian residency, i.e. environment, prior to onset may be associated with clinical phenotype (MS or NMO(SD)). Replication is needed. O-2 Benign Multiple Sclerosis: A Longitudinal Follow-Up Study of Large Western Australian Cohort MJ Pedrini1, W Xu2, Z Xu3, A Seewann4, J Burton1, WM Carroll1, AG Kermode1,5 1Centre for Neuromuscular and Neurological Disorders, Australian Neuromuscular Research Institute, UWA, Sir Charles Gairdner Hospital, Queen Elizabeth II Medical Centre, Western Australia; 2Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, PR China; 3Affiliated

msj.sagepub.com

Background: In a minority of MS patients, termed benign MS (BMS), disease never leads to substantial disability and shows little or no progression years after the first symptoms. The aim of our study was to evaluate disease status after 15, 20, 25, 30 and 35 years in a well characterized Western Australian longitudinal cohort defined as BMS based on Expanded Disability Status Scale (EDSS)

6th Pactrims Invited Lecture.

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