Pactrims Invited Lecture / Ordinary Submission

doi:10.1177/1352458514563659

. 2015 May;21(6):799–838. doi: 10.1177/1352458514563659

Pactrims Invited Lecture / Ordinary Submission

PMCID: PMC4425815 PMID: 28080249

Opening Lecture

L-1 Mechanisms of Progression in MS

Hans Lassmann (Austria)

Department for Neuroimmunology, Center for Brain Research, Medical University of Vienna, Austria

Multiple sclerosis (MS) has been defined as a chronic inflammatory disease of the central nervous system leading to plaque like primary demyelination and subsequent neurodegeneration in the white and grey matter of the central nervous system. Anti-inflammatory or immunomodulatory treatments exert a beneficial effect in the relapsing stage, but fail when patients have entered the progressive stage of the disease. The loss of therapeutic effects in the progressive stage can in part be explained by compartmentalization of the inflammatory response within the central nervous system behind a closed or repaired blood brain barrier. Demyelination and neurodegeneration in the early stages of MS appear to be mediated by a variety of different immunological mechanisms, involving cytotoxic T-cells, specific antibodies and activated macrophages or microglia. Recent data suggest that microglia activation with subsequent oxidative injury and mitochondrial damage plays a central role in the induction of tissue injury in all stages of multiple sclerosis, and this pathway of tissue damage is particularly prominent in the progressive stage of the disease. Oxidative injury is driven in relapsing MS by inflammation and oxidative burst activation in microglia. With disease progression inflammation declines, but oxidative injury is amplified by age and disease burden related mechanisms, including tissue damage related microglia activation, release of reactive oxygen species from damaged mitochondria and age related accumulation of iron in the brain and its liberation within active lesions. Mitochondrial injury results in energy deficiency, disturbing brain function. In addition it triggers ionic imbalance in neurons and axons, which further propagates axonal and neuronal demise. Thus, therapies which are effective in the progressive stage of the disease have to be based on drugs, which can enter the central nervous system through an intact blood brain barrier and they have to combine anti-inflammatory with neuroprotective treatment strategies.

Special Lecture

L-2 NMOSD – Where are we in 2014?

Dean Wingerchuk (USA)

Department of Neurology, Mayo Clinic

Neuromyelitis optica (NMO) is an inflammatory CNS syndrome consisting of myelitis and optic neuritis. Diagnostic criteria for NMO have been gradually refined over the past 15 years, most importantly by the discovery of the specific association of NMO with serum antibodies that target the astrocyte water channel aquaporin-4 (AQP4). The disorder is now recognized as an autoimmune astrocytopathy when associated with anti-AQP4 although some patients with the NMO clinical phenotype do not have detectable anti-AQP4. The concept of NMO spectrum disorders (NMOSD) was developed in 2007 to express the broader array of clinical and neuroimaging characteristics associated with anti-AQP4, including ‘partial’ forms of NMO such as recurrent longitudinally extensive myelitis (LETM) and signature brain MRI lesion patterns. The International Panel for NMO Diagnosis has recently proposed revised consensus NMOSD diagnostic criteria to encompass further advances. These revisions include definitions of core clinical and MRI characteristics related to optic nerve, spinal cord, brain stem, diencephalic, or cerebral presentations and integration with serological data (presence or absence of anti-AQP4). The proposed criteria and their implications for clinical diagnosis and treatment strategies will be discussed along with related issues such as pediatric NMOSD, opticospinal MS, and other antibody associations such as anti-myelin oligodendrocyte glycoprotein (MOG).

Main symposium-1 Markers of Progression in MS

L-3 Pathological and MRI markers of deterioration

Klaus Schmierer (UK)

Centre for Neuroscience and Trauma, Barts and The London School of Medicine and Dentistry

The reasons we keep inspecting samples of MS tissue, mainly in post mortem and sometimes in biopsy tissue, are manifold. Despite the availability of numerous disease models, the pathology of MS remains unique. Novel pathological insights (sometimes important rediscoveries of observations made many decades ago) include the significant degree of axonal damage and loss in acute inflammatory demyelinating lesions, the involvement of the grey matter, meningeal inflammation, and the non-lesional (diffuse) pathology of the MS brain. The pathology of disease deterioration in MS is a game of numbers: inflammation, the accumulation and severity of lesions, the loss of neurons and axons, gliosis – all these features can (some more straightforward than others) be quantified. However, ‘deterioration’ refers to a clinical scenario, and in order to use pathological observations for the benefit of people with MS (pwMS) translation into clinically applicable indices is required. The main tool for this purpose remains MRI. The interplay between pathological observation, and hard- and software development in MRI has resulted in (i) contrast mechanisms that can now be exploited for pwMS, such as susceptibility weighted imaging, (ii) the fine tuning of previously used indices for better assessment and monitoring of specific pathological features of MS, including quantitative techniques, such as magnetisation transfer, relaxation time measurements, diffusion and spectroscopy, and (iii) the current key measure of overall tissue loss and prediction of disability – atrophy.

L-4 Molecular Immunophenotypes in MS

David Booth (Australia)

Centre for Immunology, Westmead Millennium Institute, Sydney

We aimed to identify if there are molecular subtypes of MS by leveraging from the genes now known to affect disease susceptibility.

Background: The proportion of immune cell subsets in blood is known to be heritable, stable over time, and to affect susceptibility to autoimmune diseases such as MS. Regulation of these cell subsets underpins the successful MS therapies. By characterizing the subsets that are dysregulated in autoimmune disease, we should be able to personalize therapy, monitor disease progression and drug response, and develop new therapeutic strategies.

Methods: We have interrogated the mRNA expression of MS susceptibility genes in blood from 3 independent cohorts of untreated MS patients and controls. We have then sought the immune cell subsets driving these associations using flow cytometry. Finally, we have assessed the changes in expression of these genes for the major therapies now used in MS.

Results: We have found three molecular phenotypes of MS based on expression of MS susceptibility genes: RPS6 is high in MS, EOMES and TBX21 are co-regulated and are low in MS, ZMIZ1 and ZFP36L2 are co-regulated and underexpressed in MS. This expression is altered by therapy. By flow cytometry we have found evidence that each molecular phenotype points to dysregulation of different immune cell subsets.

Discussion: We have identified molecular heterogeneity in MS which may be useful in predicting, prior to therapy, who will respond to the currently available drugs; measure how the patient is responding on therapy, and identify new targets for therapeutic intervention.

L-5 Serum and CSF Biomarkers of Progression

Melissa Gresle (Australia)

Department of Medicine, University of Melbourne, Australia

Axonal damage is recognized as the main pathological correlate of progressive neurological decline in Multiple Sclerosis (MS). Damage to axons is a feature of both acute and chronic lesions of MS, and in early disease, the rate of axonal loss is thought to be a major determinant of the timing to secondary progressive MS. Surrogate markers for axonal injury are not, however, routinely used to monitor disease activity in MS patients. To address this need, several studies have now focussed on the detection of neuronal/axonal proteins in CSF or blood, as surrogate markers of this damage. These studies are based on the concept that contact between the cerebrospinal fluid and extracellular matrix of the brain may allow for the diffusion of neuronal breakdown products into body fluids where they can be measured as biomarkers of damage. I will review the current literature on some of the most promising CSF and serum biomarker candidates for axonal injury, with a focus on recent studies of neurofilament-heavy chain levels in serum and CSF of MS cases. This recent work highlights the potential utility of these proteins as prognostic indicators or monitoring tools for axonal injury and disease progression in MS.

PACTRIMS Educational Course Pitfalls in diagnosing MS and NMO in Asians

L-6 MS mimics in Asians

Chong Tin Tan (Malaysia)

Division of Neurology, Department of Medicine, University of Malaya

This presentation will focus on differentiation between multiple sclerosis (and its related immune demyelinating disorders), with diseases of other aetiologies. The diagnosis of multiple sclerosis (MS) is essentially based on dissemination in space and time, excluding diseases of other known aetiology. It is thus not surprising that there are many mimics particularly during initial presentation, mainly other causes of acute myelopathy, visual failure, and disseminated cerebral white matter lesions. Mimics of acute myelopathy include infective causes such as varicella zoster, dengue, HIV, HTLV-1 and mycoplasma; metabolic causes such as SCDC; vascular and other autoimmune etiologies. Mimics of acute optic neuritis include papilloedema, ischemic optic neuropathy, and Leber hereditary optic neuropathy. Mimics of disseminated cerebral white matter lesions include vascular causes such as leukoaraiosis, cerebral vein thrombosis, PRES, dural AVM, primary CNS angiitis, and CADASIL; tumor lesions such as CNS intravascular lymphoma, infection such as PML, and metabolic causes such as osmotic demyelination syndrome, mitochondrial disease and adult onset leukodystrophy. When making a diagnosis of MS, one should be particularly cautious when there is onset at extremes of age, hyperacute or progressive clinical course, symptoms reflecting predominantly gray matter involvement, imaging showing leptomeningeal involvement, marked mass effect, CSF showing low CSF glucose, and marked pleocytosis. The presence of autoimmune serology markers and CSF OG band should also be interpreted in the overall clinical context. On the other hand, clinical symptoms suggestive of demyelinating pathology include: constricting feeling or tight sensation, sensory ataxia, paroxysmal tonic spasm (PTS), Lhermitte’s sign and Uhthoff sign.

L-7 NMO mimics in Asians

Naraporn Prayoonwiwat (Thailand)

Division of Neurology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University

Neuromyelitis optica (NMO) is an inflammatory disease of the central nervous system, once considered a variant of multiple sclerosis (MS). It is now defined a separate disease after the discovery of an autoantibody (NMO-IgG) mainly targeting aquaporin-4 (AQP-4) at the footplates of astrocytes. Although NMO can be found worldwide, this autoimmune disease seems to be more prevalent among certain population, e.g. Africans, Latin Americans and East Asians. Diagnosis of definite NMO requires clinical presentations of optic neuritis (ON) and transverse myelitis (TM) with supporting evidences from brain and spinal cord magnetic resonance imaging as well as presence of NMO-IgG/AQP-4 antibody. Recurrent ON and bilateral simultaneous ON, TM with longitudinally extensive lesion (LETM) and certain characteristic brain/brainstem involvements are included in the NMO spectrum disorders (NMOSD). In addition, NMO can be associated in systemic autoimmune diseases, particularly systemic lupus erythematosus (SLE) and Sjogren’s syndrome (SS). Diagnosis of NMO may not be possible especially in the early stage and in antibody-negative patients. Differential diagnosis from their mimics is essential for the long-term management.

Typical clinical presentations of MS among Asians and Caucasians are similar. With the symptoms of optic nerve, spinal cord and brainstem dysfunctions, MS is therefore considered an NMO mimic (and vice versa). Although certain clinical features could be helpful in differentiating between NMO than MS, there still were some overlaps. Causes of inflammatory myelopathy include LETM in systemic autoimmune diseases (e.g. SLE, SS, neuro Behcet’s disease, neuro sarcoidosis), paraneoplastic myelopathy (e.g. anti-collapsin response-mediator protein: CRMP-5) and infection-related. Differential diagnosis of optic neuritis includes ischemic neuropathy and autoimmune diseases. Bilateral painless visual loss, an NMOSD presentation, can be found in toxic and nutritional optic neuropathies (e.g. vitamin B12 deficiency, tobacco-alcohol amblyopia, methanol intoxication, ethambutol toxicity), and inherited optic neuropathies (Leber hereditary optic neuropathy). Diagnosis requires careful clinical evaluation for other neurological dysfunctions and systemic disorders as well as investigations including magnetic resonance imaging, evoked potentials, cerebrospinal fluid examination and relevant serology.

Workshop Myelin Repair and Treatment of Disease Progression in MS

L-8 The Role of Remyelination in Progressive MS

Tobias Merson (Australia)

Yao Lulu Xing^1,2, Philipp T. Röth^1,2, Jo Anne S. Stratton^1,3, Bernard H. A. Chuang¹, Jill Danne^4,5, Sarah L. Ellis^4,5, Sze Woei Ng¹, Trevor J. Kilpatrick^1,3,6, Tobias D. Merson^1,2,6

¹Florey Institute of Neuroscience and Mental Health, and ²Florey Department of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, 3010, Australia. ³Department of Anatomy and Neuroscience, The University of Melbourne, Parkville, Victoria 3010, Australia. ⁴Peter MacCallum Cancer Centre, East Melbourne, Victoria 3006, Australia. ⁵Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria 3010. 6. Melbourne Neuroscience Institute, The University of Melbourne, Parkville, Victoria 3010, Australia.

Remyelination of the central nervous system (CNS) is believed to occur primarily via the generation of new oligodendrocytes derived from oligodendrocyte progenitor cells (OPCs) that reside throughout the CNS parenchyma. Recent studies suggest that neural precursor cells (NPCs) residing within the adult subventricular zone (SVZ) can also contribute to oligodendrogenesis following experimental demyelination. However the relative importance of NPCs versus OPCs during remyelination remains largely unexplored. We adopted a genetic fate-mapping approach to independently trace the progeny of NPC and OPC lineages during the course of CNS remyelination. Nestin-CreER^T2 or Pdgfra-CreER^T2 mice were crossed with transgenic reporter lines to enable Cre-dependent expression of fluorescent reporter proteins within either the NPC or OPC lineages, respectively. Following tamoxifen-mediated induction of reporter protein expression, mice were challenged with the demyelinating agent cuprizone for six weeks. Upon examination six weeks after cuprizone withdrawal, we quantified substantial numbers of NPCs marked by tamoxifen-induced YFP expression that had migrated into the demyelinated corpus callosum and differentiated into mature oligodendrocytes, particularly in the rostral forebrain across a broad region centered around the dorsolateral corner of the SVZ. Within this region NPC-derived oligodendrocytes outnumbered those generated from OPCs 4.6-fold, indicating that NPCs exhibit a significant competitive advantage over OPCs in this area. NPC-derived oligodendrocytes were also maintained long-term, being detected at similar density at both six and fourteen weeks after cuprizone withdrawal. Independent fate mapping of OPCs during the course of de-/remyelination revealed that newly-generated oligodendrocytes at six weeks recovery were distributed in a converse manner to NPC-derived oligodendrocytes, being localized predominately in the midline and lateral regions of the corpus callosum. Examination of the remyelination capacity of NPC-derived oligodendrocytes revealed that 62% of all nodes of Ranvier adjacent to the SVZ were flanked by at least one myelin paranode generated from an NPC-derived oligodendrocyte. Remarkably, g-ratios of myelinated axons in regions subject to significant NPC-derived remyelination were equivalent to unchallenged controls, and immuno-electron microscopy revealed that NPC-derived myelin was significantly thicker than that generated by pOPCs, irrespective of axonal caliber. We also demonstrate that a reduced efficiency of remyelination in the caudal CC was associated with long-term impairment in the maturation of oligodendrogenic NPCs but only transient delay in pOPC differentiation. Collectively, our data define a major distinct role for NPCs in remyelination, identifying them as a key target for enhancing myelin repair in demyelinating diseases.

Main symposium-2 Cutting Edge of NMOSD Research

L-9 What is Seronegative NMO?

Jacqueline Palace (UK)

Division of Clinical Neurology, University of Oxford

The diagnosis of seronegative neuromyelitis (NMO) and NMO spectrum disorder (NMOSD) requires the use of a sensitive aquaporin-4 (AQP4) antibody assay. The assay used varies across the world; with the NMO IgG assay using immunofluorescence being less sensitive than the cell based assay using the M23 isoform of AQP4.

Seronegative NMOSD cohorts differ from those with AQP4 antibodies having a greater preponderance of monophasic disorders, lower female to male ratios, and a greater likelihood of presenting with bilateral optic neuritis and simultaneous transverse myelitis.

Cohorts of NMOSD without AQP4 antibodies consist of a heterogeneous group of conditions, including patients with myelin oligodendrocyte glycoprotein (MOG) antibodies. However some patients are indistinguishable from those with AQP4 antibodies and should be treated in a similar manner.

The AQP4 antibody assays used, the differential diagnoses, and the management strategies in seronegative NMOSD will be discussed.

L-10 NMO Immunopathology

Tatsuro Misu (Japan)

Department of Multiple Sclerosis Therapeutics, Tohoku University Graduate School of Medicine

Neuromyelitis optica (NMO) is an autoimmune disease targeting aquaporin 4 (AQP4), localized mainly at the astrocytic foot processes. Loss of AQP4 and glial fibrillary acidic protein is a pathological hallmark of NMO lesions, suggesting the astrocyte damage and secondary demyelination in NMO. Furthermore, the lesions lacking AQP4 was appeared by passively transferred Lewis rats with human purified IgG from NMO patients, which strongly suggested its autoimmune mechanisms in NMO. T cells including Th17 cell and related cytokines are probably associated with the initial stage of lesion formation, because anti-AQP4 antibody alone could not pass the blood brain barrier (BBB) and needs breakdown of BBB by another specific and non-specific inflammation. In addition, innate immunity such as neutrophil and eosinophil may be the key for the expansion of these NMO lesions, but these phenomena remained to be well-elucidated.

The mechanism of astrocyte damage includes at least two types, complement-related cytotoxic cell lysis and functionally reversible damage. Active lesions in NMO display a wide spectrum of pathology (6 types) even within a single tissue block of an individual patient. Especially, the lesion type 1 reflects the typical perivascular deposition of complement especially at the surface of astrocytes, associated with granulocyte infiltration and astrocyte necrosis and followed by demyelination, which may lead to the global tissue destruction and the formation of cystic, necrotic lesions. In contrast, another lesion type 5 is characterized by clasmatodendrosis of astrocytes, defined by cytoplasmic swelling and vacuolation, beading and dissolution of their processes and nuclear alterations resembling apoptosis, which was associated with internalization of AQP4 and astrocyte apoptosis in the absence of complement activation. Lesion type 6 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.

The existence of orchestrated members in the mechanism of NMO suggests that different mechanisms of tissue injury operate in parallel and needs the lesion-specific therapeutic strategy in this disease.

L-11 AQP4 Immunology in NMOSD

Shuhei Nishiyama (Japan)

Department of Neurology, Tohoku University School of Medicine

Neuromyelitis optica spectrum disorders (NMOSD) is clinically characterized by severe optic neuritis、 longitudinally extensive transverse myelitis and some brain syndromes. Aquaporin 4 (AQP4)-IgG, an NMO-specific autoantibody against the water channel richly expressed in astrocytic endfeet, is a diagnostic biomarker and has a pathogenic potential in causing autoimmune astrocytopathy in NMOSD as shown in experimental studies. In this presentation, an updated overview of the biology of AQP4, humoral and cellular immunity against AQP4, and diverse pathological patterns in NMOSD will be provided. Meanwhile, despite the use of the most sensitive assay of AQP4-IgG, some patients with NMOSD are consistently seronegative. Recently, myelin oligodendrocyte glycoprotein (MOG)-IgG has been detected in a fraction of patients with AQP4-IgG-seronegative NMOSD. Unique clinical and pathological features of MOG-IgG-positive NMOSD will also be reviewed.

Main symposium-3 New Perspectives of Treatment on Idiopathic CNS Inflammatory Disease

L-12 New Perspectives on Inflammatory CNS Disease Therapies

Klaus Schmierer (UK)

Centre for Neuroscience and Trauma, Barts and The London School of Medicine and Dentistry

This presentation will focus on the treatment of people with multiple sclerosis (pwMS) and clinically isolated syndrome (pwCIS), with some comments on neuromyelitis optica (NMO) and an emphasis on the role of repurposed drugs in the current and future management of people with these conditions. The rising number of available disease modifying drugs (DMD) for people with relapsing MS (pwRMS) has expanded treatment options, however also increased the uncertainty about the best treatment strategy, particularly for colleagues who do not regularly see pwMS in their clinical practice. Broadly speaking, there are two strategies for the use of DMD in pwRMS, early induction or escalation. Assessing and explaining the benefit-risk balance of DMD are key for decision making, and to empower pwRMS to take such decisions jointly with their clinicians poses a major challenge. Even within a seemingly unified healthcare system, such as the NHS in the UK, there is heterogeneity of what is considered ‘best practise’, and influenced by restrictions of access to DMD (an issue in many countries). The question of whether or not to treat pwCIS depends on early signs of dissemination, in which case treatment should commence. Whilst there is currently no licensed DMD for pwNMO, various immunomodulatory drugs are being used, and trials with promising molecules underway. The debate whether trials should be placebo-controlled is ongoing. With two exceptions all currently licensed (and some unlicensed) DMD used in pwCIS and pwMS are repurposed drugs, which have served pwMS well for over 20 years since the introduction of beta-interferons revolutionised MS management. Whilst repurposed drugs are thus the mainstay of current MS disease modifying therapy, the more recent discussion about repurposing has focussed on generic drugs that may not only be safe and effective, but also more affordable treatments for pwMS.

L-13 Anti-HMGB1 as Potential Therapeutics for NMO

Li-Te Chin (Taiwan)

Department of Microbiology, Immunology and Biopharmaceuticals, National Chiayi University, Chiayi City, Taiwan

In theory, heavy and light chain components derived entirely from the human origin could be used to assemble mAbs in phage or non-human animals. However, the resultant pairings may not be naturally-occurring and still remain to be immunogenic as indicated in the official FDA labeling information. Therefore, this may not be the best available strategy. Alternatively, a sharp clinical contrast provided by the therapeutic immunoglobulin preparations, and especially intravenous immunoglobulin (IVIg), may well turn out to be optimistic in resolving the problem of immunogenicity. HumOrigin has developed a site-directed in vitro immunization platform to achieve this goal. High-mobility group box 1 protein (HMGB1) has cytokine activities and mediates systemic inflammation as well as immune responses. In our previous study revealed that plasma HMGB1 level can be used as a marker for neuromyelitis optica (NMO) in which severe inflammatory response is often associated clinically with transverse myelitis and optic neuritis. The role of HMGB1 is possible, given that factors inducing its release, such as extensive necrosis, demyelination, and perivascular macrophage infiltration are common clinical features. The resulting mAbs against the pre-defined epitopes of human high mobility group box 1 (huHMGB1) and that function to abrogate the HMGB1-induced proinflammatory pathway and thus HMGB1 associated- neuropathy and NMO will be discussed.

L-14 Long Term MS Management in China

Qiu Wei, Hu Xue-qiang (China)

Multiple Sclerosis Center, Department of Neurology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, China

MS is distinctive from NMO in the clinical, pathological and radiological features.

Nowadays, owing to the advanced technique of MRI, CSF, and NMO-IgG tests, we can diagnose MS at an early stage. Importantly, we can differentiate MS from NMO/NMOSDs, in which IFN-beta may deteriorate the disorders. Although MS prevalence in China (1.39/100,000) is much lower than what is reported in the Western countries (100/100,000), more and more cases are being reported. MS is not thought to be a rare disorder in the Chinese population.

Unfortunately, hitherto no clinical study of any IFN-beta therapy has yet been successfully conducted in China. While some open label, single-arm studies have demonstrated that different IFN-beta preparations are effective in reducing the occurrence of new lesions and have a favourable safety profile in Chinese patients with RRMS. As many first-line disease-modifying therapies (DMT) used in Western countries are not yet available for MS therapy in China, only minority of patients with RRMS are able to get DMT. Corticosteroids and other immunosuppresants are the most frequently prescribed therapies.

IFN-Beta and other FDA approved DMT drugs are not covered by the insurance, and the high cost has to be borne by patients. Moreover, the relatively low prevalence, paucity of specialized MS centers and long distance travel for individual patients to reach those centers seem to have been challenging. Therefore, like in other resource-poor areas, we need to seek a cost-effective strategy for the management of MS – a chronic devastating disease.

Closing Lecture

L-15 Reviewing a Decade of Discovery in Asia

Ho Jin Kim (Korea)

Research Institute and Hospital of National Cancer Center, Korea

A decade has passed since the first disease-specific autoantibody of CNS, neuromyelitis optica (NMO)-IgG, was discovered. A year later, aquaporin-4 (AQP4) was identified as a target antigen of NMO-IgG. Such breakthrough discoveries initiated dramatic advances in our understanding of NMO, which has long been considered a subtype of multiple sclerosis (MS), so-called “optic-spinal MS”. However, a series of clinical, pathological, immunological, and imaging studies have clarified that NMO is distinct from MS and is now considered an autoimmune astocytopathic disease. Additionally, the identification of anti-AQP4 antibodies in patients with only one of either index events of NMO or with recently recognized pattern of brain abnormalities, indicate a broader clinical phenotype of this disorder, so-called “NMO spectrum disorder (NMOSD)”.

The past decade has witnessed marked advance in MS therapeutics, too. Ten years ago, interferon-beta was the only available therapy in most of Asian countries. However, new therapies have been continuing to emerge and now more than 10 MS disease-modifying drugs are approved, although the availability of these drugs varies among countries. The therapeutic environment of MS has changed and is likely to change continuously.

In this talk, I’ll review the discoveries and advances in our region over the past 10 years.

Mult Scler. 2015 May;21(6):799–838.

Ordinary Submission

Oral Session 1 NMO

O-1 Comparison of Cognitive Performance and MRI-Measured Brain Volume and Cortical Thickness between Patients with Neuromyelitis Optica Spectrum Disorder (NMOSD) and Multiple Sclerosis (MS): A Preliminary Report

Su-Hyun Kim¹, Jae-Won Hyun¹, In Hye Jeong¹, AeRan Joung¹, Hyo-Jin Jo¹, Eun-Seung Yu², Kichang Kwak³, Seun Jeon³, Gilsoon Park³, Jong-Min Lee³, Sang Hyun Lee⁴, Ho Jin Kim¹

¹Department of Neurology, Research Institute and Hospital of National Cancer Center, Goyang, Korea; ²Mental Health Clinic, Research Institute and Hospital of National Cancer Center, Goyang, Korea; ³Department of Biomedical Engineering, Hanyang University, Seoul, Korea; ⁴Department of Radiology, Research Institute and Hospital of National Cancer Center, Goyang, Korea

Objective: To investigate cognitive function and MRI-measured brain volume and cortical thickness in patients with neuromyelitis optica spectrum disorder (NMOSD) in comparison with those in patients with multiple sclerosis (MS).

Methods: Forty-three patients with NMOSD, 34 with MS, and 31 normal controls (NCs) underwent neuropsychological tests and MRI examination. Cognitive impairment was considered if at least three cognitive domains were inferior to the 5^th percentile for NCs. MRI measures included global brain volume, deep gray matter (GM) volume, and cortical thickness.

Results: Cognitive impairment was seen in 28% of NMOSD and 53% of MS patients (P = 0.040). Visual memory (37%) and information processing speed (33%) were the most commonly impaired functions in NMOSD. In contrast, verbal memory (56%) was the most commonly impaired function in MS, followed by visual memory (41%) and information processing speed (41%). Performance scores of verbal memory were significantly different between NMOSD and MS, while no such differences were observed in other scores. MS patients exhibited more widespread and greater deep GM volume reduction and cortical thinning, while NMOSD patients showed regional GM volume reduction and cortical thinning. Brain volume and cortical thickness were not significantly different between NMOSD patients with and without cognitive impairment, whereas cortical thinning was associated with cognitive impairment in patients with MS (P = 0.027).

Conclusion: Cognitive impairments were less common and less extensive in NMOSD patients than MS patients. Changes in brain volume and cortical thickness did not add to the predictive value for cognitive impairment in NMOSD.

O-2 A Combined Neuroimaging and Neuropathological Study for Spinal Cord Lesions of Neuromyelitis Optica: with Special Reference to Lesion Distribution and Extension Patterns

S. Hayashida, K. Masaki, T. Yonekawa, N. Isobe, M. Watanabe, T. Matsushita, J. Kira

Departments of Neurology and Neurological Therapeutics, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

Background: Neuromyelitis optica (NMO) is an inflammatory disorder characterized by optic neuritis and longitudinally extensive spinal cord lesions (LESCLs). Previous MRI study suggests LESCLs mainly involve the central gray matter. However, fine distribution of spinal cord lesions in NMO has not been extensively studied.

Objective: To characterize the fine distribution of spinal cord lesions in Japanese NMO and NMO spectrum disorder (NMOSD) patients.

Methods: We analyzed the distribution of LESCLs on the axial plane of the 3 tesla MRI in 15 anti-aquaporin-4 (AQP4) antibody-seropositive and 16 -seronegative NMO/NMOSD cases within three spinal cord attacks. We also evaluated the lesion distribution of 40 axial sections of spinal cord from eleven autopsied NMO/NMOSD cases.

Results: On the MRI, anterior horns, central portions and posterior horns were involved in 7/15(46.7%), 14/15 (93.3%), and 14/15 (93.3%) in the seropositive cases, and 7/16 (43.8%), 13/16 (81.3%), and 13/16 (81.3%) in the seronegative cases, respectively. Anterior, lateral and posterior columns were affected in 3/15 (20.0%), 8/15 (53.3%), and 12/15 (80.0%) in the seropositive cases and 3/16 (18.8%), 9/16 (56.3%), and 15/16 (93.8%) in the seronegative cases, respectively. Pathologically, anterior horns, central portions and posterior horns were involved in 26/40 (65.0%), 25/40 (62.5%), and 28/40 (70.0%). Anterior, lateral and posterior columns were affected in 25/40 (62.5%), 33/40 (82.5%), and 39/40 (97.5%), respectively.

Conclusion: Our findings suggest that spinal cord lesions in NMO/NMOSD have a tendency to be located in the central and posterior portions. This distribution may be caused by perivascular inflammation from posterior spinal vein system.

O-3 Autoantibodies against MOG in Neuromyelitis Optica Spectrum Disorders

D. K. Sato,¹ D. Callegaro,² M.A. Lana-Peixoto,³ P. J. Waters,⁴ S. Tanaka,⁵ F. Jorge,² T. Takahashi,⁶ T. Misu,⁷ S. L. Apostolos-Pereira,² N. Talim,³ R. F. Simm,² A. M. M. Lino,² I. Nakashima,¹ K. Nomura,⁵ M. Aoki,¹ K. Fujihara⁷

¹Department of Neurology, Tohoku University School of Medicine, Sendai, Japan; ²Department of Neurology, Faculty of Medicine, University of Sao Paulo, Sao Paulo, Brazil; ³CIEM MS Research Center, Federal University of Minas Gerais, Belo Horizonte, Brazil; ⁴Nuffield Department of Clinical Neurosciences, Oxford, United Kingdom; ⁵Department of Neurology, Saitama Medical University, Saitama, Japan; ⁶Department of Neurology, Yonezawa National Hospital, Yonezawa, Japan; ⁷Department of Multiple Sclerosis Therapeutics, Tohoku University Graduate School of Medicine, Sendai, Japan

Background: Neuromyelitis optica spectrum disorder (NMOSD) is characterized by severe attacks of optic neuritis and longitudinally extensive transverse myelitis (LETM). A significant proportion of NMOSD patients are positive for aquaporin-4 (AQP4)-antibodies, but seronegative patients require further characterization and clarification of underlying pathogenesis. Autoantibodies against myelin-oligodendrocyte glycoprotein (MOG) were recently reported in AQP4-antibody seronegative NMOSD.

Objective: To evaluate the clinical characteristics and prognosis of patients with MOG antibodies in a large cohort clinically diagnosed as NMOSD.

Methods: We enrolled 290 pediatric and adult NMOSD cases from 4 tertiary centers from Japan and Brazil. Sera were tested for AQP4-antibodies and MOG-antibodies using cell based assays with transfected living cells.

Results: One hundred sixty-six NMOSD patients were positive for AQP4-antibodies and 134 were negative. Among the AQP4-antibody seronegative NMOSD, 26.1% (35/134) patients were positive for MOG antibodies, and 42.9% (15/35) had a single attack. None was positive for both antibodies. In contrast to patients with AQP4-antibodies, patients with MOG-antibodies and seronegatives did not have female predominance and brainstem lesions with nausea or hiccups were uncommon. Patients with MOG-antibodies had more limited phenotypes such as recurrent or bilateral simultaneous optic neuritis or LETM. Patients with MOG antibodies had optic neuritis with severe loss of visual acuity (below 20/200) or transverse myelitis during attacks, but usually had a good recovery (visual and motor) with less sustained disability.

Conclusions: NMOSD patients with MOG-antibodies have distinct clinical features and less disability suggesting different underlying mechanisms of AQP4-antibody positive NMOSD.

O-4 Comparison of Immunosuppressive Therapies for Prevention of Breakthrough Relapse in Patients with Neuromyelitis Optica Spectrum Disorder

In Hye Jeong¹, Boram Park², Su-Hyun Kim¹, Jae-Won Hyun¹, Jungnam Joo², Ho Jin Kim¹

¹Department of Neurology, Research institute and Hospital of National Cancer Center, Goyang, Korea. ²Biometric Research Branch, Research institute and Hospital of National Cancer Center, Goyang, Korea.

Background: Disability in neuromyelitis optica spectrum disorder (NMOSD) occurs as a result of attacks, thus minimizing the frequency and severity of attacks are primary therapeutic goals.

Objective: To compare the risk of breakthrough relapse among patients initially treated with three most commonly prescribed immunosuppressants: azathioprine, mycophenolate mofetil (MMF) and rituximab.

Methods: We retrospectively analyzed the relapses in 138 patients with NMOSD treated with azathioprine, MMF, or rituximab, at National Cancer Center, Korea from May 2005 to July 2014. The primary end point was the time to breakthrough relapse. A breakthrough relapse was defined if EDSS score at nadir of attack ≥6.0 or ≥0.5 points of increase if EDSS score was already ≥6.0. In case of optic neuritis (ON), breakthrough ON was defined as new worsening of visual acuity ≤0.1.

Results: The risk of breakthrough relapse significantly differed among 3 immunotherapies (p=0.0008 by the log-rank test). Breakthrough relapses occurred in 28.6% of patients on azathioprine (14/49) for a median of 15 months, in 11.8% on MMF (4/34) for 26 months, and in 3.6% on rituximab (2/55) for 65 months. In the multivariate analysis using Cox proportional hazards model, the hazard ratio of breakthrough relapse for azathioprine and MMF relative to rituximab was 9.38 (95% CI, 2.12-41.44; p=0.003) and 3.85 (95% CI, 0.7-21.16; p=0.121), respectively. The hazard ratio of breakthrough relapse for azathioprine relative to MMF was 3.24 (95% CI, 1.10-9.57; p=0.0332).

Conclusion: Initial treatment with rituximab or MMF significantly reduced the risk of breakthrough relapse compared to that with azathioprine.

Oral Session 2 Emerging Treatment for MS

O-5 Safety, Quality Of Life, and Walking Ability with PR-Fampridine Treatment in Clinical Practice in France: Interim Results of The LIBERATE Study

Yeh M,¹ Neau JP,² Castelnovo G,³ Soisson T,⁴ Kwiatkowski A,⁵ McNeill M⁶

¹Biogen Idec, Cambridge, MA, USA; ²CHU Poitiers - Hôpital la Milétrie, Poitiers, France; ³CHU de Nimes – Hopital Carémeau Nimes, Cedex, France; ⁴Cabinet de Neurologie, Orléans, France ⁵GHICL- Hopital Saint Vincent de Paul, Lille, Cedex, France; ⁶Biogen Idec, Maidenhead, UK

Background: Impaired walking negatively impacts MS patients’ lives and QoL. Prolonged-release (PR) fampridine is the only drug indicated to improve walking in MS.

Objective: To collect long-term, real-life data on safety, patient-reported QoL, and physician-reported walking ability in MS patients treated with PR-fampridine.

Methods: LIBERATE is an observational study in patients beginning treatment with PR-fampridine 10 mg twice daily in routine clinical practice. Data were collected at enrollment (baseline) and during follow-up visits for 6 months. Patients who discontinued treatment were encouraged to stay in the study (patients off treatment). Endpoints included incidence of AEs, physician-assessed Clinical Global Impression of Improvement (CGI-I) of walking ability and patient’s assessment of MS using the Multiple Sclerosis Impact Scale-29 (MSIS-29). Interim results from France are reported.

Results: Of the 989 patients enrolled, 765 (median EDSS, 5.5) were treated. Overall, 403 completed the 6-month follow-up (n=274 on treatment; n=129 off treatment). In total, 265/765 (35%) discontinued treatment: 167 (22%, lack of efficacy) and 88 (12%, AEs). Treated patients demonstrated improvement in MSIS-29 (mean change from baseline to month 6 [SD]) (–10.06[18.16]; n=218) vs patients off treatment (–1.10 [17.03]; n=85). CGI-I scores improved in 78%, remained stable in 14%, and worsened in 8% of patients (n=172) at Month 6, compared with 14%, 63% and 24% of patients off treatment (n=80), respectively. The most common AEs were insomnia (n=68 [7%]), headache (n=38 [4%]), and vertigo (n=30 [3%]).

Conclusions: PR-fampridine was well tolerated and associated with improvements in QoL over 6-months in French clinical practice.

O-6 Efficacy and Safety of Alemtuzumab in Treatment-Naive Patients with Relapsing-Remitting MS: Four-Year Follow-up of the CARE-MS I Study

R.A.L. Macdonell,¹ A.J. Coles,² D.L. Arnold,^3,4 H-P. Hartung,⁵ E. Havrdova,⁶ K.W. Selmaj,⁷ D.H. Margolin,⁸ J. Palmer,⁸ P. Oyuela,⁸ M.A. Panzara,⁸ D.A.S. Compston⁹; on behalf of the CARE-MS I Investigators

¹Brain Research Institute, Florey Institute of Neuroscience and Mental Health, Victoria, Australia; ²University of Cambridge, Addenbrooke’s Hospital, Cambridge, United Kingdom; ³NeuroRx Research, Montréal, Québec, Canada; ⁴Montréal Neurological Institute, McGill University, Montréal, Québec, Canada; ⁵Heinrich-Heine University, Düsseldorf, Germany; ⁶First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic; ⁷Medical University of Łódź, Łódź, Poland; ⁸Genzyme, a Sanofi company, Cambridge, Massachusetts, United States of America; ⁹University of Cambridge, Cambridge, United Kingdom

Background: In the phase 3 CARE-MS I study (NCT00530348), alemtuzumab significantly reduced relapse rate over subcutaneous interferon beta-1a (SC IFNB-1a), with manageable safety over 2 years.

Objectives: Examine 4-year efficacy/safety of alemtuzumab in patients treated with alemtuzumab during CARE-MS I, and 2-year efficacy/safety in patients switched to alemtuzumab in the extension study (crossover cohort; NCT00930553).

Methods: In CARE-MS I, treatment-naive patients with active RRMS received 2 courses of alemtuzumab (12 mg/day intravenously on 5 consecutive days and on 3 consecutive days 12 months later) or SC IFNB-1a (44 μg 3 times/week). In the extension study, patients could receive as-needed alemtuzumab re-treatment ≥1 year apart or approved disease-modifying therapy (DMT). Crossover patients received 2 alemtuzumab courses (5 days, then 3 days), 12 months apart.

Results: The extension enrolled 349 (95%) alemtuzumab-treated patients from the core study. Through 4 years, 73% received only 2 annual courses, while 21% and 5% received 1 or 2 additional courses, respectively; <5% of patients received another DMT during extension. Nine patients (3%) discontinued from the study, none due to adverse events (AEs). Among SC IFNB-1a–treated patients, 144 (83%) entered the extension and 132 (92%) received 2 courses of alemtuzumab. There were 8 withdrawals (6%) in the crossover group during the 2-year extension period, none due to AEs. Efficacy and safety data will be reported for both treatment cohorts.

Conclusions: Most patients treated with alemtuzumab did not require additional courses or other DMT during the 2-year extension; study discontinuation rates were low after alemtuzumab treatment.

O-7 Autologous Stem Cell Transplantation in Multiple Sclerosis: Results from A Single Centre

MJ Pedrini¹, G Cull², BM Augustson ², S Walters¹, C Crosbie², WM Carroll^1,3, AG Kermode ^1,3,4

¹Centre for Neuromuscular and Neurological Disorders, Western Australian Neuroscience Research Institute, University of Western Australia, Nedlands, Australia; ²Haematology Care Centre, Sir Charles Gairdner Hospital, Queen Elizabeth II Medical Centre, Nedlands, Australia; ³ Departments of Neurology, Sir Charles Gairdner Hospital, Queen Elizabeth II Medical Centre, Nedlands, Australia; ⁴Institute of Immunology and Infectious Diseases, Murdoch University, Murdoch, Australia

Background: In the last 2 decades, intensive immunosuppression followed by autologous stem cell transplantation (ASCT) has been proposed as a possible strategy for treatment of severe immune-mediated disorders, including multiple sclerosis (MS).

Objective: To review the outcome of ASCT for MS in Western Australia.

Methods: Eligibility criteria for ASCT were (1) progression of sustained disability with expanded disability status scale (EDSS) score increase of more than 1/10 over a 12 month period, (2) advanced MS with threatened loss of ambulation and (3) rapidly progressive disease not adequately assessed by EDSS. Stem cell mobilization was with cyclophosphamide (CY) 2g/m² and granulocyte-colony stimulating factor 5ug/kg bd. conditioning chemotherapy was with CY 50mg/kg and rabbit antithymocyte globulin 1mg/kg days -5 to -2. Patients were assessed at 3, 6, 12 and 24 months post-transplant.

Results: Fourteen patients underwent ASCT. Median age was 47 years; median time from diagnosis to transplant was 12 years. Diagnosis at transplant was secondary progressive MS (12), primary progressive MS (1) and neuromyelitis optica (1). About half the cohorts were neurologically stable at 24 months while the remainder had clinically relevant neurological deterioration. Two patients had meaningful improvement in bladder function. Follow-up MRI showed no Gd-enhancing lesions, but two patients developed new cerebral lesions on T2 weighted imaging.

Conclusion: In this group of patients with advanced MS, neurological function 24 months post-ASCT was essentially stable in half the cohort while the remainder experienced clinical progression. It is not possible to conclude whether ASCT altered the natural history of the disease.

O-8 CD30 Ligand is a New Therapeutic Target for Central Nervous System Autoimmunity

K Shinoda,^{1, ²} Xun Sun,³ Akiko Oyamada,² Hisakata Yamada,² Jun-ichi Kira,¹ Yasunobu Yoshikai²

¹Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; ²Division of Host Defense, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan; ³Department of Immunology, China Medical University, Shenyang, China

Background: The CD30 ligand (CD30L)/CD30 axis plays a critical role in Th1 and Th17 cell differentiation. However the role of CD30L/CD30 signaling in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) remains unknown.

Objective: To examine the role of CD30L/CD30 signaling and its therapeutic application in EAE.

Methods: EAE was induced by myelin oligodendrocyte glycoprotein (MOG) _35-55 peptide, and in vivo neutralization of CD30L/CD30 axis was performed by murine soluble CD30-Ig fusion protein.

Results: CD30 knockout (KO) and CD30L KO mice were resistant to EAE. The numbers of MOG_35-55 peptide-specific Th1 and Th17 cells were markedly reduced in the draining lymph nodes (dLNs) of CD30 or CD30L KO mice at the induction phase. Bone marrow (BM) chimera experiments indicated that CD30L on BM-derived cells was critical for the development of EAE and that CD30 signaling, but not CD30L reverse signaling in CD4 T cells, was required for their differentiation into pathogenic Th17 cells at the induction phase. Transfer of MOG_35-55 peptide-primed cells revealed an additional role for CD30L in the environment at the effector phase. In vivo neutralization of CD30L by soluble murine CD30-Immunoglobulin (mCD30-Ig) fusion protein before disease onset or even after disease onset significantly ameliorated the clinical course of EAE.

Conclusion: CD30L/CD30 signaling is critically involved in pathogenic CD4 T cell responses not only in dLNs at the induction phase but also in spinal cords at the effector phase. Thus CD30L/CD30 axis could be a new therapeutic target for central nervous system autoimmunity.

Oral Session 3 Myelin Repair and Treatment of Disease Progression in MS

O-9 Visualization of Demyelination and Remyelination by A Novel “Myelin Map” MR I: A Longitudinal Pilot Study

J Nakahara¹, K Fujiyoshi^2,3, K Hikishima⁴, J Hata⁴, S Momoshima⁵, S Takahashi¹, H Okano⁴, M Nakamura³, N Suzuki¹

¹Department of Neurology, Keio University School of Medicine, Tokyo, Japan; ²Department of Orthopaedic Surgery, National Hospital Organization Murayama Medical Center, Tokyo, Japan; ³Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan; ⁴Department of Physiology, Keio University School of Medicine, Tokyo, Japan; ⁵Department of Diagnostic Radiology, Keio University School of Medicine, Tokyo, Japan

Background: Diagnosis and treatment decision-making in multiple sclerosis (MS) greatly depend on magnetic resonance imaging (MRI). MS plaques in conventional MRI are defined as T2-hyperintense lesions. The major limitation of T2-hyperintensity is that it cannot discern remyelinated lesions from chronic demyelinated lesions. A sensitive measure to visualize myelin status is mandatory for a better clinical practice.

Objectives: We developed a novel q-space imaging-based MRI method named “Myelin Map”, and we have previously shown the ability of Myelin Map to differentiate remyelinated T2-lesions among MS plaques. In the current study, we aimed to testify the feasibility of Myelin Map to monitor demyelination and remyelination in a longitudinal axis in selected MS cases.

Methods: Four MS cases without clinical deterioration during the observation period (two relapsing-remitting (RR) MS and two secondary progressive (SP) MS), with or without treatment were included in the study. Myelin Map was performed with a 3-tesra MR scanner twice at an interval of 5-9 months for each patient.

Results: One early RRMS patient showed no interval difference in Myelin Map after 5 months. The other RRMS patient revealed a few newly-remyelinated lesions after 9 months. One SPMS patient showed both newly-remyelinated and demyelinated lesions after 9 months, whereas the other SPMS patients revealed a few newly-remyelinated lesions but no new demyelinated lesions after 7 months.

Conclusions: Our results suggest that there are inter-individual differences in remyelination capacity among MS patients. Myelin Map may be a useful tool to monitor myelin status in MS and further studies are warranted.

O-10 Quantifying the Effect of Natalizumab on the Total Disability Burden of MS Patients in AFFIRM Using an Exploratory Area under the Curve Analysis

Belachew S¹, Rudick R,¹ Shang S, ¹ Dong Q,¹ Paes D,¹ Mikol D¹

¹Biogen Idec, Cambridge, MA, USA

Background: Expanded Disability Status Scale (EDSS) progression/improvement measures may not capture all relevant changes in disability that occur to multiple sclerosis (MS) patients during clinical trials.

Objective: To assess the effect of natalizumab on disability changes during AFFIRM; a randomised, placebo-controlled trial of relapsing MS patients.

Methods: EDSS assessments were performed every 3 months. EDSS scores were plotted over time for each patient (natalizumab, n=627; placebo, n=315). The area under the EDSS/time curve was calculated then the sum of the patient’s baseline EDSS score and trial duration was subtracted. The result was the area under the curve (AUC) in EDSS years. A positive AUC indicated worsening in EDSS; a negative AUC indicated improvement. Least squares mean AUC, adjusted for baseline EDSS, was compared between groups using ANCOVA. Patient proportions with AUC ≥1.0, ≥1.5, or ≥2.0 EDSS years were compared by Fisher’s exact test.

Results: Natalizumab patients had a net improvement in disability over time (–0.15 EDSS years); placebo had a net worsening (+0.33 EDSS years; P<0.0001). Compared with placebo, natalizumab improved mean AUC by 0.53 EDSS years in patients with EDSS ≥2.5 (P<0.01) and by 0.44 EDSS years in patients with EDSS <2.5 (P<0.001). Natalizumab decreased the risk of net worsening in disability of ≥1.0, ≥1.5, and ≥2.0 EDSS years by 44% (P<0.001), 53% (P<0.001), and 55% (P<0.001), respectively.

Conclusions: AUC measurements of EDSS are useful to compare MS disability changes. Natalizumab-treated patients had less disability and were less likely to have worsening disability compared with placebo over time.

O-11 Disease-Free Outcomes with Alemtuzumab: 3-Year Follow-up of the CARE-MS Studies

M Dreyer,¹ DL Arnold,² H-P Hartung,³ KW Selmaj,⁴ DH Margolin,⁵ J Palmer,⁵ E Havrdova⁶; for the CARE-MS investigators

¹Royal Hobart Hospital, Tasmania, Australia; ²Montreal Neurological Institute and Hospital, Montreal, Quebec, Canada; NeuroRx Research, Montreal, Quebec, Canada; ³Heinrich-Heine University, Düsseldorf, Germany; ⁴Medical University of Łódź, Łódź, Poland; ⁵Genzyme, a Sanofi company, Cambridge, MA, USA; ⁶Charles University, Prague, Czech Republic

Background: Alemtuzumab demonstrated superior efficacy versus subcutaneous interferon beta-1a (SC IFN-1a), with a well-characterised safety profile, in active relapsing-remitting multiple sclerosis (RRMS) patients who were treatment-naive (CARE-MS I; NCT00530348) or who relapsed on prior therapy (CARE-MS II; NCT00548405). Alemtuzumab patients were more likely than SC IFNB-1a patients to be clinical, magnetic resonance imaging (MRI), and MS disease activity-free after 2 years.

Objective: To determine the proportion of patients who were clinical, MRI, and MS disease activity-free with alemtuzumab after 3 years.

Methods: Alemtuzumab-treated (12 mg/d intravenously on 5 consecutive days; 3 consecutive days 1 year later) CARE-MS patients continued in an extension (NCT00930553) and were optionally retreated on evidence of disease activity. Clinical disease activity (≥1 relapse or 6-month sustained accumulation of disability), MRI activity (≥1 new/enlarging gadolinium-enhancing or T₂ hyperintense lesion), and MS activity (clinical and MRI activity) were assessed at Year 3.

Results: 349 CARE-MS I and 393 CARE-MS II alemtuzumab patients entered the extension; 18% and 20% were retreated in Year 3. Most were free of clinical (83% and 76%), MRI (72% and 68%), and MS activity (64% and 55%) in Year 3. Similar proportions of patients were disease activity-free in Years 2 and 3.

Conclusions: Stable proportions of alemtuzumab patients were free of MS disease activity from Year 2 to 3, and the majority received no retreatment in Year 3, supporting the durable efficacy of alemtuzumab in RRMS.

Oral Session 4 MS Epidemiology

O-12 Prevalence and Incidence of Multiple Sclerosis in Iran

Zahra Nasr^1,2, Masoud Etemadifar²

¹Medical Students’ Research Center, Isfahan University of Medical Sciences, Isfahan, Iran; ²Isfahan Research Committee of Multiple Sclerosis (IRCOMS), Isfahan University of Medical Sciences, Isfahan, Iran

Background: Iran was considered to have a low prevalence rate of multiple sclerosis (MS) patients, but this rate has significantly increased during the recent years.

Objective: In this study we aimed to update MS prevalence and Incidence in Iran.

Patients and Methods: This study was conducted based on the data derived from the new report of Iran’s Ministry Of Health and Medical Education (MOHME) regarding the patients who have registered to obtain supports for treatment in Iran to the end of 2013.

Results: Among the 42200 registered patients, 32477 were female and 9723 were male (sex ratio: 3.34: 1). The national MS prevalence rate was calculated as 54.51/100,000 populations. Maximum prevalence rate was observed in Isfahan (89 per 100,000 of population) followed by Tehran (88/100,000). Furthermore, minimum prevalence rate was related to Sistan and Baluchistan province (7.4 per 100,000 of population). 4545 new MS cases were registered in 2013; hence the national MS incidence rate was 5.87 per 100,000 individuals in 2013.

Conclusion: According to our study results, Iran has a medium to high prevalence rate of multiple sclerosis. This rate is similar to what is seen in many western countries.

O-13 Comparative Analysis of Clinical Outcomes of Multiple Sclerosis and Related Disorders in Asian and Non-Asian Patients in A Canadian Clinic Population

Sadovnick AD^1,2, Lee JD¹, Yee IM¹, Guimond C¹, Vilariño-Güell C¹, Wu ZY³, Traboulsee AL².

¹Department of Medical Genetics, Faculty of Medicine, University of British Columbia, Vancouver, Canada; ²Division of Neurology, Faculty of Medicine, University of British Columbia, Vancouver, Canada; ³Department of Neurology and Institute of Neurology, Huashan Hospital, Fudan University, Shanghai, China

Background: It is widely believed that patients of Asian ancestry generally experience less favourable clinical outcomes of multiple sclerosis (MS) relative to Caucasian patients, although findings in this regard have been somewhat conflicting.

Objective: The objective of this study was to determine whether clinical outcomes of MS differ in patients of Asian ancestry versus those in the general clinic population at a Canadian MS clinic.

Methods: Clinical outcomes were analyzed in a retrospective cohort of patients at a Canadian MS clinic with a diagnosis of MS, neuromyelitis optica (NMO), NMO spectrum disorders, or clinically isolated syndromes suggestive of MS. Patients were stratified by ethnic origins into Asian and non-Asian cohorts. Cohort differences in the time from onset to level 6.0 disability on the Expanded Disability Status Scale were evaluated by Kaplan-Meier survival analysis and correlates of disability progression were examined with Cox proportional hazards models.

Results: Eighty-four Asian and 4,756 non-Asian patients were included in the analysis. Event-free survival in Asian patients was less than or equal to that in non-Asian patients for nearly all time points (p=0.029). However, when analysis was restricted to MS patients, median event-free survival in Asian patients was similar to that in non-Asian patients (24.2 years, 95% CI: 22.0-27.5 vs. 22.0 years, 95% CI: 21.4-22.9; p=0.46). Asian ethnicity was not associated with a greater hazard to reach the disability endpoint.

Conclusions: These results suggest that clinical outcomes of MS may be more similar in Asian and Caucasian patients than previously proposed.

Oral Session 5 MS Biomarker

O-14 Biomarkers of Neurodegeneration in Multiple Sclerosis

AJ Clarke¹, C Wang^1,2, H Beadnall¹, M Ghadiri¹, G Chohan¹, L Masters¹, Y Barnett^1,2,3, SN Hatton^1,2, J Lagopoulos^1,2, J Hagemeier⁴, R Zivadinov⁴, MH Barnett^1,2

¹Brain and Mind Research Institute, University of Sydney, Sydney; ²Sydney Neuroimaging Analysis Centre, Sydney; ³Imaging, St Vincent’s Hospital, Sydney; ⁴Buffalo Neuroimaging Analysis Centre, Buffalo, New York

Background: Although neuroaxonal injury is recognised as the primary driver of disability in multiple sclerosis, there is no universally acknowledged gold standard for the measurement of neurodegeneration.

Objectives: Characterise thalamic and whole brain volumetrics, and changes in proton magnetic resonance proton spectroscopy (¹H-MRS) data of normal appearing white matter (NAWM), to elucidate their role as potential biomarkers of disease progression in relapsing remitting multiple sclerosis (RRMS).

Methods: We studied 68 RRMS patients over 12 months with a mean Expanded Disability Status Scale (EDSS) score of 1.9 at baseline. Clinical assessment, 3.0T MRI, and NAWM ¹H-MRS were performed at 0, 3 and 12 months. Linear mixed models examined the relationship between longitudinal changes in whole and thalamus volumes, NAWM neurometabolite concentrations and disability.

Results: Increasing EDSS scores were significantly associated with decreasing total thalamic [F(1,84.2) = 14.58, p<.001] and whole brain volume [F(1,100.9) = 14.14, p<0.001]. Duration of illness was associated with increasing EDSS scores [F(1,63.1) = 10.52, p=0.002], decreasing total thalamic [F(1,69.3) = 6.89, p=0.011] and whole brain volumes [F(1,64.2) = 6.49, p=0.013] and a decreasing N-Acetylaspartate-Creatine (NAA-Cr) ratio [F(1,65.0) = 4.23, p=0.044]. Levels of NAA-Cr did not vary significantly over the 12 month period and were not associated with decreasing whole brain, thalamic volumes or worsening EDSS scores.

Conclusions: Thalamic and whole brain volumes reductions correlate with worsening disability in RRMS over a 12 month period. Thalamic volumetrics were found to be a more robust marker of disease progression than NAWM NAA-Cr levels over a short clinical timeframe.

O-15 Predictors for The Conversion of Clinically Isolated Syndrome to Multiple Sclerosis in Western Australian Cohort

MJ Pedrini¹, F Sanders², Z Xu³, J Burton^1,4, WM Carroll^1,4, AG Kermode^1,4,5

¹Centre for Neuromuscular and Neurological Disorders, Western Australian Neuroscience Research Institute, The University of Western Australia, Nedlands, Australia; ²VU University Medical Center, Amsterdam, The Netherlands; ³Affiliated Hospital of Guiyang Medical College, Guiyang, China; ⁴Department of Neurology, Sir Charles Gairdner Hospital, Queen Elizabeth II Medical Centre, Nedlands, Australia; ⁵Institute of Immunology and Infectious Diseases, Murdoch University, Murdoch, Australia

Background: Clinically isolated syndrome (CIS) such as optic neuritis, brainstem or spinal cord syndromes may represent the initial phase of multiple sclerosis (MS) but not all patients will convert to MS. The proportion of patients reported to convert to MS varies between 30-75% depending on the cohort.

Objective: To identify predictors of conversion to definite MS in patients with CIS, in the geographically isolated predominantly Anglo-Celtic population of Western Australia.

Methods: The predictive values for conversion to MS of demographic, clinical and magnetic resonance imaging (MRI) variables in patients who presented with CIS were studied.

Results: A total of 140 patients with average onset age of 38 ± 12 years were included in this study. MS was diagnosed in 86 patients (61%) and 54 patients (39%) remained as CIS. The mean age of onset was significantly lower in the MS conversion group compared to remaining CIS (36 ± 10 vs 40 ± 13, respectively). The mean time to conversion was 24.9 ± 29.2 months. 56.5% of patients converted to MS based on clinical relapse, while 43.5% based on MRI results. We identified two predictors of MS diagnosis: age at onset ≤ 35 years (p = 0.027) and initial MRI having lesions suggestive of MS (p = 0.014).

Conclusion: Based on the results, a younger age of onset and suggestive MRI lesions are strong predictors for the conversion to MS. These results are similar to those in other Anglo-Celtic cohorts.

O-16 Decreased Serum Vitamin D Levels in Japanese Patients with Multiple Sclerosis

M. Niino¹*, S. Sato², T. Fukazawa³, K. Masaki², Y. Miyazaki^1,4, D. Matsuse², T. Yonekawa², E. Takahashi¹, S. Kikuchi⁴, J. Kira²

¹Department of Clinical Research, Hokkaido Medical Center, Sapporo, Japan; ²Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; ³Sapporo Neurology Clinic, Sapporo, Japan; ⁴Department of Neurology, Hokkaido Medical Center, Sapporo, Japan

Background: Low vitamin D levels are considered a risk factor for multiple sclerosis (MS) in Western countries; however, vitamin D levels differ among ethnicities.

Objectives: To determine whether Japanese patients with MS show deficient serum vitamin D levels during winter.

Methods: Serum levels of 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1,25(OH)₂D] and vitamin D-binding protein (DBP) were measured in 40 patients with relapsing-remitting MS (RRMS), 30 patients with secondary progressive MS (SPMS) and 40 healthy controls in Hokkaido (north) and Kyushu (south).

Results: The mean 25(OH)D serum levels for both MS groups were significantly lower than those for controls (19.6 ± 11.2 nM vs. 25.5 ± 15.1 nM; p < 0.01). Among RRMS (21.7 ± 11.4 nM), SPMS (16.8 ± 10.4 nM) and control (25.5 ± 15.1 nM) groups, 25(OH)D serum levels were significantly lower in the SPMS group than in the control group (p < 0.05). There were no significant differences in 25(OH)D, 1,25(OH)₂D or DBP serum levels between subjects in the Hokkaido and Kyushu regions. There were no significant correlations between 25(OH)D, 1,25(OH)₂D or DBP serum levels and the Expanded Disability Status Scale or the Multiple Sclerosis Severity Score in patients with MS.

Conclusions: Our results suggest that 25(OH)D serum levels are lower in Japanese patients with MS than in controls. Furthermore, serum 25(OH)D, 1,25(OH)2D and DBP levels are similar between subjects in the northern and southern regions of Japan.

Oral Session 6 MS Genetics

O-17 Multiple Sclerosis Susceptibility/Resistance and Clinical Manifestations are Determined by HLA-DRB1 Alleles and Latitude in Japanese Patients

Y. Nakamura¹, T. Matsushita², S. Sato¹, M. Niino³, T. Fukazawa⁴, S. Yoshimura¹, S. Hisahara⁵, N. Isobe¹, S. Shimohama⁵, K. Yoshida⁶, H. Houzen⁷, Y. Miyazaki^3,8, S. Kikuchi⁸, J. Kira¹, the Japan Multiple Sclerosis Genetic Consortium

Departments of ¹Neurology and ²Neurological Therapeutics, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; ³Department of Clinical Research, Hokkaido Medical Center, Sapporo, Japan; ⁴Sapporo Neurology Clinic, Sapporo, Japan; ⁵Department of Neurology, School of Medicine, Sapporo Medical University, Sapporo, Japan; ⁶Department of Neurology, Asahikawa Red Cross Hospital, Asahikawa, Japan; ⁷Department of Neurology, Obihiro Kosei General Hospital, Obihiro, Japan; ⁸Department of Neurology, Hokkaido Medical Center, Sapporo, Japan

Background: Susceptibility and clinical features of multiple sclerosis (MS) are influenced by genes such as human leukocyte antigen (HLA) genes. We previously reported that MS patients with HLA-DRB1*04:05 showed a milder clinical course than those without it. The fourth nationwide survey of MS in Japan also revealed differences in clinical and magnetic resonance imaging features according to the latitude of Japan.

Objective: To clarify the differences in disease susceptibility and clinical manifestations according to HLA genes and latitude in Japanese MS patients.

Methods: We compared phenotypic frequencies of HLA-DPB1 and -DRB1 alleles and clinical manifestations between MS patients from the southernmost and northernmost parts of Japan. The study enrolled 256 MS patients and 235 healthy controls (HCs) from southern Japan and 250 MS patients and 159 HCs from northern Japan.

Results: DRB1^*04:05 allele was a susceptibility allele in both regions. DRB1^*09:01 was a protective allele only for southern Japanese while DRB1^*01:01 and DRB1^*13:02 were protective alleles for northern Japanese. No DPB1 alleles studied were associated with MS in southern or northern Japanese. Southern MS patients had higher Multiple Sclerosis Severity Scores (MSSS) and Progression Index (PI) than the northern patients. In southern MS patients, DRB1*04:05 carriers had a younger age of onset, lower MSSS, PI and Expanded Disability Status Scale scores, fewer brain magnetic resonance imaging lesions and lower frequencies of cerebrospinal fluid abnormalities than non-DRB1*04:05 carriers.

Conclusions: MS susceptibility/resistance and clinical manifestations are in part determined by HLA-DRB1 alleles and latitude in Japanese MS patients.

O-18 Multiple Quantitative Trait Loci for Anti-EBNA-1 IgG Titres are Associated with Risk of Multiple Sclerosis

Yuan Zhou¹, Gu Zhu², Dale R.Nyholt², Jac Charlesworth^1,6, Steve Simpson, Jr.¹, Ingrid van der Mei¹, Nikolaos A. Patsopoulos³, Caroline Laverty⁴, Anjali Henders², Jonathan Ellis², Grant W. Montgomery,² Rohina Rubicz⁵, John Blangero⁶, Harald H.H.Göring⁶, Nicholas G.Martin² and Bruce V Taylor¹

¹Menzies Research Institute, University of Tasmania, Hobart, Australia; ²Genetic Epidemiology, Molecular Epidemiology and Neurogenetics Laboratories, Queensland Institute of Medical Research, Brisbane, Australia; ³Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Department of Neurology, Brigham & Women’s Hospital, Boston, Massachusetts, United States of America; ⁴Monash Antibody Technologies Facility, Monash University, Melbourne, Australia, ⁵Fred Hutchinson Cancer Research Center, Seattle, United States of America; ⁶Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas, United States of America.

Background: Epstein-Barr virus (EBV) is a ubiquitous double-stranded DNA virus and infection with EBV is associated with an increased risk of multiple sclerosis (MS).

Objective: To identify genetic susceptibility loci for EBV nuclear antigen-1 IgG antibody titres (EBNA-1) and hypothesised that these loci may play an important role in MS risk.

Methods: Approximately 2.4 million SNPs were tested for their association with ELISA measured anti-EBNA-1 IgG titres in 3,760 individuals from a large unselected twin family cohort. We then conducted a meta-analysis combining our results with a large Mexican American familial GWAS cohort (N=1,956). Finally, we examined the shared polygenic risk utilising our EBNA-1 meta results (effective sample size=5,555) with the results of a large, well-validated MS meta-analysis (effective sample size=15,365).

Results: We identified one locus of strong association within the human leukocyte antigen (HLA) region, of which the most significantly associated genotyped SNP was rs2516049 (P=4.11x10^-9). SNP effect concordant analysis and genetic risk score analysis found that anti-EBNA-1 IgG titre status predicted the development of MS; however the reverse, MS status predicting anti-EBNA-1 IgG titre, was not observed. Finally, in the pooled meta-analysis using the MS meta results and EBNA-1 meta results we found several loci outside the HLA region reaching genome-wide significance.

Conclusions: Our results provide an explanation for the genetic susceptibility to MS via differential immune system reactivity to EBV infection, thus providing insight into the increased MS risk associated with increased EBNA titres.

O-19 Genome-wide Association Study for Multiple Sclerosis and Neuromyelitis Optica in the Japanese Population

Matsushita T¹, Sato S², Yamamoto K³, Madireddy L⁴, Gourraud P⁴, Baranzini S⁴, Oksenberg J⁴, Kira J², Japan MS Genetics Consortium

¹Department of Neurological Therapeutics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; ²Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; ³Department of Medical Chemistry, School of Medicine, Kurume University, Kurume, Japan; ⁴Department of Neurology, University of California, San Francisco, San Francisco, USA

Background: Multiple sclerosis (MS) and neuromyelitis optica (NMO) are complex diseases that involve both environmental and genetic factors. While genetic risk variants for MS have been identified among European by genome-wide association studies (GWAS), the variants have not been clarified in Asians.

Objective: To clarify genetic risk variants for MS and NMO in the Japanese population.

Methods: A GWAS was conducted using 533 cases with MS and 1,798 controls, and 200 cases with NMO and 1,752 controls. MS genetic burden (MSGB) score was calculated based on non-MHC established risk variants for European MS. HLA-DRB1 and DPB1 alleles were determined in 508 cases with MS, 193 with NMO and 334 controls.

Results: Twenty-six loci (FDR corrected p < 0.05) associated with MS and 33 suggestive loci (p < 1.0×10^-4) associated with NMO were identified outside the MHC. There was no common risk region between MS and NMO. Thirteen SNPs out of the 97 risk variants for European MS were replicated (p < 0.05) in the Japanese population. MSGB score was significantly higher in cases with MS than in controls (p < 2.2e-16). HLA-DRB1*04:05 and 15:01 were risk and DRB1*13:02, 01:01, and 09:01 were protective alleles for MS. HLA-DRB1*08:02 and 16:02, and DPB1*05:01 were risk alleles and DRB1*09:01 was protective allele for NMO.

Conclusion: GWAS in the Japanese population identified novel genetic risks for MS and NMO. MSGB indicated common genetic effects for MS between European and Japanese. Genetic loci associated with MS seemed to be different from loci associated with NMO.

Poster Session 1 MS Epidemiology & Genetics

P-1 A Pilot Study of Multiple Sclerosis in Indonesia

Situmeang RF, Stephanie EDP, Feliana, Tu NF, Hendrik TC, Siahaan YMT

Department of Neurology, Siloam Hospitals Lippo Village, Faculty of Medicine Pelita Harapan University, Banten, Indonesia

Background: Multiple Sclerosis (MS) has known as a debilitating neurological disease with significant effects on patient’s quality of life. There is no sufficient data of MS in Indonesia.

Objective: To determine the demographic and clinical data of MS patients in Indonesia.

Methods: A cross-sectional study of 66 patients visiting MS clinic at Siloam Hospital Lippo Village, Indonesia was performed from February 2011 to July 2014. Among them, 8 were excluded due to MS mimicking diagnosis. The diagnosis was confirmed using McDonald’s criteria 2010 and expanded disability status score (EDSS). Demographic profile of patients, clinical data, and treatments were analyzed.

Results: Female to male incidence ratio was 18:1 with the age of 21 to 30 as the most prevalent group. The mean age of onset was 30.5±11.5 years and disease duration was 4.7±4.2 years. Motor weakness (62.1%) and sensory problems (60.3%) have found as main clinical findings. From imaging feature, 61.5% patients have lesion in spinal cord, while lesion in juxtacortical being the most common in the brain. Only 22% demonstrate oligoclonal band in CSF. The incidence of MS type was relapsing-remitting (74.1%), secondary progressive (13.8%), and primary progressive (12%). The median score of EDSS was 3.0 with mean score of 3.9±2.3. Half of relapsing-remitting type patients received disease modifying treatment using Interferon β-1a.

Conclusions: This pilot study of MS profile in Indonesia showed that MS affects mostly female, young and middle age population causing disability in this group. Further studies are needed to obtain broad overview of MS in Indonesia.

P-2 Responsible Factors for Increased Incidence and Prevalence of Multiple Sclerosis in Iran

Zahra Nasr^1,2, Masoud Etemadifar¹

¹Isfahan Research Committee of Multiple Sclerosis (IRCOMS), Isfahan University of Medical Sciences, Isfahan, Iran; ²Medical Students’ Research Center (MSRC), Isfahan University of Medical Sciences, Isfahan, Iran

Previously, Iran was considered to have a low prevalence rate of multiple sclerosis (MS), but this rate has significantly increased over time. We think that gathering a number of variable explanations (genetic and environmental factors) is responsible for the increased incidence and prevalence of MS in Iran.

Improvement in diagnostic tools such as MRI and increased their availability, increased awareness of physicians and patients regarding the symptoms of the disease and improved probability of survival may be among the responsible reasons.
Preponderance of young population in Iran during the recent years may be a remarkable factor for this increase rate as MS mainly entangles young adults.
As vitamin D deficiency is highly prevalent among Iranians, it is one of the possible major environmental candidates responsible for high prevalence of MS in our country.
Some studies have revealed a correlation between the prevalence of MS and specific types of heavy industries. Highest prevalence rate of MS was related to the provinces, such as Isfahan, Tehran, and Markazi, with the highest rates of industrial activity. In contrast, Sistan and Baluchistan province is among the provinces with the lowest industrial activity and the lowest rate of MS in Iran.
Parasite infections were highly prevalent in Iran especially in provinces like Isfahan. During the recent decades, improvement of sanitary condition limited exposure to pathogens in Iranian people (hygiene hypothesis).
Based on epidemiologic studies of MS prevalence in Iran and Iranian immigrants, Iranian people are genetically vulnerable to MS.

P-3 Smoking As a Risk Factor for MS and Related Disorders in Asian Populations in Canada and China

Sadovnick AD^1,2, Lee JD¹, Zhao GX³, Yee IM¹, Guimond C¹, de Lemos M¹, Greenwood T¹, Vilariño-Güell C¹, Wu ZY³, Traboulsee AL².

¹Department of Medical Genetics, Faculty of Medicine, University of British Columbia, Vancouver, Canada; ²Division of Neurology, Faculty of Medicine, University of British Columbia, Vancouver, Canada ³Department of Neurology and Institute of Neurology, Huashan Hospital, Fudan University, Shanghai, China

Background: Tobacco smoking is one of the most firmly established environmental risk factors for multiple sclerosis (MS). However, studies of smoking in MS have been largely limited to Caucasian populations.

Objective: he objective of the present study was to determine whether a positive history of smoking is associated with susceptibility to MS and related disorders in Asian-ethnic populations in Canada and China.

Methods: Cases were recruited from MS clinics in Canada and Shanghai, China. Patients with full Asian ancestry in at least one parent and with a diagnosis of MS, neuromyelitis optica (NMO), NMO spectrum disorders, or clinically isolated syndromes suggestive of MS were included. Comprehensive personal smoking histories were collected from cases using standardized questionnaires. Comparable smoking data from ethnicity-matched control subjects were obtained from the Canadian Community Health Survey and the published literature. Association of smoking with susceptibility was evaluated with multiple logistic regression.

Results: Smoking exposure data were available from 70 and 132 cases in the Canadian and Chinese cohorts, respectively. Positive history of smoking was associated with an increased risk of MS and related disorders (OR=2.29, 95% CI: 1.29-3.94, p=0.003), primarily due to an excess of ever-smokers among MS patients (OR=3.15, 95% CI: 1.64-5.88, p<0.001). However, smoking was not associated with susceptibility to MS and related disorders in the Shanghai population.

Conclusions: These findings corroborate existing evidence implicating smoking as an important environmental risk factor for MS. Further studies in other low-risk populations are needed to confirm smoking as a universal risk factor for MS.

Poster Session 2 MS Clinical Symptomatology

P-4 Relapse Characteristics of 39 Patients with RRMS

Yingqiong Xiong^1,2, Xiaomu Wu^1,2

¹Jiangxi province people’s hospital, ²Jiangxi province institute of neurology

Background: Relapsing-remitting multiple sclerosis (RRMS) is the common type of multiple sclerosis. Much relapse can lead to further deterioration of neurological function. Find the inducing factors and intervention can prevent relapse.

Objective: The purpose of this study was to analyze clinical relapse characteristics of patients with RRMS, discuss the precipitating factor.

Method: 39 cases confirmed RRMS in hospital were retrospectively clinical observation, who returned visit because of relapse, including readmission and outpatient from January 2011 to December 2013. Observation indexes were the relapse frequency, the course of the disease, the precipitating factors.

Result: 39 patients include 12 male and 27 female, average ages (45.23±12.03). There have 24 relapse cases, 61.5% of total. Precipitating factor of relapse are cold (25%), infection (8%), tired (8%), unknown (59%). There have 15 pserdoattacks cases, 38.5% of total. Precipitating factor of pserdoattacks are anxiety (60%), fever (13%), cerebral ischemia (13%), strain of lumbar muscles (7%), fundus hemorrhage (7%).

Conclusion: A clinical characteristic of RRMS is symptoms relapse many times and easy to onset within 2 years after first visit. Disease modifying therapy (DMT) should be recommended for patients. The main precipitating factor of relapse is a cold and infection. Pserdoattacks should be identified from relapse when symptoms aggravated. The main precipitating factor of pserdoattacks is anxiety, which is associated with lower quality of life attribute to the disease. The ssessment and intervention of emotional psychological status of patients after illness can prevent pserdoattacks.

P-5 The Effect of Lower Limb Sensory Impairments on Balance of People with Multiple Sclerosis (A Review of Articles)

N Fereshtenejad¹, A Jamali¹

¹BSc in Orthotics and Prosthetics, Musculoskeletal research center, Isfahan University of Medical Sciences, Isfahan, Iran.

Background: Standing balance is one of the most important and essential activities of daily life, which is named “postural control” (1). Poor Balance, fear of falling and mobility limitation may lead to change in the quality of life, especially if injurious falls occurred (2,3). Imbalance is commonly seen in elderly people, patients with peripheral neuropathy disorders and also in multiple sclerosis patients. Studying the mechanisms which contribute to postural control disorders would help to explain interventions aimed to reduce the rate of loss of postural control and also aimed to rehabilitate these patients.

Objective: The purpose of this review study was to investigate the effect of somatosensory impairments on postural control of people with multiple sclerosis.

Method: Papers from 1950 to 2014 were examined by performing a systematic search of electronic databases including Google scholar and PubMed. Keywords used in this work include various combinations of multiple sclerosis, balance, somatosensory and their synonyms. At last, titles and abstracts were estimated and 41 literatures were accepted and grouped into two categories. One) studies which examined the impact of somatosensory on balance in healthy controls (n=41). Two) studies which examined the impact of somatosensory on balance in MS people (n=7).

Results: studies demonstrated that sensory feedbacks from cutaneous receptors of foot sole play an important role on regulating balance of healthy subjects. In these studies, researchers had investigated the postural control of healthy controls by applying interventions such as local anesthesia, ice immersion approach (cooling), placing a cuff on the leg, ischemic block techniques, changing support surface or even applying vibration.

Conclusion: We know maintaining balance requires integration of vestibular, visual, and somatosensory information and multiple sclerosis can cause malfunctions of these systems (4, 5). Also as the number of systems involved was greater, imbalance became greater in these patients (6). According to this review, balance of MS patients was lower than healthy controls and they act weaker than healthy people in perturbation tests. These studies showed that reducing light touch pressure, proprioception and vibration caused by disruption of ascending nerve fibers (myelin removal in the posterior columns of the spinal cord) and reducing nerve conduction velocity in somatosensory system caused abnormal postural responses in these patients (6). But more studies are needed in this regard.

P-6 Sensory Impairment and Its Relationship with Balance and Quality Of Life in People with Multiple Sclerosis

A Jamali¹, E Sadeghi², N Fereshtenejad¹

¹BSc in Orthotics and Prosthetics, Musculoskeletal research center, Isfahan University of Medical Sciences, Isfahan, Iran. ²PhD in Orthotics and Prosthetics, Musculoskeletal research center, Isfahan University of Medical Sciences, Isfahan, Iran.

Introduction: Balance disorder is one of the most common impairment in patients with multiple sclerosis. The results of some studies indicated the effect of sensation on balance in these patients. Although multiple sclerosis is a systematic disease and affects the total body, but these studies focused on lower limb. However, researchers have shown the effect of sensation of upper limb on balance.

Objective: The aim of this study was to determine the prevalence of sensory impairment in limbs and its relation with balance and quality of life in patients with multiple sclerosis.

Methods: In a cross-sectional study, 82 patients (age: 36.9±9 years) and 30 healthy subjects (age: 32/1± 9/5 years) were included. The prevalence of sensory impairments was assessed based on Rivermead Assessment Somatosensory Perception (RASP) technique, balance was assessed by using of functional reach test (FRT) and timed up and go (TUG), and quality of life(QoL) was assessed by 36-item Short-Form Health Survey (SF-36).statistical analysis was performed with SPSS software.

Results: Based on this study the prevalence of sensory impairments in patients with multiple sclerosis was 71/8 percent (66/7% properioception and 60/8% light touch), 61/5 percent in lower limb (66/7% properioception and 60/8% light touch) and 54/4 percent in upper limb (33/3% properioception and 43% light touch) (p<0.01). Compared to control group, balance showed a significant reduction in these patients. There was correlation between FRT and total body (r=0/3, p<0/01), lower limb (r=0/4, p<0/01) and upper limb (r=0/3, p<0/01) sensory impairment. TUG also had significant correlation with sensory impairment, (total body=-0/4, lower limb=-0/6, upper limb=-0/4) (p<0.01). Results indicated a significant reduction in quality of life in MS patients compared with the control group (p <0/05) and their sensation was directly associated with QoL scores (r=0/3, P <0.01). In this study correlation between proprioception and QoL was more remarkable.

Conclusion: According to high prevalence of sensory impairments in people with multiple sclerosis and its correlation with balance and QoL, interventions with the aim of improving sensation may improve balance and QoL and also it may minimize the secondary complications such as risk of falling and fracture.

P-7 Impact of Chronic Pain on Quality Of Life in Chinese Patients with Multiple Sclerosis and Related Disorders

Au, C.K.C.¹, Wong, A.¹, Mok, V.¹, Wong, K.S.¹, Lau, Y.L.A.¹

¹Division of Neurology, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong

Chronic pain is a major source of disability in patients with multiple sclerosis (MS) and neuromyelitis optica (NMO). Few studies examined the association of chronic pain and quality of life (QOL) in Chinese patients. We examined the prevalence of chronic pain and its association with QOL in a cohort of Chinese patients with MS or NMO. From the Hong Kong Multiple Sclerosis Registry, we recruited subjects for structured interview if 1) aged between 18-70, 2) diagnosed MS/NMO/related disorders for >1 year, 3) experienced impaired sensory function. Subjects with pain due to other neurological, systemic or psychiatric diseases were excluded. Brief Pain Inventory Short Form (BPI) and Multiple Sclerosis Quality of Life Instrument (MSQOL-54) were used to assess pain score and QOL respectively. Of 17 subjects recruited, mean onset age was 30±13 years and disease duration 10±6 years. 9/17 (53%) had MS and 7/17 (41%) had NMO. 13/17 (77%) experienced pain. 11/13 (85%) had chronic pain, who had a significant worse pain interference score compared to subjects without chronic pain (4.3 vs. 0, p<0.1). Chronic pain is associated with poorer QOL (MS: 56.7 ± 24.9, NMO: 55.2 ± 33.1, non-chronic pain 85.8 ± 19.5; p<0.05). Mean pain interference is negatively associated with QOL in physical (r= -0.823, p<0.01) and mental (r= -0.803, p<0.01) health functioning. Chronic pain is prevalent among Chinese patients and is associated with poorer physical and mental health functioning.

P-8 Identifying a Minimally Important Change Threshold for The Multiple Sclerosis Walking Scale-12 (MSWS-12)

Mehta L,¹ McNeill M,² Hobart J,³ Wyrwich K, PhD,⁴ Poon JL,⁴ Auguste P,⁴ Zhong J,¹ Elkins J¹

¹Biogen Idec, Cambridge, MA; ²Biogen Idec, Maidenhead, UK; ³Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, UK; ⁴Evidera, Bethesda, MD, USA

Background: The 12-item Multiple Sclerosis (MS) Walking Scale (MSWS-12) is the only patient-based measure of the impact of MS on walking. Minimal clinically important difference (MCID) and responder definition (RD) values have recently been proposed for interpreting meaningful changes in MSWS-12 scores.

Objective: To identify a minimally important change in the MCID/RD threshold for interpreting individual change over time on the MSWS-12 in MS patients with walking impairment (Expanded Disability Status Scale score of 4–7) participating in the 24-week, double-blind, placebo-controlled, randomised MOBILE trial.

Methods: Both anchor- and distribution-based approaches were used to estimate the MCID/RD using data collected at Week 2 and at monthly administrations of MSWS-12. The distribution-based estimate of the MCID/RD was the standard error of measurement (SEM). Iterative comparisons (triangulation) of the anchor- and distribution-based estimates with observed breaks in blinded change score data allowed for the estimation of a single best value for the MCID/RD.

Results: The anchor-based methods yielded median changes/reductions of 5.2–9.7 points on the MSWS-12 for small but important changes in walking. The distribution-based MCID/RD estimate was 6.8 points (1 SEM). Through the triangulation process, a reduction of 8 points on the MSWS-12 was selected as the best estimate of the MCID/RD.

Conclusion: An 8-point reduction on the MSWS-12 provides a reasonable threshold for estimating whether an MS subject experienced a meaningful improvement in their walking ability over 24 weeks. The application of this finding to other MS patients, i.e. with milder walking disability, and other studies, deserves further investigation.

P-9 Comparing Urinary Symptoms in MS Patients versus Devic Patients

F. Nasr Esfahani^{1, ²}, S. Ebrahimian^{1, ²}, L. Dehghani³, S. Vesal³, V. Shaygannejad³

¹Students’ Research Center, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran; ²Medical Student, Isfahan Neurosciences Research Center, Alzahra Hospital, Isfahan University of Medical Sciences, Isfahan, Iran; ³Department of Neurology, Isfahan Neurosciences Research Center, Alzahra Hospital, Isfahan University of Medical Sciences, Isfahan, Iran

Background: Multiple Sclerosis and Neuromyelitis Optica (NMO) also known as Devic disease are 2 different neurological autoimmune diseases with almost same signs and symptoms [1, 2]. One of their differences is the place and type of spinal involvement. Length of spinal segment involved in Devic disease is more, in comparison to MS disease [3]. Thus, it seems that urinary reflex become weaker and urinary symptoms are more common in Devic disease.

Objective: Aim of the present study was to measure urinary complications in Devic patients and MS patients and compare them.

Methods: Twenty patients with definitely diagnosed Devic disease and 56 patients with definitely diagnosed MS disease, with no other systemic and neurologic disorders, were included in this study. All patients were subjected to complete International Prostatic Symptom Score (IPSS) questionnaire. Data were analyzed using Mann Whitney U test by SPSS software

Results: According to statistical analyses, severe, moderate and mild urinary complications were found in 25%, 50% and 10% of Devic patients and 16.1%, 32.1% and 39.3% of MS patients, respectively. Although the differences were seen, they were not statistically significant (p=0.125). In details, frequency and urgency had higher rate in Devic patients (p<0.05) but incomplete emptying of the bladder, intermittency, weak stream, straining on urinating and nocturia, did not have any difference, statistically.

Conclusions: Frequency and urgency were more common in Devic patients. But other symptoms did not have any significantly difference.

P-10 Pain, Sleep Quality and Emotional State of the Relationship between Disease Clinical Features in Patients with Multiple Sclerosis

Hava Özlem DEDE, Taşkın DUMAN, Cahit ÖZER, İsmet MELEK, Esra OKUYUCU

Mustafa Kemal University, Medical Faculty

Objective: The aim of the study is establishing the properties of chronic pain, depression and sleep disturbance in the MS patients, and determine the relationship with the clinic features and this symptoms.

Material and Methods: Sixty MS patients who were followed by neurology department and thirty healthy voluntary in control group were included in this study. SF36 scoring, PUKI, EUS and BDI administered to all participants, and Mc-Gill Pain Questionnaire, EDSS, Functional Independence Measurement were administered to the MS patient. Brain and cervical magnetic resonance imaging were performed to the patients.

Results: Twenty four point four percent was male, seventy five point six percent was female of the 90 participants. EUS was 51.7% normal, 48.3% pathological in the patients group and 100% was normal in control group. PUKI was 53.3% normal, 46.7% pathological in the patients group and 93.3% normal, 6.7% pathological in control group. BDI was 28.3% not depression, 40.0% mild depression, 21.7% moderate depression, %10 severe depression in the patients group; in control group: 66.7% not depression, 30% mild depression, 3.3% moderate depression. Fifty one (85%) of the patients complained from pain.

Conclusion: The relationship of sleep disturbance, depression and pain was demonstrated in the study. The most effective variant was determined in this study was depression in the MS patients for pain.

Poster Session 3 MS Laboratory Study

P-11 Thyroid Dysfunction and Autoimmunity in Multiple Sclerosis Patients

Demirkaya Şeref*, Çetiz Ahmet*, Öz Oguzhan*,

*Gülhane military Medical Faculty, Neurology Department

Background: Some recent studies indicate that thyroid dysfunction can be seen in patients with Multiple Sclerosis (MS).

Objectives: We aimed to investigate thyroid functions and anti-thyroid antibodies in MS patients.

Methods: We evaluated the hospital files of 63 MS patients retrospectively. They were screened for thyroid function (free-T3, free-T4, thyroid stimulating hormone (TSH)). In 23 MS patients anti-thyroid peroxidase (anti-TPO) and in 6 MS patients anti-thyroglobulin antibodies were studied for autoimmunity.

Results: All of the patients had normal thyroid functions and autoimmune markers.

Conclusions: In content to some previous studies we could not be able to detect any thyroid diseases in patient with MS.

P-12 Frequency of Autoantibodies and Autoimmune Comorbid Diseases in Korean Patients with Multiple Sclerosis

Kyeung-Mo An, Jookyung Lee, Young-Min Lim, Kwang-Kuk Kim

Department of Neurology, Ulsan University, Asan Medical Center, Seoul, Korea

Background: Autoantibodies are more frequently detected in patients with multiple sclerosis (MS) than in the general population. However, the role of autoantibodies in the pathogenesis of MS and their associations with autoimmune comorbidity are still unclear.

Objective: The aim of this study was to determine the frequency of autoantibodies in Korean patients with MS and evaluate clinical associations with autoimmune comorbid diseases.

Methods: A total of 128 consecutive patients with MS were enrolled. The seropositivity of following autoantibodies was investigated: ANA, SS-A, SS-B, antiphospholipid, anti-TPO, anti-Tg, and RF. Presences of other autoimmune diseases were evaluated in seropositive patients.

Results: Of the 128 patients, 79 were female and 49 were male. Autoantibodies to at least one autoantigen were detected in 44 patients (F/M=24/20). ANA (21%) and SS-A (10%) were most frequently accompanied. In only 3 patients (2.3%), the presence of autoantibodies was associated with the clinical features of connective tissue diseases.

Conclusion: Autoantibodies were seropositive in about 35% of Korean patients with MS, which was comparable to the prevalence previously reported for MS in Caucasian populations. Presence of autoantibodies was not associated with systemic autoimmune diseases in most seropositive patients.

P-13 Anti-Double Stranded Dna, Anti-Nuclear Antibodies and Subtypes in Multiple Sclerosis Patients

Demirkaya Şeref*, Çetiz Ahmet*, Öz Oguzhan*,

*Gülhane military Medical Faculty, Neurology Department

Background: Many autoimmune disorders affecting central nervous system (CNS) may mimicking MS. In this aspect it is important to distinguish demyelinating diseases from other autoimmune disorders.

Objectives: We aimed to determine anti-ds DNA antibodies, anti-nuclear antibodies (ANA) in MS patients.

Methods: We evaluated the hospital files of 70 MS patients retrospectively regardless of their clinical condition and treatment options. We noted the anti-dsDNA antibodies, ANA, anti-Ro antibodies (anti-SSA), anti-La antibodies (anti-SSB), anti-Sm/RNP antibodies, anti-Sm antibodies, anti-Scl-70 antibodies,, anti-Jo1 antibodies. None of the patients had rheumatological diseases.

Results: 20 of 70 patients had positive ANA results.

Conclusions: ANA in patients with MS do not address any disease and it is controversial whether checking ANA levels or not.

P-14 Serum Level of Vitamin D₃ and Manifestation of the First Femyelinating Attack

Zahra Nasr^1,2, Masoud Etemadifar², Seyed-Hossein Abtahi^1,2

¹Medical Students’ Research Center, Isfahan University of Medical Sciences, Isfahan, Iran; ²Isfahan Research Committee of Multiple Sclerosis, Isfahan University of Medical Sciences, Isfahan, Iran

Background: Vitamin D3 status appears to play an important role since the very early stages of multiple sclerosis (MS). However, the relationship between serum vitamin D levels and type of first manifestation in CIS patients remains mainly unknown.

Objective: We hypothesized that vitamin D3 status of CIS patients could also influence the type and the location of their demyelinating attack.

Methods: Serum 25-OHD levels were measured in a total of 104 cases with a first demyelinating attack including patients with optic neuritis, brain stem syndrome and spinal cord syndrome were enrolled in the study.

Results: Serum level of 25(OH) vitamin D₃ was significantly lower in patients with spinal cord syndrome in comparison with patients with brain stem syndrome [11.30±6.82 ng/ml vs. 18.65±13.15 ng/ml, P=0.01]. Furthermore, patients with spinal cord syndrome had a lower level of vitamin D₃ in comparison with patients with optic neuritis [11.30±6.82 ng/ml vs. 14.00±10.27 ng/ml, P=0.03].

Conclusions: To conclude, we demonstrated that different types of CIS patients were characterized by a different vitamin D3 status. However, this observation should be interpreted with caution and additional studies with larger sample sizes will be required to confirm whether this association is accurate and also explain mechanisms for such finding.

Poster Session 4 MS Neuroimaging

P-15 Cortical Gray Matter Involvement in Patients with Relapsing Remitting Multiple Sclerosis; Correlation of Clinical and Cognitive Diasability, DTI Magnetic Resonance İmaging and OCT Findings

Hüsnü Efendi, Hande Biçkin, İsa Çam, Yonca Anık

Department of Neurology and Radiology, School of Medicine, Kocaeli University, Kocaeli, Turkey

Introduction: MS is an inflammatory demyelinating disease affecting both white matter (WM) and grey matter (GM). Our aim was to investigate whether cortical grey matter atrophy is associated with clinical, cognitive diasability and retinal nerve fiber layer (RNFL) thicknes in patients with multiple sclerosis.

Methods: We enrolled 40 consecutive MS patients and 20 normal controls undergoing 3T brain MRI, OCT and neuropsychological testing. Diffusion Tensor MRI (DTI) and tractography were performed. Neuropsychological test includes Paced Auditory Serial Addition Test (PASAT), the Symbol Digit Modalities Test (SDMT) and verbal fluency test (VFT) respectively.

Results: In DTI-FT measurements, FA values of cortical GM areas were lower in all MS patients and MD values of GM areas were higher in MS patients (p=0,0001). GM volume values were lower in MS (p=0,0001). RNLF thickness averages of bilateral superior and temporal quadrants in MS patients were statistically lower (p=0,001). No correlation was found between GM volume and RNFL thickness. No correlation was determined between grey matter volume values of patients group and PASAT scores (p>0,05). A negative correlation between GM volume values of patients group and VFT was determined (r=-0,340 p=0,032).

Conclusion: The results confirmed that there was significant difference in cortical GM DTI-FT and RNFL thickness between MS and controls. Whereas DTI showed significant GM involment in MS we could not find correelation with PASAT scores. GM involment in MS by unconventional MRI techniques such as DTI-FT and OCT, will make remarkable contributions to the evaluation of grey matter involvement.and axonal degenaration in MS.

P-16 Deep Gray Matter Involvement in Multiple Sclerosis; Correlation of Clinical and Cognitive Diasability with DTI Magnetic Resonance İmaging Findings

Hüsnü Efendi, Hande Biçkin, İsa Çam, Yonca Anık

Department of Neurology and Radiology, School of Medicine, Kocaeli University, Kocaeli, Turkey

Introduction: Deep gray matter (DGM) atrophy has been reported in patients with multiple sclerosis (MS). Our aim was to investigate whether a particular pattern of deep GM atrophy is associated with cognitive impairment in patients RRMS. The relationship between diffusivity markers, and atrophy of the deep GM structures, as well as clinical status of the patients was also explored.

Methods: We enrolled 40 consecutive MS patients and 20 normal controls, 3 Tesla Diffusion Tensor MRI and tractography were performed including anatomic and DTI acquisitions. Volumes, mean fractional anisotropy (FA), and mean diffusivity (MD) of the DGM structures were assessed. Neuropsychological testing contributed measures of using the Paced Auditory Serial Addition Test (PASAT), the Symbol Digit Modalities Test (SDMT) and verbal fluency test (VFT) respectively.

Results: MD was significantly decreased in the right/left thalamus of patients with MS compared with controls (p=0.0001), FA was significantly increased in the left thalamus. (p=0.006). There was no significant differences of FA in right thalamus and MD in right putamen, left globus pallidus (p>0,05). There was significant differences of caudate nucleus FAand MD patients with MS compared controls (p=0,005, p=0,001). Putamen right/left FA significantly decreased in MS group compared to controls (p=0,0001). There was significant correlation of PASAT scores and left thalamus and caudate nucleus FA and MD in MS patient compared to controls.

Conclusıons: We confirm the significant role of thalamus and caudate nucleus involment in MS-associated cognitive disorder, and further report that DGM involment as detected by DTI corralated with clinical cognitive deficits.

P-17 Magnetic Resonance Spectroscopy Measurements in Normal-Appearing White Matter as A Biomarker of Whole Brain White Matter Integrity in Relapsing Remitting Multiple Sclerosis

Sean N. Hatton^1,2, Jim Lagopoulos^1,2, Chenyu Wang^1,2, Heidi Beadnall¹, Mahtab Ghadiri¹, Gurjit Chohan¹, Lynette Masters¹, Yael Barnett^1,2,3, Michael H. Barnett^1,2

¹Brain and Mind Research Institute, University of Sydney, Sydney, Australia; ²Sydney Neuroimaging Analysis Centre, Sydney, Australia; ³St Vincent’s Hospital, Sydney, Australia

Background: Brain ¹H-magnetic resonance spectroscopy (MRS) indicates occult injury to the normal-appearing white matter (NAWM) in relapsing remitting multiple sclerosis (RRMS). Reduced N-Acetyl Aspartate (NAA) is consistent with neuro-axonal dysfunction and/or loss, elevated choline (Cho) suggests myelin breakdown and elevated myo-inositol (MI) is at least partially attributable to astrogliosis. However, the relationship between specific metabolite change/s in the NAWM and global white matter tract integrity is yet to be determined.

Objectives: Investigate whether changes in NAWM NAA/Cr, MI/Cr or Cho/Cr ratios are related to changes in global white matter tract integrity as measured using fractional anisotropy (FA), radial diffusivity (RD) and axial diffusivity (AD) in RRMS.

Methods: Eighty six RRMS patients underwent magnetic resonance imaging to obtain whole-brain diffusion weighted images, a T2-weighted fluid-attenuated inversion recovery (FLAIR) sequence and ¹H-MRS measures. Tract based spatial statistics investigated the relationship between diffusivity metrics and metabolite ratios. Significance was set at p < 0.01 TFCE-corrected.

Results: Reduced NAWM NAA/Cr was correlated with global FA reductions and AD/RD increases. Increased MI/Cr ratio correlated with reduced FA and increased RD. Controlling for T2 lesion load, NAA/Cr was only associated with decreased FA.

Conclusions: In RRMS patients, MRS of the NAWM is a sensitive biomarker of global white matter integrity. In particular, evidence of axonal injury in the NAWM correlates with global white mater fractional anisotropy. Additionally, increased white matter tract RD in subjects with high NAWM MI/Cr may indicate that non-lesional astrogliosis is primarily a function of global myelin integrity.

P-18 Local and Global Plasticity of Sensorimotor Network in Remitting Multiple Sclerosis: A Voxel-Based Functional Centrality Analysis

Fuqing Zhou^1*, Ying Zhuang², Honghan Gong¹

¹Department of Radiology, The First Affiliated Hospital, NanChang University, NanChang, Jiangxi,330006, China; ²Department of Oncology, The Second Hospital of Nanchang, Nanchang, Jiangxi Province, 330003, China

Objective: To explore the integrity and connectedness of sensorimotor network (SMN) in local and global level in remitting MS patients, using voxel-based degree and eigenvector centrality (DC and EC) analysis.

Methods: After the rs-fMRI data preprocessing using DPARSFA (http://www.restfmri.net) based on Matlab-2012a: (1) DC and EC maps were calculated and compared between the remitting MS and healthy control (HC) (n= 34), respectively; (2) DC and EC maps were also compared in paired relapsing(rapid-onset) MS and remitting MS (n=11); (3) in remitting MS group, linear regression analysis was conducted for evaluating the relationship between clinical metric and voxel-wise centrality and rest-state functional connectivity of the obtained abnormal regions.

Results: The main finding of the remitting MS show that: (1) compared with HC, not only reduced DC in the premotor, supplementary motor and related-integrated regions, which reflects the cerebral adaptive alterations, also increased DC in primary motor cortex (right M1) and parietal-integrated regions positively correlated with EDSS, which is less efficient in motor information processing; (2) compared with relapsing MS, increased DC in the bilateral M1/S1, and left operculum parietale/ temporoparietal junction, which reflects the rapid-onset central motor plasticity, also reduced DC in the premotor, supplementary motor area/ dorsal premotor, operculum and parietal pathway, which reflects a rapid-onset plasticity reshaping, trends toward subsides. (3) The alterations of EC similar to DC, when compared with HC or relapsing MS.

Conclusions: These findings in both local and global connectedness provide deeper insights about plasticity of SMN in remitting MS.

P-19 Does the Default Mode Network Reserve the “Small-World” Property in Remitting Multiple Sclerosis: A Graph Theoretical Analysis Based on Resting-State Fmri

Ying Zhuang^1,2, Fuqing Zhou^2*, Honghan Gong², Qing Wu²

¹Department of Oncology, The Second Hospital of Nanchang, Nanchang, Jiangxi Province, 330003, China; ²Department of Radiology, The First Affiliated Hospital, NanChang University, NanChang, Jiangxi,330006, China

Objective: To investigate the “small-world” property of default mode network (DMN) in relapsing-remitting multiple sclerosis (RRMS) group, using a graph theoretical analysis based on resting-state fMRI (R-fMRI).

Methods: Twenty-four MS patients remain in remitting stage and 24 age-, and sex-matched healthy controls were examined by R-fMRI and 3D-T₁WI on Trio-3.0-Tesla-MRI. The R-fMRI data was preprocessing, 20 regions of interest within DMN was defined, and calculated by Pearson’s correlation. Graph theoretical analysis was implemented and compared the property of binary functional network “small-world” network. Furthermore, the relationships associated with clinical were examined.

Results: We successfully construct functional network in DMN, and observe the “small-world” characteristics in remitting MS patients. In the range of network densities (D_min: 0.01: 0.48; D_min = 0.42), compare with control subjects, the patients have non-significantly smaller normalized clustering coefficient, larger normalize path length, and non-significantly smaller “small-world” index (P > 0.05); but a larger clustering coefficient (P = 0.031) in the left posterior cingulated cortex (PCC) on the network threshold at D_min. We also compare the area-under-a-curve (AUC) for clustering coefficient measure curves of the left PCC (density range of 0.42: 0.01: 0.48) between two groups. The AUC result is similarly with the D_min result (P = 0.031). Negative correlation is observed between the clustering coefficient of left PCC and the Paced Auditory Serial Addition Test (PASAT).

Conclusions: The DMN has “small-world” property in the remitting MS patients. The significantly increased clustering coefficient was observed in the left PCC, which may be a “side effect”.

P-20 Altered Effective Connectivity of Default Mode Network in Relapsing Remitting Multiple Sclerosis at Resting State: A Fmri Granger Causality Analysis

Fuqing Zhou^1*, Ying Zhuang², Honghan Gong^1*

¹Department of Radiology, The First Affiliated Hospital, NanChang University, NanChang, Jiangxi, 330006, China; ²Department of Oncology, The Second Hospital of Nanchang, Nanchang, Jiangxi Province, 330003, China

Objective: To explore the effective connectivity of default mode network (DMN) in relapsing-remitting multiple sclerosis (RRMS) group and compare with matched healthy control subjects, using a resting-state granger causality analysis (GCA).

Methods: Twenty-four patients with RRMS and 24 age-, and sex-matched healthy controls were examined by resting-state fMRI (R-fMRI) and 3D-T1. The R-fMRI data preprocessing and processing was performed using DPARSFA (http://www.restfmri.net) based on Matlab 2012a; the spatial patterns of DMN was constructed by seed-based (posterior cingulate cortex) correlation analysis, then 6 principal components of DMN was selected for more GCA. To further analyze the correlations between effective connectivity and clinical parameter in patients group.

Results: In this study, we observed driving hub in medial prefrontal cortex of both groups. Compared with control group, RRMS groups exhibited an altered signed-path coefficient and direction between the left and right inferior parietal lobules (t=3.071, P=0.004), the left inferior parietal lobule and the right middle temporal gyrus (t=2.053, P=0.046). Expanded disability status scale (EDSS) significant positive-related with the signed-path coefficient between left and right inferior parietal lobule (P=0.045), left inferior parietal lobule and right middle temporal gyrus (P=0.020), respectively. The correlation were not observed between the altered signed-path coefficient and the paced auditory serial addition test (PASAT), brain parenchymal fraction (BPF), modified fatigue impact scale (MFIS), total white matter lesion loads (TWMLL) (P : 0.187-0.804).

Conclusions: These findings provide evidence that abnormal effective connectivity between principal components of DMN in RRMS patients.

Poster Session 5 MS Treatment

P-21 The Follow Up of Patients with Multiple Sclerosis Before and After Treating with Disease Modifying Therapies, Modified Rio Score as A Prognostic Marker

A Soysal¹, M Özerden¹, U Uygunoğlu², AD Elmalı², E Çoban¹, BG Alparslan², N Kale¹, A Altıntaş²

¹Bakirkoy Education and Research Hospital for Psychiatric and Neurological Diseases, Neurology Department, Istanbul, Turkey; ²Istanbul University, Cerrahpasa Medical Faculty, Neurology Department, Istanbul, Turkey

Background: Modified Rio Score is based on new T2 lesions on magnetic resonance imaging (MRI) and relapses after one year of treatment and helps to predict disability over time in multiple sclerosis(MS) patients who are treated with disease modifying treatment (DMT). The score is between 0 to 3 and the risk of progression increases with higher scores.

Objective: We aim to evaluate MS patients before and after initiation of DMT and discuss modified Rio score as a prognostic marker.

Methods: In this retrospective study 2 different MS centers included 129 MS patients on DMT (93 females, 72.1 %).Neurological evaluations (EDSS scores),MRI,CSF and blood test results of the patients were all retrieved using iMED software that allows clinicians to store and maintain patients’ medical and treatment histories. In this study modified Rio scores for each patient were also obtained.

Results: The record reviews revealed that 39(30.2 %) patients were on Avonex, 32(24.8%) patients were on Copaxone,30(23.3%) patients were on Rebif and 28(23.3%) patients were on Betaferon treatment. Rio scores revealed that 71 patients had score 0,41 patients had score 1, 11 patients had score 2 and 6 patients had score 3.Treatment modification was not required for patients with score 0 and only 6 patients(15%) from score 1 group needed treatment changes. However, 5 patients (46%) from score 2 group and 3 patients from score 3 group (50%) needed DMT changes.

Conclusion: Up to date prognostic markers are still not available for MS patients’ follow-up, however Rio scoring might be beneficial for follow-up of patients and managing treatment strategies.

P-22 Drop-out Rate of Glatiramer Acetate is Influenced by Body Mass Index in Multiple Sclerosis Patients

Kurtuncu M, Cınar Balcıoglu C, Yildiz Celik S, Coban A, Pehlivan M, Eraksoy M

Background: The disease modifying treatments (DMTs) have fixed dosing regimens regardless of body mass index, which may alter serum drug concentrations. However, the adherence of DMTs depends mainly on the side effects and efficacy of the drugs that may be influenced by serum drug concentrations.

Objective: In this real-life study, we tried to detect the effect of some demographic factors on the treatment duration of glatiramer acetate (GA).

Methods: We included 339 MS patients exposed to glatiramer acetate and performed Cox’s proportional hazards analysis to assess the impact of several covariates such as gender, age at MS onset, disease duration, body mass index (BMI), oligoclonal band status, education level and smoking on the treatment duration of GA.

Results: The mean GA treatment duration was 38,1±11,8 (±standard deviation) months. Mean age at diagnosis was 29,3±9,8 years, and mean disease duration before treatment was 5,7±6,3 years. Thirty-eight percent of patients discontinued their treatment during the follow-up period. According to the Cox regression analysis; BMI made a unique statistically significant impact on the treatment duration with a hazard ratio of 0,88 (95,0% CI: 0,79-0,98; p=0,02); underweight patients having highest dropout rate (Table 1).

Conclusions: This long-term study clearly shows that low BMI has a negative influence on the treatment duration of GA. This is possibly related to the thin subcutaneous fat tissue in underweight patients that increases side effects caused by injection. BMI should also be considered as one of the factors when starting a DMT in MS patients.

P-23 Tolerability of Interferon Beta-1b for Multiple Sclerosis and Clinically Isolated Syndrome in Korea

Hung Youl Seok,¹ Byung-Jo Kim,¹ Byoung Joon Kim,² Jeeyoung Oh,³ In Soo Joo,⁴ Young-Min Lim,⁵ Kwang-Kuk Kim⁵

Department of Neurology, ¹Korea University Medical Center, ²Samsung Medical Center, Sungkyunkwan University School of Medicine, ³Konkuk University School of Medicine, ⁴Ajou University School of Medicine, ⁵Asan Medical Center, Korea

Backgrounds: Interferon beta-1b has been used for relapsing-remitting multiple sclerosis (RRMS) and clinically isolated syndrome (CIS) with excellent safety profiles. Although a recent study suggested no difference in clinical manifestations between Caucasians and Koreans, effective drug dosage and tolerability could be different among patients with different ethnicity.

Objectives: This study was performed to investigate tolerability and any factors affecting tolerability of interferon beta-1b in Korean patients with MS or CIS.

Methods: All patients who have been injecting interferon beta-1b for MS or CIS were recruited from 39 nation-wide university affiliated hospitals in Korea from August 2006 to July 2012. All subjects were asked to report any adverse events (AEs) after injecting interferon beta 1b using a self-questionnaire.

Results: A total of 355 patients (322 MS and 33 CIS) were enrolled. 96 AEs were reported by 59 patients (16.62%) except injection site reaction. 35 AEs by 23 patients (6.48%) were drug related events listed in drug information. Of 16 serious AEs reported by 9 patients (2.54%), 13 events were related to relapse and the other 3 events were 1 suicide attempt and 2 injection site infection. Any injection site reactions were reported in 38% of patients, but all events were mild. No one discontinued interferon beta-1b during study period.

Conclusion: Compared to previous studies, occurrence rate of AEs by interferon beta-1b in Korean patients with MS showed similar results.

P-24 An Open-Label, Two-Arm, Randomised Study to Characterise Flu-Like Symptoms in Relapsing Multiple Sclerosis Patients Transitioning to Peginterferon Beta-1a (ALLOW): Interim Analysis Results

R.T. Naismith¹, B. Hendin², S. Wray³, X. You⁴, E.T. Kinter⁴, B. Sperling⁴, M. Mann⁴

¹Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA; ²Phoenix Neurological Associates, Phoenix, AZ, USA; ³Hope Neurology MS Center, Knoxville, TN, USA; ⁴Biogen Idec Inc., Cambridge, MA, USA

Background: Subcutaneous pegylated interferon beta-1a (PEG-IFN) is a novel disease-modifying therapy for relapsing multiple sclerosis (RMS). In the pivotal Phase 3 ADVANCE study, PEG-IFN (125μg) dosed every two weeks demonstrated improved efficacy versus placebo, and safety consistent with other beta-interferons (IFNs) in RMS.

Objective: The ALLOW study is a Phase 3b evaluation of patients currently on IFN transitioning over to PEG-IFN. A pre-specified, interim analysis evaluated the proportion of patients who experienced new or worsening flu-like symptoms (FLS; defined as a FLS score increase of ≥2.0).

Methods: Eligible patients had been treated with a stable dose of IFN for ≥4 months immediately prior to screening. Patients remained on their IFN treatment for 4 weeks, followed by 12 weeks of PEG-IFN (4-week titration, 8-week maintenance). Patients were randomised (1:1) to continue current FLS management regimens or naproxen 500mg twice daily (24hr pre-PEG-IFN and continuing for 48hr post-PEG-IFN) for the first 8 weeks. FLS were evaluated throughout the study.

Results: In total, 50 patients (25 per arm) with available data that reached Week 12 were evaluated. Baseline demographics across groups were similar. For the primary outcome, 82% (37/45) patients reported no new/worsening FLS events following the PEG-IFN transition. In addition, patients on a structured naproxen regimen showed an improvement in new/worsening FLS vs control (14.3% [3/21] vs 20.8% [5/24], respectively). Additional FLS data will be presented.

Conclusions: Patients transitioning from previous therapy with IFN to PEG-IFN may not experience any additional FLS and that scheduled naproxen may be a beneficial pre-emptive strategy.

P-25 Persistence and Adherence in Patients Treated With an Intramuscular Interferon Beta-1a Autoinjector: Effect of Prior Use of Disease-Modifying Therapy and Other Patient Characteristics

You X,¹ Hupperts R,² Becker V³

¹Biogen Idec, Cambridge, MA, USA; ²Maastricht University, Maastricht, and Orbis Medical Center, Sittard, The Netherlands; ³Neurologische Praxis Eppendorf, Hamburg, Germany

Background: Lack of persistence/suboptimal adherence to disease modifying therapy (DMT) is associated with a return of disease activity in multiple sclerosis (MS) patients. Data from the final PERSIST study suggest that the intramuscular interferon beta-1a (IM IFNβ-1a) autoinjector (AVONEX PEN^®) is associated with high persistence/adherence rates.

Objectives: To assess the effect of prior DMT on persistence/adherence in MS patients treated with IM IFNβ-1a in a real-world clinical setting.

Methods: PERSIST was a prospective, observational, 12-month, open-label study of MS patients self-administering IM IFNβ-1a therapy by autoinjector. In this post-hoc analysis, patients were stratified by prior DMT status and other patient characteristics. The primary endpoint was physician-reported persistence at 12 months.

Results: Of 270 patients enrolled, 187 (69.3%) reported prior DMT (mean age 44.1 years; 77.5% female) and 83(30.7%) were DMT-naïve (mean age 40.7 years; 72.3% female). Overall, 232 patients comprised the intent-to-treat population, including 162 (69.8%) with and 70 (30.2%) without prior DMT. Physician-reported persistence rates were similar for patients with/without prior DMT; 95.5% (127/133) and 92.7% (51/55), respectively. Full compliance (no missed injections, all data available) was 73.6% (109/148) for patients with and 76.6% (49/64) for patients without prior DMT. Adherence was similar, with 87.3% (89/102) of patients with and 88.2% (30/34) without prior DMT reporting no missed injections during the previous 4 weeks.

Conclusion: Physician-reported persistence/adherence rates were high among patients using an IM IFNβ-1a autoinjector in a real-world clinical setting. Results were similar for patients with/without prior DMT and other patient characteristics.

P-26 Oral Fingolimod Versus Interferon-β1a in Paediatric Multiple Sclerosis: Design of A Double-blind Trial

J. Gärtner,¹ B. Banwell,² A. Ghezzi,³ G. Karlsson,⁴ Y. Chen,⁵ M. Merschhemke,⁴ N. Putzki,⁴ and T. Chitnis⁶

¹University Medicine Göttingen, Göttingen, Germany; ²The Children’s Hospital of Philadelphia, Philadelphia, USA; ³Ospedale di Gallarate, Gallarate, Italy; ⁴Novartis Pharma AG, Basel, Switzerland; ⁵Novartis Pharmaceuticals Corporation, East Hanover, USA; ⁶Partners Paediatric Multiple Sclerosis Centre, Massachusetts General Hospital, Boston, USA

Background: Approximately 3–5% of multiple sclerosis (MS) patients have disease onset during childhood. Although regularly used in children, neither basic nor escalation disease modifying therapy (DMT) approved for adult MS has been evaluated by controlled trials in children.

Objective: Here we present the design of PARADIGMS, a global study of fingolimod versus intramuscular interferon beta-1a (IFNβ1aIM) in paediatric MS.

Methods: PARADIGMS is a 24-month, randomised, double-blind/double-dummy, active-controlled, multicentre study in paediatric MS patients aged 10-17 years. Primary objective is to evaluate the efficacy of fingolimod versus IFNβ1aIM in reducing relapse frequency. Other objectives: evaluation of efficacy on MRI parameters, fingolimod safety/tolerability and pharmacokinetics assessment. Key inclusion criteria: 1 relapse in previous year/2 in previous 2 years (with/without DMT) and Expanded Disability Status Scale score 0–5.5. Key exclusion criterion is active/chronic immune system disease other than MS.

Results: In phase 3 studies, annualised relapse rate (ARR) on fingolimod was low irrespective of age, whereas control groups (placebo/ IFNβ1aIM) showed higher ARR in young adults’ versus overall control groups. The relative treatment effect of fingolimod versus controls was consistently higher in young adult patients versus overall study populations. This information was used for making sample size assumptions for the paediatric study. Approximately 190 patients will be randomised to receive fingolimod/ IFNβ1aIM (1:1).

Conclusions: PARADIGMS will be the first prospective, randomised, controlled study to evaluate therapeutic potential of a DMT in paediatric MS. PARADIGMS is recruiting globally.

P-27 Effect of Age on Efficacy of Fingolimod Treatment: Young Adult Patients with Multiple Sclerosis Demonstrate Higher Relative Reduction of Relapse Rates

T. Chitnis¹, G. Karlsson², D. A. Häring², A. Ghezzi³, D. Pohl⁴, J Gärtner⁵ and N. Putzki²

¹Partners Paediatric Multiple Sclerosis Centre, Massachusetts General Hospital, Boston, USA; ²Novartis Pharma AG, Basel, Switzerland; ³Centro Studi Sclerosi Multipla, Gallarate, Italy; ⁴Children’s Hospital of Eastern Ontario, Ottawa, Canada; ⁵University Medicine Göttingen, Germany

Background: Relapse frequency has been reported to be higher in young multiple sclerosis (MS) patients. PARADIGMS [fingolimod versus intramuscular interferon beta-1a (IFNβ1aIM)] is the first controlled study in paediatric MS patients.

Objective: To evaluate annualised relapse rates (ARR) in young adult MS patients receiving fingolimod 0.5mg/IFNβ1aIM/placebo in pivotal Phase 3 studies, to confirm sample size of the PARADIGMS study.

Methods: A post-hoc analysis of ARR (at ages 20 and 30 years) using negative binomial regression was conducted in intent-to-treat populations of FREEDOMS, FREEDOMS II (versus placebo) and TRANSFORMS (versus IFNβ1aIM) studies.

Results: Proportion of patients aged ≤20 and ≤30 years were FREEDOMS, 28/1272 (2.2%) and 325/1272 (25.6%); FREEDOMS II, 17/1083 (1.6%) and 150/1083 (13.9%); TRANSFORMS, 40/1292 (3.1%) and 355/1292 (27.5%) with mean MS duration of 2.8–5.2 years and 1.5–1.7 mean number of relapses in previous year. Estimated ARR in 20 years/30 years/overall fingolimod 0.5mg groups was: FREEDOMS, 0.16/0.19/0.18; FREEDOMS II, 0.27/0.24/0.21; and TRANSFORMS: 0.14/0.17/0.16; versus control groups was: FREEDOMS, 0.73/ 0.57/0.40; FREEDOMS II, 0.67/0.51/0.40; and TRANSFORMS, 0.60/0.48/0.33. Estimated relative reduction in ARR by fingolimod 0.5mg versus controls was (20 years/30 years/overall): FREEDOMS, 79%/67%/54%; FREEDOMS II, 59%/53% /48% and TRANSFORMS, 77%/64%/52% (all p<0.001).

Conclusions: Fingolimod 0.5mg groups showed low ARR irrespective of age, whereas controls showed higher ARR in young patients, versus overall population. The relative effect of fingolimod 0.5mg versus controls was consistently higher in young adult patients versus overall population. Approximately 190 patients will be randomised to receive fingolimod/IFNβ1aIM (1:1) in the PARADIGMS study, currently recruiting globally.

P-28 Rapid Onset of Efficacy of Teriflunomide in Patients With Multiple Sclerosis

R Macdonell,¹ M Barnett,² J Lechner-Scott,³ J King,⁴ P Truffinet,⁵ D Dukovic,⁶ JS Wolinsky⁷; for the investigators of the Phase 2 Proof-of-Concept, TEMSO, TOWER, and TOPIC studies, and the MRI-AC in Houston, TX

¹Austin Health and University of Melbourne, Melbourne, VIC, Australia; ²Brain and Mind Research Institute, Sydney, NSW, Australia; ³John Hunter Hospital, Newcastle, NSW, Australia; ⁴Royal Melbourne Hospital, Melbourne, VIC, Australia; ⁵Genzyme, a Sanofi company, Chilly-Mazarin, France; ⁶Sanofi, Bridgewater, NJ, USA; ⁷University of Texas Health Science Center at Houston, Houston, TX, USA

Background: Teriflunomide is a once-daily oral immunomodulator approved for relapsing-remitting MS that has consistently demonstrated efficacy in clinical and magnetic resonance imaging (MRI) outcomes. Steady state plasma concentrations of teriflunomide are reached at 3–3.5 months.

Objective: to determine whether teriflunomide provides protection from disease activity before reaching steady state levels using data from the phase 2 study (NCT01487096) and phase 3 TEMSO (NCT00134563), TOWER (NCT00751881), and TOPIC (NCT00622700) studies.

Methods: Nelson–Aalen estimates were used to assess the onset of teriflunomide efficacy on relapses (pooled TEMSO/TOWER and TOPIC). MRI analyses were performed every 6 weeks until Week 36 (phase 2 study), or at Weeks 12, 24, and 48 (TOPIC). Blood samples were taken at randomization, every 2 weeks for 24 weeks, then every 6 weeks until treatment end for the determination of neutrophil and lymphocyte counts (pooled phase 2, TEMSO, TOWER, and TOPIC).

Results: Efficacy onset of teriflunomide 14 mg or 7 mg on relapse was observed within 6 weeks vs placebo. In the phase 2 study, combined unique active lesions (UALs) were reduced for teriflunomide after 6 weeks vs placebo, reaching significance at Week 12. In TOPIC, teriflunomide 14 mg reduced total lesion volume (significant reduction) and UALs by Week 12 vs placebo. Mean neutrophil and lymphocyte counts decreased within 6 and 12 weeks, respectively, and remained within normal levels.

Conclusions: Efficacy onset of teriflunomide on relapses, MRI outcomes, and laboratory parameters is evident shortly after treatment initiation, before plasma steady state concentrations are reached.

P-29 MRI Outcomes in Patients With Early Multiple Sclerosis Treated With Teriflunomide: Results From the TOPIC Study

J King,¹ AE Miller,² B Taylor,³ R Macdonell,⁴ C Shaw,⁵ P Truffinet,⁶ D Bauer,⁷ and JS Wolinsky⁸; for the investigators of the TOPIC study and the MRI-AC in Houston, TX

¹The Royal Melbourne Hospital, Melbourne, VIC, Australia; ²Icahn School of Medicine at Mount Sinai, New York, NY, USA; ³Menzies Research Institute, University of Tasmania, Hobart, TAS, Australia; ⁴Austin Health and University of Melbourne, Melbourne, VIC, Australia; ⁵Geelong Hospital, Geelong, VIC, Australia; ⁶Genzyme, a Sanofi company, Chilly-Mazarin, France; ⁷Sanofi, Bridgewater, NJ, USA; ⁸University of Texas Health Science Center at Houston, Houston, TX, USA

Background: Teriflunomide is a once-daily oral immunomodulator for relapsing-remitting MS. The phase 3 TOPIC study (NCT00622700) evaluated the efficacy and safety of teriflunomide in patients with first clinical episodes suggestive of MS and magnetic resonance imaging (MRI) scan showing ≥2 T2 lesions. Teriflunomide significantly reduced the risk of relapse confirming clinically definite MS.

Objective: To report the effects of teriflunomide 14 mg on MRI activity.

Methods: A total of 614 patients received once-daily teriflunomide 14 mg or 7 mg, or placebo. MRI was performed at screening and 12, 24, 48, 72, and 108 weeks (predefined main time point for analysis) and processed at a centralized analysis centre.

Results: At baseline, 31.4% of patients had ≥1 gadolinium (Gd)-enhancing lesion, and mean total lesion volume (TLV) was 8.66 mL. Teriflunomide 14 mg significantly reduced TLV increase from baseline at all time points (P=0.04 vs placebo at 108 weeks). Teriflunomide 14 mg reduced the number of Gd-enhancing T1 lesions per scan vs placebo (0.40 vs 0.95); relative risk reduction (58.5%, P<0.001); and total enhanced volume per scan (0.03 vs 0.08; P<0.0001). Teriflunomide 14 mg significantly reduced the volume of T2-lesion component at Weeks 24, 48, and 72 (P<0.05 vs placebo); T1-hypointense lesion volume was significantly decreased from baseline at all visits (P<0.05 vs placebo) except 24 weeks (P=0.052).

Conclusions: In patients with early MS, teriflunomide 14 mg had a significant, positive impact on MRI activity, supporting the observed beneficial clinical effects.

P-30 Long-term Clinical and MRI Outcomes From Teriflunomide Extension Studies

S Vucic,¹ J Parratt,² DKB Li,³ R Macdonell,⁴ J King,⁵ P Truffinet,⁶ D Dukovic,⁷ PW O’Connor⁸; for the investigators of the phase 2 Proof-of-Concept and TEMSO studies

¹Westmead Clinical School, University of Sydney, Westmead Hospital, Sydney, Australia; ²Central Clinical School, University of Sydney, Sydney, Australia; ³University of British Columbia and MS/MRI Research Group, Vancouver, BC, Canada; ⁴Austin Health and The University of Melbourne, Melbourne,VIC, Australia; ⁵Royal Melbourne Hospital, Melbourne, VIC, Australia; ⁶Genzyme, a Sanofi company, Chilly-Mazarin, France; ⁷Sanofi, Bridgewater, NJ, USA; ⁸St Michael’s Hospital, University of Toronto, Toronto, ON, Canada

Background: Teriflunomide is a once-daily oral immunomodulator approved for relapsing-remitting MS. The teriflunomide clinical development programme demonstrated consistent efficacy and a manageable safety/tolerability profile.

Objective: To report long-term efficacy in patients treated with teriflunomide in the phase 2 (Ph2; NCT00228163) and phase 3 (TEMSO; NCT00134563) study extensions.

Methods: Patients with relapsing MS were randomized 1:1:1 to teriflunomide 14mg or 7mg, or placebo for 36 (Ph2) or 108 (TEMSO) weeks; patients completing treatment could enter extensions. Teriflunomide-treated patients remained on original dose; placebo groups were randomized 1:1 to teriflunomide 14mg or 7mg. Expanded Disability Status Scale (EDSS) score was assessed every 24 weeks, magnetic resonance imaging (MRI) performed every 48 weeks (until Week 480 [Ph2]/Week 288 [TEMSO]), and relapses reported.

Results: After core study completion, 147 and 742 patients entered the Ph2 and TEMSO extensions, respectively. At June 28, 2013, cumulative teriflunomide exposure was >3500 patient-years: 63 and 468 patients remained on-study. Changes in EDSS score over time were minimal: median scores were ≤2.50 at core study commencement in all groups/studies, and did not subsequently exceed 3.00 (to Week 528 [Ph2] or Week 288 [TEMSO]). Annualized relapse rates were lower in extensions vs core studies. Mean gadolinium-enhancing T1 lesion number was lower at final MRI scan vs core study commencement in all groups/studies.

Conclusions: Disease activity remained low in patients receiving teriflunomide in these extension studies. These data are consistent with sustained long-term efficacy with continuous teriflunomide exposure in patients with relapsing-remitting MS.

P-31 Efficacy and Safety of Alemtuzumab in Patients With Relapsing-Remitting MS Who Relapsed on Prior Therapy: Four-Year Follow-up of the CARE-MS II Study

S. Vucic,¹ A.J. Coles,² D.L. Arnold,^3,4 H-P. Hartung,⁵ E. Havrdova,⁶ K.W. Selmaj,⁷ D.H. Margolin,⁸ J. Palmer,⁸ P. Oyuela,⁸ M.A. Panzara,⁸ D.A.S. Compston⁹; on behalf of the CARE-MS II Investigators

¹Westmead Clinical School, University of Sydney, Sydney, NSW, Australia; ²University of Cambridge, Addenbrooke’s Hospital, Cambridge, United Kingdom; ³NeuroRx Research, Montréal, Québec, Canada; ⁴Montréal Neurological Institute, McGill University, Montréal, Québec, Canada; ⁵Heinrich-Heine University, Düsseldorf, Germany; ⁶First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic; ⁷Medical University of Łódź, Łódź, Poland; ⁸Genzyme, a Sanofi company, Cambridge, Massachusetts, United States of America; ⁹University of Cambridge, Cambridge, United Kingdom

Background: In the 2-year CARE-MS II study (NCT00548405), alemtuzumab had superior efficacy over subcutaneous interferon beta-1a (SC IFNB-1a), with manageable safety.

Objective: To examine 4-year efficacy/safety of alemtuzumab in patients treated with alemtuzumab during CARE-MS II, and 2-year efficacy/safety of patients who switched from SC IFNB-1a to alemtuzumab in the extension study (crossover cohort).

Methods: In CARE-MS II, patients with active RRMS who relapsed on prior therapy received 2 alemtuzumab courses (12 mg/day intravenously on 5 consecutive days and on 3 consecutive days 12 months later) or SC IFNB-1a (44 μg 3 times/week). In the extension study (NCT00930553), alemtuzumab-treated patients could receive as-needed re-treatment or approved disease-modifying therapy (DMT). Crossover patients received 2 alemtuzumab courses (5 days, then 3 days) 12 months apart.

Results: The extension enrolled 393 (93%) patients from the core study alemtuzumab arm. Through 4 years, 68% received only 2 courses, while 24% and 7% received 1 or 2 additional courses, respectively; 5% of patients received another DMT during the extension. Twenty-five patients (6%) discontinued from the study, none due to adverse events (AEs). Among patients who received SC IFNB-1a, 146 (83%) entered the extension, 131 (90%) received 2 courses of alemtuzumab. There were 7 withdrawals (5%) in the crossover group during the 2-year extension, 1 due to AE. Efficacy and safety data will be reported for Year 2 of the extension for both treatment cohorts.

Conclusions: Most alemtuzumab-treated patients did not require additional courses or other DMT during the extension; study discontinuation rates were low.

P-32 Pregnancy Outcomes in the Alemtuzumab MS Clinical Development Program

P. McCombe,¹ A. Achiron,² V. Brinar,³ D.H. Margolin,⁴ J. Palmer,⁴ P. Oyuela,⁴ D.A.S. Compston⁵; on behalf of the CAMMS223, CARE-MS I, and CARE-MS II Investigators

¹The University of Queensland Centre for Clinical Research, Royal Brisbane and Women’s Hospital, Herston, QLD, Australia; ²Multiple Sclerosis Center, Sheba Medical Center, Tel Hashomer, Israel; ³Zagreb Medical School and University Hospital Center, Zagreb, Croatia; ⁴Genzyme, a Sanofi company, Cambridge, MA, USA; ⁵Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK

Background: Alemtuzumab showed superior efficacy over subcutaneous interferon beta-1a and manageable safety in 3 randomised studies. Alemtuzumab is eliminated from the body 1 month after administration. Before elimination, there is potentially drug transfer to fetus during gestation and postpartum in breast milk. European label guidelines recommend contraception in women for ≥4 months after treatment.

Objective: To report pregnancy outcomes in the alemtuzumab MS clinical development program.

Methods: In phase 2 and 3 studies (NCT00050778; NCT00530348; NCT00548405), and their extension (NCT00930553), patients received 2 or more courses of alemtuzumab (12 or 24 mg/day intravenously on 5 consecutive days at baseline, and on 3 consecutive days ≥12 months later). Contraception was required during core studies and for 6 months after extension study treatment, but patients becoming pregnant could remain on study.

Results: As of October 17, 2013 (N=1486), 139 pregnancies occurred in 104 patients (67 live births, 14 elective abortions, 24 spontaneous abortions, 1 stillbirth, 4 unknown outcomes, and 29 ongoing). Most pregnancies (133/139) occurred >4 months after last alemtuzumab dose. Spontaneous abortion rate was age-related. Serious adverse events (SAEs) occurred in 11 fetuses/infants; each SAE was unique. Grade 4 thyrotoxic crisis occurred in a 21-day-old, full-term infant whose mother developed Basedow’s disease during pregnancy; infant recovered after treatment. Two elective abortions followed fetal defect SAEs. No pattern in fetal defects was evident.

Conclusions: Spontaneous abortion risk in alemtuzumab-treated MS patients was comparable to the general population. No patterns in fetus/infant SAEs emerged. A new pregnancy registry will collect prospective data.

P-33 Effect of Natalizumab on Progression of Disability in RRMS Patients As Measured By The Composite EDSS-Plus In AFFIRM

Belachew S¹, Dong Q,¹ Rudick R,¹ Paes D,¹ Mikol D¹

¹Biogen Idec, Cambridge, MA, USA

Background: The Expanded Disability Status Scale (EDSS)-Plus is a composite endpoint developed to assess disability in ambulatory and/or upper limb function or EDSS in patients with progressive MS and is the primary endpoint of the ASCEND study of natalizumab in SPMS.

Objectives: Post-hoc analysis to determine the effect of natalizumab on EDSS-Plus in RRMS patients from AFFIRM.

Methods: EDSS-Plus was defined as progression of disability in ≥1 of 3 measures: EDSS increase ≥1 point (0<baseline ≤5.5) or ≥1.5 point (baseline=0) or ≥0.5 point (baseline ≥6.0); or ≥20% increase from baseline in Timed 25-Foot Walk time; or 3) ≥20% increase in 9-Hole Peg Test time, confirmed at 6-months. Sensitivity analyses included progression in ≥2 measures. The proportion of progressors were compared (natalizumab, n=627; placebo, n=315).

Results: Natalizumab reduced the hazard of 6-month confirmed progression on EDSS-Plus by 42% (natalizumab 21%, placebo 31%; HR=0.58, P<0.0001). Placebo group progression was more common on EDSS (23%) than on T25FW (14%) or 9HPT (7%); progression on T25FW or 9HPT was driven by subjects with baseline EDSS≥3 (23% and 12%, respectively). Natalizumab also reduced the hazard of EDSS-Plus progression on ≥2 measures by 63% (natalizumab 3%, placebo 9%; HR=0.37, P=0.0006).

Conclusions: While progression on EDSS-Plus was more sensitive than EDSS alone, particularly in patients with baseline EDSS≥3, and significant treatment effects of natalizumab were observed, the utility of EDSS-Plus in RRMS remains to be determined, although it might have utility in RRMS patients with higher baseline EDSS who are at higher risk of conversion to SPMS.

P-34 Mesenchymal Stem Cell Therapy in Multiple Sclerosis: An Updated Review of The Current Clinical Trials

Omid Mirmosayyeb¹, Amir Pouya Tanhaie², Rokhsareh Meamar³, Vahid Shaygannejad⁴

^1-4 Isfahan Neuroscience Research Center, Alzahra Hospital, Isfahan University of Medical Sciences, Isfahan, Iran.

Introduction: Multiple Sclerosis (MS) is an autoimmune and neurodegenerative disease of the central nervous system (CNS).Stem cells (SCs) have uncovered a new view as a therapeutic tool in neurological disorders such as MS. These cells are pluripotent cells with the capacity to give rise to different cell types. There are the two main stem cell types, embryonic stem cells (ESs) and adult stem cells. In adults, stem cells include hematopoietic stem cells, mesenchymal stem cells (MSCs) and neural stem cells. MSCs are self-replicating cells which can play a role in differentiating in multidirectional pathways, such as osteoblasts, chondrocytes, myocytes, marrow stromal cells, tendon-ligament fibroblasts, adipocytes and neural cells.

Methods: We studied recent (2007-2014) clinical trials and review articles of stem cell therapy for multiple sclerosis to achieve to the best adult stem cell type and the most effective and safest route in order of managing them.In this article we will first provide an overview of the cell sources for, proposed mechanisms that contribute to the beneficial effects of stem cell transplantation and the ideal route and/or timing of stem cell-based therapies for MSC.

Results: It was found 7 clinical trials (table 1) .In some studies we detect critical adverse events that has been indicated some types of SCs act as carcinogen factors. According to our researches, the best stem cell to transfer MS patients was mesenchymal stem cells and injecting intravenously is the best way to administrate. By this goals we prevent from meningeal irritation that will happened in intrathecally administration.

Conclusion: Overall, we recommend intravenous MSCs as the best kind of stem cell therapy for autoimmune disorders like MS. It’s clear that more studies should be done to prove efficacy and safety of these therapeutic approaches.

P-35 Immune-Modulation of Potent Anti-Oxidants on Multiple Sclerosis: From Preclinical Study to Clinical Application

Shyi-Jou Chen

Tri-Service General Hospital, Taipei, Taiwan

Multiple sclerosis (MS) is a chronic disease of the central nerve system (CNS) primarily affecting young people and the pathogenesis of MS. The CNS preserves a potent antioxidant defense mechanism to scavenge reactive oxygen species (ROS). Experimental autoimmune encephalomyelitis (EAE) is a convincing animal model of MS and the immunopathogenic mechanisms of EAE is attributed to T-cell-mediated inflammatory disease of the CNS and activated T cells recruit invading inflammatory cells like macrophages and stimulate astrocytes and microglia in situ, consequently secreting icytokines, chemokines, and toxic molecules, in terms of glutamate, nitric oxide (NO) and/or ROS, contributing to axonal damage, followed by complement activation or antibody- mediated phagocytosis of axons leading to demyelination and axonal injury eventually.

In brain tissue of MS patients, expression of antioxidants was detected and enhanced in the lesions, indicating the essence of oxidative stress. Thus ROS believably play a role of distinct pathological processes on MS. Antioxidants may inhibit the development and progression of MS lesions. Therefore, antioxidant therapy may represent a striking treatment of MS.

In this review we summarize and discuss the immumodulation and potential therapeutic effects and the novel strategies of antioxidants such as Erythropoietin (EPO), melatonin, α-tocopherol (vitamin E), and α-lipoic acid (ALA) for MS treatment.

Poster Session 6 NMO Epidemiology

P-36 An Epidemiological Study of Neuromyelitis Optica in Isfahan, Iran

Zahra Nasr^1,2, Masoud Etemadifar¹, Masoumeh Dashti¹, Reza Vosughi³, Sreeram V Ramagopalan⁴

¹Isfahan Research Committee of Multiple Sclerosis, Isfahan University of Medical Sciences, Isfahan, Iran; ²Medical Students’ Research Center, Isfahan University of Medical Sciences, Isfahan, Iran; ³Health Sciences Centre, University of Manitoba, Canada; ⁴Department of Physiology, Anatomy and Genetics, University of Oxford, John Radcliffe Hospital, Oxford, UK

Background: Neuromyelitis optica (NMO) is an inflammatory disorder of the central nervous system. It has long been considered as a subtype of multiple sclerosis but recent observations suggest that NMO is a different disease with humoral pathogenic mechanisms. NMO cases have been reported from different regions of the world with a racial predilection.

Objective: In this study we aimed to analyze NMO in terms of epidemiology, clinical features and serology in a Caucasian population in Isfahan, Iran.

Methods: Across-sectional study was conducted from April 5, 2007 to August 31, 2013. All patients known to have definite NMO according to Wingerchuks’s criteria. A total number of 95 definite NMO patients (29 men and 66 women) were identified from database.

Results: The overall crude prevalence of NMO among the Caucasian population living in Isfahan province was 1.9/100,000, 95% CI, 1.6-2.3/1000000. The mean age at the onset of the disease was 30.1 ± 10.1 (range: 6.5-60, median: 28) years old. Fifty-seven patients had monophasic NMO while 38 patients had relapsing NMO.

Conclusions: Result of our study (that is the largest case series from Western Asia to our knowledge), shows a similar prevalence of NMO in Isfahan comparing to other Caucasian populations; however some differences existed in the clinical and demographic features of the disease in our cohort. In comparison with western countries it seems Iranian NMO patients have a more benign course.

P-37 Epidemiology of NeuromyelitisOptica in the World: A Systematic Review

Zahra Nasr^1,2, Masoud Etemadifar¹, Reza Vosughi³, Behrang Khalili²

¹Isfahan Research Committee of Multiple Sclerosis, Isfahan University of Medical Sciences, Isfahan, Iran; ²Medical Students’ Research Center, Isfahan University of Medical Sciences, Isahan, Iran; ³Health Sciences Centre, University of Manitoba, Canada

Background: Neuromyelitis optica (NMO) has long been considered as a subtype of Multiple Sclerosis (MS) due to the similarities between the clinical presentations. NMO cases have been reported from different regions of the world and several lines of evidence are indicative of a racial predilection for NMO.

Objective: In this study, for the first time, we aimed to provide a comprehensive review regarding the incidence and prevalence of NMO across the World.

Methods: A comprehensive literature search was performed using Pubmed, Embase, and, Web of Science. We also did manual search of reference lists from primary articles and relevant reviews.

Results: A total of 9 articles met the inclusion criteria and were reviewed in this study. Incidence data were found in four studies and ranged from 0.053 per 100,000 per year in Cuba to 0.08 in Mersey side of UK. Prevalence was reported in all studies and ranged from 0.51 per 100,000 in Cuba to 4.4 in Southern Denmark with higher female preponderance (ranged from 2.27 to 4.5). Isfahan, Iran with the mean age of onset of 30 had the lowest and south east Wales with 39.5 had the highest mean age of onset.

Conclusions: Despite increasing tendency to epidemiological study on NMO, prevalence and incidence rate in numerous countries has not been published yet. Furthermore most of the studied areas only reported the regional rate but not the whole country. Few studies report the anti AQP-4 antibodies for patients. More studies needed to explore further information about epidemiology of NMO.

P-38 Prevalence of Idiopathic Inflammatory Demyelinating Central Nervous System Disorder in Thailand

N. Prayoonwiwat¹, M. Apiwattanakul², P. Pasogpakdee³, S.Siritho^1,4, C. Chanatittarat⁵, U. Chaikledkaew.^5**

¹Division of Neurology, Faculty of Medicine Siriraj Hospital, Mahidol University; ²Division of Neurology, Prasat Neurological Institute; ³Sriphat Medical Center, Faculty of Medicine, Chiang Mai University; ⁴ Bumrungrad International Hospital; ⁵Social and Administrative Pharmacy Excellence Research (SAPER) Unit, Department of Pharmacy, Faculty of Pharmacy, Mahidol University

Background: The awareness for Thai patients with idiopathic inflammatory demyelinating central nervous system disorders (IIDCDs) receives increasing attention from clinicians and policy makers.

Objective: This study aimed to explore the prevalence, disease characteristics and medical utilization in three major multiple sclerosis (MS) clinics in university hospitals in Thailand.

Method: A total of 14,851 medical records was used to identify the IIDCDs patients based on related ICD10 codes. Data included diagnosis, Expanded Disability Status Score (EDSS), immunotherapy and symptomatic treatments. All medical utilization was categorized by treatment goals to explore disease characteristics. Daily defined dosage based on the World Health Organization was used to calculate adherence, defined as medication possession ratio (MPR) and persistence, defined as proportion of days covered.

Results: There were 418 patients with IIDCDs categorized as MS (n=132), clinical isolated syndrome (CIS) (n=32) and neuromyelitis optica (NMO) (n=254). The prevalence of IIDCDs was 0.648 per 100,000 and the incidence rate was 23.0 per 100 person-year. The median EDSS of patients with MS, CIS, or NMO was 3.0, 2.5 or 3.5, respectively. There were 78% (n=326) receiving immunotherapy. The MPR of IFN-β (91%) was higher than azathioprine (62%), while persistence of IFN-β was 50.5%. Treatment for neuropathic pain was the most frequent symptomatic treatment (79%, n=330).

Conclusion: This was the first study on the prevalence of IIDCDs in Thailand. Compared to previous studies in Asia, the prevalence was low whereas the incidence rate was considerably high. The adherence in immunotherapy was high, while persistence was quite low for IFN-β.

P-39 Large-Scale Epidemiological Survey of Disability Progression in Japanese Patients with Multiple Sclerosis and Neuromyelitis Optica

I. Nakashima,¹ N. Harada,² F. Nakaya²

¹Tohoku University School of Medicine, Sendai, Japan; ²Biogen Idec Japan Ltd., Tokyo, Japan

Background: Epidemiological data on disability and progression in Japanese patients with multiple sclerosis (MS) and neuromyelitis optica (NMO) is not well established.

Objective: To evaluate disability, progression, and degree of severity based on the Patient Determined Disease Steps (PDDS) scale.

Methods: This survey used questionnaires mailed to patients through 3 Japanese MS patient associations. Patients were asked to provide demographic/clinical information and evaluate their own disability using the PDDS and 8-item Short-Form Health Survey (SF-8) quality of life scales.

Results: Of 2823 patients with MS/NMO who received questionnaires, 1089 (38.6%) responded (74%, MS; 24%, NMO). Disability at or above gait disturbance (PDDS ≥3) was reported by 45% and 58% of MS and NMO patients, respectively. Patients with NMO were older at onset, had greater disability, and were more often female than MS patients. In MS patients, the mean time from first symptoms to treatment initiation was 4.5 years and was longer for younger onset (≤29 years) than for older onset (≥40 years) patients (6.2 vs 2.2 years). MS patients whose current disabilities were reported as “early or late cane/bilateral support/wheelchair/bedridden” often started treatment after gait disturbance. PDDS scores in MS patients correlated with SF-8 physical component scores, but not mental component scores; all SF-8 scores were lower than in the healthy Japanese population.

Conclusions: The prevalence of disability among Japanese patients with MS/NMO is higher than previously thought. Treatment is often delayed, particularly among younger onset patients. Patients with severe disability often did not start treatment until after gait disturbance.

Poster Session 7 NMO Clinical Aspects

P-40 Patients with Neuromyelitis Optica and Neuromyelitis Optica Spectrum Disorder: Turkish Multicenter Data

A.Altıntaş, R.Karabudak, B.Petek Balcı,M.Terzi, A.Soysal, S.Saip, A.Tuncer Kurne,U.Uygunoğlu, M.Nalbantoğlu, G.Gözübatık-Çelik, N.Işık, Y.Çelik, F.Gökçay, T.Duman,C.Boz, C.Yücesan, N.Çelebisoy, S.Diker, İÇ Işıkay, T.Kansu

A.Siva

Introduction: Neuromyelitis Optica(NMO) and Neuromyelitis Optica Spectrum Disorders(NMOSD) are considered to be immune-mediated diseases of the central nervous system. We aimed to explore the characteristics of Turkish NMO/NMOSD cohort.

Methods: Of 182 patients diagnosed as NMO/NMOSD who were followed by ten different centers in Turkey were included. The detailed demographic, clinical and laboratory data of patients were collected from the medical records. The patients were divided into six subgroups as follows: Classical NMO, single or recurrent attacks of transverse myelitis with longitudinally extending spinal cord lesions (LETM), recurrent optic neuritis (ON) with normal brain MRI or cranial MRI lesions not compatible with multiple sclerosis (MS), optico-spinal MS (OSMS), ON or TM accompanying systemic autoimmune diseases, ON or TM with brain lesions suggesting NMO.Patients with NMO was also subgrouped and evaluated according to age at onset as “early or late onset NMO”.

Results: The number of female was predominant (n: 149). The mean age at disease onset was 31.29± 12.40.The age at disease onset was <50 years in 166 patients (91.2%, early onset NMO/NMOSD), while it was ≥50 years (late onset NMO/NMOSD) in 16.The mean disease duration was 64.65±69.17 months. In NMO group,NMO–IgG positivity was in 62.5%. Annual progression index was significantly higher in the LETM group.The mean EDSS and progression index were higher in late onset NMO.

Conclusion: Our results revealed the lower rate of NMO IgG positivity, more severe disability in either NMO/NMOSD patients presenting with transverse myelitis or late onset NMO cases and no dependency between disability and NMO IgG status.

P-41 Neuromyelitis Optica and Neuromyelitis Optica Spectrum Disorders: The Evaluation of 86 Patients Followed by Istanbul Bilim University, Department of Neurology

Burcu Altunrende*, Ahmet Mithat Tavlı ****Ayca Altınkaya*, Baris Topcular*, Meryem Kocarslan*, Sadık Server**, Sinem Firtina***, Sedef Yenice***, Gülsen Akman Demir*.

İstanbul Bilim University Neurology Department*, Neuroradiology Department**and Biochemistry Department*** İstanbul Medipol University Neurology Department****

Background and objectives: Neuromyelitis optica (NMO) and its spectrum disorders (NMOSD) are relatively rare disorders. We aimed to evaluate clinical characteristics and disease course of the NMOSD patients followed at our department.

Patients and methods: All the patients with the diagnosis of NMO/NMOSD followed since the establishment of our multipl sclerosis clinic in April 2011, were evaluated.

Results: There were 86 patients (66 female, 20 male) with NMO/NMOSD followed at our MS unit; 24 had NMO, 42 had recurrent optic neuritis (RON); and 20 had longitudinally extensive transverse myelitis (LETM). The disease course was relapsing in 70 patients (81%). The first attack was bilateral ON (BON) and TM in 3 patients, ON and TM in 1 patient, ON in 50 patients (bilateral in 6) and TM in 26 patients. NMO IgG was positive in 12 patients with NMO (55%), 4 patients with LETM (25%), and 8 patients with RON (25%). Oligoclonal band was positive in 15 out of 44 patients (34%). In NMO/NMOSD patients, cranial magnetic resonance imaging (MRI) showed no abnormality in 48; nonspecific lesions in 37; and 1 patient had hypothalamic lesion. In spinal MRIs, 41 patients had LETM; six had suspected hyperintense T2 lesion in C5.

Conclusion: This is one of the largest single center series collected over 3 years. NMO/NMOSD seems to be over-represented in our center since it is one of the few where NMO IgG testing is available. In NMO/NMOSD, early diagnosis and treatment is important to prevent the patient from the permanent disability.

P-42 Clinical Characteristics of Early Attacks in Neuromyelitis Optica

JM Seok, MD; EB Cho, MD; HJ Cho, MD; BJ Kim, MD, PhD; KH Lee, MD, PhD; JH Min, MD

Department of Neurology, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea

Background: Neuromyelitis optica (NMO) is an autoimmune relapsing inflammatory disorder of the central nervous system characterized by optic neuritis (ON), myelitis and distinctive brain lesions. Individual attacks of NMO are generally severe and prone to have residual disability. Therefore, evaluation of the characteristics of early attacks in NMO is important.

Objective: We aimed to evaluate the clinical characteristics of the early attacks and determine factors related to following attack interval and severity.

Methods: This is a retrospective study of patients with either NMO or NMO spectrum disorder with positive anti-aquaporin-4 antibody. Initial and second attacks were reviewed including baseline characteristics, nadir and recovery EDSS, interval between attacks, lesion locations, type of acute treatment and use of immunosuppressants during inter-attack periods.

Results: Total of 49 patients were enrolled (female 46/49, 93.9%; age of onset, 40.4±16 year). Median time to next attacks were 11.8(3.3-22.4) months. The use of immunosuppressants between attacks were not statistically significant, but had tendency to delay next consecutive attack. The severity of initial attacks (nadir EDSS of initial attacks) did not correlate with that of second attacks (3.4±1.7, 3.8±1.8, p=0.354), and there was no predictive factor for each attack severity.

Conclusion: There were no significant initial attack characteristics which can predict following consecutive attack severity and time to next attack. However, use of immunosuppressant revealed tendency to delay next attack. Considering that NMO patients are vulnerable to have residual disability from each attack, importance of early use of immunosuppressant should be weighed heavily in clinical practice.

P-43 The Quality of Life in Thai Patients with Neuromyelitis Optica Spectrum Disorders

S.Siritho^1,2, P. Pasogpakdee³, M. Apiwattanakul⁴, N. Prayoonwiwat¹, S. Chankrachang⁵, C. Chanatittarat⁶,U. Chaikledkaew.^6**

¹Division of Neurology, Faculty of Medicine Siriraj Hospital, Mahidol University; 2 Prannok Road, Bangkoknoi, Bangkok 10700, Thailand; ²Bumrungrad International Hospital; 33 Sukhumvit 3, Wattana, Bangkok 10110, Thailand; ³Sriphat Medical Center, Faculty of Medicine, Chiang Mai University; 110/392 Sriphat Bld. Inthawarorot Rd., Sriphum, Muang, Chiang Mai 50200,Thailand; ⁴Division of Neurology, Prasat Neurological Institute; 312 Rajavithi Road, Phayathai, Bangkok 10400,Thailand; ⁵Division of Neurology, Faculty of Medicine, Chiang Mai University; 110/392 Sriphat Bld. Inthawarorot Rd., Sriphum, Muang, Chiang Mai 50200,Thailand; ⁶Social and Administrative Pharmacy Excellence Research (SAPER) Unit, Department of Pharmacy, Faculty of Pharmacy, Mahidol University; 447 Sri-Ayudthaya Road, Phayathai, Ratchathevi, Bangkok 10400 Thailand

**Corresponding author

Backgrounds: The prevalence of Neuromyelitis optica spectrum disorders (NMOSD) is high in Asian countries including Thailand. Although NMOSD causes a significant impact on patients’ quality of life (QOL), there has never been reported QOL or health utility (HU) in Thailand.

Objectives: To evaluate the QOL and examine the factors affecting HU and QOL using EuroQol five-dimensional questionnaire (EQ-5D) and visual analog scale (VAS) among Thai patients with NMOSD.

Methods: A multicenter cross-sectional study had been conducted. The QOL data were collected by interviewing 177 NMOSD patients during September 2011 to July 2014. All demographic, socioeconomic status, clinical data and Expanded Disability Status Score (EDSS) were also recorded.

Results: The average age at diagnosis and disease duration were 41.6±12.4, 5.1±4.9 years, respectively. The mean QOL using EQ-5D and VAS were 0.41±0.33, 0.65±0.17, respectively. Older or unemployed patients had statistically significant lower QOL scores using EQ-5D than those who were younger or employed (p<0.01). In the group of EDSS 0.0-2.5, 3.0-5.5, 6.0-7.5, 8.0-9.5, EQ-5D but not VAS could differentiate the QOL in each EDSS group. QOL scores showed positive correlation the most in mobility (0.56; p<0.0001) and the lowest in anxiety/depression dimension (0.15; p<0.039). The mean QOL scores in NMOSD patients who had EDSS ≥ 8.0 were -0.15± 0.22 which indicated that patients would rather die than live.

Conclusions: The QOL in Thai patients with NMOSD was worse than those with stroke, Diabetes Mellitus, peritoneal dialysis, acquired immune deficiency syndrome. QOL scores using EQ-5D were more responsive than VAS in detecting disease severity.

P-44 How Diagnostic Delay Affects the Medical Costs and Level of Disability in Neuromyelitis Optica Spectrum Disorder

W Kim,¹ J-W Hyun,² A Joung,² S-H Kim,² IH Jeong,² D-S Shim,¹ K-S Lee,¹ HJ Kim²

¹Department of Neurology, The Catholic University of Korea, Seoul, Korea; ²Department of Neurology, Research Institute and Hospital of National Cancer Center, Goyang, Korea

Background: The discovery of aquaporin-4 antibody (AQP4-Ab) has led to a dramatic advance in the diagnosis and treatment of neuromyelitis optica spectrum disorder (NMOSD).

Objectives: To estimate the medial costs and level of disability according to their onset years of NMOSD.

Methods: This study randomly enrolled 31 NMOSD patients from National Cancer Center, Korea. They were categorized into three groups according to the onset year of NMOSD; group 1(~year 2005: before the AQP4-Ab era, 16 patients), group 2(year 2006~2010: yet limited availability of AQP4-Ab, 9 patients) and group 3(year 2011~present: wider availability of AQP4-Ab, 6 patients). The interval from the onset to confirmed diagnosis of NMOSD and disability level measured by EDSS were compared among the groups. Direct medical costs per patient were collected by structured interviews and also compared among the groups. Indirect costs such as productivity loss of patients and caregivers were not included.

Results: The mean age was 40.3±10.5(range 22~62) years. The mean disease duration was 178.9±44.9(109~251), 74.7±11.2(69~90), and 26.2±8.0(17~38) months and the median EDSS was 5.5(2.0~8.5), 5.0(2.0~7.5) and 1.75(0~4.0), respectively. The mean interval from the disease onset to confirmed diagnosis of NMOSD was 109.8±45.2(48~184), 20.3±11.9(6~41), and 4.8±5.0 0~13) months, respectively. The estimated mean total medical cost per patient before confirmed diagnosis of NMOSD was 51±54(13~238), 31±23(7~76), and 9±7(3~21) million Korean won, respectively.

Conclusions: Direct medical costs and level of disability increase with diagnostic delay. This result highlights the importance of early and accurate diagnosis to reduce the unnecessary medical costs and disability of NMOSD.

P-45 Intravenous Immunoglobulin Treatment for Neuromyelitis Optica and Its Spectrum Disorders

Burcu Altunrende², Gülden Akdal¹, Meltem Söylev Bajin³, Aylin Yaman³, Ayca Altınkaya², Meryem Kocaslan², Gülsen Akman-Demir²

¹Department of Neurology, Dokuz Eylül University Faculty of Medicine, Izmir, Turkey; ²Department of Neurology, Bilim University Faculty of Medicine, Istanbul, Turkey; ³Department of Opthtalmology, Dokuz Eylül University Faculty of Medicine, Izmir, Turkey

Background and Objective: There are very few reports on the effects of intravenous immunoglobulin (IVIg) treatment for NMO and NMOSD. We aimed to evaluate our patients with NMO/NMOSD who were treated with IVIg.

Methods: Data from all our patients with the diagnosis of NMO/NMOSD, who received IVIg treatment were retrospectively evaluated.

Results: Nine patients had received IVIg, three of these patients had NMO, 5 had recurrent optic neuritis [RION], and one had recurrent longitudinally extensive transverse myelitis [R-LETM]. These patients were aged 20-63, and started receiving monthly IVIg from 1 to 20 years after onset of disease. Two out of three NMO patients and one RION patient and the R-LETM patient were NMO-Ig G positive.

Under current treatments the patients had continued to have attacks therefore IVIg was given in addition to the existing drug. The follow up of was between 12 to 27 months except one patient who received IVIg for acute relapse. Two of the patients with NMO had attacks under IVIg at month 10 and month 13, and month 1, month 6, and month 12, respectively, and were switched to rituximab; the patient with R-LETM also had attacks at month 2 and month 19 when the treatment was interrupted. Only one patient with RION had an attack at month 3.

Conclusion: Monthly IVIg is well-tolerated and safe and it seems to be more effective in RION. It may also be an option for NMO when current therapies are contraindicated or could not be tolerated.

Poster Session 8 NMO Neuroimaging & Laboratory Tests

P-46 MRI Characteristics of Brain Lesions in NMO-Igg-Positive Neuromyelitis Optica Spectrum Disorders

Young-Min Lim, Kyeung Mo An, Jookyung Lee, Kwang-Kuk Kim

Department of Neurology, Asan Medical Center, University of Ulsan, College of Medicine Seoul, Korea

Background: Neuromyelitis optica (NMO) with brain MRI involvement has been recently reported.

Objective: This study aimed to evaluate brain MRI lesions in NMO-IgG seropositive patients and to investigate the relationship between neuroimaging features and clinical attacks.

Methods: We analyzed the MRI findings of brain lesions in 60 NMO-IgG-positive patients. We classified MRI characteristics into three categories (rigger, round, and filbert type) according to the size and pattern, and evaluated associated clinical features.

Results: Rigger-type lesions were located in corpus callosum (36/60), hypothalamus (27/60), peri-lateral ventricle (26/60), subcortical white matter (23/60), forth ventricle area (29/60), tegmentum and basis pontis (29/60), crus cerebri (28/60), and peri-aqueduct (23/60). They were not associated with clinically apparent symptoms. Round-type lesions were located in subcortical white matter (14/60), corpus callosum (11/60), periventricular area (7/60), internal capsule (5/60), middle cerebellar peduncle (8/60), and crus cerebri (7/60). Four patients had brainstem symptoms and signs, and one patient had hemiparesis due to internal capsular lesion. Filbert-type lesions were located in subcortical white matter (7/60), corpus callosum (6/60), internal capsule (3/60), lateral ventricle (2/60), and middle cerebellar peduncle (1/60). These extensive lesions were symptomatic in 7 patients. These lesions occurred at the median 4^th relapse, and they were associated with high EDSS score and NMO-IgG titers.

Conclusions: Our study suggests that central nervous system lesions in NMO may occur in the specific regions relating to AQP4 distribution. More extensive brain lesions may be associated with higher titer of NMO-IgG and occur later in the clinical course of NMO.

P-47 Poor Recovery of Optic Neuritis in Neuromyelitis Optica Patients: Exploring the Evidence of Vasculopathy from Retinal Vessel and Brain Diffusion Weighted Image

JM Seok, MD¹; EB Cho, MD¹; HJ Cho, MD¹; JH Min, MD¹; BJ Kim, MD, PhD¹; KH Lee, MD, PhD¹

¹Department of Neurology, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea

Background: Neuromyelitis optica (NMO) is an autoimmune inflammatory disorder of the central nervous system targeting aquaporin-4, and clinically characterized by severe optic neuritis (ON), myelitis and distinctive brain lesions. Previous pathologic reports suggested that there were diverse mechanisms of injury in NMO lesions including vasculopathy.

Objective: In this study, we aimed to find the association of vasculopathy and poor recovery of optic neuritis in NMO patients.

Methods: This is a case-series study of ON patients with positive aquaporin-4 autoantibody (AQP4-Ab); all patients underwent ophthalmologic evaluation and brain MRI with diffusion weighted image (DWI). Recovery of ON was assessed using best visual acuity within 1 year after attack. Poor recovery of ON was defined as visual acuity of 20/70 or worse. And the diffusion restriction was defined as a hyperintense lesion relative to the surrounding brain on DWI and hypointense on apparent diffusion coefficient (ADC) maps.

Results: 27 patients of ON with positive AQP4-Ab were finally enrolled. 10 patients showed poor recovery of ON, and had attenuated retinal vessel. Among 10 patients with poor recovery, eight patients had diffusion restriction lesions, mostly located at corpus callosum or internal capsule (corpus callosum 6 patients, internal capsule 6 patients, brainstem 2 patients).

Conclusion: Diffusion restriction lesions and attenuated retinal vessel of ON in patients with positive AQP4-Ab suggested that vasculopathy might be one of diverse potential pathogenic mechanisms in NMO, and be associated with poor prognosis.

P-48 Cerebrospinal Fluid Aquaporin-4 Antibody Levels in Neuromyelitis Optica Attacks

D. K. Sato¹, D. Callegaro², F. M. H. Jorge², I. Nakashima¹, S. Nishiyama¹, T. Takahashi¹, R. F. Simm², S. L. Apostolos-Pereira², T. Misu³, L. Steinman⁴, M. Aoki¹ and K. Fujihara³

¹Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan; ²Department of Neurology, Faculty of Medicine, University of Sao Paulo, Sao Paulo, Brazil; ³Department of Multiple Sclerosis Therapeutics, Tohoku University Graduate School of Medicine, Sendai, Japan; ⁴Department of Pediatrics, Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA

Background: To elucidate immunopathogenetic roles of aquaporin-4 antibodies in the cerebrospinal fluid (CSF) of neuromyelitis optica spectrum disorders (NMOSD), we analyzed the relationship between aquaporin-4 antibody titers, cellular and inflammatory markers in the CSF.

Methods: We enrolled eleven NMOSD consecutive patients (10 females; 1 male) with a median age of 50 years (range 24 – 71) seen at Hospital das Clinicas, Faculty of Medicine, University of Sao Paulo with detectable AQP4 antibody in sera and CSF. Astrocyte damage was evaluated measuring glial fibrillary acidic protein (GFAP) levels and cytokines were measured using a multiplexed fluorescent magnetic bead-based immunoassay in the CSF.

Results: The serum AQP4 antibody titers were found at high-levels in all patients during attacks and remission. In contrast, AQP4 antibody titers in the CSF were remarkably higher only in samples collected during attacks. Consequently, the CSF:serum ratio found during remission (1:2,048 ± 1:1,448) was higher than during NMO attacks (1:204 ± 1:175), p = 0.0030. The CSF aquaporin-4 antibody levels during attacks (but not in sera) closely correlated with pleocytosis (r = 0.7679, p = 0.0058), inflammatory cytokines including interleukin-6 (r = 0.8091, p = 0.0026) that can regulate antibody-producing plasmablasts, interleukin-1 beta (r = 0.7517, p = 0.0076) that can disrupt the blood-brain barrier, and GFAP levels (r = 0.9439, p < 0.0001) in the CSF.

Conclusions: The amount of aquaporin-4 antibodies present in the central nervous system may have therapeutic implications, as it is associated with astrocyte injury and inflammatory responses during NMOSD attacks.

P-49 Is Vitamin D Deficiency A Risk Factor for Neuromyelitis Optica?

YEE JLL¹, TU TM², TAN K²

¹Yong Loo Lin School of Medicine, National University of Singapore; ²Department of Neurology, National Neuroscience Institute, Singapore

Background: Vitamin D deficiency has been associated with increased incidence and disease activity in Multiple Sclerosis (MS). It is not clear what role vitamin D has in the aetiology and pathophysiology of Neuromyelitis Optica (NMO). Vitamin D levels have not been reported in Asian MS and NMO patients.

Objective: To compare vitamin D levels of MS and NMO patients at disease onset and determine its association with attack severity and recovery.

Methods: We retrospectively reviewed patients at the National Neuroscience Institute from August 2008 to January 2013. We measured vitamin D levels at disease onset and correlated it to the Expanded Disability Status Score (EDSS) at disease onset and at 6 months. All MS patients were treated with pulsed steroids at relapse and Vitamin D supplementation. All NMO patients received only pulsed steroids.

Results: Twenty-six patients (16 MS, 10 NMO) were analysed. Mean vitamin D levels (ng/mL) were significantly higher in NMO compared to MS patients (21.9±10.9 vs 13.2±9.0, p=0.036). Mean vitamin D levels were inversely proportional to skin tone in MS patients: Chinese vs Malay vs Indian (13.2±6.0 vs 10.6±5.1 vs 8.7±6.7 p=0.2). Among Chinese patients, mean vitamin D levels were higher in NMO (n=10) compared to MS (n=6) patients (21.9±10.9 vs 13.2±6.0, p=0.097). Vitamin D levels did not correlate with age, gender or EDSS at disease onset or 6 months later.

Conclusions: Vitamin D levels were higher in NMO compared to MS patients, and deficiency may not be a risk factor for NMO.

Poster Session 9 Myelitis

P-50 Transverse Myelitis: Incidence, Diagnosis, Treatment and Outcome Considerations Report from Indonesia

Sucipto, Estiasari R, Komari N, Imran D

Neurology Department Faculty of Medicine University of Indonesia

Cipto Mangunkusumo Hospital Jakarta

Background: The three main transverse mielitis’ categories are demyelination, including multiple sclerosis (MS), neuromyelitis optica (NMO), idiopathic and inflammatory disorders. The clinical and diagnostic workup for transverse myelitis required.

Objective: To report incidence, diagnosis, treatment and outcome of transverse myelitis

Methods: Retrospective cross sectional study

Results: During January 2013-August 2014 there were 13 transverse myelitis cases, 7 female, mean age 33 years old. Five patients came with leg weakness, 3 with tetraparesis, 3 with blurred vision and 2 with decreased of consciousness. Four patients diagnosed as NMO, 2 patients MS and 4 patients TB myelitis. a 1.5 tesla MRI in 3 patients showed multiple areas of increased signal intensity on T2, and 3 had cord swelling. The CSF in 9 patients shows increase in cell count. Based on Expanded Disability Status Score, mild symptoms (EDSS 0-3) found in 3 patients, moderate (EDSS 3.5-5.5) in 6 patients and severe (EDSS 6-9.5) in 4 patients. Methylprednisolon was given to 8 patients (NMO 3, MS 1, TB myelitis 4), azatriophine to 2 NMO patients and plasmapharesis was done in 2 NMO patients. After the treatment was given, 8 (NMO 4, MS 1) show better functional status and 4 (TB Myelitis 3) shows no improvement.

Conclusions: Differential diagnosis of transverse myelitis is broad. Physicians should pursue an ordered, efficient, and cost-effective approach to diagnosis.

P-51 Clinical Characteristics of Recurrent Transverse Myelitis: A Single Hospital Based-Retrospective Analysis

Seol-Hee Baek, Hung Youl Seok, Byung-Jo Kim

Department of Neurology, Korea University Anam Hospital, Seoul, Korea

Background: Recurrent transverse myelitis (RTM) is suspected as initial presentation of multiple sclerosis or neuromyelitis optica spectrum disorders (NMOSD). However, some patients with RTM are not converted to those diseases.

Objective: The aim of this study is to determine whether idiopathic RTM can be distinguished from monophasic transverse myelitis (TM) or NMOSD.

Methods: We retrospectively analyzed medical records of 75 patients who visited our hospital for first ever TM between January 2005 and June 2014. Patients were grouped as follows: monophasic TM, RTM, and NMOSD. Monophasic TM was defined as patients who did not have any relapse for follow-up periods of at least more than 2 years. Clinical characteristics including demographic data were compared among those 3 groups.

Results: Of the 75 patients, 40 patients were excluded due to short term follow-up period, incomplete medical records, or conversion to other diagnosis. Finally, data of 35 patients (10 in RTM, 18 in monophasic TM, and 7 in NMOSD) were analyzed. The only statistically significant finding was that RTM groups were more prevalent in men compared to NMOSD (p=0.015). The length of spinal cord lesion in RTM (4.2±2.8) was longer than monophasic TM (2.7±1.7), although there was no significant difference between the groups (p=0.095).

Conclusions: RTM may be a variant form of seronegative NMOSD, or may be a new disease entity. Further studies with more subjects and long term follow-up data are needed to reveal the identity of RTM.

P-52 Neutrophil-to-lymphocyte Ratio is A Useful Marker for The Disease Activity in Idiopathic Acute Transverse Myelitis

Kim Y, Eom YI, Joo IS

Department of Neurology, School of Medicine, Ajou University, Suwon, Korea

Background: Idiopathic acute transverse myelitis (iATM) is a focal inflammation of the spinal cord with unknown etiology despite an extensive diagnostic workup. Neutrophil-to-lymphocyte ratio (NLR) is a simple, readily available biomarker which has been widely used to predict prognosis of inflammatory conditions.

Objective: The aim of this study is to explore the relationship of the NLR with disease activity in terms of symptom severity, lesion size and prognosis in iATM patients.

Methods: The medical records of 70 consecutive, newly diagnosed, patients with iATM between April 2008 and April 2014 were reviewed. Patients who performed laboratory test after 90 days from the onset (n=11) were excluded. The iATM patients were classified into two groups according to the NLR (low NLR≤2.0, n=27; high NLR>2.0, n=32). Clinical parameters such as sex, age of onset, the interval between the day performing laboratory test and onset (ILO), length of cord lesion and gadolinium enhancement on spinal MRI, recurrence, and the clinical severity judged by expanded disability status scale (EDSS) at nadir and at the stable state were analyzed in reference to the NLR.

Results: The NLR was positively correlated with EDSS at nadir and EDSS difference between at nadir and at the stable state (△EDSS) (r=0.287, p=0.027; r=0.321, p=0.013), and negatively correlated with ILO (r=-0.526, p<0.001). And a high NLR (NLR>2.0) was also significantly associated with length of cord lesion as well as ILO, EDSS at nadir and △EDSS (p=0.050; p<0.001; P=0.037; P=0.033).

Conclusion: Inflammatory process could be one of major pathophysiological mechanisms underlying iATM.

P-53 Peripheral Blood T Cell Alterations in Myelitis with Various Causes

Song ZY, Kawano Y, Sato S, Watanabe M, Imamura S, Yonekawa T, Masaki K, Matsushita T, Yamasaki R, Kira J

Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University

Background: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system, in which central memory T cells (Tcm) are supposed to play pathogenic roles. However, involvements of Tcm and other T cell subsets in myelitis with various causes remain to be elucidated.

Objective: To clarify the alterations of T cell subsets specific for myelitis caused by MS, neuromyelitis optica (NMO), HTLV-1-associated myelitis (HAM), and atopic myelitis (AM).

Methods: Tcm (CD45RO⁺CCR7⁺), naïve T cells (CD45RA⁺CCR7⁺), effector memory T cells (Tem, CD45RO⁺CCR7^- and TemRA cells, CD45RA⁺CCR7^-), regulatory T cells (Treg, CD25^highCD127^low) and suppressor T cells (Ts, CD8⁺CD28^-, and CD4⁺CD28^-) were measured in peripheral blood from 40 MS patients, 15 NMO patients, 9 HAM patients, 10 AM patients, and 18 healthy controls (HCs).

Results: We found that the percentages of CD8⁺ cells in lymphocytes were significantly higher in NMO patients than in MS and AM patients (both, P<0.01). In HAM patients the percentages of CD4⁺Tcm and CD8⁺ naïve T cells were significantly lower compared with HCs and MS patients (all, P<0.05) and the CD4⁺ naïve T cell percentages were lower compared with MS patients (P<0.05) while the percentages of CD8⁺Tem cells were greater compared with HCs and MS and AM patients (all, P<0.01). The percentages of CD8⁺Ts cells in NMO and HAM patients and those of CD4⁺Ts cells in NMO patients were greater than in HCs and MS and AM patients (all, P<0.05).

Conclusions: Peripheral blood Tcm, Tem, and Ts cells show alterations specific for each cause of myelitis.

Poster Session 10 Optic Neuritis

P-54 Longitudinal Follow-Up of Visual Functions in Patients after Initial Unilateral Optic Neuritis

Hradílek P., Zapletalová O., Woznicová I., Vlček F.

Department of Neurology, University Hospital of Ostrava, CZ

Aims and objectives: To examine selected clinical and paraclinical parameters in patients with first episode of acute unilateral optic neuritis (ON) within seven days of onset with prospective 3-years follow up. To detect risk factors for persistent visual impairment after initial ON.

Materials and methods: 22 patients with first episode of acute unilateral ON (15 women and 7 men) with average age 30.7+ -7.8 years were examined. Clinical signs typical for acute ON were evaluated, visual acuity, fundoscopy, presence of retro or parabulbar pain, perimeter and at the end of follow up also sensitivity for colours and contrast. Visually evoked potentials and brain MRI were performed both at onset and at the end of follow up. Ultrasound measurement of blood flow parameters in both ophthalmic arteries was performed both at onset and the end of follow up.

Results: Onset values of retro or parabulbar pain, presence of central or peripheral scotoma, demyelinating lesions, VEP and orbital ultrasound findings are presented. At the end of follow up the proportion of subjects with impaired visual acuity, colour vision, contrast sensitivity and perimeter is presented.

Conclusions: We detected 3 risk factors for impaired visual functions after initial unilateral ON:

1) Low blood flow velocities in the ophthalmic artery in eye affected with acute ON for impaired contrast sensitivity
2) Presence of demyelinating lesions on brain MRI at onset for impaired colour vision at follow up
3) Worse visual acuity at onset for persistent visual acuity impairment at follows up.

P-55 Morphological Changes of The Retina and Visual Functions in Demyelinating Diseases of The CNS

M Vališ¹, J Kremláček², Z Pavelek¹, V Lehká¹

¹Charles University in Prague, Faculty of Medicine in Hradec Králové, Czech Republic/University Hospital Hradec Králové, Neurology, Hradec Králové, Czech Republic, ²Charles University in Prague, Faculty of Medicine in Hradec Králové, Hradec Králové, Czech Republic

Background: New findings demonstrate an involvement of gray matter from the early onset of the multiple sclerosis (MS). In patients with optic neuritis (ON) reducing of the neural layer of the retina (retinal nerve fiber layer, RNFL) compared with healthy controls is presented. This is on the average about 20.38 um. RNFL thinning is registered even in patients with MS without ON (7.08 um).The reduction of the RNFL in association with a reduction in visual acuity is measured by Snellen chart.

Objectives: The aim of the work is postgraduate longitudinal monitoring of visual acuity, contrast sensitivity, VEP induced stimulations type of pattern reversal and motion onset RNFL in patients with demyelinating disease (with a focus on the initial stages) to establish the links between the monitored parameters and the clinical status of the patient and any prediction of its development.

Methods: File so far examined patients comprise a total of 18 patients, 6 males (age 33 ± 10 years) - 14 patients with a first clinical demyelinating attack (of which 3 ON) and 4 more episodes (2 ON).

Results: Preliminary statistical analysis of the relationship between morphological and functional findings demonstrated a statistically significant negative correlation between RNFL thickness and VEP latency (Spearman R from -0.65 to -0.57 ) and positive relationship with the amplitude (R from 0.48 to 0.62).

Conclusions: Negative correlation of reduction RNFL and P100 latence is consistent with literature .Correlation between reduction of amplitude P100 and RNFL was not confirmed.

Poster Session 11 Experimental Model

P-56 The Lesion Localization of Passive Transfer NMO-IgG Model in Lewis Rats

K. Kurosawa¹, T. Misu², T. Takahashi¹, D. Sato¹, S. Nishiyama, H. Kuroda¹,I. Nakashima¹, K. Fujihara¹, M. Aoki²

¹Department of Multiple Sclerosis Therapeutics, and ²Neurology

Tohoku University Graduate School of Medicine (Sendai, JP)

Background: The systemic study of lesion localization in vivo NMO models has never been studied sufficiently.

Objective: To study the lesion localization of passive transfer NMO-IgG model in Lewis rats.

Methods: NMO-IgG was purified from NMO patients serum. Purified IgG with complement inactivated by 56℃ 30 minutes were used for this study. 8 female Lewis rats (8～10 weeks of age) were immunized with an encephalitogenic mixture containing guinea pig brain myelin basic protein in complete Freund’s adjuvant for the purpose of breaking down blood brain barrier. Then the rats were infused 20mg of purified NMO-IgG intraperitoneally at the onset of tail paresis or body weight loss more than 10mg/day. Then we examined the parafin sections histopatholigically within 3days from the injection.

Results: Vasculocentric AQP4 loss were found in cerebral white matter near ventricles (6/7 cases), hypothalamus (3/7 cases), brain stem (8/8 cases), optic chiasma (3/6 cases), optic tract (2/6 cases) and spinal cord (8/8), but never observed in cerebral and cerebellar gray matter. AQP4 loss was outstandingly observed around gray matter adjacent to border between gray matter and white matter in spinal cord lesions as well as hypothalamic or chiasma lesions. Spinal cord lesions were severe especially in lumbar cords, - but there is no marked demyelination as previously reported.

Conclusions: AQP4 loss in this model is compatible with the lesion distribution in NMO patients.

P-57 Binding Properties of Anti-AQP4 Antibodies Influencing Endocytosis of AQP4 and Complement-Dependent Cytotoxicity

Yoshiki Takai

Tohoku University, Japan

Background: Neuromyelitis optica (NMO) is an autoimmune disease characterized by disease specific autoantibody NMO-IgG [aquaporin-4 (AQP4) antibody] which recognizes the extracellular domains (ECDs) of AQP4. AQP4 has two different isoforms, M1 and M23. Most of the NMO-IgGs preferentially bind to M23-AQP4, which can form a supramolecular structure called orthogonal arrays of particles (OAPs). Recently, several groups revealed NMO-IgG-induced endocytosis of AQP4 which depend on isoform. However, they reached opposite conclusions. Although this discrepancy could be derived from the difference in binding properties of antibodies they used, it is still unclear whether there is a correlation between binding properties of anti-AQP4 antibodies and endocytosis of AQP4.

Objective: To clarify whether the difference in binding properties of AQP4 antibodies influences consequent endocytosis of AQP4 and complement-dependent cytotoxicity (CDC).

Methods: Two types of monoclonal antibodies against the ECDs of mouse AQP4 were established: mAb-A efficiently recognized both M1 and M23, while mAb-B preferentially recognized M23. The effect of these antibodies on endocytosis and CDCs in stable CHO-cell lines expressing AQP4 and primary cultured astrocytes were analyzed by means of live cell imaging, Western blotting, and cell viability assay.

Results: Live imaging and Western blotting revealed that mAb-A enhanced endocytosis, followed by degradation of both M1 and M23, while mAb-B showed much less endocytosis. Consistent with these observations, a prolonged incubation with mAb-A before complement treatment rescued cells from cytotoxicity.

Conclusions: Binding properties of AQP4 antibodies influence CDC probably due to the reduction of AQP4 on the cell surface by antibody-induced endocytosis.

P-58 Peripheral Atopic Diathesis Induces Neuropathic Pain and Activation of Astrocytes in The Posterior Horns of The Spinal Cord

T. Fujii¹, R. Yamasaki², B. Wang¹, M. Kido³, K. Masaki¹, J. Kira¹

¹Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; ²Department of Neurological Therapeutics, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; ³Department of Oral Anatomy and Cell Biology, Graduate School of Dental Science, Kyushu University, Fukuoka, Japan

Background: Demyelinating disease occasionally produces intractable neuropathic pain and tactile allodynia due to spinal cord lesions. Atopic myelitis, a peculiar myelitis associated with atopic/allergic diseases such as atopic dermatitis and bronchial asthma, frequently causes neuropathic pain and dysesthesia. The mechanism of neuropathic pain in atopic myelitis remains to be elucidated.

Objective: To reproduce neuropathic pain/tactile allodynia in animals by inducing atopic disease.

Methods: We induced atopic diathesis and bronchial asthma in C57BL/6J mice (age, 6 weeks) by intraperitoneal injection of ovalbumin (OVA, 50 μg) and aluminum hydroxide (Alum, 2 mg) once a week (O+A group) for 3 weeks. As control, PBS or Alum was injected instead of O+A. Bronchial asthma was induced by further inhalation of OVA (2.5 mg/mL) after O+A or PBS/A injection for 4 consecutive days. We studied tactile allodynia using von-Frey filaments. Spinal cord and lungs were immunohistochemically examined. Astrocyte activation was assayed by measuring the numbers of cells expressing S100β, a reliable marker of astrocyte activation.

Results: O+A injection with OVA inhalation produced eosinophil infiltration in the lung. The O+A group showed marked tactile allodynia of hind limbs compared with the PBS/A group when stimulated with 0.04 g and 0.07 g filaments. The numbers of S100β-positive cells were significantly increased in the dorsal horns of the lumbar spinal cord in the O+A group than PBS/A group.

Conclusion: Peripheral atopy can induce tactile allodynia/neuropathic pain and astrocyte activation in the spinal cord. Astrocyte activation may be related to emergence of neuropathic pain in atopic conditions.

Poster Session 12 Case Presentation: MS

P-59 Case Report of Two Tumefactive Demyelinating Lesions Mimicking Brain Tumor

Eu-Jene Choi^a, Su-jin Lee^a, Young-Do Kim^a, Lee-So Maeng^b

Department of ^aNeurology and ^bHospital Pathology, College of Medicine, the Catholic University of Korea

Tumefactive demyelinating disease may present atypical imaging which mimics brain tumor. Despite MRI, it is difficult to differentially diagnose tumefactive demyelination. A 43-year-old Korean male presented with a 7-day history of right-side clumsiness. Brain MRI with gadolinium enhancement showed a large, round left frontoparietal lobe lesion with a ring pattern. Glioma or lymphoma was suspected. A 45-year-old woman presented with a 2-week history of vertigo, tinnitus and mild headache. Brain MRI with gadolinium enhancement revealed a white matter mass in the right temporal lobe with slightly peripheral multifocal abnormal signals. Brain biopsy revealed that these were not brain tumors, but rather tumefactive demyelinating lesions. This clinical, radiological and pathological report confirms that the demyelinating process should be considered in the differential diagnosis of tumor-like brain lesions. In conclusion, tumefactive demyelination is an uncommon cause of neurological symptoms. MRI, MRS or PET images can be useful diagnostic tools, and can spare patients brain biopsy.

P-60 Atypical Multiple Sclerosis in A 57-year-old Man as Chronic Lymphocytic Inflammation with Pontine Perivascualr Enhancement Responsitve to Steroid (CLIPPERS)

An-Chih Chen

Department of Neurology, Chung Shan Medical University Hoispital, Taichung, Taiwan

Background: Chornic lymphocytic inflammation with pontine perivascular enhancement(CLIPPERS) is a newly defined inflmmatory CNS disorder since 2010. However, it remain many debates and the symptoms was overlapping with multiple sclerosis(MS).

Objective: A 57-year-old previously healthy man had asymmetric numnbess and weakness for 1 month. He came to our hospital for falling down due to weakness. Physical examination revealed dysarthria, left central facial palsy and muscle power 4 points in left side limbs. Brain MRI showed multiple asymmetrical long T2 and enhancing lesions in brain stem. CSF studies showed lymphocytic pleocytosis, glucose:55mg/dL and protein:102 mg/dL. Optic neuritis was also found. Autoimmune and infection titers were all negative.

Methods: Methylprednisolone(MTP) pulse therapy was prescribed with dosage 1g/day for 5 days. The sympotms had dramatic improved. After the MTP pulse therapy, no immunosuppressant agent was used. Three days later, he felt the numbness developed again. Two weeks later, objective weakness developed. Following brain MRI showed newly long T2 lesion in brain stem and CSF studies showed inflammation as previous study. The second MTP pulse therapy started and symptoms improved again. CLIPPERS syndrome was suspected. Beta-inteferon and prednisolone(40mg/day) was prescribed after pulse therapy.

Results: After continuous steroid, the neurologic deficit was stationary. However, hyperglycemia developed in the next weeks.

Conclusion: The CLIPPERS syndrome might be a varient of multiple sclerosis. It was differience from MS from age and gender. Steroid should be continued after MTP pulse therapy. Following immunosuppressant should replace the steroid to prevent the side-effects.

P-61 Two Cases of Very Late-Onset Multiple Sclerosis Presenting with Visual Disturbances

SY Kim

Department of Neurology, Ulsan College of Medicine, Ulsan University Hospital, Ulsan, Korea

Introduction: Several studies reported that patients with late-onset MS (LOMS) were more likely to have motor and cerebellar presentations, a more progressive course and a worse prognosis than patients with earlier onset disease. However, the clinical profile of LOMS was not determined.

Case: A 71-year-old woman was admitted with left 6^th nerve palsy. Brain MRI showed multiple chronic ischemia with a small diffusion restriction lesion in right dorsal medulla oblongata. Aspirin was prescribed with a diagnosis of stroke. After 6 months later, she visited our hospital with right shoulder and forearm paresthesias and right hemiparesis. Brain MRI showed multifocal T2 hyperintensity lesions in both centrum semiovale, corpus callosum, both PVWM, brain stem, and left cerebellum, especially callososeptal interface distribution combined with multiple enhacement. Cervical MRI revealed paracentral short segment myelitis at C2-3.

A 61-year-old man was admitted with right optic neuritis. Brain MRI showed enhancement of right optic nerve and focal ill-defined T2 hyperintense lesions in subcortical white matter of both inferior frontal gyrus and right cerebellar peduncle with focal enhancing lesions.

Serological study for autoimmune disorder and AQ-4 antibody was all negative in two patients. Steroid pulse treatment was done and their neurological deficit was nearly fully recovered. Finally, a 71-year-old woman was diagnosed as clinical definite MS and a 61-year old man was diagnosed as CIS with brain lesion compatible with MS.

Conclusion: One of our patients was initially diagnosed as stroke, so the frequency of initial misdiagnosis might be high in the LOMS patients.

P-62 Case Report of Primary Progressive Multiple Sclerosis Report from Indonesia

Sucipto, Astiny D, Komari N, Estiasari R, Imran D

Neurology Department Faculty of Medicine University of Indonesia

Cipto Mangunkusumo Hospital Jakarta

Background: Multiple sclerosis is classically characterized by a relapsing-remitting course due to lesions in many parts of the CNS, There is, however, a small group of patients whom the course of the illness is progressive from onset.

Objective: To report primary progressive multiple sclerosis case in Jakarta

Methods: Case report

Results: A 27-year-old man was admitted to our hospital because of progressive blurred vision since 10 months ago. Patient also complains about dizziness and hard to coordinate his movement since 4 months ago. Patient’s visual acuity is 3/60 for right eye and 4/60 for left eye. Neurological examination revealed rotatoar nistagmus and abnormal finding in romberg, finger to nose, fast pointing, knee to heel and rebound phenomena test. Brain MRI shows multiple hyper intense lesion at cervical, brain stem, cerebellum, periventricle white matter, juxta/ subcortical and right thalamus with dissemination in space and time fullfil the Multiple Sclerosis’ criteria. Visual Evoked Potential shows demyelination type partial block at both eye’s visual tract. Cerebrospinal fluid analysis shows normal cell count, normal glucose ratio, increased protein level and positive oligoclonal band result. Patient received methylprednisolon in three phases 1x16mg orally for 6 days, 1x1000mg intravenously for 3 days and 1x1000mg intravenously for 2days. Expanded Disability Status Scale (EDSS) for this patient is 6.0. After receiving that high dose steroid therapy, the visual acuity showed no improvement.

Conclusions: Patients with multiple sclerosis who develop progressive from onset without relapses or remissions pose difficulties in diagnosis, monitoring of disease activity and treatment. The prognosis for this group of multiple sclerosis is poor.

P-63 Good Response to Fingolimod in Patient with Severe Atopic Dermatitis and Highly Active Multiple Sclerosis

Park MS, Hah JS

Department of Neurology, Yeungnam University College of Medicine, Daegu, South Korea

Background: As a second-line drug for multiple sclerosis (MS), fingolimod is used to treat patients with poor response to interferon-beta in Korea. There are some animal studies about beneficial effect of fingolimod in severe atopic dermatitis (AD). We describe a patient with relapsing-remitting MS, who suffered from severe AD and frequent relapses despite the interferon-beta treatment, simultaneously responded to fingolimod.

Case: A19–year-old man suffering from severe AD more than 10 years, experienced left hand weakness, hypethesia and paresthesia that lasted three days and his attack symptoms were spontaneous resolved two years ago. Two months later, he had relapse in cervical myelitis. After high dose intravenous methylprednisolone (IVMP) therapy, his symptoms were recovered slowly over one month and he began receiving interferon-beta therapy. However two months later, he had left hemiparesis and 8 months later, had another attack of right arm weakness and bilateral leg paresthesia. Each relapse was treated with IVMP and recovered. We switched to fingolimod with interferon-beta because relapse occurred twice in a short period of time due to lack of effect. After fingolimod therapy, he had no further relapse over 14 months and no MRI activity. Interestingly, his severe AD was improved dramatically as the same time.

Conclusion: We report a case of good response to fingolimod for severe AD and highly active MS. When considering our case, fingolimod is effective therapy for patient with poor response to interferon-beta and good candidate for treatment of intractable AD.

P-64 Efficacy of Fingolimod for Recurrent Spinal Cord Lesions in A Case of Multiple Sclerosis

Ozawa T, Warabi Y, Isozaki E

Department of Neurology, Tokyo Metropolitan Neurological Hospital, Tokyo, Japan

Background: Interferon beta (IFNβ) therapy, a first-line disease-modifying therapy (DMT) for multiple sclerosis (MS), may not be efficacious in some patients. Recently, second-line DMTs have been introduced in Asian countries. Although opticospinal MS is reported as a racial modification of MS in Asian populations, the efficacy of DMTs for Asian-type MS has only limited supporting evidence.

Objective: We report the case of a patient with conventional MS who had recurrent spinal cord lesions. She did not respond to IFNβ treatment, but she was successfully treated with fingolimod.

Case: A 31-year-old Japanese woman visited us because of paresthesia of both her legs. She was found to have two spinal cord lesions and one cerebral lesion. Oligoclonal IgG bands were detected but not the anti-aquaporin-4 antibody. We diagnosed her as having clinically isolated syndrome of MS, and we started IFNβ-1a　therapy. Eight months later, she developed a recurrent spinal cord lesion, and she was diagnosed as having MS. Subsequently, she had eight relapses, including six relapses in the spinal cord, within the next two years and two months. IFNβ-1a was stopped and tacrolimus was tried but was not efficacious. Then, fingolimod was started with minimal side effects. No relapse had occurred over the subsequent one year and five months.

Conclusions: The characteristic feature of our case was frequently recurring spinal cord lesions with an excellent response to fingolimod but not to IFNβ. Early use of fingolimod may be recommended for patients with frequently recurring spinal cord lesions and opticospinal MS in the Asian population.

Poster Session 13 Case Presentation: NMO

P-65 Neuromyelitis Optica Spectrum Disorder Presenting with Anterior Ischemic Optic Neuropathy

JY An, DS Shim, KS Lee

Department of Neurology, College of Medicine, The Catholic University of Korea,

Background: Anterior Ischemic Optic Neuropathy (AION) which occurs in individuals over 50 years of age and equally in male and female is characterized by unilateral sudden painless loss of vision with impairment of color vision and altitudinal visual field defect. Optic neuritis (ON) is the most common and often initial symptom in both neuromyelitis optica (NMO) and multiple sclerosis (MS). Almost MS patient and over half of NMO patients showed central scotoma. The clinician must depend largely on an analysis of symptoms and signs to differentiate ON from AION.

Case: A previous healthy 56 year-old man was referred for sudden onset superior visual field defect in left eye without pain for 1 week. The Ophthalmologic examination showed relative afferent pupillary defect and mild optic disc swelling in left eye with normal Ishihara test and visual acuity. VEP and orbital MRI showed normal, but AQP-4 Antibody test was positive. Visual disturbance was improved completely after 1 month with conservative treatment.

Conclusions: NMO patients showed higher incidence of non-central scotoma than MS, and altitudinal hemianopia may be characteristic of ON occurring in NMO. As altitudinal hemianopia is highly characteristic of ischemic optic neuropathy, ischemic mechanism mediated by anti-aquaporin-4 antibody may play a role in ON in NMO patients.

P-66 A Pediatric Case of Neuromyelitis Optica Spectrum Disorder: Atypical Clinical Presentation like Multiphasic Demyelinating Encephalomyelitis

Kee-Duk Park, MD¹, Yang-Ki Minn, MD², Dong-Suk Shim, MD³, Hyung Jun Park, MD¹, Seung Min Kim, MD⁴

¹Department of Neurology, Ewha Womans University College of Medicine, Seoul, Korea; ²Department of Neurology, Hallym University College of Medicine, Seoul, Korea; ³Department of Neurology, the Catholic University of Korea College of Medicine, Seoul, Korea; ⁴Department of Neurology, Yonsei University College of Medicine, Seoul, Korea

Background: Neuromyelitis optica (NMO) is a rare relapsing autoimmune disorder that preferentially causes inflammation in the optic nerve and spinal cord. Even though NMO include female preponderance, longitudinally extensive spinal cord lesions, and absence of oligoclonal IgG bands, the differential diagnosis between NMO and multiple sclerosis (MS) has long been controversial. However, the discovery of NMO-IgG clearly identified NMO as a separate disease from MS. Herein, we reported one NMO-IgG-positive boy with clinical feature like multiphasic demyelinating encephalomyelitis.

Case presentation: A 12-year-old boy was referred to our clinic due to headache and left hemiparesis. Brain MRI showed multifocal areas of T2 hyperintense lesions in internal capsule, brain stem, cerebellar peduncle, cerebral peduncle and corpus callosum with fuzzy and irregular enhancement. Brain Magnetic resonance spectroscopy showed non-specific NAA decrease with positive lactate peak, which is consistent with acute demyelination. He was diagnosed with acute demyelinating encephalomyelitis. After steroid pulse therapy, his muscle weakness improved. After six months later, he presented horizontal diplopia and gait disturbance. Brain MRI revealed new lesions in both frontoparietal areas and corpus callosum. Cerebrospinal fluid (CSF) study showed mild leukocytosis without malignant cells. There were no oligoclonal bands. He was diagnosed with multiphasic demyelinating encephalomyelitis and was treated with steroid pulse therapy. After that, his neurologic deficits subsided and Brain MRI showed marked improvement of previous lesions. However, stopping steroids caused diplopia and weakness. Three years after second event, he complained of dysarthria, vertical diplopia, and left hemiparesis. Oligoclonal band were observed in CSF but not in serum. In addition, he was seropositive NMO-IgG antibodies. He was started on interferon-alpha. However, after steroid self-discontinuation, gait disturbance developed 11 months after interferon therapy. In addition, repeat test for NMO-IgG was positive, too.

Conclusion: We experienced one NMO-IgG-positive patient with steroid-responsive brain lesions. Even though NMO is a comparatively rare disease in children, but we keep in the mind NMO as differential diagnosis of pediatric inflammatory demyelinating central nervous system diseases.

P-67 Side Effects of Interferon β-1b at Devic’s Disease

Doo Eung Kim, M.D., Jeong Ho Han, M.D., Jae Jeong Joo, M.D.

Department of Neurology, SVH Medical Center, Seoul, Korea

Background: Devic’s disease is a rare disorder which resembles multiple sclerosis (MS) in several ways, but requires a different course of treatment for optimal results. The most frequent adverse effects of Interferon β-1b are flu-like symptoms. The symptoms tend to diminish with repeated injections and may be managed with analgesics. Also IFN therapy causes immunosuppression, in particular through neutropenia and can result in some infections manifesting in unusual ways.

Case: A 63 year-old woman who had diagnosis of multiple sclerosis complaining left hemiparesis and fluctuating decreased visual acuity in her right eye and abnormal findings in pattern shift evoked potentials (PSVEPs) and on T2 weighted MR scanning. We treated her subcutaneously with 250μg interferon β-1b (IFN β-1b) every other day. There were detected pancytopenia, skin rash, and abnormal liver function test seven days after the therapy. In spite of reducing the dose of interferon injection, abnormal laboratory findings were not returned to normal.

Discussion: Currently, there is no cure for Devic’s disease, but symptoms can be treated. Some patients recover, but many are left with impairment of vision and limbs, which can be severe. IFN β induces an inhibitory effect on the proliferation of leukocytes, antigen presentation and T-cell migration across the blood-brain barrier and enhances anti-inflammatory cytokine production. Although IFN β is not currently recommended for Devic’s disease patients, we think dose adjustment for body weight or race may be helpful to reduce the side effects.

P-68 Successful Response to Mitoxantrone in a Patient with Neuromyelitis Optica refractory to Classical Immunosuppression

Jae-Yong Shin, MD¹, Kee-Yong Cho, MD¹, Soon-Won Park, MD¹, Young-Eun Park, MD. PhD^{1, ²}

¹Department of Neurology, Pusan National University School of Medicine, ²Biomedical Research Institute, Pusan National University Hospital, Pusan, Korea

Background: Neuromyelitis optica (NMO) is a CNS demyelinating disease characterized by recurrent attacks of optic neuritis and transverse myelitis. The aim of treatment is to restore neurological deficit and maintain remission. High-dose methylprednisolone is primary therapy for acute attacks, and plasma exchange (PE) is helpful for those unresponsive to steroid. For long-term remission, various immunosuppressants are recommended. We are to describe a patient with NMO, who is refractory to immunosuppression, and finally requiring mitoxantrone.

Case: A 40-year-old woman developed right optic neuritis at age 28. After the first event, she had several attacks involving optic nerves, medulla and spinal cord. Under the diagnosis of multiple sclerosis, she achieved remission with interferon beta-1b for 10 years. But, she experienced 10 cluster-attacks for next three years and 6 for recent one year. All attacks were managed by high dose methylprednisolone or PE with only partial improvement. She was re-diagnosed as NMO on the presence of anti-NMO antibody, and she started azathioprine and later changed to mycophenolate due to refractoriness. Nevertheless, she repeated relapses and finally became near-blind and wheelchair-bound state. She decided to use mitoxantrone. After one cycle, she is currently free of attacks except for a short time of leucopenia.

Conclusion: NMO has only few treatment options for long-term remission except for known immunosuppressants. Our patient experienced cluster-attacks after relapse-free time despite of immunosuppression. Mitoxantrone finally seemed to be successful for stopping relapses. It might be for a possible option for patients with NMO, who are refractory to classical immunosuppression.

Poster Session 14 Case Presentation: MS Mimics

P-69 Transverse Myelitis in Neuro-Behcet’s Disease: MRI Findings of Three Cases

Hyung Seok Lee, Young Gwang Kim, Su Jin Jung, Ha Young Shin, Seung Min Kim

Department of Neurology, Yonsei University College of Medicine, Seoul, Korea

Background: Behcet’s disease (BD) is multisystem inflammatory disorder of unknown origin. Although neurological involvement of BD is not uncommon, little is known about involvement of spinal cord. Herein we present three cases of transverse myelitis (TM) with BD.

Case1: A 25-year-old man was diagnosed as BD based on recurrent oral ulceration, recurrent right uveitis, and folliculitis for ten years. At 26-year-old, he experienced with decreased sensation below T6 and weakness of both legs. MRI of spinal cord showed extended spinal cord lesion from medullar to Th7.

Case2: A 33 year-old man with a history of frequent oral ulcer and uveitis presented with urinary incontinence, anal sphincter dysfunction and spastic paraparesis. The MRI of the spine revealed extended hyperintensity between C3 and 7 and between Th3-10.

Case3: A 40-year-old woman admitted with dysarthria, gait disturbance, visual blurring, skin rash on both calf area, tongue ulcer, and her ophthalmic evaluation revealed uveitis. Brain MRI showed T2 hyperintensity between medullar and midbrain. She was diagnosed as neurological involvement of BD and she was complete recovery after steroid therapy. Four years later, she complained of both legs weakness. Spine MRI revealed long extensive lesion from Th4 to Th10.

Conclusion: Long extensive transverse myelitis (LETM) is a characteristic feature of neuromyelitis optica, but such spinal lesions can also occur in various other autoimmune and inflammatory diseases with CNS involvement. Our study suggests that patients with a BD can also present with longitudinal spinal lesions.

P-70 A Case of CNS Vasculitis after Spinal Cord Involvement

Joong-Yang Cho, Kyuyoon Chung, Young Min Paek

Department of Neurology, Ilsan Paik Hospital, Inje University College of Medicine, Korea

Background: Primary CNS vasculitis is an uncommon disease in which lesions are limited to the brain and spinal cord. A variety of neurologic insults may cause CNS vasculitis, including infection, malignancy, ionizing radiation, cocaine ingestion, and autoimmune disease. Spinal cord involvement has been documented much less frequently than intracranial involvement. We report a case spinal symptoms developed before cerebral symptoms.

Case: A 59-year-old man was admitted our hospital due to further evaluation and management of cervical myelitis with CNS infection. At first attack, MRI revealed increased T2-weighted signal from pons to C5 level. His tentative diagnosis was NMO spectrum disorder with negative anti-AQP4 antibody. Two months later, he developed drowsy mentality and CSF analysis showed WBC; 250 cells/mm³ (neutrophil 90%), glucose; 55 mg/dL and protein; 84.6 mg/dL. He was treated with antibiotics under the impression of bacterial meningitis and transferred to our hospital. He showed gradual improvement. However, 2 months later, he developed drowsy mentality with high fever. Brain MRI showed increased T2-weighted signal in left cerebral peduncle, thalamus, BG, right thalamus, both pericallosal area, and left temporal lobe with mild enhancement. CSF study showed leukocytosis (WBC: 1,460 cells/mm³, neutrophil: 82%), low glucose level (19 mg/dL, serum: 104) and high protein level (288 mg/dL). Brain biopsy revealed: (1) vasculitis with dense perivascular infiltrates of T lymphocytes and neutrophils, and occasional fibrinoid necrosis, (2) demyelination is very mild and confined to actively inflamed areas.

Conclusions: We report a case of fulminant onset CNS vasculitis after spinal cord involvement.

P-71 A Case of Myelitis Associated With Toxocariasis

Taek-Jun Lee¹, Tae-Woo Kim¹, Seon-Young Ryu¹, Sang-Bong Lee¹

¹Department of Neurology, The Catholic university, Daejeon ST. Mary’s Hospital, Daejeon, Korea

Background: Atopic myelitis is a disease entity that is characterized by the association between allergic and central nervous system disease. We describe a 58-year-old woman who had myelitis associated with toxocara canis.

A Case: A 58 year-old woman present with paresthesia of lower limbs and Lhermitte’s sign without weakness nor voiding difficulty during 3 weeks. Her serum routine lab was normal range. However, serum IgE was elevated (347.9 IU/mL). A spine MRI revealed a T2-high signal lesion with focal enhancement in the cervical cord. The cerebrospinal fluid was clear and the pressure was normal. Serum and toxocara canis antibody titer was 2.785 (cut off value: 0.831). Serum fluorescent antinuclear antibodies and double stranded DNA antibodies titer was normal. She was diagnosed with myelitis associated with toxocariasis. The patient showed unfavorable response to steroid treatment. Follow up MRI imaging showed no significant change of T2-high signal lesion.

Conclusion: Myelitis is caused by various infectious organisms or an autoimmune mechanism. Toxocariasis is one of the common causes of hyperIgEaemia that may lead to neurologic manifestations. We report a case of myelitis associated with toxocariasis. These results indicate that parasitic infection should be considered as as possible cause of subacute myelitis.

P-72 Not All Longitudinally Extensive Myelitis are Inflammatory

T.R. Yeo¹, J.J.X. Lee¹, V.Z.Y. Ng¹, K. Tan¹

¹Department of Neurology, National Neuroscience Institute (Tan Tock Seng Hospital), Singapore, Singapore

Background: Longitudinal extensive transverse myelitis (LETM) refers to intramedullary inflammation extending over 3 or more vertebral segments on neuroimaging. Although neuromyelitis optica (NMO) is the most common underlying aetiology, other conditions can present as LETM.

Objective and Methods: To describe a case of primary spinal oligoastrocytoma mimicking LETM.

Results: A 51-year-old male presented in 2008 with bilateral thigh numbness and weakness. MRI spine showed a T2-hyperintense lesion from T7 to T12 with no contrast enhancement. No lumbar puncture was performed but blood workups for infective and autoimmune causes were normal. He presented to our hospital in 2009 with progressive lower limb weakness. Examination revealed spastic paraparesis and sensory level at T10. MRI spine showed T6 to T12 lesion with patchy contrast enhancement and cord expansion. MRI brain was normal. CSF analysis showed 6 cells/uL and protein 0.41 g/L. Anti-Aquaporin-4 antibody and CSF oligoclonal bands were negative. Pulsed methylprednisolone only provided transient improvement. Further treatment with cyclophosphamide did not yield clinical improvement and he declined further interventions. In 2014, he developed upper limb weakness. Repeat MRI spine showed an avidly enhancing cervico-medullary junction to conus lesion. Repeat MRI brain showed abnormalities in the left temporal lobe, left caudate nucleus and right insular region. Histology from thoracic cord biopsy showed oligoastrocytoma. Temozolomide treatment was commenced.

Conclusion: This case illustrates the need to consider other diagnosis of LETM in the presence of disease progression despite aggressive immunosuppression.

P-73 Longitudinal Extensive Transverse Myelitis as a Rare Complication of Mumps Infection

So Hyun AHN, Jong Seok BAE

Department of neurology, Kangdong Sacred Heart Hospital, Hallym University, College of Medicine, Seoul, Korea

Background & Significance: Longitudinally extensive transverse myelitis (LETM) is one of rare complications after mumps infections. Previously reported cases of transeverse myelitis after mumps infection were mainly complicated with encephalitis, and common in young children. Most of cases showed slow recovery from the myelitis.

Case: Recently, we encountered a 14-year-old boy who presented with acute and severe paraparesis and urinary retention. Four weeks ago, he was treated for acute mumps infection and markedly recovered from systemic symptoms. Spine MRI denoted a LETM over T levels. Serological study showed an evidence of recent mumps infection. He was treated with intravenous steroid and recovered from his acute neurological illness.

Conclusions or Comments: Despite of its rare occurrence, acute mumps infection can complicate a post-infectious LETM mimicking neuromyelitis optica (NMO) or NMO spectrum disease. Clinician should be familiar with this rare condition and its differential diagnosis.

P-74 Anti-Ma2 Antibody Encephalitis Presented with Memory Impairment and Confusion

Suk-Won Ahn, Moo-Seok Park, Jeong-Min Kim, Dong Suk Shim, Young Chul Yoon

Department of Neurology, Chung-Ang University Hospital, Seoul, South Korea

Department of Neurology, Catholic University Hospital, Bucheon, South Korea

Background: Anti-Ma2 encephalitis is one of the autoimmune encephalitis characterized by brainstem and/or limbic involvement. And this is often related testicular cancer, breast or lung cancer. Anti-Ma2 encephalitis presented eye movement abnormalities, such as vertical gaze palsy or downbeat nystagmus, often with other symptoms such as confusion or somnolence. In this case report, we describe a patient with anti-Ma2 encephalitis who had memory impairment and confusion.

Case: A 64-year-old Russian man visited to out-patient department with dysarthria, memory impairment and abnormal behavior. In the neurological examination, there are no eye movement abnormalities, motor weakness and pathological reflex. Brain magnetic resonance imaging (MRI) showed infiltrative mass lesion in the right medial temporal lobe. And second brain MRI revealed much more extensive lesions in bilateral temporal lobe. Lumbar puncture showed a mild pleocytosis with increased protein. By the systemic evaluation for hidden malignancy, chest computed tomography (CT) showed an ovoid nodule in right apex with multiple lymph nodes at both hilum and mediastinum indicating lung cancer. Conclusively, anti-Ma2 antibody was detected in the autoimmune antibody test.

Conclusion: We suggest a rare case of anti-Ma2 antibody limbic encephalitis presenting with memory impairment, confusion and infiltrating brain lesions.

P-75 Anti-NMDAR+/anti-MOG+ recurrent ADEM

K. Kaneko, D. K. Sato, T. Misu, K. Kurosawa, I. Nakashima, K. Fujihara, M. Aoki

Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan

Background: Few patients with overlapping syndrome of anti-N-Methyl-D-Asparate (NMDA) receptor encephalitis and demyelinating syndrome have been recently described, but longitudinal studies evaluating the changes in the clinical, MRI and antibody titers have not been reported.

Objective: To describe a 28 years old woman with limbic encephalitis who developed demyelinating lesions

Methods: We analyzed clinical features, MRI, and measured the antibody titers for anti-NMDAR, and anti- myelin oligodendrocyte glycoprotein (MOG), using cell-based assays.

Results: The patient showed demyelinating MRI lesions during exacerbations after the first attack of the limbic encephalitis. Moreover, she developed some features such as gait instability and saccadic eye movements that are atypical for anti-NMDAR encephalitis. The antibody titers in the CSF and serum suggested that anti-NMDAR and anti-MOG antibodies have different intrathecal synthesis and the change in the autoantibody concentrations after intravenous corticosteroids was different between these two antibodies.

Conclusions: Patients with anti-NMDAR encephalitis with clinical or MRI features resembling demyelinating syndromes should be tested for anti-MOG antibodies. The autoantibody production may be distinct between anti-NMDAR and anti-MOG antibodies, requiring longitudinal monitoring of the antibody titers in the CSF and serum.

P-76 Acute Disseminated Encephalomyelitis (ADEM) in An Elderly Woman

Jung Im Seok, M.D., Hyuk Hwan Kwon, M.D.

Department of neurology, School of Medicine, Catholic University of Daegu

Background: Acute disseminated encephalomyelitis (ADEM) in middle-aged or elderly adults is rarely reported.

Objectives: To report a case of ADEM in elderly adult.

Methods: A 71-year-old woman developed confusion, bilateral leg weakness, and urination difficulty started 1 week after preceding infection.

Results: Cerebrospinal fluid showed lymphocytic pleocytosis. Magnetic resonance imaging revealed disseminated lesions in the brain and thoracic cord. Steroid therapy improved her symptoms. Tests for NMO (Neuromyeltis optica) antibody and other autoantibodies were negative. She was diagnosed as having acute disseminated encephalomyelitis (ADEM) possibly related to the viral infection.

Conclusions: We report an elderly woman with ADEM following viral infection who recovered after steroid treatment.

P-77 Tuberculosis and Acute Disseminated Encephalomyelitis (Adem): Coincidence or Cause?

Demirkaya Şeref*, Çetiz Ahmet*, Öz Oguzhan*,

*Gülhane military Medical Faculty, Neurology Department

Background: ADEM also known as post infectious encephalomyelitis is a demyelinating disease of the central nervous system (CNS) that typically presents as a monophasic disorder associated with multifocal neurological symptoms and disability. Tuberculosis is a disease that can involve many tissues including CNS. Togetherness of ADEM and tuberculosis is very rare.

Objectives: We aimed to discuss ADEM-tuberculosis relationship via a patient.

Methods: A 20 years old male presented with weakness of left leg and arm. His neurological examination revealed left hemiparesis, brisk deep tendon reflexes and bilateral Babinski’s sign. Visual evoked potential (VEP) test was unremarkable. Tibial somatosensory evoked potentials (SEP) test revealed prolonged right tibial cortical response latency. Demyelinating lesions in bilateral centrum semiovale (nearly 1.5 cm diameter), periventricular, corpus callosum, C2, C3 (gadolinium enhancement detected) and patchy lesions in whole spinal cord thoracic region on magnetic resonance imaging (MRI). Cerebrospinal spinal fluid (CSF) examination indicated normal protein and glucose, no cells, negative Pandy’s reaction and no oligoclonal bands detected. During clinical follow-up in the hospital, the patient had chest pain complaints. Chest examination and X-ray were in normal ranges. Thorax computerized tomography (CT) indicated micronoduler infiltrating areas in right superior and left inferior segments of thorax, suspecting tuberculosis. In Broncho alveolar lavage culture mycobacterium tuberculosis complex was detected.

Results: We diagnosed the patient as mycobacterium tuberculosis associated ADEM.

Conclusions: Clinicians should consider mycobacterium tuberculosis in ADEM.

P-78 Tuberculosis Meningitis Mimicking CNS Demyelination Disease

BN Yoon, JW Kwon, JH Rha, CK Ha

Department of Neurology, Inha University Hospital, Incheon, Korea

Background: We describe a case of tuberculosis meningitis who presented with visual disturbance, hearing impairment, and abnormal brain parenchymal lesions that are similar to central nervous system (CNS) demyelination disorders.

Case Presentation: A 53-year-old man presented with a 2 week history of visual disturbance, hearing impairment, and headache. His brain MRI showed increased T2/FLAIR signal intensity in right pons, midbrain, thalamus, basal ganglia and left hippocampus. There was contrast enhancement along right trigeminal, facial vestibulocochlear nerve. Initially, we considered CNS demyelination disease, although we had to differentiate other disease such as CNS lymphoma, CNS infection diseases and metabolic encephalopathy. Followed by his cerebrospinal fluid (CSF) demonstrated 290 leukocytes (71% lymphocytes, 11% neutrophils), an increased range protein level (180 mg/dL), and a decreased glucose levels (CSF/serum 38/112 mg/dL). Adenosine deaminase in the CSF was 13.1 IU/L. screening for malignant cells was negative. Anti-aquaporin-4 antibody was not detected. We could come to diagnosis tuberculosis meningitis as a probable diagnosis for the patient. The patient was started on anti-tuberculosis medication and steroid (prednisolone 60 mg). His symptoms were gradually recovered. Follow-up MRIs revealed a decreased extent of T2/FLAIR high signal.

Discussion: Our case indicates that Tb meningitis, similar to other CNS demyelination diseases, may cause multiple cranial nerve involvement and abnormal MRI findings that show multiple lesions on brainstem and involvements of multiple cranial nerves.

P-79 CMTX Manifesting as Recurrent Alternating Hemiparesis with Recurrent Brain White Mater Lesions

Sunjae Hwang, Jin-Hong Shin, Jong-Mok Lee, Dae-Seong Kim

Department of Neurology, Pusan National University Yangsan Hospital

Background: X-linked Charcot-Marie-Tooth disease (CMTX) is caused by mutation of the connexin 32 (Cx32, gap junction protein b 1, GJB1). Although most of the patients with CMTX manifest peripheral neuropathy, few patients show predominant CNS symptoms. We present a patient associated with GJB1 mutation manifested only CNS symptom.

Case: A 17-year-old man was referred for evaluation of recurrent alternating hemiparesis. He was assumed to have a multiple sclerosis and was treated with interferon beta for 7 years by a pediatrician. At age 10, 11, 12, 14 years, a sudden hemiparesis occurred and recovered fully within a few hours. His brain magnetic resonance images showed recurrent subcortical high signal intensity in T2 weighted images disappeared after a few days. On neurological examination, no remarkable abnormality was observed. His nerve conduction study showed diffuse polyneuropathy. Sequence analysis of GJB1 gene revealed a known pathogenic mutation c.572_580dupCCGTCTTCA (p.T191_F193dup) and the patient was finally diagnosed as CMTX.

Discussion: Although Cx32 is expressed in many tissues including brain, and peripheral nerve, main clinical manifestation of GJB1 mutations is peripheral neuropathy. Cx32 is also expressed in the CNS myelin, it is unclear why only few patients manifest CNS symptom. Seven different GJB1 mutations were reported to be associated with CNS manifestation. The location of mutations are scattered in GJB1, no clear genotype relationship can be deduced. The presented case didn’t exhibit any physical evidence of peripheral neuropathy but only showed electrodiagnostic evidence. In conclusion, CMTX should be considered in the differential diagnosis of recurrent brain white mater lesions.

P-80 A Case of Relapsing-Remitting Behcet’s Disease Involving Brain and Optic Nerve

Da-eun JEONG, Suk-Won Ahn, Young Chul Youn

Department of Neurology, Chung-Ang University College of Medicine, Seoul, Korea

Background & Significance: Behçet’s disease is a multisystem disorder presenting recurrent oral and genital ulcerations as well as ocular lesions, and also involves the nervous system in a subgroup of patients. Behçet’s disease develops at a young age and is frequently presented with acute or subacute neurological manifestations. The neurological symptoms of Behçet’s disease are often included in the differential diagnosis of multiple sclerosis, stroke of the young adult, and other neurological disorders. We will present a case of Behçet’s disease of typical relapsing-remitting course.

Case: The 33-year-old man presented with dizziness and headache. In the past medical history, he had suffered from decreased visual acuity and orbital pain in the right eyes, and he had been diagnosed with the uveitis. The patient visited the ER complaining of severe headache, dizziness, decreased visual acuity and gait disturbance since one day ago. The Neurological examinations revealed binocular diplopia and ataxia in right upper limbs and lower limbs. Brain MRI showed high signal lesions in the brain stem and optic neuritis in the left eye. Apart from brain lesions and optic neuritis, the patient had the oral ulcer, genital ulcer and positive HLA B51. Under the impression of the Behcet’s disease involving nervous system, high dose steroid therapy and immune suppressant were used. However, three months later, He was re-hospitalized because of aggravated headache, dizziness and weakness, and brain MRI showed new lesions in the bilateral hemispheres followed by high-dose steroid and and immune suppressants. A few months later, he showed additional lesions and optic neuritis. After steroid pulse therapy, brain lesion and optic neuritis remarkably improved, and the patient has been treated with oral steroid and immune suppressants.

Conclusions: We described a case of relasing-remitting Behçet’s disease with recurrent brain and optic nerve involvements which mimicking multiple sclerosis or neuromyelitis optica. The neurological symptoms of Behçet’s disease should be included in the differential diagnosis of multiple sclerosis, neuromyelitis optica and other neurological disorders, because the early treatment of Behçet’s disease may ameliorate the prognosis in patients with neurobehcet disease, and can diminish and stabilize the negative effect of neurologic involvement in the disease.

P-81 Paraneoplastic Neuronopathies Mimicking Transverse Myelitis

TS Nam¹, JK Lee¹, JK Kim², SY Huh³, SH Lee¹

Department of Neurology, ¹Chonnam National University Medical School, Gwangju, South Korea, ²Dong-A University College of Medicine, Busan, South Korea, ³Kosin University College of Medicine, Busan, South Korea

Transverse myelitis (TM) is a neuroinflammatory disease that causes neural injury to the spinal cord, which can lead to the varying degrees of sensorimotor weakness with neuropathic pain, and autonomic dysfunction. Paraneoplastic neuronopathy (PN) is a rare neurologic disease that caused by the cancer-induced immune attack on the neuronal cell bodies, which can also present with motor-, sensory-, and autonomic neuronopathy. The neural symptoms in PN may proceed before the diagnosis of cancer, and thus they can be easily overlooked. Case 1 - A 42-year-old woman with gait disturbance and neuropathic limbs pain for 3 months visited to our neurologic clinic. She was initially diagnosed as having TM, because MRI of the spinal cord showed T2-hyperintensity within thoracic cord. Case 2 - A 58-year-old woman complained of sensorimotor weakness and ataxic gait for 6 months, and MRI showed diffuse T2-hyperintensity along to the whole spinal cord. Somatosensory evoked potentials and quantitative sudomotor axon reflex tests were abnormal in two patients. High-doses of intravenous methylprednisolone have been administrated under the diagnosis of TM, but their sensorimotor weakness and pain were not improved. Finally, breast cancer was diagnosed in the patient comprising case 1 three months after symptoms onset, and B-cell lymphoma was did in the patient comprising case 2 eighteen months after disease onset. In cases with PN, early detection and treatment of underlying cancer are very important for reducing neurologic disabilities. Therefore, the possibility of PN may be considered in TM patients with the unresponsiveness to the standard immunotherapy.

P-82 Methyl Bromide Induced Acute Encephalopahty Expressed as Stereotypical Lesions in Brain MRI Mimicking CNS Demyelinating Disease

BA Yoon¹, JK Kim¹, SW Sohn¹, DH Shim¹, JW Kim¹, JI Kim², SY Huh³, TS Nam⁴

Department of ¹Neurology and ²Industrial Medicine, Dong-A University College of Medicine, Busan, Korea, Department of Neurology, ³Kosin University College of Medicine, Busan, Korea and ⁴Chonnam National University Medical School, Gwangju, Korea

Acute encephalopathy is a representative manifestation from various kinds of brain or brainstem diseases, such as infections, metabolic derangements, multiple sclerosis and toxic agents. Detailed investigations will be helpful in revealing the underlying pathomechanism. We experienced three cases of acute brain or brainstem encephalopthy showing stereotypical lesions in brain MRI. Three previously healthy men visited to our hospital with dizziness, slurred speech and gait falling during the period from December 2013 to August 2014. Two men were forklift drivers and one was plant protection manager in the same import company handling fruits. All patients showed various subset of the following neurological signs; behavior change, optic neuropathy, Ophthalmoplegia, nystagmus, dysarthria, dysphagia, sensory change of limb, cerebellar ataxia and bladder dysfunction. Laboratory evaluations including cerebrospinal fluid examinations, viral markers, anti-aquaporin4 antibody, anti-ganglioside antibodies, paraneoplastic antibodies and oligoclonal band were negative in all three patients. Brain MRI in acute stage showed the stereotypical lesions at splenium of corpus callosum, pons, medulla oblongata and cerebellum. Detailed history taking revealed that methyl bromide used as pesticide in their work place could be the causative agents. From one case, blood and urine methyl bromide levels were high in acute stage and the levels were declined with the time course. We propose that interpretation of the patterns in brain MRI is important in evaluating acute encephalopathy mimicking demyelinating diseases.

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Pactrims Invited Lecture / Ordinary Submission

Opening Lecture

L-1 Mechanisms of Progression in MS

Special Lecture

L-2 NMOSD – Where are we in 2014?

Main symposium-1 Markers of Progression in MS

L-3 Pathological and MRI markers of deterioration

L-4 Molecular Immunophenotypes in MS

L-5 Serum and CSF Biomarkers of Progression

PACTRIMS Educational Course Pitfalls in diagnosing MS and NMO in Asians

L-6 MS mimics in Asians

L-7 NMO mimics in Asians

Workshop Myelin Repair and Treatment of Disease Progression in MS

L-8 The Role of Remyelination in Progressive MS

Main symposium-2 Cutting Edge of NMOSD Research

L-9 What is Seronegative NMO?

L-10 NMO Immunopathology

L-11 AQP4 Immunology in NMOSD

Main symposium-3 New Perspectives of Treatment on Idiopathic CNS Inflammatory Disease

L-12 New Perspectives on Inflammatory CNS Disease Therapies

L-13 Anti-HMGB1 as Potential Therapeutics for NMO

L-14 Long Term MS Management in China

Closing Lecture

L-15 Reviewing a Decade of Discovery in Asia

Ordinary Submission

Oral Session 1 NMO

O-1 Comparison of Cognitive Performance and MRI-Measured Brain Volume and Cortical Thickness between Patients with Neuromyelitis Optica Spectrum Disorder (NMOSD) and Multiple Sclerosis (MS): A Preliminary Report

O-2 A Combined Neuroimaging and Neuropathological Study for Spinal Cord Lesions of Neuromyelitis Optica: with Special Reference to Lesion Distribution and Extension Patterns

O-3 Autoantibodies against MOG in Neuromyelitis Optica Spectrum Disorders

O-4 Comparison of Immunosuppressive Therapies for Prevention of Breakthrough Relapse in Patients with Neuromyelitis Optica Spectrum Disorder

Oral Session 2 Emerging Treatment for MS

O-5 Safety, Quality Of Life, and Walking Ability with PR-Fampridine Treatment in Clinical Practice in France: Interim Results of The LIBERATE Study

O-6 Efficacy and Safety of Alemtuzumab in Treatment-Naive Patients with Relapsing-Remitting MS: Four-Year Follow-up of the CARE-MS I Study

O-7 Autologous Stem Cell Transplantation in Multiple Sclerosis: Results from A Single Centre

O-8 CD30 Ligand is a New Therapeutic Target for Central Nervous System Autoimmunity

Oral Session 3 Myelin Repair and Treatment of Disease Progression in MS

O-9 Visualization of Demyelination and Remyelination by A Novel “Myelin Map” MR I: A Longitudinal Pilot Study

O-10 Quantifying the Effect of Natalizumab on the Total Disability Burden of MS Patients in AFFIRM Using an Exploratory Area under the Curve Analysis

O-11 Disease-Free Outcomes with Alemtuzumab: 3-Year Follow-up of the CARE-MS Studies

Oral Session 4 MS Epidemiology

O-12 Prevalence and Incidence of Multiple Sclerosis in Iran

O-13 Comparative Analysis of Clinical Outcomes of Multiple Sclerosis and Related Disorders in Asian and Non-Asian Patients in A Canadian Clinic Population

Oral Session 5 MS Biomarker

O-14 Biomarkers of Neurodegeneration in Multiple Sclerosis

O-15 Predictors for The Conversion of Clinically Isolated Syndrome to Multiple Sclerosis in Western Australian Cohort

O-16 Decreased Serum Vitamin D Levels in Japanese Patients with Multiple Sclerosis

Oral Session 6 MS Genetics

O-17 Multiple Sclerosis Susceptibility/Resistance and Clinical Manifestations are Determined by HLA-DRB1 Alleles and Latitude in Japanese Patients

O-18 Multiple Quantitative Trait Loci for Anti-EBNA-1 IgG Titres are Associated with Risk of Multiple Sclerosis

O-19 Genome-wide Association Study for Multiple Sclerosis and Neuromyelitis Optica in the Japanese Population

Poster Session 1 MS Epidemiology & Genetics

P-1 A Pilot Study of Multiple Sclerosis in Indonesia

P-2 Responsible Factors for Increased Incidence and Prevalence of Multiple Sclerosis in Iran

P-3 Smoking As a Risk Factor for MS and Related Disorders in Asian Populations in Canada and China

Poster Session 2 MS Clinical Symptomatology

P-4 Relapse Characteristics of 39 Patients with RRMS

P-5 The Effect of Lower Limb Sensory Impairments on Balance of People with Multiple Sclerosis (A Review of Articles)

P-6 Sensory Impairment and Its Relationship with Balance and Quality Of Life in People with Multiple Sclerosis

P-7 Impact of Chronic Pain on Quality Of Life in Chinese Patients with Multiple Sclerosis and Related Disorders

P-8 Identifying a Minimally Important Change Threshold for The Multiple Sclerosis Walking Scale-12 (MSWS-12)

P-9 Comparing Urinary Symptoms in MS Patients versus Devic Patients

P-10 Pain, Sleep Quality and Emotional State of the Relationship between Disease Clinical Features in Patients with Multiple Sclerosis

Poster Session 3 MS Laboratory Study

P-11 Thyroid Dysfunction and Autoimmunity in Multiple Sclerosis Patients

P-12 Frequency of Autoantibodies and Autoimmune Comorbid Diseases in Korean Patients with Multiple Sclerosis

P-13 Anti-Double Stranded Dna, Anti-Nuclear Antibodies and Subtypes in Multiple Sclerosis Patients

P-14 Serum Level of Vitamin D3 and Manifestation of the First Femyelinating Attack

Poster Session 4 MS Neuroimaging

P-15 Cortical Gray Matter Involvement in Patients with Relapsing Remitting Multiple Sclerosis; Correlation of Clinical and Cognitive Diasability, DTI Magnetic Resonance İmaging and OCT Findings

P-16 Deep Gray Matter Involvement in Multiple Sclerosis; Correlation of Clinical and Cognitive Diasability with DTI Magnetic Resonance İmaging Findings

P-17 Magnetic Resonance Spectroscopy Measurements in Normal-Appearing White Matter as A Biomarker of Whole Brain White Matter Integrity in Relapsing Remitting Multiple Sclerosis

P-18 Local and Global Plasticity of Sensorimotor Network in Remitting Multiple Sclerosis: A Voxel-Based Functional Centrality Analysis

P-19 Does the Default Mode Network Reserve the “Small-World” Property in Remitting Multiple Sclerosis: A Graph Theoretical Analysis Based on Resting-State Fmri

P-20 Altered Effective Connectivity of Default Mode Network in Relapsing Remitting Multiple Sclerosis at Resting State: A Fmri Granger Causality Analysis

Poster Session 5 MS Treatment

P-21 The Follow Up of Patients with Multiple Sclerosis Before and After Treating with Disease Modifying Therapies, Modified Rio Score as A Prognostic Marker

P-22 Drop-out Rate of Glatiramer Acetate is Influenced by Body Mass Index in Multiple Sclerosis Patients

P-23 Tolerability of Interferon Beta-1b for Multiple Sclerosis and Clinically Isolated Syndrome in Korea

P-24 An Open-Label, Two-Arm, Randomised Study to Characterise Flu-Like Symptoms in Relapsing Multiple Sclerosis Patients Transitioning to Peginterferon Beta-1a (ALLOW): Interim Analysis Results

P-14 Serum Level of Vitamin D₃ and Manifestation of the First Femyelinating Attack