Abstract
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.
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 Xing1,2, Philipp T. Röth1,2, Jo Anne S. Stratton1,3, Bernard H. A. Chuang1, Jill Danne4,5, Sarah L. Ellis4,5, Sze Woei Ng1, Trevor J. Kilpatrick1,3,6, Tobias D. Merson1,2,6
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-CreERT2 or Pdgfra-CreERT2 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.