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PL04-TU-01 Bringing neurology to the developing world: the time is now
S2
19th World Congress of Neurology, Plenary Abstracts / Journal of the Neurological Sciences 285 S1 (2009) S1–S4
and spinal cord especially in paralytic rabies. Collapsin response mediator protein-2 was increased in brainstem and hippocampus but decreased in spinal cord of paralytic rabies. Single or multiple targeting amiRNA against CVS-rabies N mRNA yielded an efficacy of 95% reduction of CVS, street and HEP-Flury viral genome. Conclusion: Brain abnormalities were best detected by DTI. Paralytic rabies was characterized by delayed viral neuroinvasion with more intense (but transient) inflammation than furious rabies. amiRNA may be beneficial once appropriate delivery system is developed.
Tuesday 27th October PL04-TU-01 Bringing neurology to the developing world: the time is now J.A. Aarli. Neurology, University of Bergen, Bergen, Norway Neurological disorders are among the greatest threats to public health and their impact upon global health has been underestimated. The main mission of the World Federation of Neurology today is to reduce the global burden associated with neurological disorders. Our main challenge is the disproportion between the sufferings associated with neurological disorders, and the available resources to meet this problem. There are large inequalities across regions and income groups of countries, and our focus is upon the low-income countries with their extremely scanty resources. The key challenges lie in strengthening the health systems in developing countries. It is our responsibility to create standards for the prevention and care. In order to bring neurology to the developing world, a close contact with primary health care is mandatory. Training in the diagnosis and management of common and treatable neurological disorders for health providers will be essential. Rural community health centers may develop into the critical link only if they have contact with neurological centers. The decisions to provide more beds for patients with neurological disorders and to train more neurologists are political. We need a policy statement to consider neurological disorders a public health problem. The new WHO Mental Health Gap Action program illustrates the needs to step up medical care also for patients with neurological disorders. In countries where neurologists are invisible, this message will reach the health authorities and the commitment of decision-makers to coordinate the public-health efforts that are essential in bringing neurology to the developing world. PL05-TU-01 Immunogenetics and epidemiology of multiple sclerosis (Fulton Symposium Soriano Lecture) A. Compston. Department of Clinical Neurosciences, University Neurology Unit, University of Cambridge, Cambridge, United Kingdom Despite early descriptions of familial multiple sclerosis, not until the mid-1980s was it finally established, based on recurrence risks in many categories of relatives of index cases, that there must be a genetic contribution to disease susceptibility. Following description of the HLA-DR15 association in the early 1970s, little further progress was made in identifying other susceptibility loci for over three decades. In the early 1990s, reagents emerging from the human genome project allowed systematic genome screening to be performed and these were quickly used in whole genome screens for linkage and association. However, these early efforts over-estimated the effect sizes of any additional susceptibility loci and were under-powered. Only with the formation of consortia (Genetic Analysis of Multiple sclerosis in EuropeanS [GAMES], 1999, the International Multiple Sclerosis Genetics Consortium [IMSGC], 2003, and the Wellcome Trust Case Control Consortium,
phases 1 and 2, from 2005, ANZGene, from 2005, and others) was there a sufficient increase in the scale of these genetic analyses that led, from 2007, to the results that were based on studies combining adequate sample size with high density coverage of the genome. These experiments involved many billions of genotypes and presented new challenges for statistical evaluation of the results. Taken together, in 2009, the convergence of results across these screens makes it possible to list several genetic loci that appear to confer susceptibility to multiple sclerosis: these are HLADRB1, p = 8.9×10−225 , HLA-[class 1]C, p = 3.3×10−5 , cd25 (IL2-Ra), p = 9.6×10−29 , IL7R (IL7-Ra), p = 5.5×10−20 , TYK2 (Tyk2), p = 2.7×10−6 , cd226 (DNAM1), p = 5.4×10−8 , CLEC16A, p = 1.6×10−15 , LFA3 (CD58), p = 3.10×10−10 , TNFRSF1A, p = 1.59×10−11 , ICSBP1/IRF8, p = 3.73×10−9 , CD6, p = 3.79×10−9 , CXCR4, p = 3.34×10−7 , CYP27B1 [or METTL1] p = 5.4×10−11 , and CD40 p = 1.2×10−7 . These databases have also been used to validate, and in some case amend, reports that could not subsequently be confirmed. The Wellcome Trust Case Control Consortium (WTCCC) has recently completed a substantially more comprehensive genome wide association screen using an independent set of more than 10,000 cases collected through the IMSGC and involving research groups from Australia, Belgium, Denmark, Finland, France, Germany, Ireland, Italy, Norway, Poland, Spain, Sweden, the UK and the USA. Samples were genotyped using the Illumina 670 Quad chip and analysed after appropriate quality control filters had been applied. Data available from almost 6,000 UK subjects already generated as part of WTCCC2 were supplemented with those from other published studies to provide a sample of c12,000 controls. This screen was powered to identify common risk alleles with an odds ratio of ≥1.2. The results consolidate and extend the recent exponential increase in knowledge on the genetics of multiple sclerosis and will be presented in Bangkok. As now expected, the relative risk for each new contributing factor is small indicating that, alone, these genes make a small contribution to susceptibility, but the role of epistatic interactions and the extent to which the individual effects converge on coherent pathways remain to be determined. Replication is being performed using an additional cohort of 9,000 cases, and meta-analysis of all available data relating to multiple sclerosis will follow early in 2010. If all research in multiple sclerosis is motivated by the need to understand disease mechanisms and derive safe and effective treatments, the revelation that the first wave of novel genes now shown to confer susceptibility to multiple sclerosis has revealed only products involved in pathways of the immune response provides a further clue to the nature of the dominant disease mechanism in multiple sclerosis, and since the cases studied are not stratified for phenotype or other laboratory biomarkers, these data add weight to the interpretation that, although different effector mechanisms may be involved, the disease is complex but not heterogenous and driven by the core process of focal brain inflammation.
Wednesday 28th October PL06-WE-01 Epilepsy genetics: from basic science to clinical practice (Singhal Oration) S.F. Berkovic. Epilepsy Research Centre, University of Melbourne, Austin Health, Victoria, Australia Genetic factors play a role in essentially every patient with epilepsy, although these vary from crucial to clinically trivial. Enormous progress has recently occurred in the understanding of epilepsy genetics, both at a clinical genetic level and in the basic science of epilepsies. In clinical practice, assessment of the genetic component in an individual case should be part of a routine epilepsy consultation,
19th World Congress of Neurology, Plenary Abstracts / Journal of the Neurological Sciences 285 S1 (2009) S1–S4
and spinal cord especially in paralytic rabies. Collapsin response mediator protein-2 was increased in brainstem and hippocampus but decreased in spinal cord of paralytic rabies. Single or multiple targeting amiRNA against CVS-rabies N mRNA yielded an efficacy of 95% reduction of CVS, street and HEP-Flury viral genome. Conclusion: Brain abnormalities were best detected by DTI. Paralytic rabies was characterized by delayed viral neuroinvasion with more intense (but transient) inflammation than furious rabies. amiRNA may be beneficial once appropriate delivery system is developed.
Tuesday 27th October PL04-TU-01 Bringing neurology to the developing world: the time is now J.A. Aarli. Neurology, University of Bergen, Bergen, Norway Neurological disorders are among the greatest threats to public health and their impact upon global health has been underestimated. The main mission of the World Federation of Neurology today is to reduce the global burden associated with neurological disorders. Our main challenge is the disproportion between the sufferings associated with neurological disorders, and the available resources to meet this problem. There are large inequalities across regions and income groups of countries, and our focus is upon the low-income countries with their extremely scanty resources. The key challenges lie in strengthening the health systems in developing countries. It is our responsibility to create standards for the prevention and care. In order to bring neurology to the developing world, a close contact with primary health care is mandatory. Training in the diagnosis and management of common and treatable neurological disorders for health providers will be essential. Rural community health centers may develop into the critical link only if they have contact with neurological centers. The decisions to provide more beds for patients with neurological disorders and to train more neurologists are political. We need a policy statement to consider neurological disorders a public health problem. The new WHO Mental Health Gap Action program illustrates the needs to step up medical care also for patients with neurological disorders. In countries where neurologists are invisible, this message will reach the health authorities and the commitment of decision-makers to coordinate the public-health efforts that are essential in bringing neurology to the developing world. PL05-TU-01 Immunogenetics and epidemiology of multiple sclerosis (Fulton Symposium Soriano Lecture) A. Compston. Department of Clinical Neurosciences, University Neurology Unit, University of Cambridge, Cambridge, United Kingdom Despite early descriptions of familial multiple sclerosis, not until the mid-1980s was it finally established, based on recurrence risks in many categories of relatives of index cases, that there must be a genetic contribution to disease susceptibility. Following description of the HLA-DR15 association in the early 1970s, little further progress was made in identifying other susceptibility loci for over three decades. In the early 1990s, reagents emerging from the human genome project allowed systematic genome screening to be performed and these were quickly used in whole genome screens for linkage and association. However, these early efforts over-estimated the effect sizes of any additional susceptibility loci and were under-powered. Only with the formation of consortia (Genetic Analysis of Multiple sclerosis in EuropeanS [GAMES], 1999, the International Multiple Sclerosis Genetics Consortium [IMSGC], 2003, and the Wellcome Trust Case Control Consortium,
phases 1 and 2, from 2005, ANZGene, from 2005, and others) was there a sufficient increase in the scale of these genetic analyses that led, from 2007, to the results that were based on studies combining adequate sample size with high density coverage of the genome. These experiments involved many billions of genotypes and presented new challenges for statistical evaluation of the results. Taken together, in 2009, the convergence of results across these screens makes it possible to list several genetic loci that appear to confer susceptibility to multiple sclerosis: these are HLADRB1, p = 8.9×10−225 , HLA-[class 1]C, p = 3.3×10−5 , cd25 (IL2-Ra), p = 9.6×10−29 , IL7R (IL7-Ra), p = 5.5×10−20 , TYK2 (Tyk2), p = 2.7×10−6 , cd226 (DNAM1), p = 5.4×10−8 , CLEC16A, p = 1.6×10−15 , LFA3 (CD58), p = 3.10×10−10 , TNFRSF1A, p = 1.59×10−11 , ICSBP1/IRF8, p = 3.73×10−9 , CD6, p = 3.79×10−9 , CXCR4, p = 3.34×10−7 , CYP27B1 [or METTL1] p = 5.4×10−11 , and CD40 p = 1.2×10−7 . These databases have also been used to validate, and in some case amend, reports that could not subsequently be confirmed. The Wellcome Trust Case Control Consortium (WTCCC) has recently completed a substantially more comprehensive genome wide association screen using an independent set of more than 10,000 cases collected through the IMSGC and involving research groups from Australia, Belgium, Denmark, Finland, France, Germany, Ireland, Italy, Norway, Poland, Spain, Sweden, the UK and the USA. Samples were genotyped using the Illumina 670 Quad chip and analysed after appropriate quality control filters had been applied. Data available from almost 6,000 UK subjects already generated as part of WTCCC2 were supplemented with those from other published studies to provide a sample of c12,000 controls. This screen was powered to identify common risk alleles with an odds ratio of ≥1.2. The results consolidate and extend the recent exponential increase in knowledge on the genetics of multiple sclerosis and will be presented in Bangkok. As now expected, the relative risk for each new contributing factor is small indicating that, alone, these genes make a small contribution to susceptibility, but the role of epistatic interactions and the extent to which the individual effects converge on coherent pathways remain to be determined. Replication is being performed using an additional cohort of 9,000 cases, and meta-analysis of all available data relating to multiple sclerosis will follow early in 2010. If all research in multiple sclerosis is motivated by the need to understand disease mechanisms and derive safe and effective treatments, the revelation that the first wave of novel genes now shown to confer susceptibility to multiple sclerosis has revealed only products involved in pathways of the immune response provides a further clue to the nature of the dominant disease mechanism in multiple sclerosis, and since the cases studied are not stratified for phenotype or other laboratory biomarkers, these data add weight to the interpretation that, although different effector mechanisms may be involved, the disease is complex but not heterogenous and driven by the core process of focal brain inflammation.
Wednesday 28th October PL06-WE-01 Epilepsy genetics: from basic science to clinical practice (Singhal Oration) S.F. Berkovic. Epilepsy Research Centre, University of Melbourne, Austin Health, Victoria, Australia Genetic factors play a role in essentially every patient with epilepsy, although these vary from crucial to clinically trivial. Enormous progress has recently occurred in the understanding of epilepsy genetics, both at a clinical genetic level and in the basic science of epilepsies. In clinical practice, assessment of the genetic component in an individual case should be part of a routine epilepsy consultation,