Florence, Italy September 30 - October 1, 2011

Transcription

1 FINAL PROGRAM AND ABSTRACT BOOK Cognition disorders in MS Florence, Italy September 30 - October 1, 2011

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3 General information Venue The conference takes place at the: Convitto della Calza Piazza Della Calza, , Florence, Italy Language The official language of the conference will be English. Location Florence lies on the River Arno and is known for its history and its importance in the Middle Ages and in the Renaissance, especially for its art and architecture. The historic centre of Florence was declared a World Heritage Site by UNESCO. Thanks to his numerous monuments and museums - including the Duomo, Santa Croce, the Uffizi, Ponte Vecchio, Piazza della Signoria and Palazzo Pitti - is one of the most desirable destination for tourists in the world. Scientific secretariat Serono Symposia International Foundation Salita di San Nicola da Tolentino, 1/b Rome, Italy Project Manager: Serena Dell Ariccia Tel.: +39 (0) Fax: +39 (0) info@seronosymposia.org Serono Symposia International Foundation is a Swiss Foundation with headquarters in 14, rue du Rhône, 1204 Geneva, Switzerland Organizing secretariat Meridiano Congress International Via Mentana, 2/B Rome, Italy Congress coordinator: Debora Urbinelli Tel.: +39 (0) Fax: +39 (0) d.urbinelli@meridiano.it 1

4 Cognition disorders in MS Serono Symposia International Foundation conference on: Cognition disorders in MS Florence, Italy - September 30 - October 1, 2011 Aim of the conference Increasingly, scientists and healthcare professionals working in multiple sclerosis (MS) are focusing their attention on cognition disorders. In the past, it was mainly the severe cognition defects of later and severe MS stages that posed difficult problems in clinical practice. Now the very early cognition disorders are arousing interest because, even if they are sub-clinical, they represent signs of neurodegenerative processes evolution. This interest is stimulating discussion about diagnostic methods and therapeutic approaches that are complex and require a multidisciplinary management. The aim of this conference is to provide scientists and health care professionals working in MS with the opportunity to share their knowledge and experience in order to discuss solutions to optimize cognition the management of cognition disorders. Learning objectives Participants in this conference will: Be updated on the main research outcomes in the field of cognition disorders Discuss the best approaches for the diagnosis and the differential diagnosis of cognition disorders Share solutions to optimize management of cognition disorders Target audience Health care professionals and scientists working in MS. Accreditation Serono Symposia International Foundation ( is accredited by the European Accreditation Council for Continuing Medical Education (EACCME) to provide the following CME activity for medical specialists. The EACCME is an institution of the European Union of Medical Specialists (UEMS), The conference Cognition disorders in MS (Florence, Italy - September 30 -October 1, 2011) is designated for a maximum of 9 hours of European external CME credits. Each medical specialist should claim only those credits that he/she actually spent in the educational activity. EACCME credits are recognized by the American Medical Association towards the Physician's Recognition Award (PRA). To convert EACCME credit to AMA PRA category 1 credit, please contact the AMA. This program has been submitted for CME accreditation from the Italian Ministry of Health. All Serono Symposia International Foundation programs are organized solely to promote the exchange and dissemination of scientific and medical information. No forms of promotional activities are permitted. There may be presentations discussing investigational uses of various products. These views are the responsibility of the named speakers, and do not represent an endorsement or recommendation on the part of Serono Symposia International Foundation. This program is made possible thanks to the unrestricted Educational grant received from: Centre d Esclerosi Multiple de Catalunya, ComtecMed, Congrex Sweden, Congrex Switzerland, Cryo-Save, Datanalysis, Esaote, European Society of Endocrinology, Fondazione Humanitas, Fundación IVI, ISFP International Society for Fertility Preservation, ISMH International Society of Men s Health, K.I.T.E., Merck Serono, Ministry of Health of the State of Israel, Sanofi Aventis, University of Catania, Vall d'hebron University Hospital. 2

5 Scientific organizers Maria Pia Amato Department of Neurological and Psychiatric Sciences University of Florence Florence, Italy Giancarlo Comi Department of Neurology Institute of Experimental Neurology Vita-Salute San Raffaele University Milan, Italy Scientific committee Maria Pia Amato Department of Neurological and Psychiatric Sciences University of Florence Florence, Italy Ralph Benedict Department of Neurology Division of Cognitive and Behavioral Neurosciences State University of New York at Buffalo School of Medicine and Biomedical Sciences Buffalo, New York, USA Giancarlo Comi Department of Neurology Institute of Experimental Neurology Vita-Salute San Raffaele University Milan, Italy John DeLuca Department of Physical Medicine and Rehabilitation University of Medicine and Dentistry of New Jersey New York, USA Lauren Krupp National Pediatric Multiple Sclerosis Center Stony Brook University Medical Center Stony Brook, New York, USA Dawn Langdon Department of Psychology Royal Holloway University of London London, UK Xavier Montalban Multiple Sclerosis Center of Catalonia Unit of Clinical Neuroimmunology Vall d Hebron University Hospital Barcelona, Spain Alan J. Thompson UCL Institute of Neurology Queen Square, London, UK 3

6 List of speakers and chairmen Anat Achiron Multiple Sclerosis Center Sheba Medical Center Tel-Hashomer, Israel Maria Pia Amato Department of Neurological and Psychiatric Sciences University of Florence Florence, Italy Ralph Benedict Department of Neurology Division of Cognitive and Behavioral Neurosciences State University of New York at Buffalo School of Medicine and Biomedical Sciences Buffalo, New York, USA Bruno Brochet Neurobiology of Myelin Disorders Laboratory University Victor Segalen Bordeaux Cedex, France Massimiliano Calabrese Department of Neurosciences First Neurology Clinic University Hospital of Padova Padova, Italy Carlo Caltagirone University of Rome Tor Vergata IRCCS Santa Lucia Foundation Rome, Italy Giancarlo Comi Department of Neurology Institute of Experimental Neurology Vita-Salute San Raffaele University Milan, Italy Nicola De Stefano Neurology & Neurometabolic Unit Department of Neurological and Behavioral Sciences University of Siena Siena, Italy John DeLuca Department of Physical Medicine and Rehabilitation University of Medicine and Dentistry of New Jersey New York, USA Anthony Feinstein Department of Psychiatry University of Toronto and Sunnybrook and Women s College Health Sciences Centre Toronto, Ontario, Canada Massimo Filippi Neuroimaging Research Unit Department of Neurology at the Scientific Institute and University Ospedale San Raffaele Milan, Italy Päivi Hämäläinen Masku Neurological Rehabilitation Centre Masku, Finland Lauren Krupp National Pediatric Multiple Sclerosis Center Stony Brook University Medical Center Stony Brook, New York, USA Dawn Langdon Department of Psychology Royal Holloway University of London London, UK Xavier Montalban Multiple Sclerosis Center of Catalonia Unit of Clinical Neuroimmunology Vall d Hebron University Hospital Barcelona, Spain Ugo Nocentini University of Rome Tor Vergata IRCCS Santa Lucia Foundation Rome, Italy Emilio Portaccio Department of Neurological and Psychiatric Sciences University of Florence Florence, Italy 4

7 Maria Assunta Rocca Neuroimaging Research Unit Department of Neurology at the Scientific Institute and University Ospedale San Raffaele Milan, Italy Alex Rovira Unit of Magnetic Resonance Department of Radiology Vall d Hebron University Hospital-IDI Barcelona, Spain Sandro Sorbi Department of Neurological and Psychiatric Sciences Neurological clinic University of Florence Florence, Italy Alan J. Thompson UCL Institute of Neurology Queen Square, London, UK 5

8 Scientific Program September 30 - October 1, 2011 Friday - September Registration at the Welcome desk Serono Symposia International Foundation (SSIF) Opening G. Comi, Italy Institutional welcome G.F. Gensini, Italy Welcome opening M.P. Amato, Italy Plenary Session I Chairmen: G. Comi, Italy - S. Sorbi, Italy L1: Epidemiology and functional impact A. Achiron, Israel L2: Neuropsychological pattern D. Langdon, UK L3: Cognitive issues in paediatric MS M.P. Amato, Italy Coffee break Plenary Session II Chairmen: M.P. Amato, Italy - C. Caltagirone, Italy L4: Psychometric assessment R. Benedict, USA L5: Conventional neuroimaging M. Filippi, Italy L6: Advanced neuroimaging N. De Stefano, Italy Discussion Coffee Break Workshops Session I Each workshop will last 45 minutes. Participants will choose two workshops and will register to them. In case of unavailability SSIF will propose an alternative workshop on a space available basis. WKS 1 Pathophisiology J. DeLuca, USA WKS 2 Longitudinal studies and insights from genetics E. Portaccio, Italy - U. Nocentini, Italy WKS 3 Affective disorders and their relationships with cognitive impairment A. Feinstein, Canada WKS 4 Cognitive disorders and MS phenotypes P. Hämäläinen, Finland Lunch Workshops Session II Each workshop will last 45 minutes. Participants will choose two workshops and will register to them. In case of unavailability SSIF will propose an alternative workshop on a space available basis. WKS 5 Cortical changes M. Calabrese, Italy WKS 6 Functional MRI and cognition M.A. Rocca, Italy WKS 7 Assessment batteries B. Brochet, France WKS 8 Extensive and focused assessment tools A. Rovira, Spain End of the day 6

9 Saturday - October 1 Plenary Session III Workshops Session III Chairman: A. Thompson, UK L7: DMDs treatment and cognition G. Comi, Italy L8: Other pharmacological treatments L. Krupp, USA L9: Behavioural approaches J. DeLuca, USA Discussion Coffee break Each workshop will last 45 minutes. Participants will choose two workshops and will register to them. In case of unavailability SSIF will propose an alternative workshop on a space available basis. WKS 9 Immunomodulatory treatments and cognition M.P. Amato, Italy WKS 10 New oral therapies X. Montalban, Spain WKS 11 Cognition enhancers R. Benedict, USA WKS 12 Cognitive rehabilitation D. Langdon, UK Concluding remarks End of the meeting and closing lunch 7

10 Disclosure of faculty relationships Serono Symposia International Foundation adheres to guidelines of the European Accreditation Council for Continuing Medical Education (EACCME) and all other professional organizations, as applicable, which state that programs awarding continuing education credits must be balanced, independent, objective, and scientifically rigorous. Investigative and other uses for pharmaceutical agents, medical devices, and other products (other than those uses indicated in approved product labeling/package insert for the product) may be presented in the program (which may reflect clinical experience, the professional literature or other clinical sources known to the presenter). We ask all presenters to provide participants with information about relationships with pharmaceutical or medical equipment companies that may have relevance to their lectures. This policy is not intended to exclude faculty who have relationships with such companies; it is only intended to inform participants of any potential conflicts so participants may form their own judgments, based on full disclosure of the facts. Further, all opinions and recommendations presented during the program and all program-related materials neither imply an endorsement, nor a recommendation, on the part of Serono Symposia International Foundation. All presentations solely represent the independent views of the presenters/authors. The following faculty provided information regarding significant commercial relationships and/or discussions of investigational or non-emea/fda approved (off-label) uses of drugs: Anat Achiron Declared no potential conflict of interest. Maria Pia Amato Declared to be a member of a company advisory board, board of directors or other similar group: A. Board Biogen Idec. She declared also benefits from a relationship with commercial enterprises: Biogen-Dompè; Merck Serono; Bayer Schering; Novartis. Ralph Benedict Bruno Brochet Massimiliano Calabrese Carlo Caltagirone Giancarlo Comi John DeLuca Nicola De Stefano Anthony Feinstein Massimo Filippi Päivi Hämäläinen Lauren Krupp Declared receipt of grants and contracts from: Accorda Therapeutics; Shire; EMD Serono and honoraria or consultant fees from: Bager; Teva; Biogen. He also declared to be a member of a company advisory board, board of directors or other similar group: Biogen; EMD Serono. Declared no potential conflict of interest. Declared no potential conflict of interest. Declared receipt of grants and contracts and of honoraria or consultation fees from Novartis. Declared receipt of honoraria or consultation fees from: Merck Serono; Biogen Dompè; Sanofi- Aventis. Declared receipt of grants and contracts from NIH; NMSS; Memen Pharmaceuticals; Biogen Idec. He also declared receipt of honoraria or consultation fees from Memen Pharmaceuticals and Biogen Idec. He is Board Member of National Academy of Neuropsychology and American Psychological Association. He is also member of Scientific Advisory Board of William Peterson University. Declared receipt of grants and contracts from FISM and receipt of honoraria or consultation fees from Merck Serono; Bayer; Biogen Idec; Teva; Sanofi Aventis. He also declared to be member of a company advisory board, board of directors or other similar group: Merck Serono. He declared participation in company sponsored speaker s bureau from Merck Serono and Teva. Declared receipt of grants and contracts from MS Society of Canada. Declared receipt of honoraria or consultation fees from: Merck Serono; Teva; Biogen. Declared receipt of grants and contracts from: Bayer Schering Pharma; Biogen-Dompè; Genmab; Merck Serono; Teva; FISM and receipt of honoraria or consultation fees from: Bayer Schering Pharma; Biogen-Dompè; Genmab; Merck Serono; Teva. He is also member of a company advisory board, board of directors or other similar group: Teva Pharmaceutical Industries LTD; Genmab. He declared also participation in company sponsored speaker s bureaus: Bayer Schering Pharma; Biogen-Dompè; Genmab; Merck Serono; Teva Pharmaceutical Industries LTD. Declared receipt of honoraria or consultant fees from: Bayer; Sanofi-Aventis; Biogen. Declared no potential conflict of interest. 8

11 Dawn Langdon Xavier Montalban Ugo Nocentini Emilio Portaccio Maria Assunta Rocca Alex Rovira Alan J. Thompson Declared receipts of grants and contracts from Bayer healthcare and receipt of honoraria or consultation fees from Bayer Schering AG. He also declared participation in company sponsored speaker s bureaus: Bayer Healthcare; Bayer Australia; Merck Serono; Serono UK; Teva; Sanofi-Aventis. Declared receipt of honoraria or consultation fees from Bayer Schering, Biogen Idec, Merck-Serono, Novartis, Teva, Sanofi-Aventis, Almirall. Declared receipt of grants and contracts from Novartis and receipt of honoraria or consultation fees from BMD Serono. Declared receipt of grants and contracts from: Biogen, Merck Serono; Sanofi Aventis. Declared participation in company sponsored speaker s bureaus from Biogen-Dompè. Declared receipt of grants or contracts from Bayer Schering and NeuroTEC. He also declared receipt of honoraria or consultation fees from Novartis. Declared receipt of consultation fees from: Biogen Idec, Teva Pharmaceutical, Merck Serono, DIGNA Biotech, Novartis Pharma, Eisai Ltd, GE Healthcare. He also declared receipt of honoraria from: Biogen Idec Canada; SSIF; NIHR. He declared to be member of MSIF International Medical and Scientific Board (chairman) and member of NMSS Research programs Advisory Committee. He declared also benefits from a relationship with commercial enterprises: Sage Publications; Multiple Sclerosis Journal; Elsevier; Remedica. The following faculty have provided no information regarding significant relationship with commercial supporters and/or discussion of investigational or non-emea/fda approved (off-label) uses of drugs as of September 21, Sandro SorbiDeclared no potential conflict of interest. 9

12 Abstracts

13 L1 - Epidemiology and functional impact Anat Achiron Multiple Sclerosis Center, Sheba Medical Center, Tel-Hashomer, Israel Cognitive impairment is a major problem in multiple sclerosis (MS) and adversely affects patients' quality of life. Cognitive decline can appear early in the disease process and has been reported even at disease onset. However, up to 27.9% of relapsing-remitting MS patients with disease duration >10 years were found to be cognitively resilient. We have previously shown cognitive impairment in 53.7% of MS patients evaluated at the early stage of the onset of neurological symptomatology. Verbal abilities and attention span were most frequently affected and cognitive impairment did not correlate with neurological disability or MRI disease burden. In a group of 150 relapsing-remitting MS patients with disease duration up to 15 years, we characterized the time-frame of specific appearance of cognitive impairments and demonstrated that verbal fluency and verbal memory were first affected followed by a decrease in visuospatial learning, delayed recall and then by decrease in attention and information processing speed. This significant cognitive involvement in MS requires a comprehensively and accurately performed cognitive assessment. We have shown that computerized cognitive testing has the advantages of increased sensitivity due to precise measurement of response time and frequency of errors, minimal ceiling or floor effects due to adaptive testing designs and no learning effects. Using the Mindstreams Computerized Cognitive Battery (MCCB) we have recently completed a wide-range cohort assessment of 1500 consecutive MS patients that were examined within a mean period of 9.7 years from disease onset (median 7.6 years, range 0.1 to 55 years) and identified that information processing speed and executive functions were the most frequent abnormalities in the MS population with 33.9% and 30.9% of patients performing below one standard deviation of the average, respectively. Better understanding the epidemiology of cognitive involvement at the onset and in the long-term disease course of MS as well as cognitive resilience, may help to identify or predict MS patients at increased risk and facilitate the identification of possible protective factors associated with better cognitive health. 1 - Chappel SC, Howles C 1991 Reevaluation of the roles of luteinizing hormone and follicle-stimulating hormone in the ovulatory process. Human Reproduction Filicori M, Cognigni GE, Pocognoli P et al Current concepts and novel applications of LH activity in ovarian stimulation. Trends in Endocrinology and Metabolism 14,

14 L2 - Neuropsychological pattern Dawn Langdon Department of Psychology, Royal Holloway University of London, London, UK Reported MS cognitive impairment prevalence rates are between 43% and 70%. They occur in all disease stages, including Clinically Isolated Syndrome (CIS) and early relapsing-remitting MS (RRMS). Group studies suggest accumulation of range and severity of cognitive deficits with disease progression. However, statistically cognition is only loosely related to disease duration and physical disability (in some instances clearly dissociated) and is more strongly related to brain MRI parameters, especially atrophy. Cognitive deficits typically involve a few cognitive domains, spare language and are often undetected at consultation. Information processing speed is the most vulnerable cognitive ability, followed by episodic memory, and executive function. It has been suggested that reduced information processing speed underlies all other cognitive deficits in MS. There is high interpatient variability, in part due to varying compensation capacities (cognitive reserve). 1 - Chappel SC, Howles C 1991 Reevaluation of the roles of luteinizing hormone and follicle-stimulating hormone in the ovulatory process. Human Reproduction Filicori M, Cognigni GE, Pocognoli P et al Current concepts and novel applications of LH activity in ovarian stimulation. Trends in Endocrinology and Metabolism 14,

15 L3 - Cognitive issues in paediatric MS Maria Pia Amato Department of Neurological and Psychiatric Sciences, University of Florence, Florence, Italy Multiple sclerosis (MS) more frequently affects young adults, but an estimated 2 to 5% of all people with MS have a pediatric onset MS (POMS) before the age of 16 years. In adults with MS, cognitive problems occur in 40 to 65% of the cases. The profile of cognitive impairment shows prominent involvement of episodic memory, complex attention, speed of information processing, visuo-spatial abilities and executive functions, whereas language and intelligence quotient (IQ) are relatively preserved. Cognitive functioning in POMS has been less well studied, but children may be especially prone to cognitive impairment given that the neuropathologic processes of MS, including inflammation, blood brain barrier breakdown, and demyelination, co-occur with the myelination in the developing CNS and can damage networks involved in cognition. Moreover, the disease occurs during key formative years in the academic career. Recent research in the field has highlighted the relevance of cognitive impairment in POMS with an estimated prevalence of significant dysfunction ranging from 30 to 50%. The profile of cognitive impairment is only partially overlapping with that known in the adults, since language and general intelligence can be involved, particularly in subjects with younger age at MS onset. Moreover, cognitive impairment has a negative impact on everyday and academic performance of the subjects, independently of the degree of physical disability. Assessment of cognitive and psychosocial issues is therefore essential in POMS to orient counselling and therapeutic decision-making. 1 - Chappel SC, Howles C 1991 Reevaluation of the roles of luteinizing hormone and follicle-stimulating hormone in the ovulatory process. Human Reproduction Filicori M, Cognigni GE, Pocognoli P et al Current concepts and novel applications of LH activity in ovarian stimulation. Trends in Endocrinology and Metabolism 14,

16 WKS 1 - Pathophisiology John DeLuca Department of Physical Medicine and Rehabilitation, University of Medicine and Dentistry of New Jersey, New York, USA It is now universally accepted that up to 65% of MS patients have cognitive impairment. Despite this knowledge, the underlying pathophysiology of this cognitive impairment is poorly understood. This workshop will explore the complexities of understanding the CNS mechanisms associated with cognitive impairment in MS and engage in discussions regarding current knowledge and future directions. 1 - Chappel SC, Howles C 1991 Reevaluation of the roles of luteinizing hormone and follicle-stimulating hormone in the ovulatory process. Human Reproduction Filicori M, Cognigni GE, Pocognoli P et al Current concepts and novel applications of LH activity in ovarian stimulation. Trends in Endocrinology and Metabolism 14,

17 WKS 2 - Longitudinal studies and insights from genetics Emilio Portaccio 1 and Ugo Nocentini 2 1 Department of Neurological and Psychiatric Sciences, University of Florence, Florence, Italy 2 University of Rome Tor Vergata, IRCCS Santa Lucia Foundation, Rome, Italy Longitudinal studies Emilio Portaccio The natural history of multiple sclerosis (MS)-related cognitive dysfunction is one of the least explored fields of the research in this area. Published studies suffer from many methodologic limitations and have often provided inconsistent findings. These surveys are mainly based on selected clinical series, with small sample size, brief duration of the follow-up and, sometimes, exceedingly high rates of drop-outs. Several uncontrolled studies provided controversial and inconsistent results on the evolution of neuropsychological performance in MS. However, focusing on controlled studies with longer follow-up period and taking into account changes in neuropsychological performance at the individual level, the majority of the findings point to a cognitive deterioration over time. A worsening cognitive status may be expected in about one third of the patients over 2-3 years. Therefore, it is suggested that once cognitive dysfunction is established, it does not remit to any significant extent, with the possible exception of transient cognitive changes reported during a relapse. During a sufficiently long follow-up period, it tends to progress independently of disability accumulation, although at different rates and within the context of great inter-patient variability. Predictors of the individual cognitive outcome are also poorly defined. Cognitive status at entry has been found in association with subsequent progression in the medium-term, whereas patients with a more severe course tend to have a worse cognitive outcome in longerterm evaluations. Insights from genetics Ugo Nocentini The MS is a sporadic disease but its risk is increased for patient's relatives, thus suggesting the existence of genetic determinants (1). The most investigated genetic factors of MS are related to immune system (2,3). Cognitive dysfunction is common (43 to 70 %) in MS patients with relevant consequences for those affected (4). An extreme individual variability exists in terms of quantitative and qualitative characteristics of this dysfunction. The search for factors influencing the presence as well the severity of cognitive impairment has obvious relevance. Following the studies conducted in Alzheimer disease and other conditions impacting on cognitive functioning, the investigation on the possible role of genes on the risk of cognitive impairment in MS has concentrated on apolipoprotein E genes polymorphisms. The most recent and methodologically sound studies did not reported any association between allelic configuration of the apolipoprotein E gene and cognitive functioning of MS patients (5,6,7). The HLA haplotype DR15 is more frequent in MS patients than in general population (2,3) but a single study did not found any association between this HLA aplotype and SDMT (8). However, although SDMT is highly sensitive to cognitive impairment of MS patients (9), this test is not invariably altered in all the possible conditions of MS cognitive impairment. Also the investigation on the association between cognitive impairment in MS patients of other single nucleotide polymorphisms associated with risk of developing MS has given negative results (8). Studies performed on Brain Derived Neurotrophic Factor (BDNF) have obtained interesting results: differences in BDNF genotype have shown an influence on performances in working memory and visual processing, as well on cerebral grey matter volume (10,11,12). A complex interaction between genetic and environmental factors is behind the risk of developing MS: that interaction has not been studied in relation to the occurrence and severity of cognitive dysfunction in MS. Considering that our knowledge on the determinants of cognitive impairment of MS patients is almost marked by uncertainties, studies aimed at the identification of potentially modifiable determinants of risk are strongly needed Sadovnick AD, Baird PA. Neurology, 1988, 38 (6): McElroy JP, Oksemberg JR. Neurol Clin, 2011, 29: Sadovnick AD. Autoimm Rev, 2011, doi: /j.autrev Chiaravalloti ND, DeLuca J. Lancet Neurol, 2008, 7 (12): Portaccio E et al. Acta Neurol Scand, 2009, 120: Van der Walt A et al. Neurology, 2009, 73: Ghaffar O et al. Neurology, 2010, 74: Jensen CJ et al. PLoS ONE 5 (4): e10003.doi /journal.pone Benedict RH and Zivadinov R. Nat Rev Neurol, 2011, 7: Zivadinov R et al. Hum Mol Genet, 2007, 16: Weinstock-Guttman B et al. Pathophysiology, 2010, 18: Cerasa A et al. Behav Brain res, 2010, 207:

18 WKS 3 - Affective disorders and their relationships with cognitive impairment Anthony Feinstein Department of Psychiatry, University of Toronto and Sunnybrook and Women s College Health Sciences Centre, Toronto, Ontario, Canada Multiple Sclerosis is associated with various disorders of affect, including major depression, bipolar affective disorder, pseudobulbar affect (PBA) and euphoria. The relationship between these various disorders on the one hand, and cognitive impairment on the other, has not been well studied, with the partial exception of depression. However, there are some limited data that suggests each of these behavioural disorders is linked to certain aspects of cognitive impairment. Here it is important to note that 40-60% MS patients, even in the absence of disordered affect, will have cognitive problems. The evidence suggests that at least one behavioural problem, namely depression, adds to this cognitive burden. Major depression will affect almost one in two MS patients over the course of their lifetime. Depression is a major determinant of quality of life and is responsible for the elevated suicide rate in MS patients. Clinically significant depression may exacerbate cognitive problems in MS patients, in particular leading to more extensive executive function defects. It is unclear whether this is reversible with treatment of the underlying depression. Such a response has been found in traumatic brain injury but has yet to be explored in MS subjects. Depression is often treatable, either with a selective serotonin/noradrealine re-uptake inhibitor (SSRI/SNRI) and/or cognitive behaviour therapy. Unfortunately, data show that depression is frequently overlooked in a busy out patient, neurologic setting. Tentative evidence has linked pseudobulbar affect (PBA) and euphoria with more extensive cognitive problems. The latter condition, affecting 9-13% of MS patients, is associated with marked physical disability, extensive lesion burden on brain MRI, cerebral atrophy and global cognitive impairment. There is no effective treatment for this condition. Pseudobulbar affect, however, which involves up to 10% of MS patients, is treatable with an SSRI or a tricyclic antidepressant. Recently, a novel drug - dextromethorphan hydrobromide and quinidine sulfate -has gained FDA approval for treating this disorder. Data suggest that patients with PBA are more likely to be cognitively impaired than those without. Deficits pertaining to frontal lobe mediated tasks have been elicited in PBA subjects. There are as yet to cognitive data pertaining to bipolar affective disorder and psychosis. Both conditions appear more commonly in MS patients than dictated by chance alone. With the exception of euphoria, all other disorders of affect are treatable. This highlights the fact that they should not be overlooked as part of the management strategy for all MS patients. 1 - Chappel SC, Howles C 1991 Reevaluation of the roles of luteinizing hormone and follicle-stimulating hormone in the ovulatory process. Human Reproduction Filicori M, Cognigni GE, Pocognoli P et al Current concepts and novel applications of LH activity in ovarian stimulation. Trends in Endocrinology and Metabolism 14,

19 WKS 4 - Cognitive disorders and MS phenotypes Päivi Hämäläinen Masku Neurological Rehabilitation Centre, Masku, Finland Cognitive, behavioural, and emotional problems are common manifestations of multiple sclerosis (MS). Cognitive impairments can be observed from the earliest stages of the disease and in all subtypes of MS including the clinically isolated syndromes (CIS) and relapsing-remitting (RR), secondary progressive (SP), and primary progressive forms of the disease. While processing speed, attention, and higher level working memory seem to be compromised already at early stages of the disease (CIS, RR), more widespread cognitive decline and deficits in various memory processes as well as executive functions have been associated with later stages and progressive types of the disease (SP, PP). The difference in the cognitive profiles between the secondary progressive and the primary progressive types of the disease seems to be controversial. In most of the studies, only subtle differences have been found suggesting slightly more severe and widespread cognitive deficits in SP than in PP MS. In longitudinal studies, patients with SP form of the disease seem to deteriorate over time more than patients with PP MS. The objective of the workshop is to discuss the differences in the cognitive profiles of different MS subtypes. The introduction will cover shortly the pathophysiological differences as well as the differences in cognitive profiles between the different disease types and stages. Discussion about clinical implications will be encouraged. 1 - Chappel SC, Howles C 1991 Reevaluation of the roles of luteinizing hormone and follicle-stimulating hormone in the ovulatory process. Human Reproduction Filicori M, Cognigni GE, Pocognoli P et al Current concepts and novel applications of LH activity in ovarian stimulation. Trends in Endocrinology and Metabolism 14,

20 L4 - Psychometric assessment Ralph Benedict Department of Neurology, Division of Cognitive and Behavioral Neurosciences, State University of New York at Buffalo School of Medicine and Biomedical Sciences, Buffalo, New York, USA Cognitive deficits are not readily observable in routine neurological examinations, and self-reported cognitive complaints are confounded by mood and other subjec tive symptoms. Consequently, an accurate diagnosis of MS-associated cognitive disorder depends on reliable, performance-based measures of cognitive ability. The Wechsler Adult Intelligence Scale (WAIS) is a classic example of such technology, with carefully standardized instructions, scoring criteria, extensive age-based normative data, and information derived from widespread research concerning reliability and validity. Neuropsychological testing refers to the application of similar procedures in cognitive domains such as language, visual or spatial processing, memory, and executive function allowing inferences about the integrity of cerebral function on the one hand, and conclusions about patient capacity for work and activities of daily living on the other. Confidence in such findings depends on the reliability and validity of the tests used by clinicians. In this lecture, the psychometrics of conventional neuropsychological tests such as the Rao Repeatable Battery and the MACFIMS will be reviewed. Abbreviated methods, that are more cost-effective than extensive batteries, will be examined, with an emphasis on optimal outcome measures for clinical trials. 1 - Chappel SC, Howles C 1991 Reevaluation of the roles of luteinizing hormone and follicle-stimulating hormone in the ovulatory process. Human Reproduction Filicori M, Cognigni GE, Pocognoli P et al Current concepts and novel applications of LH activity in ovarian stimulation. Trends in Endocrinology and Metabolism 14,

21 L5 - Conventional neuroimaging Massimo Filippi Neuroimaging Research Unit, Department of Neurology at the Scientific Institute and University Ospedale San Raffaele, Milan, Italy Improving the knowledge of the pathophysiology of cognitive impairment in MS and the mechanisms responsible for its evolution over time might contribute to the development of robust outcome measures and identification of targets for innovative treatment strategies. Due to their ability to detect MS-related abnormalities, MRI techniques are a valuable tool to achieve these goals. Seminal studies of patients with MS found only a modest association between T2 lesion burden of the whole brain or in specific sites of the cerebral white matter (WM) and neuropsychological test performance. The quantification of volume decrease (atrophy) of the whole brain or selected brain regions (i.e., third ventricle, corpus callosum, bicaudate ratio) is more strongly correlated with MS-associated cognitive dysfunction. These measures of brain atrophy are thought to be markers of the most destructive aspects of MS pathology. In most studies, brain volume measures are correlated better with patients cognitive performance than T2 lesion volumes, both in cross-sectional and longitudinal studies. More recently, grey matter (GM) involvement in MS has received increased interest. The assessment of GM atrophy and the topographic distribution of such a damage can help to differentiate cognitively impaired from cognitively preserved patients. With the introduction of new imaging techniques such as double inversion recovery and phasesensitive inversion recovery, an improved visualization of MS cortical lesions has been achieved. An increase of cortical lesions over time was shown to correlate with impaired neuropsychological test performance and cortical lesions and atrophy independently predicted cognitive impairment. Furthermore, assessment of lesions and atrophy of GM structures critical for the function of specific cognitive domains could provide additional pieces of information. In line with this, hippocampal atrophy has been associated with deficits in memory encoding and retrieval, whereas the formation of new hippocampal lesions over a 3-year period was related to impairment of visuospatial memory. The application of conventional MRI techniques has contributed to improve the understanding of the mechanisms responsible for the development of cognitive deficits in patients with MS. Available data suggest that focal WM lesions do play a role, but the overall effect of focal lesions on MS-related cognitive impairment is limited. The location of lesions in critical brain areas appears to be important and, in this context, the improved capability to detect cortical lesions is likely to provide additional pieces of information central to this issue. Irreversible tissue loss, measured in terms of global and regional atrophy on conventional MRI, is also associated with cognitive deficits and is a robust measure of disease burden. 1 - Chappel SC, Howles C 1991 Reevaluation of the roles of luteinizing hormone and follicle-stimulating hormone in the ovulatory process. Human Reproduction Filicori M, Cognigni GE, Pocognoli P et al Current concepts and novel applications of LH activity in ovarian stimulation. Trends in Endocrinology and Metabolism 14,

22 L6 - Advanced neuroimaging Nicola De Stefano Neurology & Neurometabolic Unit, Department of Neurological and Behavioral Sciences, University of Siena, Siena, Italy Recent MR studies have emphasized the importance of neurodegeneration in multiple sclerosis and how this can have an impact on cognition. In this respect, advanced neuroimaging techniques such as proton MR spectroscopy (by monitoring levels of N- acetylaspartate, a putative marker of axonal integrity) and other quantitative MR techniques (by assessing focal and diffuse greay matter damage) have been particularly illuminating. Recent results have shown that focal and diffuse abnormalities of the gray matter begin and contribute to cognitive impairment from the earliest disease stages. Moreover, grey matter damage may evolve most rapidly at these stages and might be, to some extent, independent of white matter changes. Such a model of MS argues strongly for the use of advanced MR biomarkers for an early and accurate assessment and monitoring of cognition in MS. 1 - Chappel SC, Howles C 1991 Reevaluation of the roles of luteinizing hormone and follicle-stimulating hormone in the ovulatory process. Human Reproduction Filicori M, Cognigni GE, Pocognoli P et al Current concepts and novel applications of LH activity in ovarian stimulation. Trends in Endocrinology and Metabolism 14,

23 WKS 5 - Cortical changes Massimiliano Calabrese Department of Neurosciences, First Neurology Clinic, University Hospital of Padova, Padova, Italy Although the mechanisms leading to the clinical manifestations of MS are not fully elucidated yet, it is increasingly perceived that the severity of the MS clinical outcome does not simply result from the extent of tissue destruction, but it rather represents a complex balance among tissue damage, tissue repair, and cortical reorganisation. Over the past decade, important insight into MS pathophysiology has been achieved by applying modern magnetic resonance imaging (MRI) based techniques. Nevertheless, the relationship between several clinical evidences related to cognitive function in MS, some MRI findings and parameters, in particular white matter T2 lesion burden, remains very weak. This might be explained, at least partly, with the variable effectiveness of reparative and recovery mechanisms following MS-related tissue damage. However, recent pathological and in vivo studies have indicated that grey matter pathology may be a main factor in determining the clinical course of MS. Indeed, inflammation and neurodegeneration occur early in the cortex of MS patients, causing both focal (cortical inflammatory lesions) and diffuse (atrophy) damage, thus having a major impact on patient s physical and cognitive disability. Cortical adaptive plasticity has been recently suggested to contribute in limiting functional impairment, particularly in the early stages of the disease and its failure associated to the increase in physical and cognitive disability and to the beginning of the progressive phase of the disease. 1 - Chappel SC, Howles C 1991 Reevaluation of the roles of luteinizing hormone and follicle-stimulating hormone in the ovulatory process. Human Reproduction Filicori M, Cognigni GE, Pocognoli P et al Current concepts and novel applications of LH activity in ovarian stimulation. Trends in Endocrinology and Metabolism 14,

24 WKS 6 - Functional MRI and cognition Maria Assunta Rocca Neuroimaging Research Unit, Department of Neurology at the Scientific Institute and University Ospedale San Raffaele, Milan, Italy Cognitive impairment affects a large proportion of patients with multiple sclerosis (MS) and has a profound impact on their daily-life activities. Improving the knowledge of the pathophysiology of cognitive impairment in MS and of the mechanisms responsible for its evolution over time might contribute to development of better outcome measures and targets for innovative treatment strategies. Functional magnetic resonance imaging (fmri) provides information about the plasticity of the human brain and, therefore, has the potential to provide important pieces of information about cortical reorganization following MS-related structural damage, which should improve our understanding of the factors associated to the accumulation of progressive disability in this disease. fmri changes have been described in virtually all patients with MS and different clinical phenotypes when investigating the visual, cognitive, and motor systems. These functional changes have been related to the extent of brain damage within and outside T2- visible lesions as well as to the involvement of specific central nervous system structures. In addition, it has also been suggested that a maladaptive recruitment of specific brain regions might be associated to the appearance of clinical symptoms in MS, such as fatigue and cognitive impairment. Brain functional changes have been shown to be dynamic over time, not only after an acute relapse, but also in clinically stable patients or after drug administration, thus providing an additional paraclinical tool to monitor treatments. fmri studies from clinically impaired MS patients may be influenced by different task performance between patients and controls. As a consequence, new strategies have been introduced to assess the role, if any, of brain reorganization in severely impaired patients, including the analysis of resting state networks. The enhancement of any beneficial effects of this cortical adaptive plasticity should be considered as a potential target of therapy for MS. 1 - Chappel SC, Howles C 1991 Reevaluation of the roles of luteinizing hormone and follicle-stimulating hormone in the ovulatory process. Human Reproduction Filicori M, Cognigni GE, Pocognoli P et al Current concepts and novel applications of LH activity in ovarian stimulation. Trends in Endocrinology and Metabolism 14,

25 WKS 7 - Assessment batteries Bruno Brochet Neurobiology of Myelin Disorders Laboratory, University Victor Segalen, Bordeaux Cedex, France Forty to sixty percent of patients with multiple sclerosis (MS) have cognitive dysfunction. Cognitive impairment can be detected at early stages of the disease, in patients with clinically isolated syndromes suggestive of MS or at early stages of MS. Their frequency increases from these early stages to established relapsing-remitting and secondary progressive MS. Cognitive abnormalities are also frequently observed in primary progressive MS. However, the specific neuropsychological tests employed and the associated criteria for designating a test as abnormal are critical for determining the frequency of cognitive deficit. Large or shorts batteries have been proposed to explore these dimensions, including the Brief Repeatable Neuropsychological Battery for MS (BRNB) and the Minimal Assessment of Cognitive Function in MS (MACFIMS). These batteries include tests of information processing speed (IPS), attention and memory which are the most frequently impaired functions. However detection of cognitive impairment in MS patients in daily practice is not an easy task because applying these batteries to every patients is not feasible. Different approaches have been studied to screen patients for cognitive impairment. Self-report using cognitive questionnaire like the Multiple Sclerosis Neuropsychological Questionnaire (MSNQ) has been found to be unreliable. Recently the screening value of the Symbol-Digit- Modalities test (SDMT), a test of IPS, has been challenged and this test appears to be a valuable screening tool to orientate patients to larger cognitive testing. Recent developments, concerning screening for cognitive impairment in MS, will be discussed. 1 - Chappel SC, Howles C 1991 Reevaluation of the roles of luteinizing hormone and follicle-stimulating hormone in the ovulatory process. Human Reproduction Filicori M, Cognigni GE, Pocognoli P et al Current concepts and novel applications of LH activity in ovarian stimulation. Trends in Endocrinology and Metabolism 14,

26 WKS 8 - Extensive and focused assessment tools Alex Rovira Unit of Magnetic Resonance, Department of Radiology, Vall d Hebron University Hospital-IDI, Barcelona, Spain Cognitive impairment occurs in about 40 65% of patients with multiple sclerosis (MS), having a major impact on social functioning, including working abilities and quality of life. Conventional MRI (cmri) measures, such as number/volume of PD/T2-weighted lesions, which are highly sensitive for detecting MS plaques in CNS white matter, are considered the most important paraclinical tool for diagnosing and monitoring MS. However, these cmri measures show weak or absent correlation with the clinical disease course, in particular progression of disability and cognitive impairment (the so called clinical-radiological paradox). The paradox can be partially explained by the non specificity of cmri in assessing the underlying lesion substrate, and by their insensitivity to quantify extent of damage in the so-called normal appearing brain tissue (both grey and white matter), facts that substantially contribute to irreversible disability progression and cognitive impairment. Over the last 20 years, the MRI research community has dedicated an enormous effort to overcome these limitations by developing and applying different MR techniques (structural, metabolic and functional) that better assess the pathologic processes underlying the progression of clinical disability and cognitive impairment (demyelination and axonal loss). The two most specific MR methods for detecting this neurodegenerative component of the disease are quantitative analysis of global and regional brain volume, particularly the grey matter, and proton MR spectroscopy measurement of n-acetyl-aspartate, a marker of axonal loss and dysfunction. Other less specific MRI techniques for determining axonal loss, such as magnetization transfer imaging and diffusion tensor imaging, also provide a sensitive measure of the diffuse process that appears relevant to cognitive impairment. Unfortunately, none of these MR surrogates for neuroaxonal loss and diffuse disease has been validated as markers of cognitive impairment. In this workshop the advantages and disadvantages of MRI in assessing and predicting cognitive impairment in MS patients will be interactively discussed. - Amato et al. Arch Neurol 2007; 64: Benedict et al. Mult Scler 2005; 13: Benedict et al. J Neuroimaging 2004; 14:36S-45S - Calabrese et al. Arch Neurol 2009; 66: Calabrese et al. Neurology 2010;74: Filippi et al. Neurology 2010;75: Lanz et al. J Neurol 2007; 254 [Suppl 2]: II/43-II/48 - Lazeron et al. Mult Scler 2000; 6: Mathiesen et al. Arch Neurol 2006; 63: Morgen et al. NeuroImage 2006; 30: Rocca et al. Hum Brain Mapp 2009;30: Roosendaal et al. Neuroimage 2009;44: Roosendaal et al. Mult Scler 2009;15: Roosendaal et al. Mult Scler 2009;15: Rovaris et al. J Neurol Sci 2006; 245: Rovaris et al. Neurology 2008;71: Sastre-Garriga et al. J Neurol Sci 2009; 282: Tiemann et al. Mult Scler 2009; 15:

27 L7 - DMDs treatment and cognition Giancarlo Comi Department of Neurology, Institute of Experimental Neurology, Vita-Salute San Raffaele University, Milan, Italy Cognitive dysfunction is a common symptom of multiple sclerosis (MS) that affects around 40 65% of patients. 1 Impaired cognitive function can contribute to disability, loss of employment, decreased ability to fulfil social roles and reduced overall quality of life. The pathophysiology of cognitive impairment is probably multifactorial, involving lesions in grey and white matter, normal-appearing white and grey matter and the direct effects of inflammation. Several studies have found associations between MS lesions on brain magnetic resonance imaging (MRI) and cognitive impairment; 2 therefore, treatments that have a positive effect on MRI measures of disease may also have cognitive benefits. Considering that remission of cognitive symptoms is unlikely, and cognitive performance decreases with worsening disability, identifying effective treatments to prevent cognitive decline is an important issue. Cognitive assessments were not included in most pivotal studies of DMDs and the effects of these agents on cognitive symptoms have not been established; data available from retrospective and subgroup analyses of pivotal studies and from post-marketing studies are both limited and conflicting. In patients with RRMS, significant improvements in measures of information processing, learning and memory have been reported for im IFN β-1a, 3 and in visual memory for IFN beta-1b, 4 compared with placebo. Improvements in cognitive performance have been reported in patients with clinically isolated syndrome treated with IFN β-1b, 5 but the effects of other DMDs in these patients have yet to be studied. Similarly, IFN β-1b may protect against cognitive decline in patients with secondary progressive MS. 6 In the pivotal trial of GA in RRMS, no beneficial effects on cognitive symptoms were been reported after 1 2 years 7 or in a subgroup of patients re-assessed after 10 years follow-up. 8 Recent results suggest that the immunosuppressant natalizumab may have a beneficial effect on memory/executive functions in patients with active RRMS, 9 although no significant benefits of this agent were reported in the pivotal trials. 10,11 Findings from post-marketing studies in patients with RRMS suggest that early treatment with DMDs may protect against cognitive decline, 12 with one study reporting similar results for the IFNs as for GA. 13 Whether the emerging treatments for MS, including oral agents, will have cognitive benefits remains to be seen. 01. Amato MP et al. J Neurol Sci 2006;245: Patti F et al. Mult Scler 2009;15: Fischer JS et al. Ann Neurol 2000;48: Pliskin NH et al. Neurology 1996;47: Kappos L et al. Lancet Neurol 2009;8: Langdon D et al. Mult Scler 2009;15:S Weinstein A et al. Arch Neurol 1999;56: Schwid SR et al. J Neurol Sci 2007;255: Mattioli F et al. Neurol Sci 2011;32: Rudick RA et al. N Engl J Med 2006;354: Polman CH et al. N Engl J Med 2006;354: Patti F et al. Mult Scler 2010;16: Canale S et al. Mult Scler 2009;15:P

28 L8 - Other pharmacological treatments Lauren Krupp National Pediatric Multiple Sclerosis Center, Stony Brook University Medical Center, Stony Brook, New York, USA Cognitive impairment, affecting over 50% of individuals with MS, is a major cause of disability that remains extremely resistant to symptomatic therapy. A variety of agents, some effective in other conditions associated with cognitive dysfunction, have failed to show a consistent positive treatment effect. Clinical trials with amantadine, L amphetamine, donepezil, modafinil, memantine, pemoline or rivastigmine have yielded either negative or inconsistent results. The trials with these agents have varied in sample size, eligibility criteria, study duration, and primary outcome. Some initial studies were associated with an improved primary outcome but subsequent trials did not replicate the findings. While these negative results are extremely disappointing, certain lessons can be gleaned from the experience. Examination of the eligibility criteria across studies highlights the challenges associated with their application. Inclusion criteria have ranged from minimal cognitive impairment to requiring more severe dysfunction. Both approaches can have advantages and disadvantages. Recruiting MS subjects with very severe cognitive impairments can be difficult; such individuals can be in nursing homes or have other neurologic deficits that would exclude them from the trial (e.g. visual loss, quadraparesis). Conversely, subgroup analyses suggest that more cognitively impaired individuals are those most likely to respond to treatment. Exclusion criteria also vary across trials and it remains unclear as to whether subjects on benzodiazepines, anticholinergic agents, or other symptomatic therapies should be excluded. Several steps can be undertaken to improve clinical trial design. Sample sizes should be chosen based on more conservative estimates of treatment effects. A multicenter approach has the advantage of more quickly enrolling the necessary sample size and increases the confidence in the results (due to greater generalizability). Identifying those MS subgroups most likely to respond to intervention and designing eligibility criteria accordingly is critical. Treatment trials should be replicated before clinicians reach conclusions affecting their practice. Improved study design is only one part of the equation. We also need to identify more effective and targeted interventions that can both enhance cognitive performance as well as improve quality of life. 1 - Chappel SC, Howles C 1991 Reevaluation of the roles of luteinizing hormone and follicle-stimulating hormone in the ovulatory process. Human Reproduction Filicori M, Cognigni GE, Pocognoli P et al Current concepts and novel applications of LH activity in ovarian stimulation. Trends in Endocrinology and Metabolism 14,

29 L9 - Behavioural approaches John DeLuca Department of Physical Medicine and Rehabilitation, University of Medicine and Dentistry of New Jersey, New York, USA Relatively few behavioral approaches to improving cognitive problems in MS have been reported. Most of those have been plagued by methodological problems. The area that has received the majority of attention is in learning and memory, and thus, will be the primary focus of the presentation. This talk will describe the methodological issues with the existing behavioral studies, present illustrations of well designed studies, provide preliminary findings of these studies, and discuss future needs and directions. 1 - Chappel SC, Howles C 1991 Reevaluation of the roles of luteinizing hormone and follicle-stimulating hormone in the ovulatory process. Human Reproduction Filicori M, Cognigni GE, Pocognoli P et al Current concepts and novel applications of LH activity in ovarian stimulation. Trends in Endocrinology and Metabolism 14,

30 WKS 9 - Immunomodulatory treatments and cognition Maria Pia Amato Department of Neurological and Psychiatric Sciences, University of Florence, Florence, Italy Cognitive dysfunctions are frequent in multiple sclerosis (MS) and have a negative impact on employment and quality of life. Pathophysiology of impaired mental activities is probably multifactorial including sensory deafferentation, lesion-related disconnection of associative areas (cortico-cortical and cortico-thalamic), involvement of normal appearing white and gray matter, and direct effects of products of inflammation. Available disease modifying drugs (DMDs) may have a role in MS-related cognitive dysfunction because they positively impact some of the pathogenetic mechanisms, reducing the burden of lesions and the progression atrophy in the brain. Pivotal phase III clinical trials have effectively shown some benefit also in terms of the patients cognitive outcome, confirmed by some post marketing studies. However, results of these studies must be interpreted with great caution because many methodological problems may undermine the quality of the results. 1 - Chappel SC, Howles C 1991 Reevaluation of the roles of luteinizing hormone and follicle-stimulating hormone in the ovulatory process. Human Reproduction Filicori M, Cognigni GE, Pocognoli P et al Current concepts and novel applications of LH activity in ovarian stimulation. Trends in Endocrinology and Metabolism 14,

31 WKS 10 - New oral therapies Xavier Montalban Multiple Sclerosis Center of Catalonia, Unit of Clinical Neuroimmunology, Vall d Hebron University Hospital, Barcelona, Spain Although the first-line injectable disease-modifying drugs interferon (IFN) β and glatiramer acetate remain the mainstay of MS therapy, treatment options are widening with the emergence of new oral therapies. The only oral therapy recently licensed for the treatment of MS is the sphingosine 1-phosphate receptor modulator fingolimod. Three other oral agents are in advanced clinical trials: teriflunomide, laquinimod and dimethyl fumarate which have shown clinical and MRI efficacy in Phase III trials 1. Phase III trials of fingolimod 2,3 reported patient scores on the Multiple Sclerosis Functional Composite, which has a component that investigates cognition (paced auditory serial addition test; PASAT), but the effects of treatment on PASAT subscale scores were not reported separately. However, an ongoing 18-month trial will compare the effects of fingolimod and IFN β-1b on cognition as measured using the Brief Repeatable Battery of Neuropsychological Tests and the Delis Kaplan Executive Function System scale. There is as yet no firm evidence demonstrating the efficacy of these new oral therapies on cognition outcomes and there is need of new specific studies on this topic to make a link between the positive effects of the new oral compounds on MRI outcomes. 1. Cohen JA et al. N Engl J Med 2010;362: Kappos L et al. N Engl J Med 2010;362:

32 WKS 11 - Cognition enhancers Ralph Benedict Department of Neurology, Division of Cognitive and Behavioral Neurosciences, State University of New York at Buffalo School of Medicine and Biomedical Sciences, Buffalo, New York, USA The two strategies for assessing the effects of medication to ameliorate MS associated cognitive impairment include (a) adding cognitive measures to the pivotal trials with disease modifying therapies; or (b) using symptomatic cognitive enhancing therapies. In this workshop, we will discuss studies from the latter group, designed to provide symptomatic relief for MS associated impairment. Efforts to treat slowed processing have mostly emphasized stimulants whereas acetylcholinesterase inhibitors have been tested in studies addressing defective anterograde, episodic memory. Some positive results have been reported, but often followed by replication failure. After a critique of this literature, we will discuss some of the more unexpected results and their implications for future studies. Specific methodological shortcomings will be presented such as inadequate sample size, deciding whether or not to treat all MS patients or just those with cognitive impairment, optimal study duration, and selecting outcome measures that are sensitive, responsive, and clinically meaningful. While each of these issues are challenging, our experience with conducting clinical trials for MS associated cognitive impairment is growing, trial design is improving, and the number of pharmacologic options is broadening. We will discuss some new studies that are underway. In addition, despite the limitations in this research, we will also discuss what options are available for clinicians attempting to use medications off-label help patients as much as is possible, given the state of the current literature. 1 - Chappel SC, Howles C 1991 Reevaluation of the roles of luteinizing hormone and follicle-stimulating hormone in the ovulatory process. Human Reproduction Filicori M, Cognigni GE, Pocognoli P et al Current concepts and novel applications of LH activity in ovarian stimulation. Trends in Endocrinology and Metabolism 14,

33 WKS 12 - Cognitive rehabilitation Dawn Langdon Department of Psychology, Royal Holloway University of London, London, UK There are methodological challenges for those seeking to evaluate a cognitive rehabilitation intervention in MS. MS patients experience a varying, progressive disease that is often clinically silent and virtually unpredictable on a short term, individual basis, in both the physical and cognitive domains. This may in part account for the paucity of evidence for cognitive rehabilitation. The studies of fairly intensive attention training are rather contradictory. In addition, access to and individual suitability of retraining programmes restricts their usefulness. It seems safe to conclude that they are unlikely to cause harm and, if sufficiently precisely targeted, may bring improvement. It appears that a computerised programme that was individually tailored to each patient s performance was effective at improving memory function and it may be that individually tailored training is most likely to be effective. The use of stories as context also appears to be a way of improving memory function. One successful study used fairly intensive training in therapist-led groups, which requires considerable expertise and other resources. However once again, within the group the therapist may have been able tailor exercises to individual needs, which may have increased the likelihood of improving memory function. There are less retraining programmes that have targeted executive skills. Overall, it seems that involving direct training of executive skills by a therapist is the most successful intervention strategy. 1 - Chappel SC, Howles C 1991 Reevaluation of the roles of luteinizing hormone and follicle-stimulating hormone in the ovulatory process. Human Reproduction Filicori M, Cognigni GE, Pocognoli P et al Current concepts and novel applications of LH activity in ovarian stimulation. Trends in Endocrinology and Metabolism 14,

34 Our future health depends on today s medical experts minds, therefore, the Serono Symposia International Foundation (SSIF), in partnership with the European Neurological Society (ENS), has decided to establish a prestigious award to recognize and reward excellence in medical education. The Serono Symposia International Foundation (SSIF) is seeking candidates among medical experts who are continuing to drive medical education forward through their research and dedication in the field of neurology. The criteria for candidate application cover a wide range of skills and attributes that SSIF is looking for in a potential candidate and winner of the SSIF award. The Award Committee composed of Members of the SSIF Scientific Committee and Board of Directors Members and ENS Members will assess the candidate s professional dedication and leadership to continuining medical education. If you are a physician and/or scientist from 35 to 50 years old working in: degenerative dementias and/or multiple sclerosis and/or neurodegenerative disease entailing movement disorders and/or Parkinson s disease The SSIF Award will be a great opportunity for you! SSIF award Rewarding scientific excellence in medical education Find out more and apply to the SSIF award on The winner of the SSIF award will receive Euro 10,000, less any taxes deductable, and will become a member of the SSIF advisory committee. Applications are open for submission from May 28, 2011 until December 31, 2011.

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40 Serono Symposia International Foundation Representative Office Salita di San Nicola da Tolentino 1/b Rome, Italy T +39.(0) F +39.(0) Headquarters 14, Rue du Rhône Geneva, Switzerland Your continuing medical education partner Copyright Serono Symposia International Foundation, All rights reserved.