24-25 February Siena, Italy

Transcription

1 WORKSHOP FINAL PROGRAMME AND ABSTRACT BOOK Clinical and research application of MRI in diagnosis and monitoring of multiple sclerosis February Siena, Italy

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3 Clinical and research application of MRI in diagnosis and monitoring of multiple sclerosis Overview MR imaging has dramatically improved the accuracy in the diagnosis and in the quantification of tissue damage in multiple sclerosis (MS). Today it is the most important paraclinical tool for the monitoring of treatment efficacy and safety, both in clinical practice and clinical trials settings. Advanced MRI has speeded up the discovery of new pathogenetic mechanisms and functional consequences of MS. Aim of this workshop is to comprehensively summarize the main applications of MRI to MS field from diagnosis to treatment monitoring. The use of MRI markers as endpoint in clinical trials will be also discussed. An overview of the main software packages suitable to assess lesions and atrophy in brain and spinal cord will be illustrated. Learning objectives By attending this workshop, participants will be able to: Illustrate and apply MRI diagnostic criteria Explain the key elements of differential diagnosis on MRI Describe basic principles and application of quantitative MRI Target audience Neurologists treating patients with MS and with a interest in MRI. Chairs Nicola De Stefano Department of Neurological and Behavioural Sciences University of Siena Siena, Italy Claudio Gasperini Department of Neurosciences Hospital S. Camillo Forlanini Rome, Italy 1

4 CME Provider EXCEMED is a non profit foundation dedicated, since the last four decades, to the development of high-quality medical education programme all over the world. EXCEMED adheres to the guidelines and standards of the European Accreditation Council for Continuing Medical Education (EACCME ) which states that continuing medical education must be balanced, independent, objective, and scientifically rigorous. Continuing medical education EXCEMED ( 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 CME workshop Clinical and research application of MRI in diagnosis and monitoring of multiple sclerosis held on February 2016 in Siena, Italy, is designated for a maximum of 8 (eight) hours of European CME credits (ECMEC). 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 (AMA) towards the Physician's Recognition Award (PRA). To convert EACCME credit to AMA PRA category 1 credit, please contact the AMA. EXCEMED adheres to the principles of the Good CME Practice group (gcmep). 2

5 Faculty Marco Battaglini Department of Neurological and Behavioural Sciences University of Siena Siena, Italy Nicola De Stefano Department of Neurological and Behavioural Sciences University of Siena Siena, Italy Claudio Gasperini Department of Neurosciences Hospital S. Camillo Forlanini Rome, Italy Antonio Giorgio Department of Neurological and Behavioural Sciences University of Siena Siena, Italy Carla Tortorella Department of Medical Basic Sciences, Neurosciences and Sense Organs University of Bari Bari, Italy 3

6 Programme

7 Wednesday, 24 February 2016 Thursday, 25 February Opening and welcome N. De Stefano (Italy) L1: How to use MRI for diagnosing MS: past, current and future diagnostic criteria C. Gasperini (Italy) L2: What are we looking at: sensitivity and specificity of MRI N. De Stefano (Italy) L3: What we should pay attention for: key elements for an MRI differential diagnosis N. De Stefano (Italy) Coffee break L4: MRI to assess prognosis C. Gasperini (Italy) L5: MRI to assess treatment response C. Gasperini (Italy) L6: MRI to assess safety during treatment N. De Stefano (Italy) L7: MRI as suitable endpoint in clinical trials: state of the art and future proposals C. Gasperini (Italy) L8: Brain function beyond structure: the role of advanced imaging A. Giorgio (Italy) L9: Future MRI markers in MS N. De Stefano (Italy) Coffee break L10: Real assessments of MRI lesions and Atrophy: the post-processing landscape M. Battaglini (Italy) Visit to the MRI Unit A. Giorgio and M. Battaglini (Italy) Final discussion and wrap-up Concluding lunch and participants departure General discussion Lunch Clinical cases session C. Tortorella (Italy) Round up End of the first day Legend: L : Lecture; : Discussion; : Clinical cases 5

8 General information Language The official language of this workshop is English. CME Provider EXCEMED - Excellence in Medical Education Programme and Relations Manager: Serena Dell'Ariccia T F serena.dellariccia@excemed.org Medical Advisor: Doriana Landi doriana.landi@gmail.com For any logistic information please contact: Meridiano Congress International Congress Manager: Denise Latino T F denise.latino@meridiano.it 6

9 Disclosure of faculty relationships EXCEMED adheres to guidelines of the European Accreditation Council for Continuing Medical Education (EACCME ) and all other professional organizations, as applicable, which state that programmes 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 programme (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 that participants may form their own judgements, based on full disclosure of the facts. Further, all opinions and recommendations presented during the programme and all programme-related materials neither imply an endorsement nor a recommendation on the part of EXCEMED. All presentations represent solely 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: Marco Battaglini Declared no potential conflict of interest. Nicola De Stefano Declared the receipt of honoraria and consultation fees from Novartis, Merck Serono, Biogen and Roche. He declared to be member of Novartis, Merck Serono, Biogen and Roche advisory boards, board of directors or other similar groups and the participation to speakers bureau sponsored by Novartis, Merck Serono and Genzyme.. Claudio Gasperini Declared the receipt of grants and contracts from Teva. He declared the receipt of honoraria and consultation fees from Teva, Biogen Merck Serono and Bayer. Antonio Giorgio Declared no potential conflict of interest.. Carla Tortorella Declared the receipt of Honoraria and consultation fees from Merck Serono, Biogen, Teva, Shering and Genzyme. She declared to be member of Merck Serono, Biogen, Teva and Shering advisory boards, board of directors or other similar groups.. 7

10 Abstracts

11 L1. How to use MRI for diagnosing MS: past, current and future diagnostic criteria Claudio Gasperini Department of Neurosciences, Hospital S. Camillo Forlanini, Rome, Italy Magnetic resonance imaging (MRI) has been formally included in the diagnostic work-up of patients presenting with a clinically isolated syndrome (CIS) suggestive of multiple sclerosis (MS) in 2001 by a Panel of International (IP) experts. MS diagnosis requires the demonstration of disease dissemination in space (DIS) and time (DIT) and the exclusion of other conditions that can mimic MS by their clinical and laboratory profile. MRI can support and substitute clinical information for the diagnosis of MS allowing an earlier and accurate diagnosis and, as a consequence, earlier treatment. MRI criteria for MS are based on features of focal lesions in the white matter (WM) of the central nervous system (CNS) that are considered typical for this condition in terms of distribution, morphology, evolution and signal abnormalities on conventional MRI sequences. Based on available literature from research studies, several modifications of MRI diagnostic criteria have been proposed over the course of years, which were mainly based on simplification of lesion count models for demonstrating DIS, timing of acquisition of MRI scans for demonstrating DIT, and weighting the value of spinal cord imaging. This evidence has been reviewed in 2007 by the European multicenter collaborative research network that studies MRI in MS (MAGNIMS) leading to a proposal for new MRI criteria to be applied in MS. These MAGNIMS criteria are currently included in the most recent revision of the IP criteria. New data regarding the application of MRI for demonstrating DIS and DIT have become available and a new proposal to modify the diagnostic work-up will be presented. 9

12 L2. What are we looking at: sensitivity and specificity of MRI Nicola De Stefano Department of Neurological and Behavioural Sciences, University of Siena, Siena, Italy Conventional and non-conventional MR techniques have demonstrated to provide structural, biochemical, and functional indices able to give accurate information on the status of CNS system. This quantitative MR metrics allow accurate cross-sectional and longitudinal measurements of different brain structures and their use in multiple sclerosis (MS) has facilitated the diagnosis of the disease and has enhanced greatly our understanding of the pathophysiology of this disorder, providing better specificity and sensitivity than clinical measures. We will focus on recent data that have used quantification of focal demyelinating lesions and diffuse tissue damage, discussing advances and limitations of a modern use of MRI in the management of MS patients. 10

13 L3. What we should pay attention for: key elements for an MRI differential diagnosi Nicola De Stefano Department of Neurological and Behavioural Sciences, University of Siena, Siena, Italy Conventional MRI is crucial for an early diagnosis of MS, which allows an early treatment. However, the exclusion of other neurological disorders before making the definite diagnosis of MS is also essential. The limited specificity of abnormalities disclosed by MRI may increase the likelihood of diagnosis of multiple sclerosis in patients affected by other disorders. The available criteria for diagnosis of MS must take advantage of the potential of MRI to detect features not suggestive of MS. Recognition of such features in the work-up of patients suspected of having MS may reduce the likelihood of a false positive diagnosis. We will discuss these potential red flags and how they should be used in the setting of clinically suspected MS. 11

14 L4. MRI to assess prognosis Claudio Gasperini Department of Neurosciences, Hospital S. Camillo Forlanini, Rome, Italy The utility of magnetic resonance imaging (MRI) in predicting the occurrence of a second neurologic episode and, therefore, conversion to clinically definite MS in patients with a first demyelinating event, is well established. The place and contribution of imaging in evaluating the long-term prognosis is less obvious, as illustrated in a prospective cohort study of 140 patients with a first neurologic episode suggestive of MS. Untreated patients reevaluated after a mean follow- up of 20 years, brain T2 lesion volume at all time points, namely, baseline and 5, 10, 14, and 20 years, correlated moderately with EDSS at the end of follow-up. Similar conclusions were reached when analysis was restricted to the subgroup of patients with clinically definite MS. The change in T2 lesion volume on brain MRI over the first 5 years of the disease also correlated with concurrent change in EDSS and weakened thereafter. While patients with a higher number of T2 lesions at baseline on brain imaging were more likely to be disabled 20 years later, about one-third of patients with more than 10 T2 lesions at baseline had minimal disability at the end of follow- up. The potential role of brain and spinal cord atrophy such as the unconventional MRI sequences will be discussed. 12

15 L5. MRI to assess treatment response Claudio Gasperini Department of Neurosciences, Hospital S. Camillo Forlanini, Rome, Italy Several new drugs have recently been approved for the treatment of multiple sclerosis (MS), creating an imperative for clinicians to make prompt treatment decisions for patients with suboptimal treatment response. This is difficult due to the inherent uncertainties in defining response or non-response to therapy in a chronic inflammatory and demyelinating disease such as MS, but it is certainly complicated by the lack of a standardized definition of the clinical outcomes used to assess improvement of worsening of the disease recently. Many studies have evaluated the role of clinical (i.e. relapses and disability progression) and magnetic resonance imaging (MRI) markers (i.e., white matter lesions) to define responder or non-responders to Interferon (IFN), reporting conflicting results., due to the large heterogeneity in both measured markers and outcome assessments. This heterogeneity precludes a valuable comparison of the different markers and scores of response across different studies. We will provide new insight into the role of markers of response to MS therapy, focusing on MRI lesions (alone or in combination with clinical variables). 13

16 L6. MRI to assess safety during treatment Nicola De Stefano Department of Neurological and Behavioural Sciences, University of Siena, Siena, Italy The use of magnetic resonance imaging (MRI) techniques has provided specific information on the heterogeneous pathologic substrate of MS lesions, offering the ability to observe and quantify the evolution of lesions and normal-appearing brain tissue. Moreover, the process of identifying effective therapies for MS patients has been aided by the use of serial MRI to sensitively detect sub-clinical disease modifying treatment effects at an earlier stage than is possible using clinical disease activity measures. Against this background, the major contribution of MRI to monitoring safety during specific MS treatments for a better management of the single MS patient will be discussed. 14

17 Clinical cases session Carla Tortorella Department of Medical Basic Sciences, Neurosciences and Sense Organs, University of Bari, Bari, Italy The main objective of the clinical case session will be to summarize the core applications of MRI to the MS field from diagnosis to treatment monitoring in clinical practice. In this practical session, participants will learn to recognize MS from MS disease mimicking, gathering clinical and MRI data. Furthermore, the role of MRI in monitoring MS therapy and identifying treatment-relatedside effects will be discussed. Several case studies and patient experiences will be illustrated, drawing attention to the role of MRI in: 1. Preclinical diagnosis and radiologically isolated syndromes (RIS). 2. Differential diagnosis (MS vs neuromyelitis optica spectrm disorders-nmosd, acute disseminated encephalomyelitis ADEM, other autoimmune vasculitis). 3. Treatment monitoring and safety issues connected to treatment-related adverse events (progressive multifocal leukoencephalopathy -PML). Interaction will be encouraged by using MRI scans and photography. 15

18 L7. MRI as suitable endpoint in clinical trials: state of the art and future proposals Claudio Gasperini Department of Neurosciences, Hospital S. Camillo Forlanini, Rome, Italy MRI is used both in the diagnosis of Multiple Sclerosis (MS) and in monitoring disease activity in patients with established MS. The MRI can show the development of new damage as it occurs over time. T2-weighted and gadolinium enhanced T1-weighted MRI scans measure plaque burden and breakdown of the blood-brain barrier, respectively, in MS lesions. Using Conventional MRI data, it is possible according the new Mc Donald Criteria, satisfy the dissemination in space and time since the first episode simplifying the diagnostic process with fewer required MRI examinations. This allow more rapid diagnosis of MS preserving equivalent specificity and/or sensitivity in comparison with past criteria. Moreover, the evaluation of MRI activity is widely used outcome measures for monitoring disease activity in clinical trials and clinical practice. Several studies shows that MRI parameters: - Reflects early step in lesion development. - It is 5/10 times more sensitive than clinical relapses. - Shows moderate cross sectional relationship with relapse and disability. - Shows moderate predictive value for relapse in patients with early disease. - Shows concordance of effect of treatment on clinical and MRI outcome moderate to good especially in studies examined with effect in individual patients. - Shows good predictive value for treatment response. MRI it is a good surrogate marker in monitoring disease activity both in clinical trials and clinical practice. 16

19 L8. Brain function beyond structure: the role of advanced imaging Antonio Giorgio Department of Neurological and Behavioural Sciences, University of Siena, Siena, Italy Conventional MRI of the central nervous system is crucial for an early diagnosis and reliable monitoring of patients with multiple sclerosis (MS). Focal white matter (WM) lesions, as detected by MRI, are the pathologic hallmark of the disease and show some relationship with clinical disability, especially in the long term. Grey matter (GM) involvement occurs from disease onset in the form of focal (i.e., cortical lesions) and diffuse (i.e., atrophy) pathology. Both of them accrue over time and show close relationship with physical disability and cognitive impairment. The application of advanced quantitative MRI techniques such as magnetization transfer imaging (MTI), diffusion tensor imaging (DTI), proton MR spectroscopy (1H-MRS) and iron imaging has allowed to demonstrate since early stages of disease the presence of subtle and widespread MS pathology outside focal WM lesions in the so called normal appearing brain. In addition, studies using functional MRI have demonstrated that brain plasticity is driven by MS pathology, playing adaptive or maladaptive role towards clinical status of patients and explaining, at least in part, the clinicoradiological paradox of MS. 17

20 L9. Future MRI markers in MS Nicola De Stefano Department of Neurological and Behavioural Sciences, University of Siena, Siena, Italy Several modern MR techniques have been developed and applied during the last couple of decades, providing a number of imaging biomarkers that, complemented with conventional MRI measures, are able to better capture the complexity of the pathological process occurring in the MS brain. They have provided specific information on the heterogeneous pathologic substrate of MS lesions, offering the ability to observe and quantify the evolution of lesions and normal-appearing brain tissue. Moreover, the process of identifying effective therapies for MS patients has been aided by the use of serial MRI to sensitively detect sub-clinical disease modifying treatment effects at an earlier stage than is possible using clinical disease activity measures. Despite this, however, the role of MRI as surrogate for clinical endpoints is still controversial. Against this background, the MRI markers that could best contribute in the future to the understanding of the disease progression and the management of the single MS patient will be discussed. 18

21 L10. Real assessments of MRI lesions and Atrophy: the post-processing landscape Marco Battaglini Department of Neurological and Behavioural Sciences, University of Siena, Siena, Italy During this lesson, various methods for assessing brain atrophy and the volume and number of lesions will be briefly described, both in the cross-sectional and longitudinal settings. In particular, the differences between segmentation and registration methods for calculating atrophy will be discussed in detail and examples of software for each of these categories will be provided. Therefore, a pipeline for measuring brain volumes at a single point in time will be shown -- including the new lesion filling algorithms and new methods of assessing deep grey matter (GM) volumes. This pipeline will be explained by using the SIENAX algorithm. The next step will be to use the SIENA algorithm as an example of a similar pipeline for longitudinal changes in volumes. Finally, the problem of lesion segmentation will be addressed. Pros and cons of automated and semi-automated softwares will be reviewed, with particular attention to two main questions: i) how to create an effective gold standard for software validation and ii) when to use supervised methods and unsupervised methods. The lesson will end with the description of new software for calculating changes in volume and number of lesions. 19

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26 All EXCEMED programmes 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 EXCEMED. This programme is made possible thanks to an educational grant received from Merck KGaA, Darmstadt, Germany

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28 Improving the patient's life through medical education EXCEMED - Excellence in Medical Education Headquarters 14, Rue du Rhône Geneva, Switzerland Representative Office Salita di San Nicola da Tolentino 1/b Rome, Italy T F Copyright EXCEMED, All rights reserved.