Clinical and research application of MRI in diagnosis and ... · diagnosis and monitoring of multiple sclerosis Overview MR imaging has dramatically improved the accuracy in the diagnosis

Clinical and research application of MRI indiagnosis and monitoring of multiple sclerosis24-25 February 2016 - Siena, Italy

WORKSHOPFINAL PROGRAMME AND ABSTRACT BOOK

Clinical and research application of MRI in diagnosis and monitoring of multiple sclerosis

OverviewMR 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 andclinical 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 treatmentmonitoring. The use of MRI markers as endpoint in clinical trials will be also discussed. An overview of the main software packagessuitable to assess lesions and atrophy in brain and spinal cord will be illustrated.

Learning objectivesBy 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 audienceNeurologists treating patients with MS and with a interest in MRI.

ChairsNicola De StefanoDepartment of Neurological and Behavioural SciencesUniversity of SienaSiena, Italy

Claudio GasperiniDepartment of NeurosciencesHospital S. Camillo ForlaniniRome, Italy

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CME ProviderEXCEMED is a non profit foundation dedicated, since the last four decades, to the development of high-quality medical educationprogramme 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 educationEXCEMED (www.excemed.org) is accredited by the European Accreditation Council for Continuing Medical Education (EACCME®) toprovide the following CME activity for medical specialists. The EACCME® is an institution of the European Union of MedicalSpecialists (UEMS), www.uems.net

The CME workshop “Clinical and research application of MRI in diagnosis and monitoring of multiple sclerosis” held on 24-25February 2016 in Siena, Italy, is designated for a maximum of 8 (eight) hours of European CME credits (ECMEC). Each medicalspecialist should claim only those credits that he/she actually spent in the educational activity. EACCME® credits are recognized bythe American Medical Association (AMA) towards the Physician's Recognition Award (PRA). To convert EACCME® credit to AMA PRAcategory 1 credit, please contact the AMA.

EXCEMED adheres to the principles of the Good CME Practice group (gCMEp).

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Faculty

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Marco BattagliniDepartment of Neurological andBehavioural SciencesUniversity of SienaSiena, Italy

Nicola De StefanoDepartment of Neurological and Behavioural SciencesUniversity of SienaSiena, Italy

Claudio GasperiniDepartment of NeurosciencesHospital S. Camillo ForlaniniRome, Italy

Antonio GiorgioDepartment of Neurological andBehavioural SciencesUniversity of SienaSiena, Italy

Carla TortorellaDepartment of Medical Basic Sciences, Neurosciences and Sense OrgansUniversity of BariBari, Italy

Programme

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08.45 Opening and welcome N. De Stefano (Italy)

09.00 L1: How to use MRI for diagnosing MS: past,current and future diagnostic criteria C. Gasperini (Italy)

09.30 L2: What are we looking at: sensitivity andspecificity of MRI N. De Stefano (Italy)

10.00 L3: What we should pay attention for: keyelements for an MRI differential diagnosis N. De Stefano (Italy)

10.30 Coffee break

11.00 L4: MRI to assess prognosis C. Gasperini (Italy)

11.30 L5: MRI to assess treatment response C. Gasperini (Italy)

12.00 L6: MRI to assess safety during treatment N. De Stefano (Italy)

12.30 General discussion

13.00 Lunch

14.00 Clinical cases session C. Tortorella (Italy)

16.30 Round up

17.00 End of the first day

09.00 L7: MRI as suitable endpoint in clinical trials: stateof the art and future proposals C. Gasperini (Italy)

09.30 L8: Brain function beyond structure: the role ofadvanced imaging A. Giorgio (Italy)

10.00 L9: Future MRI markers in MS N. De Stefano (Italy)

10.30 Coffee break

11.00 L10: Real assessments of MRI lesions and Atrophy:the post-processing landscapeM. Battaglini (Italy)

11.30 Visit to the MRI Unit A. Giorgio and M. Battaglini (Italy)

12.30 Final discussion and wrap-up

13.00 Concluding lunch and participants departure

Wednesday, 24 February 2016

Legend: L : Lecture; : Discussion; : Clinical cases

Thursday, 25 February 2016

General information

LanguageThe official language of this workshop is English.

CME ProviderEXCEMED - Excellence in Medical Education

Programme and Relations Manager: Serena Dell'AricciaT +39 06 420413 251 - F +39 06 420413 [email protected]

Medical Advisor: Doriana [email protected]

For any logistic information please contact:

Meridiano Congress InternationalCongress Manager: Denise LatinoT +39 06 88 595 213 - F +39 06 88595 234 [email protected]

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Disclosure of faculty relationships

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EXCEMED adheres to guidelines of the European Accreditation Council for Continuing Medical Education (EACCME®) and all otherprofessional 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 otherproducts (other than those uses indicated in approved product labeling/package insert for the product) may be presented in theprogramme (which may reflect clinical experience, the professional literature or other clinical sources known to the presenter). We askall presenters to provide participants with information about relationships with pharmaceutical or medical equipment companies thatmay have relevance to their lectures. This policy is not intended to exclude faculty who have relationships with such companies; it isonly intended to inform participants of any potential conflicts so that participants may form their own judgements, based on fulldisclosure of the facts. Further, all opinions and recommendations presented during the programme and all programme-relatedmaterials neither imply an endorsement nor a recommendation on the part of EXCEMED. All presentations represent solely theindependent views of the presenters/authors.

The following faculty provided information regarding significant commercial relationships and/or discussions of investigational ornon-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 andRoche. 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 byNovartis, Merck Serono and Genzyme. .

Claudio Gasperini Declared the receipt of grants and contracts from Teva. He declared the receipt of honoraria andconsultation 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, Sheringand Genzyme. She declared to be member of Merck Serono, Biogen, Teva and Shering advisoryboards, board of directors or other similar groups..

Abstracts

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Magnetic resonance imaging (MRI) has been formally included in the diagnostic work-up of patients presenting with a clinicallyisolated syndrome (CIS) suggestive of multiple sclerosis (MS) in 2001 by a Panel of International (IP) experts. MS diagnosis requiresthe demonstration of disease dissemination in space (DIS) and time (DIT) and the exclusion of other conditions that can mimic MSby their clinical and laboratory profile. MRI can support and substitute clinical information for the diagnosis of MS allowing an earlierand 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 areconsidered typical for this condition in terms of distribution, morphology, evolution and signal abnormalities on conventional MRIsequences. Based on available literature from research studies, several modifications of MRI diagnostic criteria have been proposedover the course of years, which were mainly based on simplification of lesion count models for demonstrating DIS, timing ofacquisition of MRI scans for demonstrating DIT, and weighting the value of spinal cord imaging. This evidence has been reviewed in2007 by the European multicenter collaborative research network that studies MRI in MS (MAGNIMS) leading to a proposal for newMRI 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 thediagnostic work-up will be presented.

L1. How to use MRI for diagnosing MS: past, current andfuture diagnostic criteria

Claudio GasperiniDepartment of Neurosciences, Hospital S. Camillo Forlanini, Rome, Italy

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Conventional and non-conventional MR techniques have demonstrated to provide structural, biochemical, and functional indicesable to give accurate information on the status of CNS system. This quantitative MR metrics allow accurate cross-sectional andlongitudinal measurements of different brain structures and their use in multiple sclerosis (MS) has facilitated the diagnosis of thedisease and has enhanced greatly our understanding of the pathophysiology of this disorder, providing better specificity andsensitivity than clinical measures. We will focus on recent data that have used quantification of focal demyelinating lesions anddiffuse tissue damage, discussing advances and limitations of a modern use of MRI in the management of MS patients.

L2. What are we looking at: sensitivity and specificity ofMRI

Nicola De StefanoDepartment of Neurological and Behavioural Sciences, University of Siena, Siena, Italy

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Conventional MRI is crucial for an early diagnosis of MS, which allows an early treatment. However, the exclusion of otherneurological disorders before making the definite diagnosis of MS is also essential. The limited specificity of abnormalities disclosedby MRI may increase the likelihood of diagnosis of multiple sclerosis in patients affected by other disorders. The available criteriafor diagnosis of MS must take advantage of the potential of MRI to detect features “not suggestive” of MS. Recognition of suchfeatures in the work-up of patients suspected of having MS may reduce the likelihood of a false positive diagnosis. We will discussthese potential “red flags” and how they should be used in the setting of clinically suspected MS.

L3. What we should pay attention for: key elements foran MRI differential diagnosi


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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 ofimaging in evaluating the long-term prognosis is less obvious, as illustrated in a prospective cohort study of 140 patients with a firstneurologic episode suggestive of MS. Untreated patients reevaluated after a mean follow- up of 20 years, brain T2 lesion volume atall time points, namely, baseline and 5, 10, 14, and 20 years, correlated moderately with EDSS at the end of follow-up. Similarconclusions were reached when analysis was restricted to the subgroup of patients with clinically definite MS. The change in T2lesion volume on brain MRI over the first 5 years of the disease also correlated with concurrent change in EDSS and weakenedthereafter. While patients with a higher number of T2 lesions at baseline on brain imaging were more likely to be disabled 20 yearslater, about one-third of patients with more than 10 T2 lesions at baseline had minimal disability at the end of follow- up. Thepotential role of brain and spinal cord atrophy such as the unconventional MRI sequences will be discussed.

L4. MRI to assess prognosis


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Several new drugs have recently been approved for the treatment of multiple sclerosis (MS), creating an imperative for clinicians tomake prompt treatment decisions for patients with suboptimal treatment response. This is difficult due to the inherent uncertaintiesin defining response or non-response to therapy in a chronic inflammatory and demyelinating disease such as MS, but it is certainlycomplicated by the lack of a standardized definition of the clinical outcomes used to assess improvement of worsening of the diseaserecently. 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 valuablecomparison of the different markers and scores of response across different studies. We will provide new insight into the role ofmarkers of response to MS therapy, focusing on MRI lesions (alone or in combination with clinical variables).

L5. MRI to assess treatment response


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The use of magnetic resonance imaging (MRI) techniques has provided specific information on the heterogeneous pathologicsubstrate 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 detectsub-clinical disease modifying treatment effects at an earlier stage than is possible using clinical disease activity measures. Againstthis background, the major contribution of MRI to monitoring safety during specific MS treatments for a better management of thesingle MS patient will be discussed.

L6. MRI to assess safety during treatment


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The main objective of the clinical case session will be to summarize the core applications of MRI to the MS field from diagnosis totreatment 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 multifocalleukoencephalopathy -PML).

Interaction will be encouraged by using MRI scans and photography.

Clinical cases session

Carla TortorellaDepartment of Medical Basic Sciences, Neurosciences and Sense Organs, University of Bari, Bari, Italy

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MRI is used both in the diagnosis of Multiple Sclerosis (MS) and in monitoring disease activity in patients with established MS. TheMRI can show the development of new damage as it occurs over time. T2-weighted and gadolinium enhanced T1-weighted MRIscans 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 sincethe first episode simplifying the diagnostic process with fewer required MRI examinations. This allow more rapid diagnosis of MSpreserving 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 clinicalpractice. 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 effectin 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.

L7. MRI as suitable endpoint in clinical trials: state of theart and future proposals


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Conventional MRI of the central nervous system is crucial for an early diagnosis and reliable monitoring of patients with multiplesclerosis (MS). Focal white matter (WM) lesions, as detected by MRI, are the pathologic hallmark of the disease and show somerelationship with clinical disability, especially in the long term. Grey matter (GM) involvement occurs from disease onset in the formof focal (i.e., cortical lesions) and diffuse (i.e., atrophy) pathology. Both of them accrue over time and show close relationship withphysical disability and cognitive impairment. The application of advanced quantitative MRI techniques such as magnetizationtransfer imaging (MTI), diffusion tensor imaging (DTI), proton MR spectroscopy (1H-MRS) and iron imaging has allowed todemonstrate since early stages of disease the presence of subtle and widespread MS pathology outside focal WM lesions in the socalled “normal appearing” brain. In addition, studies using functional MRI have demonstrated that brain plasticity is driven by MSpathology, playing adaptive or maladaptive role towards clinical status of patients and explaining, at least in part, the “clinico-radiological paradox” of MS.

L8. Brain function beyond structure: the role of advancedimaging

Antonio GiorgioDepartment of Neurological and Behavioural Sciences, University of Siena, Siena, Italy

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Several modern MR techniques have been developed and applied during the last couple of decades, providing a number of imagingbiomarkers that, complemented with conventional MRI measures, are able to better capture the complexity of the pathologicalprocess 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 ofidentifying effective therapies for MS patients has been aided by the use of serial MRI to sensitively detect sub-clinical diseasemodifying treatment effects at an earlier stage than is possible using clinical disease activity measures. Despite this, however, therole of MRI as surrogate for clinical endpoints is still controversial. Against this background, the MRI markers that could bestcontribute in the future to the understanding of the disease progression and the management of the single MS patient will bediscussed.

L9. Future MRI markers in MS


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During this lesson, various methods for assessing brain atrophy and the volume and number of lesions will be briefly described, bothin the cross-sectional and longitudinal settings. In particular, the differences between segmentation and registration methods forcalculating atrophy will be discussed in detail and examples of software for each of these categories will be provided. Therefore, apipeline for measuring brain volumes at a single point in time will be shown -- including the new lesion filling algorithms and newmethods of assessing deep grey matter (GM) volumes. This pipeline will be explained by using the SIENAX algorithm. The next stepwill be to use the SIENA algorithm as an example of a similar pipeline for longitudinal changes in volumes. Finally, the problem oflesion segmentation will be addressed. Pros and cons of automated and semi-automated softwares will be reviewed, with particularattention to two main questions: i) how to create an effective gold standard for software validation and ii) when to use supervisedmethods and unsupervised methods. The lesson will end with the description of new software for calculating changes in volume andnumber of lesions.

L10. Real assessments of MRI lesions and Atrophy: thepost-processing landscape

Marco BattagliniDepartment of Neurological and Behavioural Sciences, University of Siena, Siena, Italy

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All EXCEMED programmes are organized solely to promote the exchange and dissemination of scientific and medical information. No forms of promotionalactivities are permitted. There may be presentations discussing investigational uses of various products. These views are the responsibility of the namedspeakers, and do not represent an endorsement or recommendation on the part of EXCEMED. This programme is made possible thanks to an educational grantreceived from Merck KGaA, Darmstadt, Germany

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Clinical and research application of MRI in diagnosis and ... · diagnosis and monitoring of multiple sclerosis Overview MR imaging has dramatically improved the accuracy in the diagnosis