Welcome to todays MS Research Update Webinar. Acknowledgement

Transcription

1 Welcome to todays MS Research Update Webinar Topic: MRI Brain Volumetrics in MS Your Presenter is: Dr Heidi Beadnall Your Facilitator is: Andrea Salmon Acknowledgement We acknowledge and pay respect to the traditional custodians past and present on whose lands we meet today. We acknowledge the deep feelings of attachment and the relationship of Aboriginal people to country and respect the cultural authority of the elders in each community 1

2 Follow Up This presentation has been prepared and is presented by an independent expert. The information presented is based on research and does not include management strategies Individuals should seek further advice regarding their situation by contacting MS Connect on MS Research Australia MS Research Australia is dedicated to funding and coordinating multiple sclerosis research in Australia, as part of the worldwide effort to solve MS. Its mission is to accelerate research towards the prevention, better treatments and ultimately a cure for MS. Dr Heidi Beadnall is currently undertaking a PhD, through the University of Sydney, in the area of Multiple Sclerosis neuroimaging and brain atrophy. She consults in the Royal Prince Alfred Hospital Multiple Sclerosis and Neuroimmunology clinics. phone Page 2

3 MRI & MRI Brain Volumetrics in Multiple Sclerosis Dr Heidi Beadnall The Brain and Mind Centre, The University of Sydney Content Overview MS Background Basic Pathology Natural History MRI in MS Clinical Practice Diagnosis Prognosis Treatment Monitoring MRI Brain Volumetrics & Atrophy Background Research to date Techniques? Future use in MS Clinical Practice Questions 3

4 Immune System in MS Autoimmunity = Immune system attacks itself Multiple Sclerosis is considered an autoimmune disease driven predominantly by T cells & mediated by macrophages But other immune system cells (B cells & regulatory T cells) & primary injury to the oligodendrocytes (that form myelin) are all thought to be contributory MH Barnett. PhD Thesis 2007 MS is a Central Nervous System disease %20lesson/bhp13.htm natmind/anatmd2.html 4

5 Neuron = Nerve Cell Myelin MS Background MS is classically characterised by inflammation & destruction of myelin Demyelination is an important & well known aspect of MS Axon damage has continued to gain attention recently and there is now substantial evidence that axonal damage plays an important role in MS s-biology-textbook/the-animal-body-basic-form-andfunction-33/animal-primary-tissues-193/muscle-tissuesand-nervous-tissues /images/fig-ch33_02_13/ textbook/the-animal-body-basic-form-and-function-33/animal-primary-tissues- 193/muscle-tissues-and-nervous-tissues /images/fig-ch33_02_13/ 5

6 MS disease processes: Theory Demyelination/Remyelination Axonal Destruction/ Nerve Loss Degeneration of Chronically Demyelinated Trapp B, et al. Curr Op Neurol Axonal Pathology in white matter lesions multiple-sclerosis-research.blogspot.com/2012/02/education-inflammation-chicken-or-egg.html MS Lesion Demyelination + axonal transection Axonal ovoids = axonal transection MRI T1 hypointensities or black holes When chronic represent permanent extensive tissue destruction = demyelination + axonal loss 6

7 Structures Involved in MS Known for being a white matter disease White matter plaques Classic feature Readily visible with conventional MRI Grey matter also involved Cortical & deep grey matter structures GM lesions not generally seen with standard MRI Normal appearing brain (on MRI) Abnormalities can be detected at the cellular level MS: Inflammatory & Neurodegenerative 7

8 Natural History of MS Pre-clinical Brain Volume CIS RRMS SPMS Clinical Threshold Axonal Degeneration Total lesion load (T2 lesion volume) MRI lesion activity McDonald MS Poser CDMS Number of lesions Sydney Neuroimaging Analysis Centre 2013 MRI in Current MS Clinical Practice 8

9 MRI in Current MS Clinical Practice Diagnosis Prognosis Treatment Monitoring MRI & MS Diagnosis There is no single test that allows us to diagnose MS Currently MS is diagnosed based on: The 2010 McDonald Criteria for Diagnosis of MS Diagnosis can be made on clinical grounds alone MRI can support, supplement or even replace some clinical criteria MRI findings are used more than in previous versions of the diagnostic criteria In some cases MRI criteria allows earlier diagnosis and therefore treatment MRI findings/characteristics can often help differentiate between MS and MS mimics Polman C, et al. Ann Neurol,

10 The 2010 McDonald Criteria for Diagnosis of MS Relapsing-Remitting MS Diagnosis Dissemination in Space Separation in space = Lesions present in more than one region of the CNS Dissemination in Time Separation in time= Lesions present at different times via MRI or clinical criteria Essentially diagnosis made if: 2 clinical attacks OR 1 clinical attack + MRI criteria met Polman C, et al. Ann Neurol, 2011 The 2010 McDonald Criteria for Diagnosis of MS Primary Progressive MS Diagnosis One year of disease progression AND 2 of the following 3 Dissemination in Space in the Brain Dissemination in Space in the Spinal Cord Positive Cerebrospinal Fluid Polman C, et al. Ann Neurol,

11 Dissemination in Space (DIS) Polman C, et al. Ann Neurol, 2011 Dissemination in Time (DIT) Polman C, et al. Ann Neurol,

12 Attack/relapse criteria MRI & MS Prognosis Baseline MRI measures appear to be of some prognostic value but do not fully correlate with clinical disability measures. Group level evidence Especially studied in CIS cohorts with prediction of progression to definite MS & increased disability accumulation Higher T2 lesion load Presence infratentorial lesions (including brainstem) Presence spinal cord lesions Forms a useful guide in clinical decision making & initial treatment decisions - but no certainty at the individual patient level Wattjes MP, et al. Nat Rev,

13 MRI & MS Prognosis Higher T2 lesion load Presence infratentorial lesions (including brainstem) Presence spinal cord lesions multiple-sclerosis-research.blogspot.com /2015/01/education-whats-mri.html db62/multiple-sclerosis.html waiting.com/brainstem.html MRI & MS Treatment Monitoring Clinical relapses/attacks AND Presence/absence of new (interval) &/or gadolinium enhancing lesions on MRI 13

14 Current Treatment Goals in MS NEDA 3 (No Evidence of Disease Activity) concept fits with current aggressive MS treatment goals NEDA 3 = No clinical activity + (clinical relapses) No clinical progression + (disability progression) No MRI activity (No new/enlarging T2 lesions & no new gadolinium enhancing T1 lesions) MRI & MS Treatment Monitoring Judgement of NEDA 3 on a particular treatment Sufficient time to work Re-baseline imaging NEDA 3 can be difficult to achieve with current therapies Not 100% effective Act on inflammation component Not practical in current treatment landscape to change therapy every time a single interval MRI lesion appears Implications of MRI scanner change, MRI slice thickness, MRI reporting, break in treatment etc. 14

15 MRI scan frequency MS clinical practice Baseline (new diagnosis/patient) MRI Brain & MRI whole spinal cord Repeat MRI Brain after 3-6 months initially Confirm MS diagnosis; monitoring; not on treatment Repeat MRI Brain 6 months after starting a new treatment Re-baseline Repeat MRI Brain 12 monthly if clinically & radiologically stable Widen gap gradually if ongoing stability Consider repeat MRI Brain and/or MRI spinal cord Clinical relapse suspected; concerning or unexpected symptoms/signs Gadolinium administration Give if will aid diagnosis +/- change management decisions Don t give if contraindicated??safety issues with multiple dosing - uncertain Need for New Biomarkers in MS Biomarker = a measurable indicator of the severity or presence of some disease state Current MS biomarkers are imperfect at predicting disease outcomes & long term disability in MS Thus there is continued research into finding new biomarkers to address this knowledge gap.. Including MRI biomarkers.. 15

16 Brain Volume Loss / Atrophy in MS Brain Atrophy (shrinkage) in MS Myelin loss + axonal loss + nerve loss = loss of brain tissue/volume Loss of brain volume over time = BRAIN ATROPHY (SHRINKAGE) 16

17 Whole Brain Atrophy Rates: Healthy controls versus MS patients Healthy adults -0.1 to -0.3% per year Untreated MS patients -0.5 to -1.35% per year Treated MS patients Depends on treatment & individual patient factors Proposed treatment goal: Aim for the same brain atrophy rates as in the normal health population Brain volume loss <-0.4% per year De Stefano N, et al. JNNP 2015 Brain Atrophy in Multiple Sclerosis Focal White Matter Lesions Tissue loss within lesions (myelin/axons) Wallerian Degeneration Remote effect of axonal transection within lesions Diffuse/global injury to normal appearing white and grey matter and/or neurones Genetic influences 17

18 Brain Atrophy in MS Affects all brain regions White matter & grey matter Grey matter cortical & deep grey (e.g. thalamus) Selective grey matter volume loss Clinically Isolated Syndrome Early MS Simon JH. Mult Scler Fisher E et al. Ann Neurol MRI Brain Volume & Atrophy Assessment in MS Specialised MRI techniques & computer software Detect small changes in brain volumes In MS research populations MRI measured brain atrophy is associated with physical & cognitive disability in MS patients Rudick RA et al. J Neurol Sci July 15; 282(1-2): Calabrese M et al. Arch Neurol Sept; 66(9): Goodin et al. J Neurol Neurosurg Psychiatry Mar; 83(3):

19 Important Research Findings MRI Brain Volume & Atrophy in MS Brain atrophy occurs early in MS & is consistent across MS subtypes Significant correlation between annualised whole brain volume change and annualised change in EDSS (disability score) Significant correlation between total grey matter volume and EDSS Grey matter volume loss correlated strongly with disability Thalamic atrophy occurs early in disease & is associated with conversion to clinically definite MS Thalamic atrophy is associated with a wide range of physical and cognitive deficits De Stefano N et al. Neurology 2010; 74: Minneboo et al, JNNP 2008 Bermel et al, Lancet Neurology 2006 Queens Square CIS cohort 20 year follow up Davies et al. 2005, Henry et al 2009, Zivadinov et al Minagar et al. 2013, Shiee et al. 2012, Batista et al. 2012, Hulst

20 Baseline normalised whole brain volume strongly correlated with follow up EDSS [at approximately 2 years; RRMS] Greater whole brain atrophy in the first 2 years correlated with greater disability (EDSS) at 8 year follow up [RRMS] Whole brain atrophy over 1-2 years predicted EDSS at 10 year follow up Whole brain atrophy & lesion load predicted long term clinical disability Treatment effects on disability progression correlated with treatment effects on brain atrophy [meta-analysis; RRMS] Minneboo A et al. JNNP 2008; 79: Fisher E et al. Neurology 2002; 59: Popescu et al, JNNP 2013 Popescu et al, JNNP 2013 Sormani MP, et al. Ann Neurol MS research shows that at the group/population level: Reduced brain volume correlates with increased physical & cognitive disability Increased brain atrophy correlates with increased physical & cognitive disability 20

21 MRI Brain Volumetrics & Atrophy in MS Research Clinical Trials MRI measured brain volumes & atrophy have been acknowledged as important MRI biomarkers in MS: Prognostic value Disability progression & neurodegeneration Brain volumes/atrophy have been included as an MRI outcome measure in multiple MS clinical drug trials Disease modifying therapies (DMTs) Novel neuroprotective & repair agents MRI Brain Volume & Atrophy Assessment in MS Not currently used in routine MS Clinical Practice 21

22 MRI Brain Volumetric Analysis: Issues & barriers to use in clinical practice Multiple technical, biological, disease-related & treatment-related factors effect measurements Evidence at group level but not at individual level Multiple techniques in research setting No single accepted method Measurement errors of techniques/methods need to be lower for individual patient use Manual & semi-automated techniques Time consuming, costly, specialized skills needed Fully automated techniques Commercial (cost),?higher measurement error Certain MRI sequences required Usually done as part of standard clinical protocols at MS specialised centres Brain Atrophy Measurement in Multiple Sclerosis Factors affecting volume measurement Head position, slice plane Head/skull size Biological effects Sex, Aging, Hydration status, Diurnal variation Disease & treatment effects MS related - Tissue loss & repair MS related - Acute inflammation/oedema More impact on WM than GM measurements Steroid effect DMT effects Variable depending on agent Co-morbid disease effects (non-ms diseases) 22

23 Brain Atrophy in Multiple Sclerosis MRI Measurement Techniques Brain Atrophy in Multiple Sclerosis MRI Measurement Techniques Eyeball neuroradiologists, neurologists Not quantitative Quantitative 2D linear Easy implementation, poor reproducibility Quantitative 3D Sensitive, reproducible Multiple methods developed Varied popularity Pros & cons of different techniques 23

24 Brain Atrophy in Multiple Sclerosis Segmentation-based vs Registration-based MRI analysis Segmentation-based Single time-point [Cross-sectional] Brain volume or fraction measurement Whole brain, white matter (WM), grey matter (GM), CSF volumes/fractions [regional volumes possible] Higher measurement errors Quality of MRI effects results Not recommended for longitudinal studies WM lesions can be incorrectly attributed as GM SIENAX, BPF etc. Registration-based Two time-points [Longitudinal] Percentage brain volume change measurement Whole brain volume change only [regional volumes not possible] Sensitive to change over time; low error rate Less sensitive to MRI quality Used for longitudinal studies only SIENA, BBSI etc. techrep/tr04ss2/tr04ss2/node14.html Brain Atrophy in Multiple Sclerosis MRI Measurement Techniques Manual Time consuming; specialised analyst; $$ Semi-automated Less time consuming; specialised analyst some manual components; $$ Visual checking; gold standard currently New fully automated Quick; no manual intervention; $$ (commercial) Accuracy needs to be checked against current gold standards Ongoing technology developments to improve accuracy MSmetrix, NeuroQuant etc. 24

25 Automated MRI volumetric techniques SIENAX versus NeuroQuant/MSmetrix cross-sectional: Whole Brain Volume Wang C, Beadnall HN, et al. JNNP

26 SIENA versus MSmetrix longitudinal pipeline: Annualised Percentage [Whole] Brain Volume Change % r = strong positive correlation p value < % Beadnall HN, Ly L, et al. ANZAN 2016 MRI Brain Volumetrics & Atrophy in Clinical MS Practice 26

27 Brain Atrophy in Multiple Sclerosis Next Steps, translation into clinical practice AIMS: Provide MS neurologists with a longitudinal disease monitoring tool in individual patients. Provide MS neurologists with a cross-sectional tool, against normative datasets, that can be applied to individual patients, to assist with prognosis. Brain Atrophy in Multiple Sclerosis Translation into clinical practice - actions MRI-related factors Optimise MRI acquisition Minimise artefacts, best quality scans possible Standardize MS MRI protocols & Brain atrophy protocols Single centres & across centres Collect data from healthy controls acquired using the same MRI protocols MS patients will be compared to MRI brain atrophy analysis pipelines Standardize pipelines Fully automated Reduce variability, reduce measurement error Make user-friendly Improve availability Address resourcing Costs, technically demanding, time consuming?reimbursement,?automated (commercial costs) 27

28 Brain Atrophy in Multiple Sclerosis Translation into clinical practice - actions MS-related & MS treatment-related factors Note timing of steroids & DMT commencement (pseudoatrophy effect) Re-baseline MRIs as needed Note timing of clinical relapses & gadolinium enhancing lesions Re-baseline MRIs as needed Biological & other non-ms related factors Use normalised volumes (head/skull size) Collect large normative datasets age, sex Avoid extremes of hydration Make note of/ correct for comorbidities Brain Atrophy in Multiple Sclerosis Translation into clinical practice - actions Validate techniques in individual MS patients Continued clinical research Use as a longitudinal clinical tool in individuals features: Same MRI scanner, protocols, parameters, analysis technique, analysis centre?same time of day Long follow up periods to smooth out biological & treatment-related brain volume fluctuations (but not too long!) 28

29 Future Treatment Goals in MS NEDA 4 NEDA 4 = No clinical activity + (relapses) No clinical progression + (disability progression) No MRI activity + (No new/enlarging T2 lesions & no new gadolinium enhancing T1 lesions) No MRI progression (No brain volume loss >0.4%/year) MRI Brain Volumetrics & Atrophy in Clinical MS Practice Potential to be useful tools to help prognosticate & predict patient disability at the individual level At diagnosis & early in disease help predict long term disability?role in RIS, CIS Potential to guide treatment choice & monitor treatment response at the individual level Start with more effective therapy Consider up-titration to more effective medication?role with future reparative agents 29

30 MRI Brain Volumetrics & Atrophy in Clinical MS Practice Patients & MS Neurologists need to understand the benefits & limitations of this technology Important not to misinterpret information & make incorrect decisions Add to knowledge not the whole answer For advice or assistance, contact MS Connect ACT/ NSW/ Victoria: QLD: SA/NT: WA: (08) TAS: For updates about research, contact MS Research Australia For information about the Longitudinal Study, visit Page 30

31 Library & Publications In the Library & Publications section of our website you can find information about: MS Library services How to borrow both ebooks and print books on topics such as wellness, and managing multiple sclerosis and its symptoms Accessing our online library catalogue MS publications, including Intouch magazine, newsletters, booklets and information sheets Visit our website for more information Page Library & Publications Page 31

32 Resources Related to Thinking & Memory Title: Facing the Cognitive Challenges of Multiple Sclerosis Author: Jeffery Gingold Availability: Print and ebook When attorney Jeffrey N. Gingold misplaced his wife on the living room couch, and became lost while driving just blocks from his home, little did he know that he was experiencing a hidden symptom of multiple sclerosis: cognitive difficulties. Facing the Cognitive Challenges of Multiple Sclerosis is a courageous and compelling personal account of one man's anguishing struggle with this aspect of the disease. It was written for the silent majority of MS patients who are privately dealing with MS cognitive symptoms and potential disabilities. The National Multiple Sclerosis Society estimates that over 400,000 people in the U.S. have been diagnosed with multiple sclerosis, and there are millions more worldwide. Conservatively speaking, half of them will encounter varying degrees of cognitive difficulties. Facing the Cognitive Challenges of Multiple Sclerosis brings this hidden disability into the open. It is an essential resource that will educate individuals coping with multiple sclerosis, and inform their families, caregivers, doctors and therapists. Title: Multiple Sclerosis: Understanding the Cognitive Challenges Author: Nicolas LaRocca Availability: Print Multiple Sclerosis: Understanding the Cognitive Challenges is the first comprehensive discussion of MS-related cognitive dysfunction, including the changes that can occur, their assessment and treatment, and strategies for dealing with their impact in daily life. Written by two clinical psychologists with special expertise in MS, and with contributions by two leading neuropsychologists, the book answers all questions patients may have about their condition, including: A definition of cognition and discussion of the processes that underlie human thought The emotional and social impact of cognitive changes The neuropsychological evaluation of cognitive symptoms Detailed overview of treatment options Vignettes describing the real-life experiences of a person with cognitive dysfunction Extensive references to the scientific literature Page NDIS Support The NDIS is the Biggest social reform changing the way supports and services are purchased and delivered for people with a disability The NDIS has commenced rolling out across NSW, ACT, Victoria and Tasmania it will occur in different ways across the regions MS is here to help you understand what the NDIS means, and assist you to prepare for a planning meeting We have resources available on our website click on the large NDIS button MS is registered with NDIA to deliver Support Coordination, Residential Respite, Social Support Day Program (Vic) Exercise physiology and personal training (NSW) Specialist Continence Assessment (NSW), Physiotherapy and Occupational Therapy (NSW and Vic). Want to learn more? Please call MS Connect on Page 32