MAGNIMS MRI in monitoring disease activity and progression

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1 Teaching Course 3 MAGNIMS MRI in monitoring disease activity and progression Chairs: C. Enzinger (Graz, AT) N. De Stefano (Siena, IT) 7 Chances and challenges in monitoring disease activity and progression in MS C. Enzinger (Graz, AT) 8 MRI as a tool to identify inadequate treatment response in MS in clinical practice N. De Stefano (Siena, IT) 9 MRI in the detection of opportunistic infections and paradoxical reactions T. Yousry (London, GB)

2 Teaching Course 3 MAGNIMS MRI in monitoring disease activity & progression S & S C. Enzinger (Graz, AT) Department of Neurology, Model of the evolution of MS Repairing-Remitting Secondary Progression Clinical Disability CIS RR-MS SP-MS Clinical Threshold Brain Volume Inflammation RIS Axonal Loss M R I Inflammation, demyelination, axonal transection, plasticity, remyelination Inflammation, persistent demyelination Compston A, Coles A. Lancet. 2002;359: Reduced inflammation, chronic axonal degeneration, gliosis Chances & Challenges Heterogeneity of MS MRI phenotypes of patients after a first clinical episode suggestive of MS 1

3 N de Stefano Monitoring natural disease course Judging treatment effect / response Detecting side effects of treatment T Yousry What can/should we monitor? In what manner? How frequently? General recommendations for MS disease monitoring MRI protocols for disease monitoring should be identical with MRI scans for diagnostic purposes. Brain MRI is the modality of choice for MS disease monitoring. Contrast-enhanced T1-weighed sequences: acute inflammation FLAIR/T2-weighted sequences: clinically silent disease progression (e.g., active T2 lesions) The recommended frequency of serial MRI during disease monitoring is strongly related to the specific clinical setting (e.g., treatment efficacy, drug safety). In contrast to diagnosis, spinal cord MRI is not recommended for disease monitoring on a regular basis. Lancet Neurol 2012; 11: C F: ACTIVE LESION: C: Active demyelinating lesion evidenced by particles positive for myelin proteolipid protein within macrophages D: Sea of macrophages E: Reactive astrocytes (white arrows) and axonal swellings (green arrow) F: Perivascular inflammation G,H: CHRONIC ACTIVE LESION: G: Active macrophages at plaque edge H: Iron map of area boxed in G: most iron within macrophages 2

4 Contrast enhancing lesion on T1-weighted scan: Inflammation / active lesion Gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) 8 unpaired electrons in outer layer strongly paramagnetic, toxic (chelate) shortening of T1- and T2 Gd enhanced MRI indicates break down of BBB Active lesions enhance for 2 6 weeks Modification of enhancement by dosage of and delay after contrast material application Imaging parameters Steroid treatment Outcome variables Active scans Number of contrast-enhancing lesions / scan or cumulative Average duration of enhancement: 3.07 weeks (median: 2 weeks) Persistence related to max. enhanced volume and initial growth in enhancement One year, 26 RRMS, weekly MRI for 8 weeks, e.o.w. for 16 weeks, monthly thereafter: quantitative analysis of each new EL (n 113) during first 6 weeks Distribution of new ELs according to enhancement duration: non-gaussian, skewed toward enhanc. 2 weeks (dark gray: 21 lesions potentially affected by corticotherapy, light gray: 92 natural history lesions) Serial MRI after MP (31 courses) 13 patients with definite MS Gd-enhanced MRI before and after MP, then monthly 609 active lesions on 195 examinations Directly after treatment 78% reduction in number of EL No beneficial effect on rate of disappearance of related T2-abnormalities. MP effect temporary (on average 9.7 weeks) 3

5 New lesion formation (enlarging lesions) Occurrence of new (focal) T2 lesions is consistent with new areas of MS related tissue damage Modifications by Imaging parameters (sequence, slice thickness, etc.) Outcome variables Number of new T2 lesions Number of enlarging T2 lesions Number of newly active lesions (new and enlarging T2 and new contrast enhancing lesions) Serial MRI: identical protocol and repositioning are essential The shaded portions represent discrete areas of enhancement at the lesion border, and the lines represent possible MRI scan sections originating from different angulations. D indicates the displacement resulting from the repositioning error in a follow-up scan. Thus, the following results would be obtained: Line AB: Baseline scan, one lesion line AC: 3 lesions, one of which enhances line AE: 3 lesions, the first being new or a confluence, the second being an enlargement of a previous one, the third being new; the previously enhanced lesion disappeared Goodkin DE, Vanderburg-Medendorp S, Ross J. Arch Neurol Jun;50(6): Serial MRI obtained in a patient with relapsing-remitting multiple sclerosis. A B C D Proton-density (PD)-weighted MR images obtained at baseline (A), and one (B), two (C), and three (D) years after. Please note the disease progression with new and enlarging focal lesions over time. Wattjes M. et al. Nat Rev Neurol Sep 15. doi: /nrneurol [Epub ahead of print] 4

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7 Subtraction analysis of repeated MRI to identify new / enlarging lesions A B C Example of subtraction MRI in a patient with relapsing-remitting MS. FLAIR T2-weighted images at year 0 (y0) (A) and at year 1 (y1) (B), and subtracted images (y1-y0) (C). The arrows indicate the new and enlarging lesions (C). Wattjes M. et al. Nat Rev Neurol Sep 15. doi: /nrneurol [Epub ahead of print] Monitoring natural history of MS Which situations? Radiologically isolated syndrome (RIS) Clinically isolated syndrome (CIS) MS without disease modifying treatment Which MRI parameters? Gadolinium-enhancing lesions New T2-lesions When? One repeated MRI 6-12 months after initial work-up Further scans depending on clinical situation / symptoms Following-up the natural course of disease Follow-up brain imaging after 3-6 months is recommended in CIS patients with an abnormal baseline MRI, not fulfilling the 2010 McDonald diagnostic criteria. If not conclusive, a third brain MR scan might be acquired 6-12 months later. In RIS subjects, a follow-up brain MR after 3-6 months is also recommended. Spinal cord follow-up MR imaging in CIS patients in order to demonstrate DIS and DIT has limited value and should not be routinely performed. 6

8 Judging treatment efficacy In which patients and when? Clinical suspicion of treatment failure / inadequate response Routinely after the first year of treatment? Which MRI parameters to consider? Gadolinium-enhancing lesions New T2-lesions Atrophy estimation not yet ready for clinical use! Outcome variables Definition of inadequate treatment response during 24 months of follow-up Presence of relapses Disease progression (increase EDSS 1 for 6 months) Predictor variables R+ = 1 relapse within first year P+ = increase of 1 EDSS point within first year MRI+ = > 2 active lesions (new or enlarging T2 or Gd+ lesions) 7

9 Different MR criteria proposed for predicting treatment response based on observational studies Wattjes M. et al. Nat Rev Neurol Sep 15. doi: /nrneurol [Epub ahead of print] Increased vigilance vs. premature conclusions drawn from MRI Model of the evolution of MS Repairing-Remitting Secondary Progression Clinical Disability CIS RR-MS SP-MS Clinical Threshold Brain Volume Inflammation RIS Axonal Loss M R I Inflammation, demyelination, axonal transection, plasticity, remyelination Inflammation, persistent demyelination Compston A, Coles A. Lancet. 2002;359: Reduced inflammation, chronic axonal degeneration, gliosis Problems regarding individual assessment of atrophy A B C D Evolution of brain volume over 6 years in RR-MS patient Strong interindividual variability of brain volume and volume changes Multiple factors affecting brain volume (Noxa, hydration, drugs, etc.) Variability of estimation dependent on MRI technique and analysis Brain volume brain atrophy 8

10 Follow-up MRI for monitoring treatment effects in MS Routine follow-up brain MRI, including T2-weighted and contrast-enhanced T1-weighted sequences, recommended 6-12 months after the onset of treatment effect. New T2 lesions count requires high quality comparable MRI scans and interpretation by highly qualified individuals. There is still not enough data supporting the use of brain volume changes for predicting treatment response in individual patients. Wattjes M. et al. Nat Rev Neurol Sep 15. doi: /nrneurol [Epub ahead of print] MRI in the detection of treatment related adverse effects Important findings are: opportunistic infections (e.g., PML, herpes infection) unexpected disease activity including paradoxical reactions (e.g., tumefactive demyelination) comorbidities (e.g., vascular, neoplastic) MRI protocol and frequency of imaging strongly depend on the specific drug and the patients risk profile (e.g., treatment duration, serostatus for JCV, previous treatment with other immunosuppressive drugs). T2-weighted, FLAIR and diffusion weighted images are useful screening sequences for PML lesion detection. Wattjes M. et al. Nat Rev Neurol Sep 15. doi: /nrneurol [Epub ahead of print] MRI phenotyping of MS 9

11 Lublin new definitions Conclusions Besides its merits in diagnosing MS, MRI is helpful in the assessment of the clinical course of the disease. Routine MRI controls without exact clinical motivation and indication are not justified. Akquisition and interpretation of MRI data have to follow high quality standards MRI may provide pertinent ancillary information in these situations: Disease activity after first clinical manifestation / diagnosis without disease modifying treatment Identifying inadequate treatment response / treatment failure Unclear clinical evolution (e.g. relapses yes / no; progression?) Monitoring of potential adverse treatment-related side effects Selected References (alphabetical) Enzinger C et al. MAGNIMS study group. Nonconventional MRI and microstructural cerebral changes in multiple sclerosis. Nat Rev Neurol 2015 [in press]. Barkhof F et al. MRI monitoring of immunomodulation in relapse-onset multiple sclerosis trials. Nat Rev Neurol Dec 6;8(1): Fazekas F, Soelberg-Sorensen P, Comi G, Filippi M. MRI to monitor treatment efficacy in multiple sclerosis. J Neuroimaging Apr;17 Suppl 1:50S-55S. Filippi M et al. Association between pathological and MRI findings in multiple sclerosis. Lancet Neurol Apr;11(4): Rovira À et al. MAGNIMS study group. Evidence-based guidelines: MAGNIMS consensus guidelines on the use of MRI in multiple sclerosis-clinical implementation in the diagnostic process. Nat Rev Neurol Aug;11(8): Epub 2015 Jul 7. Wattjes MP et al. MAGNIMS study group. Evidence-based guidelines: MAGNIMS consensus guidelines on the use of MRI in multiple sclerosisestablishing disease prognosis and monitoring patients. Nat Rev Neurol Sep 15. [Epub ahead of print] 10

12 Christian Langkammer Michael Khalil Stefan Ropele Franz Fazekas 11

13 MRI as a tool to identify inadequate treatment response in MS in clinical practice Nicola De Stefano, MD Department of Medicine Surgery and Neuroscience, University of Siena, Siena, Italy The advent of a large number of new therapies in multiple sclerosis (MS) warrants the development of tools able to select the best treatment option for each new MS patient, making imperative for clinicians prompt treatment decisions in patients with suboptimal treatment response. This is difficult due to the uncertainties in defining response or non-response to therapy in a chronic inflammatory and demyelinating disease such as MS 1-2, 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 3. 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 nonresponders to Interferons (IFN), reporting conflicting results Data ranged from studies suggesting that one active lesion has a predictive value larger than relapses in increasing the risk of short-term disability

14 progression 7-8, to other studies proposing a substantial increase in number of active lesions over the first year of IFN treatment, better if in combination with clinical events, as necessary to increase the risk of disability progression at follow-up 3,8-11. On this basis, a meta-analysis aiming at establishing the relevance of MRI markers in predicting patients at higher risk of treatment failure failed to combine in a quantitative summary estimate most of the published studies, due to the large heterogeneity in both measured markers and outcome assessments 12. More recently, integrated strategies combining MRI and clinical markers in scoring systems provided a potentially useful approach for the management of MS patients in clinical practice 3. We will focus on the many definitions of clinical response to therapy and explore the markers able to predict such response. Also, it will highlight advantages and limitations of the existing scoring systems to predict the response to therapy in the light of a future expansion of these models to biological markers and to other classes of new emerging therapies for MS.

15 REFERENCES 1. Rio, J. et al. Defining the response to interferon-beta in relapsing-remitting multiple sclerosis patients. Ann Neurol. 59, (2006). 2. Rio, J. et al. Relationship between MRI lesion activity and response to IFNbeta in relapsing remitting multiple sclerosis patients. Mult Scler 14, (2008). 3. Sormani MP, De Stefano N. Defining and scoring response to IFN-β in multiple sclerosis. Nat Rev Neurol. 2013;9: Rio, J., Comabella, M. & Montalban, X. Predicting responders to therapies for multiple sclerosis. Nat. Rev. Neurol. 5, (2009). 5. Rudick, R., Lee, J., Simon, J., Ransohoff, R. M. & Fisher, E. Defining interferon β response status in multiple sclerosis patients. Ann. Neurol. 56, (2004). 6. Prosperini, L. et al. One-year MRI scan predicts clinical response to interferon β in multiple sclerosis. Eur. J. Neurol. 16, (2009). 7. Prosperini L et al Interferon beta failure predicted by EMA criteria or isolated MRI activity in multiple sclerosis. Mult Scler 20(5): (2014). 8. Rio, J. et al. Relationship between MRI lesion activity and response to IFNbeta in relapsing remitting multiple sclerosis patients. Mult Scler 14, (2008). 9. Sormani M. et al. Scoring treatment response in patients with relapsing multiple sclerosis. Mult Scler Mult Scler. 2013;19:605-12

16 10. Romeo M. et al. Clinical and MRI predictors of response to interferon-beta and glatiramer acetate in relapsing-remitting multiple sclerosis patients. Eur J Neurol, Epub ahead of print (2013). 11. Sormani M et al. Refining response to treatment as defined by the Modified Rio Score. Mult Scler. 2013;19: Dobson R et al Assessing treatment response to interferon-β: is there a role for MRI? Neurology. 21;82(3): (2014). 13.

17 Detection of Opportunistic Infections & Paradoxical Reactions TA Yousry Institute of Neurology Queen Square MS Treatment 1 st line agents (Interferons) Relative risk reduction 30% Absolute risk reduction 0.3 relapses/y Baldwin Curr Opin Neurol 2013 Natalizumab Humanized monoclonal antibody α4-integrin cellular adhesion molecule Natalizumab MS Treatment Relative risk reduction 68% Absolute risk reduction 0.55 relapses/y Rudick JAMA Neurol 2013 Baldwin Curr Opin Neurol 2013 Natalizumab Treatment effect Annual relapse rate 68% Disability progression 54% (sustained for 6 M) Gd-lesions in 2 nd year 92% New/enlarging T2-lesions 83% (over 2y) Natalizumab Very good effect However, 2 PML cases in 2005 (3 rd in Crohn) Suspension Safety study: PML risk 1/1000 (95% CI per 1000) mean treatment period 17.9M Readmission in 2006

18 Dilemna MS Chronic disease Treatment PML Acute, deadly disease Natalizumab Strategies to establish a PML diagnosis as early as possible using Clinical vigilance MRI pattern CSF analysis Criteria based on MR Criteria Shortcomings 2 PML (Natalizumab/MS) patients PML in HIV patients Need to establish new recommendations MR Challenge in Natalizumab Treated MS Patients Identification of early PML signs Differentiation early PML from new MS lesions Is the PML pattern similar? PML vs MS Boster Arch Neurol 2009

19 Basic pattern (PML-MS) Location Subcortical (U-fibers) 100% Signal T2w/DWI hyper 100% T1w hypo 94% Border GM sharp 100% WM ill-defined 100% Basic pattern + Variations >3cm 93% Peri T2 hyper 73% >3cm + Peri T2 hyper 67% Yousry Annals Neurol 2012 Yousry Annals Neurol 2012 Basic Pattern >3cm/Peri T2 Contrast Enhancement PML Presym 33% Early (< 14d) 41% FU (>14d) 75% IRIS Acute (<14d) 71% Post (>14d) 100% IRIS-Post-IRIS T1 Hyperintensity Pre-sym Early IRIS

20 CE Lindå N Engl J Med 09 DD Problems at Presentation High lesion load MS vs PML Lesion < 3cm Filling gyrus Band cortex/subcortex Unusual pattern 1) High lesion load PML vs MS MS vs PML T1 hypointensity DWI 2) Lesion < 3cm a) Band-like July Jan Jun 08 2) Lesion < 3cm b) Filling Gyrus 9 July July 08 7 Aug Aug 08 21Aug Aug 08 Lindå N Engl J Med 09 3 Sep Sep Sep 08

21 Early PML Punctate Lesions T2/FLAIR 72% Enhancement 83% PML IRIS T2/FLAIR 86% Enhancement 71% Punctate Lesions IRIS T lymphocyte infiltration of VR PL Infiltrated VR? Sign of early inflammation in Early PML PML & IRIS simultaneous? Punctate Lesions 3) Unusual Pattern Wattjes JNNP ) Unusual Pattern 3) Unusual Pattern Wattjes MS 2014

22 3) Unusual Pattern 3) Unusual Pattern Wattjes MS 2014 Wattjes MS ) Unusual Pattern Wattjes MS 2014 Characteristics Features Location Subcortical U-fibers; cortex & BG; often bilateral Size Usually >3cm Borders GM Sharp WM ill defined Progression Increase in size and new appear Mass effect No Signal T2w Hyperintense T1w Typically hypointense Hyperintensity PML-IRIS FLAIR Hyperintense; >T2W images DWI Always hyperintense; rim Perilesional Small, punctate T2-hyperintense lesions in immediate vicinity of main lesion Enhancement Frequent punctate and/or rimlike Atrophy Not in early phase PML-IRIS

23 However y man, diagnosed MS in 06 frequent relapses April 08 Natalizumab August 08: new onset confusion, altered behavior, left hemianesthesia, worsening gait and balance Pre-sym Early IRIS Post-IRIS Twyman JNS 10 JC negative Unusual MS plaque Risk April 08 August 08 Twyman JNS 10 October 08 Bloomgren NEJM 2012 Risk Factors Duration of Exposure Anti-JCV serum antibodies Prior immunosuppressive use Duration of natalizumab treatment (25-49 infusions) Baldwin Curr Opin Neurol 2013

24 Natalizumab Oct 2007-Dec th administration Jan 12 Breast Ca Tys stopped Mar Cog+Mot sy 20 Oct, , Dec, Jun, May, 2012 MR Algorithm 23 Mar, Nov, 2011 Blinkenberg MSJ 13 Kappos Lancet Neurol 2011 Carruthers Science Direct 2014 Recommendation Location Subcortical Grey matter Cortex 50% Deep 28%-57% Border GM: sharp WM: ill defined MR signal T2 + DWI hyper T1 hypo T1 shortening IRIS Size > 3cm Contrast 50-80% Punctate T2/contrast IRIS T1 Hyperintensity Sequences Recommendation FLAIR/T2 DWI (T1-Gd) Frequency 4-6m Clinical suspicion PML Typical MR pattern Summary Early diagnosis crucial, best in silent phase MR has a central role in assessing patients treated with Natalizumab