1. MULTIPLE SCLEROSIS NEW TECHNIQUES Matilda A. Papathanasiou Assist.professor of Neuroradiology Dpt of Radiology University of Athens Medical School ’’ΑΤΤΙΚΟΝ’’ University Hospital.

2. OVERVIEW Review indications for imaging-protocol Review imaging findings in clinical setting New imaging techniques –Findings –Implications –Limitations

3. MRI WHO ? HOW ?

4. MRI INDICATIONS Ι 1.Initial evaluation after a CIS or based on past history that is suspicious 2.Baseline imaging evaluation in MS 3.Spinal cord imaging a.Symptoms s.c. (+ brain) b.Findings in brain MR ? J.H. Simon, D. Li, et al Standardized MR Imaging Protocol for Multiple Sclerosis: Consortium of MS Centers Consensus Guidelines AJNR Am. J. Neuroradiol., Feb 2006; 27: 455 - 461

5. MRI INDICATIONS ΙΙ 4.Follow up 1. when clinical indications a.Unexpected worsening b.Reassess burden for initiation of Tx c.Suspicion of secondary Dx 2.routine periodically (yearly) optional 5.Contrast initial baseline exam Periodic follow up J.H. Simon, D. Li, et al Standardized MR Imaging Protocol for Multiple Sclerosis: Consortium of MS Centers Consensus Guidelines AJNR Am. J. Neuroradiol., Feb 2006; 27: 455 - 461

6. J.H. Simon, D. Li, et al Standardized MR Imaging Protocol for Multiple Sclerosis: Consortium of MS Centers Consensus Guidelines AJNR Am. J. Neuroradiol., Feb 2006; 27: 455 - 461 SequenceDiagnostic Scan Comment for CIS 1 3 plane (or other) scout Recommended Set up axial sections through subcallosal line 2 Sagittal Fast FLAIR Recommended Sagittal FLAIR sensitive to early MS pathology, such as in corpus callosum 3 Axial FSE PD/T2 Recommended PD series sensitive to infratentorial lesions that may be missed by FLAIR series 4 Axial Fast FLAIR Recommended Sensitive to white matter lesions and especially juxtacortical–cortical lesions 5 Axial Gd enhanced T1Recommended Standard dose of 0.1 mmol/kg scan starting minimum 5 min after injection

7. K. Kollia et al, AJNR, 30:699 –702 Apr 2009

10. ‘’Black holes’’

11. 1.1 Gd+ or 9 T2-hyperintense lesions if there is no enhancing lesion 2.At least one infratentorial lesion 3. At least one juxtacortical lesion 4.At least 3 periventricular lesions (Note: One spinal cord lesion can be substituted for one brain lesion.) MRI criteria dissemination in space McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis οf multiple sclerosis. Ann Neurol 2001;50:121–27 3 of 4

12. PERIVENTRICULAR - JUXTACORTICAL

13. JUXTACORTICAL

14. INFRATENTORIAL

15. MRI criteria dissemination in time 1. MRI > 3mo after clinical event, Gd+ site # original 2. MRI > 3 mo after clinical event, Gd- repeat MRI in additional 3mo new Τ2 or new Gd+ McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis οf multiple sclerosis. Ann Neurol 2001;50:121–27

16. ENHANCEMENT

17. SPINAL CORD 50-90% MS up to 25% only site involved cervical dorsolateral, < 2 vertebral bodies < half transverse diameter Multifocal Cord atrophy

21. DIFFERENTIAL DIAGNOSIS  Ischemic lesions (small vessel disease)  Migraine  Vasculitis collagen v d  Encephalitis (ADEM, SSPE)  Trauma  Mets  Sarcoid  Dilated perivascular spaces VR  UBO (20%)  tumor (solitary lesions)

22. DIAGNOSIS MS is a clinical Dx MRI supports or provides alternative dx

23. Findings with increased specificity for MS ?

24. Plaques along calososeptal interface and periventricular extension (Dawson fingers) (sensitivity 93%, specificity 98%) MA Gean et al. Radiology 1991 180:215-221

25. Lesions indicative MS Brain stem, subcortical, spinal cord Posterolateral pons, cerebelar peduncles Enhancement MS vs small vessel

26. BRAIN CORD MS(25)100% 92% O. Ν. D(66) 65% 6% Bot J.C.,Barkhof F.et al Differentiation of Multiple Sclerosis from Other Inflammatory Disorders and Cerebrovascular Disease: Value of Spinal MR Imaging Radiology 2002 223: 46-56; CVD 17 CONNECTIVE TD 18 SLE 13 SJOGREN 7 SARCOID 5 INTERMED UVEITIS 6 Combine MRI brain+spinal cord “In contrast to MS, cord lesions are very uncommon in OND. This finding can help differentiate these disorders”

27. CLINICORADIOLOGIC PARADOX Poor correlation of conventional imaging/clinical MRI 4-10x more sensitive in detecting lesions /clinical Gd enhancement 5-10x /clinical

28. NEW TECHNIQUES Volumetric MRI Volumetric MRI Magnetization transfer Magnetization transfer Diffusion Tensor Imaging Diffusion Tensor Imaging MR Spectroscopy Cortical imaging Cortical imaging Functional MRI

29. NEW TECHNIQUES Volumetric MRI Volumetric MRI Magnetization transfer Magnetization transfer Diffusion Tensor Imaging Diffusion Tensor Imaging MR Spectroscopy Cortical imaging Cortical imaging Functional MRI

30. VOLUMETRIC MRI –LESION LOAD total lesion volume Τ2, T1 total lesion activity enhanced Τ1 –BRAIN ATROPHY

31. VOLUMETRIC MRI LESION LOAD (T2 lesion) T2 lesion volume increases 10%/year in early RRMS T2 lesion load SPMS > RRMS Clinical trial studies however Τ2 lesions heterogenous Τ2 load does not include NAWM

32. VOLUMETRIC MRI LESION LOAD ( Τ1 lesion ) Τ1 Gd lesion load RRMS > SPMS Τ1 lesion load (Gd or black holes) correlate clinical outcome (EDSS) better than Τ2 Clinical trial studies

33. LESION LOAD CONCLUSIONS Lesion load does not account for patient’s functional state Information monitoring natural history Information monitoring treatment effects

34. ATROPHY 40 y.o. woman

35. VOLUMETRIC MRI ATROPHY –Global 0.6-1.0% yearly MS ( 0.1-0.3% nl) –Not reversible –Early prognosis –all MS subtypes, even early and CIS –Cortex / WM –GM volume loss affects different regions

36. RRMS/nl Brain voxels with significant GM loss in MS patients are shown in yellow (P <.05, corrected). A. Giorgio et al Brain Atrophy Assessment in Multiple Sclerosis: Importance and Limitations Neuroimag Clin N Am 18 (2008) 675-686

37. ATROPHY CONCLUSIONS –Correlates with clinical disability > lesion load –Correlates with cognitive impairment –Evident before clinical disability –Multicenter trials –Is the distribution of atrophy clinically significant? –programs ’’in-house’’

38. NEW TECHNIQUES Volumetric MRI Volumetric MRI Magnetization transfer Magnetization transfer Diffusion Tensor Imaging Diffusion Tensor Imaging MR Spectroscopy Cortical imaging Cortical imaging Functional MRI

39. MAGNETIZATION TRANSFER Ss So MTR = [ (So–Ss) / So] x 100% proportional to concentration of myelin

40. PD PD with MT saturation pulse ROI traced around lesions Copied on images without MT PD PD without MT saturation pulse

42. MTR lesions, ΝAWM MTR the first measurable abnormality not seen on conventional MRI ΝΑWM T1 black hole <Τ1 isointense < perilesional < remote < ΝΑWM < nl progressive ΜΤR till a new lesion on Τ2 ΜΤR on follow-up 1-4 yrs

43. MAGNETIZATION TRANSFER IMAGING CONTROLS > RRMS > SPMS NAGM NAWM Ge Y, Grossman RI et al Magnetization transfer ratio histogram analysis of NAGM and NAWM in multiple sclerosis: J Comput Assist Tomogr 2002; 26: 62 - 68.

44. MTR CONCLUSIONS Measurable marker MS # nl Diffuse pathology ΝΑWM, NAGM ** Monitoring disease - treatment Histograms differ in clinical subtypes Gray matter MTR reductions correlate with cognitive tests NOT Individual patient management Clinical practice Need standardize (sequence, RF pulse, coils) Multicenter trials

45. NEW TECHNIQUES Volumetric Volumetric Magnetization transfer Magnetization transfer Diffusion Tensor Imaging Diffusion Tensor Imaging MR Spectroscopy Cortical imaging Cortical imaging Functional MRI

46. Diffusion ADC quantification

47. Diffusion FRACTIONAL ANISOTROPY direction

48. FA map

49. Diffusion Tensor Imaging Information –Tissue microstructure and architecture including size, shape and organization –Quantitative method for evaluating tissue integrity –FA info basis for fiber tractography i.e. anatomic pathways of white matter connectivity

50. FIBER TRACTOGRAPHY Reduced number of fibers when they traverse white matter lesions in the patient MSCONTROL

51. DTI lesions Lesions ADC and FA which indicates disruption of myelin and axonal structures that leads to disorganization and increase in extracellular space Highest ADC in black holes SPMS > RRMS

52. DTI NAWM Lesion > NAWM perilesional > remote > nl Corpus callosum > NAWM wallerian Histogram for global DTI

53. Diffusion Imaging Diffusion Imaging CONCLUSIONS Measurable marker MS # nl Generalized pathology Need standardize Multicenter trials

54. NEW TECHNIQUES Volumetric Volumetric Magnetization transfer Magnetization transfer Diffusion Tensor Imaging Diffusion Tensor Imaging MR Spectroscopy Cortical imaging Cortical imaging Functional MRI

55. SPECTROSCOPY NAA in chronic plaques, ‘’black holes’’ in acute plaque NAA is partially reversible –Cho, Lac, MI NAWM, progress to new lesion The regional changes in all the metabolites are dynamic and variable over time and should be interpreted with caution

56. SPECTROSCOPY WBNAA Quantification whole brain ΝΑΑ RRMS < controls Loss ΝΑΑ 3,6x faster than atrophy precedes??

57. SPECTROSCOPY CONCLUSIONS Measurable marker MS # nl Reversible Generalized pathology WBNAA Need standardize Multicenter trials

58. NEW TECHNIQUES Volumetric Volumetric Magnetization transfer Magnetization transfer DiffusionTensorImaging DiffusionTensorImaging MR Spectroscopy Cortical imaging Cortical imaging Functional MRI

59. CORTICAL IMAGING

60. CORTEX DIR demonstrates cortical lesions >1.5T volumetry atrophy cortex MTR, DTI, NAA measurable markers in cortex MS # nl f-MRI plasticity

61. 8Τ1,5Τ A. Kangarlu, E.C. Bourekas, A. Ray-Chaudhury, and K.W. Rammohan Cerebral Cortical Lesions in Multiple Sclerosis Detected by MR Imaging at 8 Tesla AJNR Am. J. Neuroradiol., Feb 2007; 28: 262 - 266. Lesions in the cortex

62. NEW TECHNIQUES Volumetric Volumetric Magnetization transfer Magnetization transfer Diffusion Tensor Imaging Diffusion Tensor Imaging MR Spectroscopy Cortical imaging Cortical imaging Functional MRI

63. Maria A. Rocca,et al Evidence for axonal pathology and adaptive cortical reorganization in patients at presentation with clinically isolated syndromes suggestive of multiple sclerosis NeuroImage, 18, 2003, Pages 847-855 controls CIS

64. f-MRI visual, motor cognitive tasks Cortical reorganization does occur CIS, RR, PPMS Extent of activation correlates with degree of structural damage more activation bilateral complex tasks

65. Role of functional cortical reorganization Adaptive role recovery, compensation Failure or exhaustion with increasing disease duration or burden irreversible disability

66. CONCLUSIONS Ι CLINICAL APPLICATION MS is a clinical diagnosis MRI supports the diagnosis or provides alternative dx Conventional sequences –reproducible positioning, protocol

67. CONCLUSIONS ΙΙ NEW TECHNIQUES Lesion load, ΝΑWM, MTR,WBNAA Volumetry MT DTI Spectroscopy Gray matter f-MRI MRI SPEC MTR DTI f-MRI 8T

68. THANK YOU FOR YOUR ATTENTION MRI SPEC MTR DTI f-MRI 8T