1. eEdE-81
SEEING THE SAME LANDSCAPE WITH NEW EYES: IMAGING GLIAL NEOPLASMS IN THE ERA OF NEWER IMAGING MODALITIES
TANVIR RIZVI, MBBS, MD, DM ; SUGOTO MUKHERJEE, MBBS, MD
University of Virginia Health System

2. DISCLOSURES
The authors have no financial or nonfinancial relationships to disclose

3. OUTLINE
Review advances in MR imaging for Glial Neoplasms
Diffusion-weighted imaging (DWI) and Diffusion Tensor Imaging (DTI) role in grading glial neoplasms and preoperative planning
Perfusion-weighted imaging (PWI) role
Proton MR Spectroscopy (MRS) role in characterization and differentiating from entities like pseudo-progression
Functional BOLD MRI (fMRI) in preoperative planning employing different paradigms
Intraoperative MRI (IoMRI) role during surgery

4. ADVANCED IMAGING: INTRODUCTION
MR imaging has emerged as the modality of choice to evaluate intracranial tumors and continues to have ever-expanding and multifaceted role.
Conventional sequences provide immense amount of data including location, signal intensities and enhancement characteristics of mass lesions.
Newer imaging modalities can yield further refinement of differential diagnosis or treatment plan.
Improve preoperative assessment, expand surgical approaches, aid in radiation treatment planning and help in evaluating therapeutic options.
Advanced techniques generate physiologic data and information on chemical composition.

5. DIFFUSION-WEIGHTED IMAGING
Echo-planar technique maps rate at which extracellular water molecules diffuse through tissue. Mobility of water molecules determined by both cellularity of environment and thermal agitation.
Fluid (csf)- No impedance to flow of water molecules: No diffusion restriction.
Brain tissue rates of diffusion slower.
Pathologic processes further restrict diffusion thereby reducing apparent diffusion coefficient (ADC). ADC inversely proportional to cellular density due to limitation of water movement in interstitial spaces [1].

6. DIFFUSION-WEIGHTED IMAGING
ADC value of high-grade gliomas lower than low-grade gliomas [2] (darker on ADC maps). DWI, ADC maps and contrast enhanced T1W axial images of lower to higher grade glial neoplasms are shown.

7. DIFFUSION TENSOR IMAGING
Displacement vs. tract disruption from tumor, surgery
Peritumoral invasion index of tumor invasiveness. Conventional imaging overlap of edema and tumor cells.
DTI measures direction and magnitude of water diffusion based on data obtained from 6 or more gradient directions as opposed to 3 directions in DWI.
Anisotropy or directionally dependent water diffusion due to myelin sheath restricting water movement across WM tracts.
Fractional anisotropy (FA) is mathematical index derived from DTI data that implies microstructural integrity of brain tissue.
Fiber tracking techniques can reveal relationship between glioma and adjacent WM tracts [3].
Low grade gliomas deviate rather than destruct or infiltrate adjacent WM.
Knowing WM tracts from functional cortex helps surgical planning, reduces surgery time and minimizes need for intraoperative cortical stimulation.

8. DIFFUSION TENSOR IMAGING
DTI, post-contrast axial T1 and FLAIR images in a grade IV GBM of left medial temporal lobe with extension to superior cerebral peduncle show disruption of corticospinal tracts on left (arrow) with intact CST on right. By convention anterior-posterior tracts are labelled green; cranio-caudal blue and right-left red.
Post-contrast axial T1 pre and post surgery in a right temporal GBM. Axial and coronal DTI show disruption of corticospinal tract on right side post-surgery.

9. DIFFUSION TENSOR IMAGINGB
Axial T2 and post-contrast axial T1 images (A) show a left thalamic grade 1 pilocytic astrocytoma. There is significant reduction in tumor size post-radiation on T2W and post-contrast axial T1 images (B). DTI shows no significant disruption and mild displacement of corticospinal tract and uncinate fasciculus.

10. PERFUSION MRI
3 types: Dynamic Susceptibility contrast (DSC) perfusion, dynamic contrast material-enhanced perfusion and arterial spin labelling (ASL).
DSC perfusion most widely used currently. Negative enhancement technique using T2 and T2* effects of contrast material. High gadolinium concentration causes T2 shortening in adjacent tissues. Degree of dephasing and resultant signal change during bolus gadolinium injection can be measured and plotted as a time-signal intensity curve with area under the curve proportional to cerebral blood volume (CBV) [4]. Relative CBV measurements (rCBV) obtained. Adversely affected by hemorrhagic and post-surgical changes.
Dynamic-contrast enhanced T1-weighted perfusion imaging with calculation of K trans value (Contrast transfer coefficient) provides better assessment of permeability between intra and extravascular spaces and vessel leakiness.

11. PERFUSION MRI
Strong correlation between grade of astrocytoma and relative CBV measurements. Worsened tumor grade- rCBV increases.
Oligodendroglioma even low grade tend to have significantly elevated rCBV. Likely due to extensive angiogenesis and dense capillary networks.
Lymphoma lower relative CBV compared to GBM. Also lymphomas may show increased signal relative to baseline in recovery phase due to contrast material leakage within interstitial space.

12. PERFUSION MRI
33/M presents with complex partial seizures in 7/2011. Grade III Oligoastrocytoma. Resection 9/6/2011. Completed external beam Radiotherapy and Temodar.
12/29/2011
4/26/2012
11/6/2014
Treatment Avastin + CCNU
8/18/2015
Biopsy 8/2015 GBM
7/10/2015
Avastin + Vorinostat
3/19/2015

13. PERFUSION MRI
Axial FLAIR and Post-contrast Axial T1W images show significant increase in recurrent tumor burden in left parietal lobe with additional foci in left frontal and left parietal periventricular locations. Perfusion MRI shows significant increase in rCBV, which is seen as a dip in the curve on left side related to T2 shortening from gadolinium compared to normal curve on right side.

14. PERFUSION MRI: PSEUDOPROGRESSION & RADIATION NECROSIS
In 20-40% patients with CNS neoplasms undergoing RT and adjuvant chemotherapy, size of enhancing lesion and associated T2 prolongation temporarily increases, known as pseudoprogression.
Can simulate tumor progression and treatment failure[5] resulting in inappropriate discontinuation of effective therapy.
More often in those with concurrent RT + Chemotherapy typically 6-12 weeks after treatment.
Represents local inflammatory response and increased vascular permeability[6].
Clinically asymptomatic and associated with increased survival.
Decrease rCBV within enhancing lesion on perfusion MRI.
Areas of enhancement, T2 prolongation and significant edema mimicking recurrence in radiation necrosis. Edema and mass effect disproportionate to size of enhancing lesion.
Hypoperfusion with reduced rCBV on Perfusion MRI. Recurrent glioma/ mets: Increased rCBV.

15. PROTON MR SPECTROSCOPY
Analysis of different metabolites within the brain.
Initial diagnosis of brain tumors, directing biopsy, grading and treatment assessment.
Single or multivoxel.
Major metabolites:
NAA (2.02)- Normal neuronal marker
Choline (3.2)- Cell membrane marker
Creatine (3.0): energy marker
Lactate (1.33): Metabolic acidosis
Lipids (0.9): Tissue breakdown and cell death.

16. PROTON MR SPECTROSCOPY
Most CNS tumors: Elevated choline-creatine and choline-NAA ratios (>2.2 separates high from low grade) [2].
Increased cellularity (Elevated choline), significant decrease normal neurons (reduced NAA) and hypermetabolism (moderate decrease Creatine) [7].
Lipid-lactate peaks not present in normal brain. Present in areas of necrosis with anaerobic glycolysis.
Primary CNS lymphoma: Elevated Cho-Cr and Cho-NA ratios. Lactate-lipid peaks in upto 90%.
Pitfall: Acute demyelinating plaque: Elevated Cho-Cr and reduced NAA-Cr ratio mimic tumor. Conventional imaging to differentiate.
High grade neoplasm elevated lipid; Low grade neoplasm and gliomatosis: High MI peak.
Pseudoprogression: Decreased metabolites and increased lactate-lipid doublet.
8 year old male with brainstem glioma shows T2 hyperintense pontine lesion with raised choline and reduced NAA on MR Spectroscopy

17. PSEUDOPROGRESSION 5.28.15 5.30.15 Postop 5.28.15 8.20.15 10.30.15
51/M MGMT hypermethylation negative GBM s/p resection with RT & concurrent Temodar completed

18. PSEUDOPROGRESSION
Perfusion MRI shows decreased rCBV and PET-CT shows hypometabolism in enhancing lesion seen around surgical cavity in left frontal lobe. MR Spectroscopy shows low choline and NAA with lipid lactate doublet at 1.3 ppm.

19. FUNCTIONAL MRI
The extent of resection, a major factor affecting long-term survival in brain tumor patients can largely be determined by proximity of the lesion to the eloquent brain regions prior to resection [1].
Outlining of eloquent brain regions prior to resection: Combination of fMRI and DTI.
Functional MR imaging based on blood oxygen-level dependent (BOLD) contrast effect and neurovascular coupling.
When certain cognitive task is being performed, activation of certain brain regions and networks of brain regions increases, which leads to related increase in cerebral blood flow.
This increase (neurovascular coupling) results in relative excess of oxyhemoglobin in the regional vascular bed.
Echo-planar T2* gradient-echo sequences sensitive to changes in hemoglobin oxygenation states with greater concentration of diamagnetic oxyhemoglobin compared to paramagnetic deoxyhemoglobin resulting in increased relative MR signal.

20. FUNCTIONAL MRI
Changes of MR signal secondarily reflect regional cerebral neuronal activity [8].
Signal changes small: Repeated measurements needed. Block imaging paradigms used.
Alternating periods of active task (sensorimotor, language or vision) and a control task (rest) performed over a 4-6 minute span. Tasks and control periods statistically compared on a voxel-by-voxel basis to identify task-related signal changes.
Post-processing including motion correction, filtering and anatomic coregistration to optimize exam quality.
Processing programs more widely available as integrated component of clinical scanners, workstation and neuronavigation software packages.
“Resting state” or “functional connectivity” MR do not require active task[9]. Can assess multiple cognitive domains with single sequence. Useful in children, sedated patient s or those with deficits who cannot perform task. In domain of research.

21. FUNCTIONAL MRI: MOTOR PARADIGMS
COMPLEX FINGER TAPPING
SIMPLE FINGER TAPPING
FOOT MOVEMENT- ANKLE FLEXION/SIDE TO SIDE
TONGUE MOVEMENT
LIP PUCKERING
PASSIVE HAND/FOOT STIMULATION

22. FUNCTIONAL MRI: MOTOR PARADIGMS
COMPLEX FINGER TAPPING
SIMPLE FINGER TAPPING

23. FUNCTIONAL MRI: MOTOR PARADIGM
LIP MOVEMENT
FOOT FLEXION

24. FUNCTIONAL MRI: SPEECH PARADIGM
Broca’s Area:
Inferior frontal Gyrus- BA 44,45
Pars opercularis and triangularis
Constant
Wernicke’s Area:
Less well defined.
Classic WA- Parts of angular, supramarginal superior and middle temporal gyri and planum temporale
Verbal fluency
Word generation
Verb Generation
Naming
Sentence Completion
Passive listening
Comprehension
Language dominance:
R HANDED – 95% LHD
L HANDED - 70% LHD,
AMBIDEXTROUS – 85% LHD

25. FUNCTIONAL MRI: SPEECH PARADIGM
WORD GENERATION:
Try to think of words beginning with provided letter.
Activity predominantly in Broca’s Area.
NAMING PARADIGM:
What do you write with: A. Pencil B. Car C. Paper D. Pillow
Activity in Broca’s and Wernicke’s Area
VERB GENERATION:
If you see: clothes cards horse
Think: wash play ride

26. FUNCTIONAL MRI: SPEECH PARADIGM
LATERALITY: SENTENCE COMPLETION PARADIGM
Higher grade tumors: Lower sensitivity and specificity compared to lower grade tumors due to cerebrovascular changes within and adjacent to higher grade neoplasms.
Multiple language paradigms essential to enhance sensitivity and fully capture language networks.

27. FUNCTIONAL MRI: VISUAL MOTOR PARADIGM
Visual flashes (Colored green): Keep eye on flashes.
Motor (Colored red): When see word tap, repeatedly tap fingers on keyboard.

28. SUMMARY OF fMRI PARADIGMS

29. INTRAOPERATIVE MRI
Blend of MR imaging performed in an operative suite.
Allows precise navigation and resection of intracranial lesions.
First operating theater with MRI in Brigham and Women’s hospital in 1994.
65-92% cases where neurosurgeons thought achieved gross total resection, ioMRI showed more tumor that could be resected [10].
3 types:
Original open system with stationary magnet and stationary patient. Limitation of ease of access, instruments and monitoring equipment.
Stationary magnet/movable patient (can use other modalities like PET and binary fluoroscopy).
Movable magnet/stationary patient.
Clearly designated 5G line: Zone IV. MRI safe or MR conditional instruments.

30. INTRAOPERATIVE MRI A B C D
Intraoperative magnetic resonance imaging (MRI) suite shows patient gantry in the operative suite (A). The magnetic bore is brought in from its resting “bay” for scanning (B). The movable magnet is ready to scan the stationary patient (C,D) during surgery and once that is done is sent back to its “bay”. Note the yellow colored area refers to the 5-G line where only the MR safe devices can be used.

31. INTRAOPERATIVE MRI
Axial 3D T1 post-contrast and T2 Space images (top row) show a left mesial temporal heterogeneously enhancing mass lesion, which was resected. Intraoperative MRI (lower row) shows gross total resection

32. POST-SURGICAL ROLE OF DWI
Immediate post surgical: Areas of restricted diffusion may be seen from surgical resection or ischemia may be seen around surgical cavity. At follow-up, these areas enhance and mimic tumor recurrence. Compare new areas of enhancement with areas of restricted diffusion at immediate postoperative imaging. If match: Enhancement most likely reactive changes or subacute ischemia rather than recurrence.
New or enlarging area of restricted diffusion and signal abnormality in postoperative margin that previously showed no diffusion restriction: Likely tumor recurrence.
Pre and postoperative images show diffusion restriction in left posterior temporal lobe related to venous ischemia from Vein of Labbe sacrifice during removal of left temporal GBM.

33. LET US REVIEW WHAT YOU HAVE LEARNT
As the glial tumor grade increases, ADC value
Increases
Decreases
Remains unchanged.
is unpredictable.

34. LET US REVIEW WHAT YOU HAVE LEARNT
As the glial tumor grade increases, ADC value
Increases
Decreases
Remains unchanged.
is unpredictable.

35. LET US REVIEW WHAT YOU HAVE LEARNT
What happens to rCBV in pseudoprogression
Depends upon amount of enhancement
Increases
Depends upon FLAIR signal
Decreases

36. LET US REVIEW WHAT YOU HAVE LEARNT
What happens to rCBV in pseudoprogression
Depends upon amount of enhancement
Increases
Depends upon FLAIR signal
Decreases

37. LET US REVIEW WHAT YOU HAVE LEARNT
Which metabolite is most frequently raised in malignant CNS tumors
NAA
Creatinine
Choline
Alanine

38. LET US REVIEW WHAT YOU HAVE LEARNT
Which metabolite is most frequently raised in malignant CNS tumors
NAA
Creatinine
Choline
Alanine

39. LET US REVIEW WHAT YOU HAVE LEARNT
Which of the following statements is correct regarding language mapping ?
Wernicke’s area is much better defined.
Broca’s area is less clearly defined.
Multiple language paradigms enhance sensitivity and specificity of language lateralization.
Language lateralization is more accurate in higher grade neoplasms compared to lower grade ones.

40. LET US REVIEW WHAT YOU HAVE LEARNT
Which of the following statements is correct regarding language mapping?
Wernicke’s area is much better defined.
Broca’s area is less clearly defined.
Multiple language paradigms enhance sensitivity and specificity of language lateralization.
Language lateralization is more accurate in higher grade neoplasms compared to lower grade ones.

41. LET US REVIEW WHAT YOU HAVE LEARNT
Which line is important for safety reasons in intraoperative MRI
0.5G
1.5G 5G
10G

42. LET US REVIEW WHAT YOU HAVE LEARNT
Which line is important for safety reasons in intraoperative MRI
0.5G
1.5G 5G
10G

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Lee MH, Smyser CD, Shimony JS. Resting-state fMRI: a review of methods and clinical applications. AJNR Am J Neuroradiol 2013;34(10):1866–1872.
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