Neuroimaging in Epilepsy. Ted Passe, MD Neuroradiology Mayo Clinic Rochester, MN

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2 Neuroimaging in Epilepsy Ted Passe, MD Neuroradiology Mayo Clinic Rochester, MN

3 Objectives Imaging modalities in epilepsy Anatomic CT/MRI Functional MRS, SPECT, PET, fmri, MSI, DTI Intra-op MRI Characteristic imaging findings in epilepsy Infectious / Inflammatory Mesial Temporal Sclerosis Malformations of Cortical Development Vascular malformations Neoplastic Methods of improved lesion detection Dedicated seizure protocol Higher resolution 3T MRI Subspecialized image interpretation

4 What is CT? CT=computed tomography CT is an X-ray based system A tube rotates around the patient projecting X-rays through the patient from many angles A ring of X-ray detectors collects an image from each projection angle around the patient 1 st generation CT scanners had 1 detector. Newer CT scanners have multiple detectors (16, 32, 64, 256+) which allow increased speed and resolution

5 History of CT Invented 1972 by engineer Godfrey Houndsfield EMI laboratories, England Nobel prize in Medicine 1979 Knighted 1981 Original axial CT image from a dedicated CT scanner circa 1975 This image is a coarse 128 x 128 matrix

6 CT Revolutionized Neuroradiology

7 CT Then and Now

8 CT Images Cross sectional images are made up of "pixels" (picture elements). Each 2D pixel represents a 3D "voxel" (volume element) of tissue being imaged Smaller pixels higher resolution (think HD TV) A pixel represents the ability of the atoms within the voxel to attenuate (decrease) an X-ray beam Contrast varies with density of tissue Bone/metal=bright white Muscle=gray Air=black Pathological processes are identified by alterations in anatomy and attenuation

9 Wooden Foreign Matter 18-yo female near to an explosion Wood fragment penetrated skull

10 Head CT Indications in Epilepsy Emergent imaging necessary If MRI not available If MRI contraindicated To evaluate for calcium MRI remains much more sensitive than CT in epilepsy workup

11 Tonsillar Abscess

12 What is MRI?

13 Patient in powerful magnetic field Protons align with the field What is MRI? Gradients and RF pulses create signal Reflected RF signal received by coils Computer processing used to create images in multiple planes Unlike CT or CR, no ionizing radiation

14 MRI Safety Static Magnetic Field: The powerful superconducting magnetic field is the most dangerous aspect of MRI and is ALWAYS ON!!! External metal objects can become missiles Can turn off pacemakers or electrical devices Can dislodge/torque metal implants (eye, aneurysm clips) Can erase credit cards/magnetic cards

15 MRI: Safety RF power deposition Causes heating within the body Challenging issue at high field MRI as Specific Absorption Rate (SAR) proportional to square of Bo RF deposition quadruples at 3T FDA SAR limit: 4 W/kg body and 3 W/kg head Limits pulse sequences (FSE - strong RF pulses) Neurostimulators are relatively contraindicated Depth electrodes Vagal nerve stimulators

16 VNS Safety Safety guidelines required for VNS as MRI can: Induce heat in the VNS lead tissue injury Change pulse generator settings or activate device MRI Protocol: Transmit/receive coil only No scans with body coil or receive only coils Pulse generator output programmed to 0 ma before MRI and reprogrammed after MRI Static MRI field less than or equal to 3 Tesla SAR less than 1.3 W/kg Time varying intensity: less than 10 Tesla/sec

17 Sag T1 Conventional MRI Cor T2 Ax FLAIR Ax Diffusion Weighted Image Ax T2

18 Standard Magnetic Resonance Imaging is Inadequate for Patients With Refractory Focal Epilepsy Sensitivity of lesion detection in medically refractory epilepsy: 1. 39% non-expert radiologist on standard MRI 2. 50% experienced neuroradiologist (>3 yrs epilepsy center) standard MRI +11% 3. 85% experienced neuroradiologist with focused Epilepsy MRI +46% Note: most problems with under-detection, #1 MTS, #2 focal cortical dysplasia Von Oertzen, et al. J Neurol Neurosurg Psychiatry

19 Seizure Protocol Routine head Sag T1 FLAIR, Ax T2, Ax FLAIR, Ax DWI Cor Hi Res T2 FSE (3 mm) Assess architectural distortion Cor FLAIR Assess for increased signal Cor SPGR 3D volume Assess for hippocampal atrophy Qualitative and/or quantitative GRE and/or SWI Assess for chronic hemorrhage Double IR Increased sensitivity for cortical dysplasia DTI - FA maps routine, tractography case by case Gadolinium for tumor, AVM or neurocutaneous syndromes

20 Advanced Imaging Techniques in Epilepsy A patient with Epilepsy may be classified as nonlesional for 2 reasons: 1) A lesion may not exist; that is, the structural abnormality that gives rise to seizures may be at the channel level or be spatially distributed in such a way that it would not be accurately termed a lesion, or 2) A lesion exists but is so subtle that standard clinical imaging is not sensitive enough to discriminate between the lesion and surrounding healthy brain tissue. As with any technology and disease, this definition is dynamic, as that future imaging techniques will be developed and new disease mechanisms will be discovered, making detection of the epileptogenic underlying abnormality an ever-changing target. Goal to move each patient from non-lesional to lesional epilepsy Pardoe H, Kuzniecky R. Epilepsy Curr

21 Hi Resolution 3D Volume MRI

22 Hi Resolution 3D Volume MRI

23 Hi Resolution 3D Volume MRI

24 3T (and now 7T) MRI FDA approved 3T MRI in 2001 Double the magnetic field strength 3 Tesla=60,000 X Earth s magnetic field Boltzmann equation: S/N ~ Bo Other MR improvements (not just 3T) Coil technology Gradient technology Computing power

25 3T Superior to 1.5T in Epilepsy Evaluation Retrospective study of 25 epilepsy patients 3T correctly identified structural lesions in 88% of epilepsy patients vs. 74% at 1.5T 3T also had significantly better: Lesion conspicuity Tissue contrast Phal PM, et al. AJR Am J Roentgenol

26 MTS 1.5T vs. 3T 1.5T SPGR 3T SPGR

27 MTS 1.5T vs. 3T 1.5T - Hi Res T2 3T Hi Res T2

28 Brief Summary Structural imaging MRI better than CT Improve lesion detection via: Use dedicated seizure protocol Use 3T MRI Use surface coil to further increase S/N Review by experienced neuroradiologist

29 Epilepsy: Pathologic Substrates Infectious/inflammatory Mesial Temporal Sclerosis Malformations of cortical development Vascular malformations Neoplastic

30 26-yo Male: New Onset Seizure

31 What is the imaging diagnosis?

32 Neurocysticercosis #1 cause of adult-onset seizure worldwide Dissemination of the pork tapeworm larva Increasing incidence in US due to immigration CT classic calcified scolex Transient worsening with antiparasitic tx Vasogenic edema

33 Disseminated Neurocysticercosis

34 Racemose Cysticercosis

35 39-yo Female: Seizure, Confused

36 39-yo Female: Seizure and Confused MRI 4 Days Later FLAIR Diffusion Gradient Echo

37 MRI 2 Days Later FLAIR FLAIR Cor T2

38 Herpes Encephalitis Adult #1 cause of sporadic viral encephalitis Overall rare: 3 cases/100,000/year Adults HSV-1 Retrograde spread of latent virus from a peripheral ganglion (trigeminal/olfactory) Involves limbic system, temporal and frontal lobes Untreated 70% mortality Treatment: IV acyclovir Treated: 40% recover w/o deficit; 30% mortality

39 70-yo Female with Memory Problems and Seizure Ax T2 Ax T2

40 70-yo Female with Memory Problems and Seizure FLAIR FLAIR

41 70-yo Female with Memory Problems and Seizure Diffusion Diffusion

42 Creutzfeldt Jakob Disease T2 FLAIR Diffusion

43 Creutzfeldt Jakob Disease Progressively fatal spongiform encephalopathy Prion protein causative agent Rare: 1/million/year Rapidly progressive dementia, myoclonic jerks MR: increased signal caudate, putamen, cortex DWI>FLAIR>T2 sensitivity

44 Confusion While Tapering AEDs

45 Confusion While Tapering AEDs Sag T1 Sag FLAIR

46 Transient Splenium Lesions Pathophysiology of this lesion in the SCC in patients with epilepsy or on AEDs remains unknown Lesions of the SCC on MRI appear to be a benign, rare finding, not requiring specific treatment, although follow-up MRI may be reassuring Our data suggest that the rapid taper of AEDs may be a factor contributing the development of a lesion in the SCC in patients on AEDs Association with Influenza, Migraine with Aura, etc REVIEW OF SIX PATIENTS ON POLYTHERAPY ANTIEPILEPTIC AGENTS WITH A TRANSIENT FOCAL LESION IN THE SPLENIUM OF THE CORPUS CALLOSUM Sarah Engkjer, RN, BSN, Theodore Passe, MD, Mary Gustafson, PharmD, John R. Gates, MD

47 Transient Splenium Lesions

48 Hippocampal Diffusion Abnormality Recent or ongoing seizure activity

49 Pulvinar Abnormality

50 Sudden Onset Left Sided Numbness and Confusion

51 PCA Occlusion with Acute Infarcts

52 30-yo with Partial Complex Seizures; Right Temporal Lobe Abnormal EEG 3T Cor SPGR 3T Cor Hi Res T2

53 Mesial Temporal Sclerosis (MTS) Primary findings: hippocampal atrophy and gliosis Atrophy on Cor SPGR T1 Increased FLAIR signal T2 increased signal and architectural distortion Secondary findings Enlargement of ipsilateral temporal horn/choroidal fissure Thinning of fornix Atrophy of mammilary body Loss of normal interdigitations of hippocampal head

54 Dual Pathology 5%-20% of MTS Patients Have an Extra-hippocampal Lesion Left MTS Post-traumatic encephalomalacia and gliosis

55 MTS Dual Pathology

56 MTS Dual Pathology

57 Malformations of Cortical Development Common finding in intractable epilepsy 3 categories of MCD depending on stage of brain maturation when insult occurred 1. Neuronal and glial proliferation (<10 wks) Microcephaly, hemimegalencephaly, Tuberous Sclerosis 2. Neuronal migration (10-20 wks) Heterotopias nodular, band heterotopia, lissencephaly 3. Late cortical organization (>20 wks) Polymicrogyria, schizencephaly, cortical dysplasia

58 11-yo Boy with Seizure Disorder

59 Subependymal nodules Glial/neuronal cells, often calcify Cortical/subcortical tubers Balloon cell migrational anomaly Triangle shape, apex toward ventricle T2 hyperintensity radiates toward ventricle Subependymal Giant Cell Astrocytoma (SEGA) Enhancing nodule at foramen of Monro Can cause obstructive hydrocephalus Tuberous Sclerosis

60 Nodular Grey Matter Heterotopia Subependymal and/or subcortical WM Round/oval nodules Follow grey matter on all MR pulse sequences If bilateral, associated with cognitive delay Seizure-free outcome after temporal lobe epilepsy is poor, if nodule not resected

61 Nodular Gray Matter Heterotopia 3T 25-yo female with a seizure disorder

62 Chronic Seizures 1.5T vs. 3T MRI 1.5T 3T

63 Chronic Seizures 1.5T vs. 3T MRI 1.5T 3T

64 Agyria-Pachygyria-Band Spectrum of Cortical Malformations Spectrum of disorders caused by deficient neuronal migration during embryogenesis. Mutation in LIS1 gene and DCX gene LIS1 mutation post to ant gradient of abnormality DCX mutation ant to post gradient of abnormality Dobyns WB, Das S. LIS1-Associated Lissencephaly/Subcortical Band Heterotopia Mar 3 [Updated 2014 Aug 14]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle;

65 Lissencephaly (Smooth Brain) Reduced sulcation decreased number + depth of sulci Classic figure 8 appearance Interfere with translocation of migrating neurons along radial glial cells to cortex Mutation in LIS1 gene and DCX gene LIS1 mutation parieto-occipital region DCX mutation frontal lobes 4-yo female seizure disorder

66 Subcortical Band Heterotopia SBH due to milder mutation of LIS1 or DCX Frontal DCX Parieto-occipital LIS1 Thick or thin band of gray matter in white matter parallel to normal appearing cortex Poor surgical outcome 6-yo female dev delay + seizures

67 Subcortical Band Heterotopia 18-yo female with chronic seizure disorder FLAIR T1 T2

68 25 Year Old Male Chronic Seizures LIS1 associated band heterotopia

69 Focal Cortical Dysplasia Abnormal cortical lamination Blurring grey white matter junction Increased T2/FLAIR signal Cortical thickening on 3 contiguous slices Can be subtle or not visible on MRI FA Map T2 13-yo female with seizure disorder

70 Polymicrogyria Malformation of late cortical organization Excessive small gyri and sulci Focal limited or extensive Multifocal Bilateral and symmetric vs. asymmetric Diffuse MRI bumpy irregular cortical surface and subcortical junction

71 Polymicrogyria 1999 vs 2007

72 Schizencephaly CSF cleft from subarachnoid space to lateral ventricle lined by dysplastic cortex/polymicrogyria Closed lip vs. open lip open lip worse prognosis 1/3 bilateral (worse prognosis) Imaging DDX vs. porencephaly (no gray matter lining) Small dimple in ventricle wall

73 Intractable Epilepsy

74 Cavernous Malformations Most common vascular malformation associated with epilepsy Identify with MRI Get GRE to assess for other lesions Can be hereditary Can be symptomatic due to bleed

75 Chronic Hemorrhage GRE Blooming 55-yo female with seizures

76 MRI AVM

77 13-yo Female Seizures

78 13-yo Female Seizures

79 13-yo Female Seizures

80 Sturge Weber Syndrome AKA encephalotrigeminal angiomatosis Port wine stain V1 and V2 distribution Orbit and forehead region Ipsilateral Leptomeningeal Angiomatosis Abnormal venous drainage pattern Typically parietooccipital region Ipsilateral choroid plexus enlargement

81 Neoplasms Source in 20% of intractable epilepsy Typically low grade Typically cortical location 2/3 temporal lobe

82 Common Epileptogenic Tumors Low grade astrocytoma Fibrillary vs. pilocytic Oligodengroglioma Ganglioglioma Dysembryoplastic Neuroepithelial Tumor (DNET) Pleomorphic Xanthoastrocytoma (PXA)

83 32-yo Female Long History of Seizures; Prior Head CT Report Normal

84 Ganglioglioma

85 19-yo Male: New-onset Seizure Cor SPGR T1 Cor FLAIR Cor Hi Res T2

86 53-yo Male: New-onset Seizures Path = Glioblastoma

87 58-yo Female: New-onset Seizure Metastasis

88 4-yo Female: New-onset Seizure

89 Stealth Localization MRI Initial DDX Dysplastic changes Low grade neoplasm Localization MRI Signal gone Edema due to seizure activity and/or encephalitis

90 Functional Imaging Modalities MRI-based MR spectroscopy Functional MRI Diffusion Tensor Imaging/Tractography Nuclear medicine PET SPECT Magnetoencephalography/Magnetic Source Imaging

91 MR Spectroscopy MR Imaging and MR Spectroscopy differ only in the manner in which the data are processed and presented MRS obtains metabolite peaks rather than images Allows non-invasive sampling of brain s chemical environment Single voxel and multivoxel techniques

92 MR Spectroscopy in Epilepsy Primary use in TLE Decreased NAA (a putative neuronal cell marker) due to neuronal loss Increase choline gliosis Best marker NAA/(Cho + Cr) ratio 90% correct lateralization in TLE 20%-40% bilateral MRS abnormality Prelim evidence suggests higher likelihood of surgical failure in TLE bilateral

93 Normal Single Voxel Proton Spectra Choline: 3.24 ppm Creatine: 3.02 ppm NAA: 2.02 ppm

94 MTS

95 MTS Spectroscopy Right Temporal Lobe Left Temporal Lobe Right: Mild decrease NAA Left: Moderate decrease NAA Normal Control

96 Spectroscopy of SEGA

97 Multivoxel Spectroscopy

98 Multivoxel Spectroscopy Voxel #16 Voxel #17 Voxel #18 Voxel #13

99 FDG PET FDG evaluates glucose metabolism TLE: interictal hypometabolism in >85% Useful if MRI + EEG are discordant or if normal MRI Not needed if EEG and MRI match Less useful in frontal lobe epilepsy Co-registration with MRI FDG=Fludeoxyglucose (18F)

100 Hybrid PET/MRI Currently typically co-register to MRI Hybrid PET-MRI New combination modality Initial experience: 29 patients with epilepsy surgery* 24/29 No difference with PET/MRI 4 new MRI lesions with concordant PET 1 new PET abnormality All 5 new lesions were clinically significant *Shin HW, et al. Seizure

101 FDG PET: Temporal Lobe Epilepsy Boca Radiology Group

102 FDG PET: Temporal Lobe Epilepsy New England PET Imaging

103 C 11 -Flumazenil PET Flumazenil benzo antagonist labeled with C 11 Labels central GABA receptors Decreased binding with intractable TLE Reports: >sensitivity than FDG-PET in TLE + MCD Limitations Surgical outcomes not yet known Short half-life limits availability Newer F 18 -flumazenil being tested with longer T 1/2

104 C 11 -Flumazenil PET University of Washington

105 Single-photon Emission Computerized Tomography (SPECT) Technetium 99m Measures cerebral blood flow Interictal hypoperfusion Ictal hyperperfusion 90% localize in TLE Uses similar to PET Discordant MRI and EEG Problems Not useful if multiple seizure onset False lateralization if delayed injection (>20 secs)

106 Ictal SPECT A. Interictal PET hypometabolism B. Ictal SPECT hyperperfusion

107 SISCOM (Subtraction Ictal SPECT COregistered to MRI) Sensitivity of ictal SPECT increased significantly when ictal and interictal images are subtracted Subtracted image superimposed on Hi-Res MRI Further increases sensitivity and specificity Surgical outcomes under study

108 SISCOM Mayo Foundation

109 Functional MRI BOLD effect (Blood Oxygen Level Dependent): changes in venous blood oxygenation accompany changes in regional brain activity Cortical activation increased blood flow >O2 utilization increase in oxyhemoglobin T2 and T2*-weighted MRI are sensitive to changes in blood oxygenation (oxyhemoglobin vs. deoxyhemoglobin) Paramagnetic affects of oxyhemoglobin decreased signal on T2* MR sequence Subtle changes (<2% signal change at 1.5T, greater at 3T) Statistical comparison of signal in rest and active paradigms targeting specific brain regions Allows detection of areas of brain activated by a specific task Primary role surgical localization

110 Functional MRI Paradigms Motor activation (finger tapping) Sensory activation Visual activity Auditory stimulation Language paradigms Memory tasks

111 fmri On-Off Paradigm Columbia fmri

112 Motor Activation

113 Language Paradigms

114 fmri Surgical Planning

115 Diffusion MRI Diffusion MRI is a specific pulse sequence that measures the micro-molecular translational motion of water molecules (Brownian motion) to obtain information on the microscopic behavior of the tissues Clinical applications Stroke imaging Diffusion Tensor Imaging White Matter Tractography

116 Diffusion MRI Complex Math

117 Diffusion MRI Basics Gradients with equal amplitude but opposite polarity are applied over a given interval Gradients of sufficiently high amplitude make the sequence sensitive to motion at the microscopic level During the typical imaging time of 50 msec, the average water molecule diffuses 10 microns Stationary tissue will be dephased and rephased equally, whereas spins which have moved during the interval will suffer a net dephasing and signal loss Thus, protons that diffuse the farthest will have the greatest loss of signal

118 Diffusion MRI in Stroke Imaging DWI is very sensitive to acute infarcts Revolutionized stroke imaging Hypothesis as Na/K/ATPase pump fails, cells swell Resultant restricted diffusion DWI lightbulb bright infarcts DWI drawback: both T2 + diffusion components ADC maps (apparent diffusion coeffecient) show the mean diffusion within each voxel (decreased diffusion decreased signal)

119 CT Acute onset Right sided weakness Right facial droop Slurred speech

120 Diffusion vs Conventional MRI FLAIR Diffusion

121 Diffusion Tensor Imaging Diffusion imaging measures free motion of H 2 O Ex: restricted diffusion in acute infarcts Diffusion Tensor Imaging measures anisotropy (the degree of directionality to H 2 O motion) Allows mapping of white matter tracts (axons) Disrupted vs. displaced in tumor surgery planning Subtle cortical dysplasia or migrational anomaly

122 In-vivo Water Diffusion Diffusion of water is hindered by cell membranes, myelin Diffusion of water Greatest in CSF Reduced in gray matter and isotropic Reduced in white matter but anisotropic

123 Diffusion in Biological Tissue Motion of water through tissue Faster in some directions than others Kleenex newspaper Anisotropy: diffusion rate depends on direction isotropic anisotropic Gordon Kindlmann - Scientific Computing and Imaging Institute, University of Utah

124 Independent Verification

125 Direction Encoded FA Maps

126 White Matter Tractography: Fiber Mapping

127 Corpus Callosum Splenium Fibers

128 Corticospinal Tract ROIs

129 Corticospinal Tracts

130 19-yo Male with HA Grade III Anaplastic Oligoastrocytoma T2 T1 + Gad Cor T2

131 DTI Fiber Mapping

132 Left-Sided Weakness

133 Bx: Grade III Anaplastic Astrocytoma

134 Tractography: Tumor Surrounds Corticospinal Tracts

135 Pre-op and Intra-op Integration MSI Language Sensory Motor DTI/Fiber Mapping Arcuate fasciculus Corticospinal tracts Optic radiations Intra-op MRI Integration

136 Multimodal Surgical Planning with Intra-operative MRI 14-yo with seizure disorder Prior biopsy diagnosis: Dysembryoneoplastic Neuroepithelial Tumor (DNET)

137 Conventional MRI DNET

138 DNET Follow-up: Growth of Central Enhancing Nodule 12/19/07 2/26/08

139 DTI/Fiber Mapping Arcuate Fasciculus Corticospinal tracts

140 Brainlab Integration

141 Brainlab Integration 2 MSI Data

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143 Intra-op Imaging and Stereotactic Guidance Intra-op #1 Ax T2 Intra-op Final T2 Intra-op Final T1 + gad 90% tumor resection, 100% enhancing nodule resection, no deficits post-op

144 Conclusions Imaging modalities in epilepsy Anatomic CT/MRI Functional fmri, MRS, SPECT, PET, and MSI Imaging characteristics of common epilepsy pathology Methods of improved lesion detection Subspecialized image interpretation Dedicated seizure protocol High resolution 3T MRI Multimodality integration Pre-op planning Intra-op navigation