Neuroimaging in Epilepsy

Ted Passe, MDNeuroradiology

Mayo Clinic Rochester, MN

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

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

• 1st generation CT scanners had 1 detector. Newer CT scanners have multiple detectors (16, 32, 64, 256+) which allow increased speed and resolution

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

CT Revolutionized Neuroradiology

CT Then and Now

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

Wooden Foreign Matter

• 18-yo female near to an explosion

• Wood fragment penetrated skull

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

Tonsillar Abscess

What is MRI?

What is MRI?

• Patient in powerful magnetic field

• Protons align with the field

• 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

MRI Safety

• Static Magnetic Field: The powerful super-conducting 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

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

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

ConventionalMRI

Sag T1

Ax FLAIR

Ax Diffusion Weighted Image

Cor T2

Ax T2

“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 MRI2. 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. 2002.

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

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. 2014.

Hi Resolution 3D Volume MRI

Hi Resolution 3D Volume MRI

Hi Resolution 3D Volume MRI

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

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. 2008.

1.5T SPGR 3T SPGR

MTS 1.5T vs. 3T

MTS 1.5T vs. 3T

1.5T - Hi Res T2 3T – Hi Res T2

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

Epilepsy: Pathologic Substrates

• Infectious/inflammatory

• Mesial Temporal Sclerosis

• Malformations of cortical development

• Vascular malformations

• Neoplastic

26-yo Male: New Onset Seizure

What is the imaging diagnosis?

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

Disseminated Neurocysticercosis

Racemose Cysticercosis

39-yo Female: Seizure, Confused

39-yo Female: Seizure and ConfusedMRI 4 Days Later

FLAIR Diffusion Gradient Echo

MRI 2 Days Later

FLAIR FLAIR Cor T2

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

Ax T2 Ax T2

70-yo Female with Memory Problems and Seizure

FLAIR FLAIR

70-yo Female with Memory Problems and Seizure

Diffusion Diffusion

70-yo Female with Memory Problems and Seizure

Creutzfeldt – Jakob Disease

T2 FLAIR Diffusion

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

Confusion While Tapering AEDs

Confusion While Tapering AEDs

Sag T1 Sag FLAIR

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

Transient Splenium Lesions

Hippocampal Diffusion Abnormality

Recent or ongoing seizure activity

Pulvinar Abnormality

Sudden Onset Left Sided Numbness and Confusion

PCA Occlusion with Acute Infarcts

30-yo with Partial Complex Seizures; Right Temporal Lobe Abnormal EEG

3T Cor SPGR 3T Cor Hi Res T2

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

Dual Pathology – 5%-20% of MTS Patients Have an Extra-hippocampal Lesion

Post-traumatic encephalomalaciaand gliosis

Left MTS

MTS Dual Pathology

MTS Dual Pathology

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

11-yo Boy with Seizure Disorder

Tuberous Sclerosis

• 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

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

Nodular Gray Matter Heterotopia – 3T

25-yo female with a seizure disorder

Chronic Seizures – 1.5T vs. 3T MRI

1.5T 3T

Chronic Seizures – 1.5T vs. 3T MRI

1.5T 3T

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. 2009 Mar 3 [Updated 2014 Aug 14]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of

Washington, Seattle; 1993-2015.

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 lobes4-yo female – seizure disorder

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 outcome6-yo female – dev delay + seizures

Subcortical Band Heterotopia

FLAIR T1 T2

18-yo female with chronic seizure disorder

25 Year Old Male – Chronic Seizures

LIS1 associated band heterotopia

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

13-yo female with seizure disorder

FA Map T2

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

Polymicrogyria 1999 vs 2007

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

Intractable Epilepsy

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

Chronic Hemorrhage – GRE Blooming

55-yo female with seizures

MRI – AVM

13-yo Female – Seizures

13-yo Female – Seizures

13-yo Female – Seizures

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

Neoplasms

• Source in 20% of intractable epilepsy

• Typically low grade

• Typically cortical location

• 2/3 temporal lobe

Common Epileptogenic Tumors

• Low grade astrocytoma

• Fibrillary vs. pilocytic

• Oligodengroglioma

• Ganglioglioma

• Dysembryoplastic Neuroepithelial Tumor (DNET)

• Pleomorphic Xanthoastrocytoma (PXA)

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

Ganglioglioma

19-yo Male: New-onset Seizure

Cor SPGR T1 Cor FLAIR Cor Hi Res T2

53-yo Male: New-onset Seizures

Path = Glioblastoma

58-yo Female: New-onset Seizure

Metastasis

4-yo Female: New-onset Seizure

Stealth Localization MRI

• Initial DDX

• Dysplastic changes

• Low grade neoplasm

• Localization MRI

• Signal gone…

• Edema due to seizure activity and/or encephalitis

Functional Imaging Modalities

• MRI-based• MR spectroscopy

• Functional MRI

• Diffusion Tensor Imaging/Tractography

• Nuclear medicine • PET

• SPECT

• Magnetoencephalography/Magnetic Source Imaging

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

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

Normal Single Voxel Proton Spectra

Choline: 3.24 ppm Creatine: 3.02 ppm NAA: 2.02 ppm

MTS

MTS Spectroscopy

Right: Mild decrease NAA Left: Moderate decrease NAA Normal Control

Right Temporal Lobe Left Temporal Lobe

Spectroscopy of SEGA

Multivoxel Spectroscopy

Multivoxel Spectroscopy

Voxel #16

Voxel #18

Voxel #17

Voxel #13

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)

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. 2015.

FDG PET: Temporal Lobe Epilepsy

Boca Radiology Group

FDG PET: Temporal Lobe Epilepsy

New England PET Imaging

C11-Flumazenil PET

• Flumazenil – benzo antagonist labeled with C11

• 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 F18-flumazenil being tested with longer T1/2

C11-Flumazenil PET

University of Washington

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)

Ictal SPECT

A. Interictal PET hypometabolismB. Ictal SPECT hyperperfusion

SISCOM (Subtraction Ictal SPECT CO-registered 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

SISCOM

Mayo Foundation

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

Functional MRI – Paradigms

• Motor activation (finger tapping)

• Sensory activation

• Visual activity

• Auditory stimulation

• Language paradigms

• Memory tasks

fMRI – On-Off Paradigm

Columbia fMRI

Motor Activation

Language Paradigms

fMRI – Surgical Planning

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

Diffusion MRI – Complex Math

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

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)

CT

• Acute onset

• Right sided weakness

• Right facial droop

• Slurred speech

Diffusion vs Conventional MRI

FLAIR Diffusion

Diffusion Tensor Imaging

• Diffusion imaging measures free motion of H2O

• Ex: restricted diffusion in acute infarcts

• Diffusion Tensor Imaging measures anisotropy (the degree of directionality to H2O motion)

• Allows mapping of white matter tracts (axons)

• Disrupted vs. displaced in tumor surgery planning

• Subtle cortical dysplasia or migrational anomaly

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

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

Independent Verification

Direction Encoded FA Maps

White Matter Tractography: Fiber Mapping

Corpus Callosum – Splenium Fibers

Corticospinal Tract ROIs

Corticospinal Tracts

19-yo Male with HAGrade III Anaplastic Oligoastrocytoma

T2 T1 + Gad Cor T2

DTI Fiber Mapping

Left-Sided Weakness

Bx: Grade III Anaplastic Astrocytoma

Tractography: Tumor Surrounds Corticospinal Tracts

Pre-op and Intra-op Integration

• MSI • Language

• Sensory

• Motor

• DTI/Fiber Mapping• Arcuate fasciculus

• Corticospinal tracts

• Optic radiations

• Intra-op MRI Integration

Multimodal Surgical Planning with Intra-operative MRI

• 14-yo with seizure disorder

• Prior biopsy diagnosis:

• Dysembryoneoplastic Neuroepithelial Tumor (DNET)

Conventional MRI – DNET

DNET Follow-up: Growth of Central Enhancing Nodule

12/19/07 2/26/08

DTI/Fiber Mapping

Arcuate Fasciculus Corticospinal tracts

Brainlab Integration

Brainlab Integration 2 – MSI Data

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

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