Imaging in epilepsy1

Imaging in Epilepsy
Presenter – Dr. Narendiran. S
Chair person – Dr. Ravindranadh. CM

Overview
• Introduction
• Cortical Zones of Epilepsy- imaging modalities used to identify
• Computerised Tomography
• MRI with various sequences
• Epileptogenic conditions
• SPECT, PET,& fMRI
• Conclusion

Introduction
• Epilepsy is a chronic disease characterized by recurrent seizures
that may affect 1% of the population.
• Approximately 60% of patients with epilepsy suffer from focal
epilepsy syndrome.
• 15% of which are poorly controlled medically.
• Neuroimaging plays an important role in workup of patients with
epilepsy.
• Neuro imaging helps in
• Establishing the diagnosis
• Identification of epileptogenic zone
• Mapping of eloquent cortex

Overview
• Introduction
• SPECT, PET, fMRI
• Conclusion

Cortical Zones
• The symptomatic zone
• The irritative zone
• The seizure onset zone
• The Epileptogenic lesion
• The functional deficit zone
• The Epileptogenic zone
• The Eloquent cortex
• The High Frequency
Oscillation zone
Rosenow F, Lüders H. Presurgical evaluation of epilepsy. Brain. 2001

The Symptomatogenic zone
• Area of cortex which produces the ictal symptoms when activated
by an epileptiform discharge.
• Defined by a careful analysis of ictal symptomatology
• Careful history
• Ictal video recordings.
• Best method of identifying is direct cortical electrical stimulation.
• Usually different from the epileptogenic zone.

The Era of Symptomatogenic zone (1884-1935)
• In the 19th century epilepsy surgeries were solely
based on semiology with lateralising and
localising values.
• However currently correlation of
symptomatogenic zone with other zone and
imaging modalities is of paramount importance.
• An understanding of localising and lateralising
values of semiologies are important to decide
whether the actual lesion in MRI is cause for the
epileptic seizures.
Hughling Jackson
William Macewen

The Irritative zone
• Area of cortical tissue that generates interictal epileptiform
discharges.
• Can be considered as mini seizures
• When sufficiently strong in the eloquent area can produce clinical
symptoms.
• But generally isolated spikes don’t produce seizures.
• A run epileptiform discharges spreading to the symptomatogenic
zone can produce seizures.
• Identified by – EEG, MEG, fMRI triggered by interictal spikes.

The seizure onset zone
• Area of cortex where seizures are actually generated.
• May not always correlate with the epileptogenic zone.
• Maybe smaller or extensive than the epileptogenic zone.
• Currently no method that permits the accurate measurement of
the seizure onset zone.
• Multiple seizure onset zones with various threshold may exist
within a single epileptogenic zone.
• Measured by scalp EEG, intracranial electrodes or ictal SPECT.

The Era of Irritative & Seizure onset zone (1935 beginning)
• Dependent on the ability to record
ictal and interictal discharges.
• Richard Caton first recorded
electrical signals from brain of
rabbits & monkeys.
• EEG – Hans Berger.
• ECoG – Foerster & Altenberger.
• MEG – 1982 (UCLA) Hans Berger – Unknown year

Irritative zone
Seizure onset Zone
Scalp EEG/Video EEG
(Gold standard)
Intracranial electrodes
MagnetoEncephaloGraphy
Ictal SPECT

Functional deficit zone
• Area of cortex that is functionally abnormal during the interictal
period.
• Destructive effect of lesion or abnormal neurotransmission.
• Has a complex relationship with epileptogenic zone and is difficult
to establish presurgically.
• Patients show extensive area of functional deficit when compared
to epileptogenic zone.
• However is helpful in clear localisation & lateralisation.
• Can be measured by neurological , neuropsychological evaluation,
FDG-PET, interictal SPECT.

Functional deficit zone
FDG- PET
Inter-ictal SPECT
Neuropsychological assessment

Epileptogenic Zone
• Area of cortex indispensable for the production of seizures.
• Actual epileptogenic zone + potential epileptogenic zone.
• Unfortunately, no modality to identify the epileptogenic zone
completely.
• Sometimes a potential epileptogenic zone might become evident
of after surgery.
• If patient is seizure free after surgery we conclude that the
resected cortex included the epileptogenic zone.
• So it is indirectly inferred by defining the other zones correctly.

Epileptogenic lesion
• Radiographic lesion causing the epileptic seizures.
• Not all radiographically visible lesions are epileptogenic.
• Sometimes only part of the lesion maybe epileptogenic.
• Hence requires correlation with other parameters like VEEG
monitoring or seizure semiology.
• Usually identified by imaging – high resolution MRI.

Eloquent cortex
• Cortex related reproducibly to a given function.
• Major concern of surgery, apart from removing epileptogenic
zone, is to minimize damage to the eloquent cortex.
• The possible deficits has to be atleast predicted and explained to
the patients presurgically.
• Identified by – direct stimulation, MEG, fMRI, tractography and
sometimes PET.

Direct cortical stimulation
fMRI
Tractography
Eloquent ZonePET activation studies

• Introduction
• SPECT, PET, fMRI
• Conclusion

Computerised Tomography
• Uses ionizing radiation.
• Generates excellent hard tissue imaging contrast with moderately
good soft tissue resolution.
• Easily available.
• Economical.
• Invaluable in emergency situations.

CT in epilepsy
•Can pick up 30% of causes of epilepsy
•A good indication for new-onset seizures in an emergency,
•Not a substitute for MRI in the investigation of epilepsy.
Fernando et al.,Handb Clin Neurol. 2016 ;

Calcifications and epilepsy
• Infection
• Neurocysticercosis
• TB
• cerebral toxoplasmosis
• TORCH infection
• Metabolic
• hypoparathyroidism
• pseudohypoparathyroidism
• Fahr disease
• Previous cerebral insult
• healed cerebral abscess
• healed infarct
• healed hematoma
• Vascular malformation
• cerebral AVM
• Sturge-Weber syndrome
• von Hippel-Lindau syndrome

MRI
• Patients with focal epilepsies when focus not found should
undergo MRI.
• Three Tesla scanners generate 2–3-mm-thick slices with good
contrast within an acceptable acquisition time per sequence.
• Useful because epilepsy patients may not lie still for a longer
duration.
• Localising and delineating the extent of the underlying lesion and
its relation to eloquent cortex forms a crucial part.
• 15–30% of patients with refractory focal epilepsy – MRI negative
The Lancet Neurology 2016

MRI under epilepsy protocol
• It should have a minimum of the following sequences
i. Three-dimensional volumetric T1-weighted imaging (1 mm isotropic
voxels)
ii. T2-weighted imaging (axial and coronal)
iii. FLAIR imaging (axial and coronal)
iv. T2* gradient echo or susceptibility-weighted imaging (axial)

Three-dimensional volumetric T1-weighted imaging
• Provides excellent grey–white matter contrast
allows the assessment of cortical thickness and
detection of malformations of cortical
development.
• Images can be reformatted into any plane and post-
processing techniques can be used to improved
detection of abnormalities- Curvilinear
reconstruction

Curvilinear reconstruction
Curvilinear reformatting of volumetric T1-weighted images
improves the display of gyral structure and helps to identify
subtle abnormalities not seen on planar slices

T2-weighted imaging (axial and coronal)
• Allows assessment of hippocampal architecture and cystic tissue
components of other lesions.
• The two orthogonal planes allow small lesions to be distinguished
from partial volume effects

Fluid-Attenuated Inversion Recovery Imaging
• This imaging method is sensitive to hippocampal sclerosis, focal
cortical dysplasia, tumours, inflammation, and scars.

T2 gradient echo or susceptibility-weighted imaging (axial)
• This method is sensitive to calcified and vascular lesions, such as
cavernomas and arteriovenous malformations.

Double inversion recovery
• Improved lesion-to-background contrast
• Simultaneous suppression of signal from both
cerebrospinal fluid and normal white matter.
Bruno et al.,Br J Radiol. January 2016;

FCD in DIR
Bruno et al.,Br J Radiol. January 2016;

DWI & ADC
• Post ictally diffusion
restriction with low ADC
• Interictally high ADC.

Fractional Anisotropy Map
• Describes the degree of
diffusion anisotropy in each
voxel.
• In white matter where
anisotropy is high the bright
end of the gray scale is
assigned.
• In gray matter where
anisotropy is low, the dark end
of the gray scale is applied

MR Spectroscopy
• Non-invasive way of investigating brain chemistry.
• Proton spectroscopy is clinically established.
• Important brain metabolites such as N-acetylaspartate (NAA),
creatine (Cr) and choline (Cho) can be measured.
• Resonances - identified by their position in the spectra, expressed
in parts per million (ppm) relative to a standard frequency.
• NAA – Neuronal integrity
• Choline – Cell membrane integrity
• Lactate – Ischemia.

Mesial Temporal Lobe Sclerosis
• Most common cause of medically intractable complex partial
seizures.
• Ancillary Findings: Mnemonic MAFIA.
• Mamillary body atrophy
• Amygdala atrophy
• Fornix atrophy
• Ipsilateral parahippocampal white matter atrophy
• Atrophic or small temporal lobe with enlarged temporal horn

Mesial Temporal Lobe Sclerosis
90% has grade 3
or grade 4
(3–5%) has atypical variants either
confined to the CA1 field or CA4 field.

Hippocampal- Anatomy
1 = hippocampal head
2 = hippocampal body
3 = hippocampal tail
4 = mesencephalon
5 = amygdala
6 = hippocampal digitations
7 = temporal horn of the lateral ventricle
8 = uncal recess of the lateral ventricle
9 = splenium of the corpus callosum
10 = subsplenial gyri
11 = crura of the fornices
Dekeyzer, Sven et al. “"Unforgettable" - a pictorial essay on anatomy and pathology of the hippocampus” Insights into imaging

Hippocampus at the level of mammillary bodies

Hippocampus at the level of red nucleus

Hippocampus at the level of superior colliculus

DWI - MTS
• As a result of neuronal loss, the extracellular space is enlarged and
thus diffusion of water molecules is greater on the affected side,
resulting in increased values on the affected side (higher signal on
ADC).
• Conversely, due to neuronal dysfunction and swelling, diffusion is
restricted following a seizure, and thus values are lower

MRS - MTS
• Decreased NAA and decreased NAA/Cho and NAA/Cr ratios
• Reduced NAA in the medial temporal cortex, lateral temporal
cortex, and insular cortex in the ipsilateral side.
• Bilateral NAA reduction over the cerebral hemispheres in both the
ipsilateral and the contralateral sides.
• Reduced NAA in the EEG-defined ipsilateral hippocampus.
• Only hippocampal data - 60% sensitivity.
• Whole temporal lobe data - 87% sensitivity and 92% specificity.
Capizzano, Arístides A et al. “Multisection proton MR spectroscopy for mesial temporal lobe epilepsy” AJNR.

Volumetric analysis
• Hippocampal asymmetry
is a stronger classifier of
seizure lateralization.
• Quantitative MR imaging
can depict the presence
and laterality of
hippocampal atrophy in
TLE
Farid et al 2012

T2 - Relaxometry
• In patients with intractable temporal lobe epilepsy (TLE), 15% do not
have detectable hippocampal atrophy on MRI.
• Comparison of T2 relaxation times at the hippocampus – T2
Relaxometry.
• Hippocampal T2 mapping provides evidence of hippocampal damage
in the majority of patients with intractable TLE who have no evidence
of atrophy on MRI
• Can correctly lateralize the epileptic focus in most patients –
Bernasconi et al.
• Automated T2 relaxometry – Further improved detection than manual
analysis.
Winston, Gavin P et al. “Automated T2 relaxometry of the hippocampus for temporal lobe epilepsy” Epilepsia 2017.

T2 Relaxometry
• Bernasconi et al:
• All TLE patients with hippocampal atrophy.
• 9/11 (82%) patients with normal MRI had abnormally high HT2 ipsilateral to the
epileptic focus.
• Bilateral abnormal HT2 - found in 6/14 (43%) of patients with unilateral
hippocampal atrophy
• 2/11 (18%) of patients with normal MRI.
• But change always greater in ipsilateral hippocampus.

Malformations of Cortical Development
• Focal Cortical Development
• Heterotopia
• Polymicrogyria
• Microcephaly
• Lissencephaly
• Hemimegancephaly
• Schizencephaly

Focal Cortical Dysplasia
• Largely or purely intracortical malformations.
• Two major types
• FCD type I
• FCD type II
• Type I – Cytoarchitectural abnormalities without dysmorphic
neurons or balloon cells
• Type II – Dysmorphic neurons & balloon cells.
• Balloon cells – Pluripotent brain cells which fail to differentiate.
Kabat J, Król P. Focal cortical dysplasia - review. Pol J Radiol. 2012.

Classification

Imaging
• Cortical thickening
• Blurring of WM-GM junction
• Abnormal architecture of subcortical layer
• Segmental and/or lobar hypoplasia/ atrophy.
• Altered signal from white matter
• Transmantle sign
• Altered signal from gray matter
• Abnormal sulcal or gyral pattern
Type Ia & Ib
Type IIa & IIb

Imaging
• FCD type Ia – Commonly seen in temporal region
• FCD type Ib - Extratemporal regions.
• FCD type IIa & IIb – Predilection towards frontal lobe.
• Dual pathologies classified as Type III according to
Blumcke’s/ILAE’s.

FCD – Type Ia
1. Abnormal gyration
2. Mild hypoplasia of
right frontal cortex
3. Mild blurring GM-WM
junction.

FCD – Type Ia
Dual Pathology
(FCD + HS)
Blumcke’s
Type IIIa

FCD – Type Ib
Type Ib
associated with
DNET
Blumcke’s
Type IIIb

FCD type IIb
1. Funnel shaped T2/FLAIR
hyperintensity in right frontal
cortex.
2. Transmantle sign
3. Thickened cortex.

Heterotopias
• Conglomerate masses of gray matter in an abnormal location.
• Subependymal (periventricular), subcortical, and band heterotopias.
• Band heterotopias are syndromic & associated with Type I
Lissencephaly.
• Microscopically – neuronal & glial tissue without arrangement.
• Result from impaired migration of neurons from the germinal matrix in
the wall of the lateral ventricle to the cortex.
A. James Barkovich, Ruben I. Kuzniecky Neurology Dec 2000

Subependymal Heterotopias
• Most common
• Also known as periventricular
heterotopias.
• Associated with
• Filamin I gene on X chromosome.
• MCPH1 gene on chromosome 8.
• ASPM gene on chromosome 1.
• ARFGEF2 on chromosome 20.
Visible on CT, if
large

Subependymal Heterotopias

Subcortical Heterotopias
• Less common than subependymal heterotopias.
• Focal SCH patients have variable motor and intellectual
disturbances depending on the size of the lesion.
• Bilateral, large, thick SCH present with moderate to severe
developmental delay and motor dysfunction.
• Almost all develop localisation related refractory epilepsy.

Imaging
• Diffuse reduction in size of the
hemisphere
• Distorted ventricles
• Diminished and abnormal
white matter
• Thinned overlying cortex with
shallow sulci
• Distorted basal ganglia

Band Heterotopias
• Also called double cortex syndrome.
• Well-defined & well-marginated layer of neurons in the white
matter.
• Band of arrested migrating neurons.
• Syndromic – associated with Type I Lissencephaly.
• MRI - Smoothly marginated layer of gray matter coursing parallel
to the lateral ventricle.
• Anterior predilection suggests mutations of DCX
• Posterior predilection suggests mutations of LIS1

Band Heterotopias

Polymicrogyria
• One of the most common malformations of cortical development.
• Considered a disorder of neuronal organization.
• Deeper layers of the cerebral cortex develop abnormally and multiple
small gyri form within the cortex.
• Histo - Derangement of the normal six-layered lamination of the
cortex, associated derangement of sulcation & fusion of the molecular
layer across sulci.
• Wide variety of clinical presentations
• Hemiparesis
• Quadriparesis
• Refractory Epilepsy
Barkovich, A James. “Current concepts of polymicrogyria” Neuroradiology

Polymicrogyria
Barkovich, A James. “Current concepts of polymicrogyria” Neuroradiology

Tuberous Sclerosis Complex
• Second most common phakomatoses after NF1.
• AD disorder - results from mutations in the TSC1 or TSC2 genes.
• associated with hamartoma formation inmultiple organ systems
• Neurological - Infantile spasms, intractable epilepsy, cognitive
disabilities, and autism.
• Modulate cell function via the mTOR signaling cascade.
• Mediate cell body size, dendritic arborization, axonal outgrowth
and targeting, neuronal migration, cortical lamination, and spine
formation.
Orlova et al. The tuberous sclerosis complex Ann NY Acad Sci 2010

Tuberous Sclerosis Complex
Orlova et al. The tuberous sclerosis complex Ann NY Acad Sci 2010
Diagnostic criteria for
TSC

Imaging
Calcified Subependymal Nodules in plain CT & Gradient ECHO

Imaging
T2 & FLAIR showing cortical tubers

Imaging
T1 and T2 showing sub ependymal nodules

Imaging
SEGA in Plain CT & T2 MRI

Rasmussen’s Encephalitis
• Chronic inflammatory disease of a brain hemisphere in children.
• Acute phase - Cytotoxic T-cell reaction against neurons &
astrocytes.
• Chronic phase - Tissue destruction & low inflammatory activity
with a decreasing number of T cells and reactive astrocytes.
• Serial imaging shows progressive atrophy.

Clinical presentation
• Intractable focal onset seizures- Epilepsia partialis continua.
• Three stages –
• Prodromal stage – Low seizure frequency with mild hemiparesis.
• Acute phase – Increase in seizure frequency Progressive neurological
function deterioration.
• Chronic phase – Burnt out stage.
• Should be identified in the acute phase to reduce neurological
deterioration.

Imaging
• Peri-insular
atrophy
• Hyperintense
signal change
MRI stages of Rasmussen’s Encephalitis

Imaging
Marked brain atrophy
in the chronic stage
with caudate and
cerebellar atrophy

Imaging
Progressive
gliosis, atrophy
and hyperintense
signal change

SPECT
• SPECT image represents the regional cerebral blood flow during
the seizure.
• The critical issue about an ictal SPECT scan is the timing of tracer
injection.
• Done promptly at the beginning of a seizure, the probability of
visualizing an epileptogenic focus increases.
• Interictal studies are based on the observation that regional
cerebral perfusion and metabolism are reduced at the
epileptogenic focus.
Ajay kumar et al J Nucl Med Technol, 2017

Ictal SPECT
• True ictal SPECT shows an area of hyperperfusion in the
epileptogenic region, surrounded by an area of hypoperfusion.
• Might be caused by shifting of blood flow to the seizure focus or
might represent an inhibitory zone that limits the seizure spread.
• Helpful in defining the seizure onset zone.
• Difficult in patients with short duration of seizures.

SPECT with SISCOM
SPECT coregistered to an MRI
(SISCOM) of the brain shows a
region of focal hyperperfusion over
th right posterior temporal head
region.

PET imaging
• Most commonly used PET tracer in epilepsy is 18F-FDG.
• Measures glucose metabolism related to the synaptic & neuronal
activity of the brain tissue.
• Interictal PET typically shows reduced radiotracer uptake in
epileptogenic zone.
• Neuronal loss
• Diaschisis – Contralateral cerebellar & transcallosal.
• Reduced receptor density.
• Disadvantage – Shows large areas of hypometabolism, cannot be
relied upon for surgical margin.

Temporal & Extratemporal lobe epilepsy
• Sensitivity of 85%–90% in detection of the epileptic brain region in
cases of temporal lobe epilepsy.
• Can help to identify the epileptic temporal lobe in almost half of
patients with noncontributory EEG.
• Difficult to distinguish medial from lateral temporal lobe epilepsy
on the basis PET patterns.
• Decreased sensitivity in extratemporal lobe epilepsy.
• Helps in prognosticating seizure free outcome post surgery.
• C- Flumazenil PET has more sensitivity to TLE.

Temporal & Extratemporal lobe epilepsy

Functional MRI
• Technique that maps the physiological or metabolic consequences
of altered electrical activity in the brain.
• Not based on ionizing radiation and thus can be repeated.
• Has high spatial resolution when compared to EEG/MEG (high
temporal resolution).
• Based on the concept that neuronal stimulation leads to local
increase in energy and oxygen consumption in functional areas
and the fact that deoxy Hb is paramagnetic.
Kesavadas C, Thomas B. Clinical applications of functional MRI in epilepsy. Indian J Radiol Imaging. 2008

Functional MRI
• Initial dip due to increase
deoxyHb transiently.
• Positive and overshoot due to
increase in oxyHb and over
compensation.
• ‘initial dip’ corresponds to the
neuronal activity both
temporally and spatially.

Functional MRI - setup
• Motor function - self-triggered
movements .
• Language functions – auditory
& visual
• Verbal generation tasks and
semantic decision making
tasks.

Role in Epilepsy
• Mapping the eloquent cortex.
• Lateralising the language functions.
• Mapping memory
• Localising spontaneous ictal activity
• EEG coupled with fMRI
• Spike triggered fMRI.

Disadvantages
• Associated mental subnormality in epileptic patients limits their
cooperation in task performance.
• Long term effects of AEDs – unclear.
• Ictal and interictal epileptic activity in a patient with epilepsy can
influence the lateralization of mesiotemporal memory functions
and language functions.
• Head motion can produce artefacts.

PET activation studies
• Improve the delineation of dysfunctional areas of brain.
• Performed with H2 15O - used to delineate the functional anatomy
of a variety of cognitive and other cerebral tasks.
• Used in surgical planning in patients with epileptogenic areas
close to eloquent areas.
• But fMRI plays a better role in delineating eloquent cortex.

Tractography
• Used to identify white matter tracts and their relationship to
epileptogenic tissue and eloquent cortex.
• Used to improve surgical planning in order to minimize postoperative
deficits.
• Quantification of water molecule diffusion & characterization of the
degree and direction of anisotropy.
• Malformations or acquired insults cause disruption to the
microstructural environment – reduction in anisotropy.

Tractography
• Extension of DTI – directional information obtained in each voxel is
used to generate virtual, three-dimensional white matter maps.
• Used to locate and assess the pathophysiological effects of chronic
epilepsy on the white matter anatomy.
• Aids preoperative planning, and prevent damage to eloquent cortical
functions.
• Assess the structural reorganization of higher cortical functions such as
language & memory.

Reorganization of cortical networks
• Alteration in language
networks in TLE patients
– can be identified
presurgically.

Visual field tractography
• VFDs after ATLR occur
in the superior
homonymous field
contralateral to the
resection.
• Due to disruption of
fibers of Meyer’s loop

Conclusion
• A comprehensive presurgical evaluation includes identifying and
defining the extent of the various zones.
• Various imaging modalities help in identifying these zones.
• None of the imaging modalities are singly helpful.
• All are complementary to one another.

Imaging in epilepsy1

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