REVIEW ARTICLE


Neuroimaging of Epilepsy
C O N T I N UU M A UD I O By Samuel Lapalme-Remis, MDCM, MA, FRCPC;
I NT E R V I E W A V AI L A B L E Dang K. Nguyen, MD, PhD, FRCPC
ONLINE
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ABSTRACT
PURPOSE OF REVIEW: This article provides an overview of imaging modalities,
important imaging pathologies, and the role each imaging modality can
play in the diagnosis, evaluation, and treatment of epilepsy, including
epilepsy surgery.

RECENT FINDINGS: The Harmonized Neuroimaging of Epilepsy Structural

Sequences (HARNESS-MRI) protocol was proposed to standardize MRI
imaging for all patients with seizures. The role of 7-Tesla MRI in finding
previously occult epileptogenic lesions is under investigation, and the
technique is increasingly used. Developing MRI postprocessing techniques
can increase the sensitivity of MRI. Improvements in functional imaging
techniques such as EEG–functional MRI (fMRI) and magnetic source
imaging provide complementary methods of identifying seizure foci. New
epileptogenic pathologies such as multinodular and vacuolating neuronal
tumors (MVNT) are being discovered, and the importance of others, such
as encephaloceles, is better appreciated.

SUMMARY: Brain imaging is a critical component of the diagnosis and

evaluation of patients with epilepsy. Structural imaging modalities such as
MRI and CT allow for the identification of a wide variety of potentially
epileptogenic lesions. For patients with drug-resistant epilepsy under
consideration for resective surgery, both structural and functional
neuroimaging may be needed for focus identification and surgical planning
for preservation of neurologic function.
CITE AS:
CONTINUUM (MINNEAP MINN)
2022;28(2, EPILEPSY):306–338.

INTRODUCTION

E
Address correspondence to
Dr Nguyen, 1000 Saint-Denis,
pilepsy is a paroxysmal disease of the brain that presents diagnostic and
Montreal, Quebec, H2V 2L9, treatment challenges for neurologists. From the beginning of the
Canada, [email protected]. disease course, brain imaging assists neurologists in reaching the
RELATIONSHIP DISCLOSURE: correct diagnosis, selecting initial treatments, and estimating the
Drs Lapalme-Remis and Nguyen prognosis for treatment response. For patients whose disease later
report no disclosures.
demonstrates resistance to pharmacologic treatments, neuroimaging becomes
UNLABELED USE OF even more important when considering epilepsy surgery because multiple
PRODUCTS/INVESTIGATIONAL imaging modalities are often necessary to maximize the likelihood of localizing
USE DISCLOSURE:
Drs Lapalme-Remis and Nguyen
the epileptogenic onset zone, thus optimizing seizure freedom and minimizing
report no disclosures. the risk of neurologic impairment.
Traditionally, epilepsy was diagnosed after a patient had at least two
© 2022 American Academy unprovoked seizures occurring greater than 24 hours apart. A definition
of Neurology. proposed by the International League Against Epilepsy (ILAE) in 2014 allows for

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a new scenario in which the diagnosis of epilepsy can be made before the second KEY POINTS
seizure arises.1 When a patient has a single documented seizure and clinical
● The finding of an
evaluation identifies factors that would represent a greater than 60% risk of epileptogenic lesion on
seizure recurrence, the diagnosis of epilepsy can be made, often leading to brain imaging in a patient
treatment with an antiseizure medication. The most common factors that can with a single seizure may
lead a clinician to reach this conclusion are an epileptiform EEG abnormality or a lead to the diagnosis of
epilepsy if the treating
potentially epileptogenic lesion on structural brain imaging. An evidence-based
neurologist estimates a risk
guideline of the American Academy of Neurology (AAN) and American Epilepsy of seizure recurrence
Society on the management of an unprovoked first seizure in adults identified a greater than 60%.
significant brain imaging abnormality as associated with an increased risk of
seizure recurrence within 2 years (Level B evidence). The hazard ratio for seizure ● In adults with an
unprovoked first seizure,
recurrence in patients with abnormal brain imaging was calculated at 2.44, significant brain imaging
higher even than for patients with an EEG with epileptiform abnormalities abnormalities are associated
(hazard ratio, 2.16).2 with an increased risk of
Furthermore, it can be challenging to confirm that an event was, in fact, a seizure recurrence within
2 years.
seizure when patients are unable to recall the event, especially if it was not
witnessed. In such instances, EEG and brain imaging are helpful in establishing ● Brain imaging assists
an epilepsy diagnosis (CASE 3-1). neurologists in estimating
Beyond assistance with confirming the diagnosis, neuroimaging at an early whether a paroxysmal event
was likely a seizure,
stage may allow the neurologist to better classify the patient’s epilepsy type and
determining whether a
identify appropriate treatments. In the 2017 ILAE classification of the epilepsies, patient has epilepsy,
seizures are stratified into focal, generalized, and unknown types.3 classifying the epilepsy
Distinguishing between a focal and generalized onset may be especially difficult type, selecting treatments,
predicting the prognosis,
when patients present with bilateral tonic-clonic seizures without a clear
and completing a
description of the initial symptomatology and with inconclusive EEG data. An presurgical workup.
epileptogenic lesion on MRI can help support a focal-onset epilepsy, offering
more appropriate therapies early on and promoting early consideration of ● A first seizure associated
surgical treatment if pharmacologic treatments prove ineffective. with a cavernous
malformation is strongly
Following seizure and epilepsy types, the ILAE epilepsy classification associated with recurrent
framework stresses the importance of identifying the etiology of the epilepsy, seizures, with a 5-year risk
divided into structural, genetic, infectious, metabolic, immune, or unknown of 94%. Only about half of
cause. Many of these etiologies are diagnosed principally by neuroimaging, patients achieve seizure
freedom with antiseizure
which will guide any specific treatment of the epilepsy beyond antiseizure medications alone.
medications and help establish the prognosis.
Indeed, from the time of the first seizure, imaging data are needed to establish
the prognosis of a patient’s epilepsy and prepare the patient and their family
and/or caregiver for what may come next. As mentioned earlier, a neuroimaging
abnormality, in general, is associated with a higher risk of seizure recurrence
after a first seizure. Depending on the specific abnormality, more detail can
generally be provided and specific interventions proposed. For example, a first
seizure associated with a cavernous malformation almost assures recurrent
seizures, with a 5-year risk of 94%. When treated with an antiseizure medication,
47% to 60% of patients can achieve seizure freedom, a lower proportion than is
found among patients with all-cause epilepsy. Furthermore, a longer duration
of cavernous malformation–related epilepsy is associated with worse postsurgical
outcomes, so early surgery in such patients has been proposed after the failure of
a single antiseizure medication,4 at least in the case of patients with nondominant
temporal lobe epilepsy. Other etiologies portending a poor prognosis for seizure
control without surgery include mesial temporal sclerosis and periventricular
nodular heterotopia, the former offering a greater likelihood of seizure freedom

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NEUROIMAGING OF EPILEPSY

CASE 3-1 A 29-year-old right-handed woman was seen in clinic for an episode of
loss of consciousness that had occurred 3 weeks previously during an
overnight transcontinental flight. She was on a business trip, and no
family or friends traveled with her. She had no memory of the loss of
consciousness, recalling only that she regained consciousness to find
herself lying on the floor of the aisle surrounded by flight personnel. She
was confused for a few minutes but returned to normal quickly. She had
no tongue laceration or incontinence.
The patient had not received any information about the manifestations
of the loss of consciousness from flight personnel or other witnesses and
did not seek medical care when she landed at her destination. After
returning home, she reported the episode to her family physician, who
referred her to an urgent neurology clinic. On questioning, she reported a
similar episode approximately 12 months previously, also while traveling
internationally with disturbance in her sleep schedule. Neurologic
examination was normal.
Although the episodes were
suspicious for bilateral
tonic-clonic seizures, the
patient was hesitant to
accept a diagnosis of epilepsy
or begin treatment, given the
lack of corroborating data.
An EEG obtained the same
day of the clinic visit was
normal. An EEG with sleep
deprivation and MRI were
requested within 1 week.
MRI was performed first and
revealed the presence of
periventricular nodular
heterotopia (FIGURE 3-1).
This MRI finding supported
a diagnosis of epilepsy,
and the patient FIGURE 3-1
began treatment with an MRI from the patient in CASE 3-1 identified the
antiseizure medication presence of a large periventricular nodular
without recurrence. The heterotopia (arrow) adjacent to the right lateral
ventricular atrium, seen here as a solid mass
sleep-deprived EEG was isointense to the cortex on a coronal
canceled. T2-weighted slice.

COMMENT In cases in which a diagnosis of epilepsy is suspected but unconfirmed or a

patient requires objective evidence of epilepsy beyond a clinical history to
accept a diagnosis of epilepsy, imaging revealing epileptogenic lesions
may serve to support the diagnosis. In this case, the MRI findings obviated
the need for a sleep-deprived EEG, which could have placed the patient at
a higher risk of a third seizure.

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after surgical resection than the latter. However, adults who develop epilepsy KEY POINTS
after a stroke generally respond well to treatment5; although data are mixed, one
● In the acute setting, a CT
randomized controlled treatment trial demonstrated seizure freedom in 85% to scan of the head is often
94% of treated patients.6 necessary to ensure that
Neuroimaging is, therefore, an essential step in the evaluation of any patient the seizure was not caused
presenting with one or more possible seizures. In the acute setting, urgent by a threatening intracranial
pathology.
imaging is often necessary to ensure that a seizure was not caused by a
threatening intracranial pathology, such as a stroke, hematoma, vascular ● The International League
malformation, tumor, trauma, or infection, that might require specific and Against Epilepsy
potentially urgent treatment. The urgent imaging of patients with new-onset Neuroimaging Task Force
seizures is not discussed in this article; refer to the October 2016 Continuum issue recommends that MRI be
performed for all patients
on neuroimaging.7 But even in the clinic, at a distance from the event in an presenting with a first
apparently stable and neurologically intact patient, appropriate selection and seizure or newly diagnosed
interpretation of imaging modalities are important facets of the evaluation epilepsy where resources
of epilepsy. allow.

● The Harmonized
STRUCTURAL DIAGNOSTIC IMAGING IN EPILEPSY Neuroimaging of Epilepsy
All patients with seizures or epilepsy should receive head imaging early in their Structural Sequences
disease course as part of their basic diagnostic and prognostic workup. (HARNESS-MRI) protocol is
recommended for all
patients with seizures. It
MRI consists of three mandatory
MRI is the mainstay of epilepsy imaging; it is highly sensitive to many types of sequences and two optional
intracranial pathology and provides a level of structural detail unattainable by sequences, optimized for
3-Tesla (T) scanners but
other forms of imaging. The ILAE Neuroimaging Task Force reviewed the role of
compatible with 1.5T
MRI in epilepsy diagnosis and proposed methods to improve its yield.8 The Task scanners.
Force recommended that, resources allowing, MRI be performed for all patients
presenting with a first seizure or newly diagnosed epilepsy. Neurologists should
not rely on a report of a normal examination; if the MRI was done at another
center where the MRI protocol was suboptimal or the radiologist was not
experienced with neuroimaging of epilepsy, a repeat examination can provide
a higher yield (CASE 3-2).
To ensure that appropriate sequences are obtained and to standardize imaging
practices across different centers, the ILAE Neuroimaging Task Force
recommends using the Harmonized Neuroimaging of Epilepsy Structural
Sequences (HARNESS-MRI) protocol for all patients with seizures. This
protocol, which is optimized for 3-Tesla (T) scanners but remains compatible
with a 1.5T scanner, consists of three mandatory sequences and two optional
sequences. The sequences are summarized in TABLE 3-1. Taken together, these
sequences permit evaluation of the brain’s anatomy and morphology, pathologic
lesions, and the internal structures of the hippocampus. When clinically
indicated, the optional postgadolinium T1-weighted sequence can evaluate
tumors, vascular malformation, or infectious processes, and T2 susceptibility-
weighted imaging (SWI) is sensitive to blood products and calcifications.

CT
When MRI was first used in the early 1980s for patients with epilepsy, studies
immediately demonstrated the superiority of the new technique over CT
scanning, both in sensitivity and specificity, of identifying epileptogenic lesions.9
The importance of CT imaging in epilepsy has since been greatly reduced.
Nevertheless, being faster, cheaper, and more rapidly available, CT is often used

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NEUROIMAGING OF EPILEPSY

as the initial imaging modality in patients presenting with acute seizures to

exclude major intracranial pathology, and in environments with limited
resources, it may be the only imaging modality available. Furthermore, in the
evaluation of a limited set of pathologies, the images obtained by CT may be
complementary to those of MRI.
In particular, calcified lesions such as neurocysticercosis are well visualized on
CT and well differentiated from hemosiderin deposits, which can be challenging
on MRI. Certain tumors or tubers containing areas of calcification may also
benefit from characterization by CT as a complement to MRI. CT angiography
offers excellent resolution of many vascular abnormalities such as arteriovenous
malformations and arteriovenous fistulas and can assist with their
characterization. Finally, CT offers superior resolution of the bony skull

CASE 3-2 A 27-year-old right-handed woman was seen in the emergency

department for increased seizure frequency in the context of a 15-year
history of drug-resistant focal epilepsy. Seizures were characterized by a
sensation of thoracic pressure associated with anxiety, often followed by
a period of impaired awareness with automatisms. Seizures during sleep
were also common. The patient had recently moved from another
country, where she had been investigated for her epilepsy. A 1.5-Tesla (T)
MRI report from her original country of residence was obtained and
described a normal examination.
The patient underwent a presurgical evaluation including a repeat MRI
using a 3T scanner with the Harmonized Neuroimaging of Epilepsy
Structural Sequences (HARNESS-MRI) protocol (FIGURE 3-2); it revealed
left hippocampal sclerosis. The patient later underwent a successful left
amygdalohippocampectomy and anterior temporal lobectomy.

COMMENT Especially in the evaluation of drug-resistant focal epilepsy, neurologists

should not rely on a report of a normal MRI without examining the source
images themselves to ensure quality and accuracy or without requesting a
repeat MRI using an epilepsy protocol.

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structures. A skull base CT can be helpful in the diagnosis of a suspected
encephalocele, confirming the location of the bone defect through which it
protrudes (FIGURE 3-3).

EPILEPTOGENIC LESIONS ON IMAGING

A great variety of different intracranial pathologies may be epileptogenic in
certain patients, but imaging may also reveal findings with no causal link to a
patient’s symptoms. It is the clinician’s responsibility to determine whether a
lesion is the likely culprit for a patient’s seizures. To do so, it is necessary to have
knowledge of the epileptogenicity of different lesions in general before carefully
reviewing a patient’s relevant clinical data, including history, examination,
seizure symptomatology, EEG, location of the lesion, and laboratory data. Only

FIGURE 3-2
Three-Tesla MRI from the patient in CASE 3-2 shows increased T2 signal of the left hippocampus
(arrows) on axial (A) and coronal (B) fluid-attenuated inversion recovery (FLAIR) sequence and
loss of hippocampal internal architecture on a coronal T2-weighted image (arrow) (C).

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NEUROIMAGING OF EPILEPSY

then can the neurologist make an educated hypothesis as to the role of the lesion
in causing the patient’s symptoms, and that hypothesis must be subject to
reevaluation as more information becomes available over time.
For example, an arachnoid cyst is usually an incidental finding in the
evaluation of a patient with suspected seizures and can be dismissed as the
epileptogenic lesion if its location is not highly compatible with the patient’s
symptomatology and EEG findings. However, highly epileptogenic lesions such
as mesial temporal sclerosis or cavernous malformations require a far lower
threshold, and a putative diagnosis can be made in the clinic if the history and
seizure symptomatology are compatible with the lesion.
This section reviews different lesion types that are known to cause epilepsy,
focusing on representative pathologies of different etiologic categories, as well as
others that have received recent attention. A detailed description of all potential
epileptogenic lesions seen on imaging is beyond the scope of this review; more
comprehensive lists can be found in the tables. For the purpose of this review,
lesions have been classified into six categories: malformations of cortical
development, vascular lesions, tumors, gliosis and lesions caused by physical
deformation of the brain, autoimmune conditions, and infectious causes.

TABLE 3-1 Harmonized Neuroimaging of Epilepsy Structural Sequences

(HARNESS-MRI) Protocol Mandatory and Optional Sequencesa

Sequence
Sequence name type Focus Clinical scenario

Magnetization-prepared rapid T1-weighted Optimal evaluation of brain anatomy Mandatory for all
gradient echo (MPRAGE)/three- and morphology patients
dimensional spoiled gradient echo/
three-dimensional turbo field echo

Three-dimensional fluid-attenuated T2-weighted Assessment of signal anomalies, in Mandatory for all

inversion recovery (FLAIR) particular, hyperintensities related to patients
gliosis and increased extracellular
space; enhances the visibility of
hyperintense cortical Lesions

High in-plane resolution two- T2-weighted Examination of hippocampal internal Mandatory for all
dimensional coronal (turbo spin echo) structure (images are acquired patients
perpendicular to the long axis of the
hippocampus by using high resolution)

Gadolinium-enhanced T1-weighted Assessment for contrast enhancement Optional; when tumor,

vascular malformation,
or infectious process is
suspected

Susceptibility-weighted imaging (SWI) T2*-weighted Assessment of venous blood, Optional; when tumor,
hemorrhage, iron deposits, and vascular malformation,
calcifications or infectious process is
suspected

a
Data from Bernasconi A, Epilepsia.8

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 Malformations of KEY POINTS
Cortical Development
● CT remains useful in the
Malformations of cortical evaluation of potentially
development are a heterogeneous epileptogenic calcifications,
group of mostly congenital brain vascular abnormalities, and
lesions arising from disrupted encephaloceles.
cerebral cortex development
● Malformations of cortical
that can be caused by genetic, development are a
infectious, vascular, or other heterogeneous group of
etiologies.10 The dominant mostly congenital and
classification scheme for potentially epileptogenic
brain lesions arising from
malformations of cortical disrupted cerebral cortex
development separates development that can be
malformation types according to caused by genetic,
the stage of development during infectious, vascular,
or other etiologies.
which it is disrupted, thus
dividing them into malformations ● Focal cortical dysplasia is
due to abnormal neuronal cell a common cause of drug-
proliferation or apoptosis, resistant focal epilepsy that
may escape detection on
abnormal neuronal migration, or
routine MRI.
abnormal cortical organization
(postmigrational development).11
Depending on the nature
and extent of the malformation
of cortical development, a wide
spectrum of impairment is possible.
FIGURE 3-3 Certain malformation types, such
Coronal skull-base protocol CT (A) and three- as some forms of microcephaly or
dimensional skull-base reconstruction (B)
demonstrating inferior bony defect of left middle hemimegalencephaly, are
cranial fossa (A, B, arrows) in a patient with left associated with failure to thrive,
anterior left temporal anteroinferior encephalocele. severe intellectual disability, and
Images courtesy of Lily C. Wong-Kisiel, MD, and Robert J.
drug-resistant epilepsy, often
Witte, MD, Mayo Clinic, Rochester, Minnesota.
from the neonatal period.
However, many malformations of
cortical development are
compatible with normal development and cognitive function, sometimes passing
unnoticed through childhood and adolescence but leading eventually to the
development of focal epilepsy, often intractable to medications. This section
focuses on examples of malformations for which epilepsy can be the primary or
only manifestation. A more complete list is provided in TABLE 3-2.

FOCAL CORTICAL DYSPLASIA. Focal cortical dysplasia is a term encompassing a

variety of focal brain malformations that have in common disordered cortical
lamination, and in some types, abnormal cell types. Focal cortical dysplasias are
thought to be caused by disturbances in neuronal cell proliferation, cortical
organization, or both. Being focal by definition and often subtle in their
expression, focal cortical dysplasias are a common culprit of “MRI-negative”
focal epilepsy; in fact, patients with focal epilepsy and normal MRIs evaluated
at epilepsy centers are generally presumed to have a focal cortical dysplasia
that escapes visualization or was missed by the untrained eye.

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NEUROIMAGING OF EPILEPSY

Focal cortical dysplasias are classified into three subgroups, each of which has
multiple types.12 Briefly, focal cortical dysplasia type I is characterized on
pathologic inspection by alterations in the cytoarchitecture of neurons and can
affect large or small regions of the cortex. Focal cortical dysplasia type I is often
subtle and often invisible or missed on MRI imaging. When visualized on MRI, it
may appear as regions of hypoplasia or thin cortex, blurring of the gray-white
matter interface, or abnormally shaped or deep sulci.
Focal cortical dysplasia type II is characterized by disruption of the cortical
lamination, accompanied by morphologically abnormal cell types. Focal
cortical dysplasia type IIa contains only dysmorphic neurons, whereas focal
cortical dysplasia type IIb also contains balloon cells. Focal cortical dysplasias
type II are generally easier to detect on MRI than focal cortical dysplasias type I.
Like focal cortical dysplasia type I, focal cortical dysplasia type II may be
characterized by blurring of the gray-white junction or abnormal gyral or sulcal
patterns. However, it may also present additional features, including areas of
thickened cortex, increased T2/fluid-attenuated inversion recovery (FLAIR)
signal in the adjacent subcortical white matter, or the well-described
transmantle sign, seen in cortical dysplasia type IIb, which is a long region of
T2/FLAIR hyperintense signal tapering between the affected region of cortex
and the ventricular wall (FIGURE 3-4). Some focal cortical dysplasias type II are
located at the bottom of sulci, making them a challenge to identify, but when
found, bottom-of-sulcus dysplasia is often highly amenable to successful
surgical treatment.13
Focal cortical dysplasia type III refers to dysplasia that is found in the same
region of the brain as another lesion such as hippocampal sclerosis or a vascular
malformation. The focal cortical dysplasia itself may have imaging characteristics
of focal cortical dysplasias type I or type II or may not be visible at all (CASE 3-3).
An important feature of focal cortical dysplasias to be considered in
pediatric epilepsy is that they can be masked by the maturation of myelination

TABLE 3-2 Malformations of Cortical Development and Other Congenital Structural

Causes of Epilepsy That Can Be Seen on Imaging

◆ Dysgyria
◆ Focal cortical dysplasia
◆ Hemimegalencephaly
◆ Lissencephaly
◆ Megalencephaly
◆ Microcephaly
◆ Periventricular nodular heterotopia
◆ Polymicrogyria
◆ Schizencephaly
◆ Subcortical band heterotopia
◆ Sturge-Weber syndrome (vascular phakomatosis)
◆ Tuberous sclerosis (neurocutaneous syndrome)

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 KEY POINTS

● The transmantle sign

denotes a long region of T2/
fluid-attenuated inversion
recovery (FLAIR)
hyperintense signal tapering
between the affected
region of cortex and the
ventricular wall, usually
associated with focal
cortical dysplasia type IIb.

● Because focal cortical

dysplasia can be masked by
the maturation of
myelination in childhood, it
is essential to obtain high-
FIGURE 3-4 quality MRI early in the
MRI showing a left frontal focal cortical dysplasia, probable type IIb. A, Axial fluid- course of epilepsy.
attenuated inversion recovery (FLAIR) image shows a region of cortical thickening with an
extensive ribbon of hyperintensity in the subcortical region underlying the abnormal cortex. ● Periventricular nodular
B, On a coronal T2-weighted image, a blurry tapering region of hyperintensity (arrow) is visible heterotopias are solid
between the affected cortex and the adjacent ventricular wall (transmantle sign). masses of neurons that line
lateral ventricle walls after
aborted migration of
later in childhood.14 It is therefore important to obtain high-quality images neurons destined for the
early in the course of epilepsy to avoid losing the opportunity to visualize a cortex. Seizures can emerge
focal cortical dysplasia, which may become more subtle or invisible with time from one or more nodules,
areas of the overlying
(FIGURE 3-6). cortex, or a complex
network.
Periventricular Nodular Heterotopia
Periventricular nodular heterotopias are solid masses of neurons that line ● Periventricular nodular
heterotopias are
lateral ventricle walls after aborted migration of neurons originally destined conspicuous on MRI or CT as
for the cortex. Patients may have single or multiple nodules. Epilepsy often solid masses isointense/
develops in late adolescence or early adulthood and is frequently drug isodense to gray matter;
resistant. Although the nodules themselves may be epileptogenic, the their location in a region
where pathologic lesions
overlying cortex (to which the neurons were destined) is often abnormal, with rarely occur makes them
areas of subtle focal cortical dysplasia. Seizures can therefore emerge from one easy to miss.
or more nodules, areas of overlying cortex, or a complex network of
interactions between nodules (eg, the overlying cortex and sometimes the
hippocampus).15
On MRI, the periventricular nodular heterotopias appear as solid masses
isointense to gray matter lining the ventricular walls, sometimes with a
ribbonlike morphology, usually in the anterior or posterior regions of the
lateral ventricles; multiple heterotopias may be present in the same patient
(FIGURE 3-7). Careful attention should also be paid to the overlying cortex for
signs of focal cortical dysplasia. Unless it is small, a periventricular nodular
heterotopia is conspicuous on MRI or CT, but its location in a region where
pathologic lesions rarely occur makes it easy to miss when not specifically
looked for.

Vascular Lesions
Many different abnormalities of brain vasculature may cause epilepsy, and many
mechanisms of epileptogenesis can occur across different lesion types. For

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NEUROIMAGING OF EPILEPSY

example, arteriovenous malformations may cause seizures by acute bleeding,

posthemorrhagic encephalomalacia, the presence of sclerotic brain parenchyma
within capillary beds, or the adjacent development of a focal cortical dysplasia
type III. Arteriovenous fistulas may provoke seizures because of the buildup of
cerebral edema caused by high pressure within the cerebral venous system. In
general, the characterization of vascular lesions benefits from multiple imaging
modalities including MRI, CT angiogram, and, for some lesion types,
conventional angiography.

CAVERNOUS MALFORMATIONS. Cerebral cavernous malformations are vascular

lesions composed of immature endothelium channels without intervening
brain tissue. These often evolve over time and may bleed acutely,
sometimes causing neurologic symptoms. In some patients, cerebral
cavernous malformations are highly epileptogenic, likely due to
hemosiderin deposits that accumulate around the lesion rather than due to
the lesion itself. On imaging, the lesions may appear in any region of the
central nervous system (CNS) and be of highly variable size. Larger
cerebral cavernous malformations may be visible on CT as a hyperdense
lesion with regions of variable calcification. On MRI, cerebral cavernous
malformations may have a classic “popcorn” appearance caused by the
presence of variable blood products contained in different endothelium

CASE 3-3 A 27-year-old man was assessed at an epilepsy center for drug-resistant
focal epilepsy. He experienced bilateral tonic-clonic seizures as a child but
had been successfully weaned off antiseizure medications at age 14. His
seizures recurred at age 22. These were characterized by an onset of
palinopsia and oscillopsia, followed by a rising sensation of heat, nausea,
hypersalivation, alteration of consciousness, and confusion with preserved
language, rarely followed by evolution to a bilateral tonic-clonic seizure.
Brain MRI showed a region of encephalomalacia and hemosiderin in the right
occipital lobe, suggestive of a chronic ruptured vascular lesion (FIGURE 3-5).
Recorded seizures first showed EEG onset in the right posterior temporal
region, then spreading to the anterior temporal region.
Seizure symptomatology and imaging suggested that the primary seizure
focus was in the right parieto-occipital region, with propagation to the
ipsilateral mesial temporal structures. A right occipital lesionectomy was
performed. Surgical pathology showed that the region of encephalomalacia
was caused by an obliterated primitive vascular malformation. In the
adjacent cortex, neuronal lamination was anomalous, consistent with focal
cortical dysplasia type III.

COMMENT Focal cortical dysplasia type III arises in the presence of an adjacent lesion
during development and may explain the epileptogenesis of a static
encephalopathy, in this case a long-ruptured vascular malformation. In this
patient, the focal cortical dysplasia could not be radiologically
distinguished from the patient’s known lesion.

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channels. T2* sequences such as gradient recalled echo (GRE) or SWI
will show areas of hypointensity, as well as the epileptogenic hemosiderin
rim that surrounds the whole structure (FIGURE 3-8). Unlike most other
vascular structures, cerebral cavernous malformations have no feeding
arteries or draining veins, making them radiographically silent
on angiography.

Tumors
All varieties of brain tumors can cause seizures, and seizures are often their
presenting symptom, leading to diagnosis through neuroimaging. Malignant
tumors such as high-grade gliomas and metastases from systemic cancers may
cause seizures, but their treatment is primarily directed at preserving the life and
neurologic function of the patient rather than controlling seizures. Some intra-axial
tumors such as gangliogliomas are benign and almost never expand, but they are
epileptogenic and usually operated for the sole purpose of controlling epilepsy.
Extra-axial tumors such as meningiomas cause epilepsy less frequently, but they
may become epileptogenic as they expand and distort the adjacent cortex, often
requiring surgery by the time they cause symptoms. Low-grade gliomas, discussed
in the following section, hold a middle ground between highly malignant and
benign tumor types. Although they may expand and threaten the patient’s life and
neurologic function, for years or decades the primary difficulty they present may

FIGURE 3-5
MRI from the patient in CASE 3-3 shows a region of encephalomalacia and hemosiderin
deposits (A, B, arrows) in the right occipital region on axial T1 (A) and coronal fluid-
attenuated inversion recovery (FLAIR) image (B). Although pathology of the adjacent
cortex (C) revealed focal cortical dysplasia type IIIc with cortical dyslamination, neuronal
loss most dramatic in cortical layers 2 and 3 (area within the box), and reactive gliosis (area
within the circle), no focal cortical dysplasia was visible on MRI imaging.
GFAP = glial fibrillary acidic protein; NEUN = neuron-specific nuclear protein.
Pathology images courtesy of France Berthelet, MD, and Romain Cayrol, MD, Centre hospitalier
de l'Université de Montréal.

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NEUROIMAGING OF EPILEPSY

FIGURE 3-6
Images showing the evolution of a focal cortical dysplasia through infancy to adolescence. A,
MRI showing the prominence of a right frontal focal cortical dysplasia (arrow) when imaged
by a dual echo T2-weighted sequence in a patient at the age of 8 months. B, When the patient
was 2 years old, the same focal cortical dysplasia was undetectable on fluid-attenuated
inversion recovery (FLAIR) because of ongoing changes in myelination. C, At the age of
14 years, the focal cortical dysplasia (arrow) became visible again, but it remained subtle
compared with the initial MRI.
Images courtesy of David Dufresne, MD, Université de Sherbrooke.

FIGURE 3-7
MRI showing multiple periventricular nodular heterotopias in one patient. A, Axial T1-weighted
image shows multiple periventricular nodular heterotopias (arrows) lining the occipital horns
of the lateral ventricles. B, Coronal T2-weighted image shows an additional nodule (arrow)
adjacent to the right hippocampus. The nodules represent masses of neurons that have failed
to migrate normally and are therefore isointense to cortex on all sequences.

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FIGURE 3-8
Right hippocampal cavernous malformation causing focal epilepsy. A, On axial noncontrast
CT, the malformation (white arrow) appears as a mostly hyperdense, round mass containing
areas of lesser density. B, On axial T1-weighted image, the mass (black arrow) reveals areas of
various intensities (classic “popcorn” appearance) with a deeply hypointense rim. C, The
same rim of hypointensity (white arrow) is visible on the coronal T2-weighted image. D,
Susceptibility-weighted imaging (SWI) shows the lesion (white arrow) as thoroughly
hypointense, reflecting the chronic deposition of blood products throughout the lesion.

be epilepsy, requiring adjustments in therapy as they evolve over time. A more

complete list of tumors causing epilepsy is provided in TABLE 3-3.

LOW-GRADE GLIOMAS. Low-grade gliomas, which include grade II astrocytomas,

oligodendrogliomas, or oligoastrocytomas, are a common cause of focal seizures.
These infiltrating tumors often cannot be fully resected and are treated with a
variable combination of surgery, radiation therapy, and chemotherapy, growing
slowly and at times progressing to a higher-grade tumor. Epilepsy that was well
controlled for a time may suddenly become more difficult to treat, requiring
repeat neuroimaging to ensure tumor stability.
On MRI, low-grade astrocytomas are hypointense on T1-weighted and
hyperintense on T2-weighted sequences, with a moderate mass effect. When
calcifications are present, these will show blooming on T2* images. They show
neither contrast enhancement nor restricted diffusion. Their imaging

Benign or Slowly Progressive Intracranial Tumors Strongly Associated With TABLE 3-3
Epilepsy That Can Be Seen on Imaging

◆ Dysembryoplastic neuroepithelial tumor (DNET)

◆ Gangliocytoma
◆ Ganglioglioma
◆ Grade II astrocytoma
◆ Hypothalamic hamartoma
◆ Meningioma
◆ Multinodular and vacuolating neuronal tumor (MVNT)
◆ Oligoastrocytoma
◆ Oligodendroglioma

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NEUROIMAGING OF EPILEPSY

KEY POINTS

● Cerebral cavernous
malformations may have a
classic “popcorn”
appearance on MRI. T2*
sequences such as gradient
recalled echo (GRE) or
susceptibility-weighted
imaging (SWI) show areas of
hypointensity and the
epileptogenic hemosiderin
rim that surrounds the
structure.

● Low-grade gliomas are

infiltrating tumors causing
focal seizures. They are
treated with surgery, FIGURE 3-9
radiation therapy, and Biopsy-confirmed right frontal grade II astrocytoma, stable for several years, in a patient
chemotherapy. Their with focal motor seizures. The patient underwent multiple tumor resections but refused
continued growth may lead radiation therapy. A, Coronal fluid-attenuated inversion recovery (FLAIR) image shows
to a more drug-resistant diffuse subcortical hyperintensity (arrow) with limited mass effect. B, Axial postcontrast
epilepsy. T1-weighted image shows that the area of tumor adjacent to resection cavity (arrow) is
diffusely hypointense but does not enhance.
● Dysembryoplastic
neuroepithelial tumors
(DNETs) are among the most characteristics are often similar to those of oligodendrogliomas, but
common tumors causing oligodendrogliomas generally have more calcification and may show foci of
focal epilepsy. MRI displays contrast enhancement. Oligoastrocytomas combine histologic features of these
a classic “bubbly”
two tumor types and are usually indistinguishable on imaging alone, but they are
appearance, with multiple
lobulated regions of generally more heterogeneous in appearance (FIGURE 3-9).
hyperintensity on T2-
weighted sequences. DYSEMBRYOPLASTIC NEUROEPITHELIAL TUMORS. Dysembryoplastic neuroepithelial

● Multinodular and
tumors (DNETs) are among the most common tumors causing focal epilepsy.
vacuolating neuronal tumors These benign tumors, thought to be congenital, are usually static over decades or
(MVNTs) are recently grow very slowly. They are, however, highly epileptogenic and are a frequent
described epileptogenic target of epilepsy surgery. On imaging, most tumors are located in the temporal
lesions with an MRI
appearance of multiple
or frontal lobes, usually within the cortex. On CT, they appear as a wedge-shaped
discrete ovoid intra-axial hypodense mass and may contain calcifications or cause remodeling of adjacent
nodules found at the bony structures. MRI shows the classic “bubbly” appearance, with multiple
junction of superficial lobulated regions of hyperintensity on T2-weighted sequences. The calcifications
subcortical white matter
seen on CT also appear as a blooming artifact on T2* sequences. DNETs do not
and a deep cortical ribbon,
often surrounding a sulcus. avidly enhance or cause edema (FIGURE 3-10).

MULTINODULAR AND VACUOLATING NEURONAL TUMORS. Multinodular and

vacuolating neuronal tumors (MVNTs) are epileptogenic lesions first reported in
2013.16 Although initially classified as tumors, a 2018 analysis of the genetic and
pathologic features of resected specimens suggests that they may, in fact, be
more analogous to a malformative lesion than a neoplasm.17 Clinically, MVNTs
may be asymptomatic or cause adult-onset focal epilepsy, with seizure
symptomatology dependent on the site of the lesion. Typical MRI findings are of
a collection of multiple discrete ovoid intra-axial nodules, described as “bubbly,”
found at the junction of superficial subcortical white matter and a deep cortical
ribbon, often surrounding a sulcus. They are hypointense on T1-weighted

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FIGURE 3-10
MRI of a patient with right posterior temporal dysembryoplastic neuroepithelial tumor
(DNET) causing focal seizures with impaired awareness. A, Coronal fluid-attenuated inversion
recovery (FLAIR) image shows a small, discrete lesion (arrow) of mixed intensity with areas
isointense to CSF giving the classic “bubbly” appearance. B, Axial postcontrast T1-weighted
image shows the same “bubbly” appearance (arrow) with areas of faint contrast
enhancement.

images and hyperintense on T2/FLAIR, typically nonenhancing, often with

internal nodularity. Little expansion of the brain region is involved and no edema
or mass effect is present (FIGURE 3-11).18 MVNTs do not usually enlarge over
time or recur when resected, even with incomplete resection. Given their
indolent course, MVNTs are usually resected only when the epilepsy is
drug resistant.

FIGURE 3-11
MRI of a patient with left posterior temporal multinodular and vacuolating neuronal
tumors (MVNTs) causing focal seizures with impaired awareness. Coronal (A) and axial (B)
T2-weighted images show multiple discrete small nodules (arrows) at the junction of
superficial subcortical white matter and the cortex surrounding the bottom of a sulcus.
Axial fluid-attenuated inversion recovery (FLAIR) image (C) shows the nodules (arrow)
more clearly as T2 hyperintensities. The lesion is barely visible on axial postcontrast
T1-weighted image (D) as scattered hypointensities (arrow) that were nonenhancing.

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NEUROIMAGING OF EPILEPSY

CASE 3-4 A 59-year-old right-handed woman presented to an epilepsy center for

evaluation of drug-resistant epilepsy since childhood. Around the age of
12 months, she had experienced several febrile seizures lasting longer
than 60 minutes. Later in childhood, she developed episodes of chest-
and throat-tightening, déjà vu, and intrusive mental images, initially
without frank alterations of consciousness, that were never medically
evaluated. While pregnant at the age of 29, she began having bilateral
tonic-clonic seizures following these symptoms, which persisted
monthly despite treatment with phenytoin prescribed by a neurologist.
At age 52, while under the care of a second neurologist, phenytoin was
replaced by carbamazepine. The bilateral tonic-clonic seizures largely
ceased, but she continued to have frequent episodes of chest- and
throat-tightening, déjà vu, and intrusive mental images, followed by frank
alteration of consciousness and manual automatisms, as well as postictal
disinhibition and confusion. She was referred to the epilepsy center by an
orthopedic surgeon caring for her son after she entered a discussion with
the surgeon about her personal struggle with epilepsy.
On evaluation at the epilepsy center outpatient clinic, EEG showed
right temporal spikes, and MRI showed right mesial temporal sclerosis
(FIGURE 3-12). The patient continued to have focal seizures with impaired
awareness despite replacement of carbamazepine with levetiracetam
and, later, the addition of lacosamide. Inpatient continuous EEG
monitoring confirmed the right temporal origin of her seizures, and after
complete presurgical evaluation, she underwent a right anterior temporal
lobectomy. Pathology confirmed hippocampal sclerosis. The patient
remained seizure free after surgery.

FIGURE 3-12
Coronal MRI shows right hippocampal hyperintensity and atrophy on fluid-attenuated
inversion recovery (FLAIR) image (A, arrow) and loss of internal structure on T2-weighted
image (B, arrow).

COMMENT The diagnosis of epilepsy with mesial temporal sclerosis can be made in
the clinic based on history, EEG, and MRI. Patients with mesial temporal
sclerosis often benefit from surgical treatment of their epilepsy and should
be referred to a comprehensive epilepsy center.

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Gliosis and Lesions Caused by Physical Deformation of the Brain KEY POINTS
Injury to the brain is the most common cause of focal or multifocal epilepsy.
● Mesial temporal sclerosis
Whether caused by trauma, perinatal injury, or stroke in adulthood, is a surgically treatable form
encephalomalacia can be epileptogenic, although knowledge as to why it of drug-resistant epilepsy
becomes so in some patients and not in others is incomplete. Mesial temporal that can be diagnosed in
(hippocampal) sclerosis is another way in which a gliotic process can cause the clinic.
epileptogenicity. Other physical deformations of the brain, such as in
● On MRI, mesial temporal
encephaloceles, can become seizure foci as well and may exhibit signs of gliosis sclerosis is characterized by
on postoperative pathology. hippocampal atrophy, T2/
FLAIR hyperintensity, and
loss of internal architecture.
MESIAL TEMPORAL SCLEROSIS. Mesial temporal lobe epilepsy with hippocampal Supportive imaging findings
sclerosis, whose imaging findings are commonly referred to as mesial temporal include temporal lobe
sclerosis, is a classic, surgically treatable syndrome of often drug-resistant epilepsy atrophy or asymmetry of the
fornix and mammillary
that can be diagnosed in the clinic (CASE 3-4). Pathologically, hippocampal sclerosis bodies.
shows segmental neuronal cell loss with sparing of the CA2 subfield, gliosis, and
depletion of granule cells. In addition to hippocampal sclerosis, patients with mesial ● An encephalocele is a
temporal sclerosis also show changes in adjacent structures such as the anterior region of brain herniation
through a defect of bone
temporal lobe, amygdala, or entorhinal cortex. Mesial temporal sclerosis represents
and dura mater. Anterior
a collection of pathologic changes that may be the cause of seizures, may be caused temporal encephaloceles
by seizures, or both. In many patients, who often have a history of prolonged are a surgically treatable
febrile seizures, mesial temporal sclerosis is the only pathologic change in the cause of temporal lobe
epilepsy, often missed
brain, and its surgical removal carries a high likelihood of seizure freedom. In
during image interpretation.
other patients, seizures arise in different regions of the brain but propagate to a
temporal lobe, which can develop secondary epileptogenesis and eventually
undergoes hippocampal atrophy and becomes another seizure focus. This can
also occur when one temporal lobe with mesial temporal sclerosis leads to the
generation of a second focus of mesial temporal sclerosis in the contralateral lobe.
The imaging findings of mesial temporal sclerosis should be known to every
neurologist who treats patients with epilepsy and specifically looked for when
reviewing images. Hippocampal atrophy is the most specific feature and should
be assessed primarily with multiple coronal slices. The hippocampus loses its
normal oval shape and becomes flattened, and the adjacent temporal horn of the
lateral ventricle appears widened. On T2/FLAIR, the hippocampus may display a
hyperintense signal. On coronal T2-weighted sequences, the internal architecture
of the hippocampus may appear blurred or frankly lost, reflecting the pathologic
changes. Other structures can also be abnormal; supportive imaging findings
include temporal lobe atrophy or asymmetry of the fornix and mammillary
bodies with a reduced volume on the ipsilateral side.

ENCEPHALOCELE. An encephalocele is a region of brain herniation through a defect

of bone and dura mater. Although encephaloceles may develop following
trauma, neurosurgery, or CSF leaks, no cause is identified in many cases. It is
thought that distortions of the brain parenchyma, as it protrudes through the
bone, may be epileptogenic. Although they can cause epilepsy in many regions of
the brain, encephaloceles of the anterior temporal region have recently been
recognized as a relatively common and surgically treatable cause of temporal
lobe epilepsy, which is frequently missed on imaging. In one case series,
temporal encephaloceles were found in nearly 2% of all patients referred to an
epilepsy center for drug-resistant epilepsy.19

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NEUROIMAGING OF EPILEPSY

On MRI, protrusion of the

brain parenchyma with
surrounding CSF through the
skull defect may be observed, but
it can be subtle in the case of
small encephaloceles (FIGURE 3-13).
Sensitivity can be increased with
the use of a 3T scanner with
particular attention to axial and
sagittal sections using a high-
contrast T2-weighted turbo spin
echo sequence. Associated MRI
signs of idiopathic intracranial
hypertension such as flattening
of the orbital globe or empty sella FIGURE 3-13
turcica are often observed in the Coronal fluid-attenuated inversion recovery
same patients.20 In uncertain (FLAIR) MRI showing an inferior temporal
encephalocele in a patient with right temporal
cases, skull-base CT may identify focal seizures. The encephalocele (arrow) can be
the skull defect through which seen protruding through the skull base. The area
the encephalocele protrudes. of protruding encephalocele is hyperintense,
which may represent gliosis within the brain
parenchyma.
Autoimmune Conditions
A great variety of autoimmune
and inflammatory conditions, both systemic and limited to the CNS, are known to
cause epilepsy, sometimes only in the acute phase and sometimes leaving epilepsy as
a permanent sequela; for more information about this, refer to the article
“Autoimmune-Associated Seizures” by Lisa Gillinder, MBBS, FRACP, and Jeffrey
Britton, MD, FAAN,21 in this issue of Continuum. Imaging findings may be absent or
nonspecific to the causative entity, but some autoimmune conditions can produce
characteristic imaging findings.

RASMUSSEN ENCEPHALITIS. Rasmussen encephalitis is a rare, chronic, progressive

inflammatory disease of the brain of unknown etiology, most frequently seen in
children and causing devastating seizures and neurologic deficits, typically
limited to a single hemisphere. Patients usually present with seizures, often
highly drug-resistant, and neurologic impairment follows progressively. Imaging
is unremarkable at first, but cortical swelling and T2 hyperintensity later develop.
The swelling then resolves, and the cortex begins to atrophy, but T2
hyperintensity remains. Eventually, the hyperintensity resolves, but significant
atrophy remains permanent in the “burnt-out” stage (FIGURE 3-1422).23

AUTOIMMUNE GLIAL FIBRILLARY ACIDIC PROTEIN ASTROCYTOPATHY. Autoimmune

glial fibrillary acidic protein (GFAP) astrocytopathy is a recently described
inflammatory disease of the brain causing meningoencephalitis. Approximately
one-fifth of patients with GFAP astrocytopathy develop seizures, often resistant
to medications.24 It is mentioned here because it presents with a typical imaging
pattern that should not be missed in a patient presenting with encephalopathy and
seizures. In a majority of patients, contrast-enhanced T1-weighted MRI images
show diffuse perivascular enhancement radiating out from the lateral ventricles,
and less frequently, the fourth ventricle into the cerebellum (FIGURE 3-15). Other,

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FIGURE 3-14
Serial MRI findings in a 52-year-old-woman with adult-onset Rasmussen encephalitis.
A, Axial fluid-attenuated inversion recovery (FLAIR) image at 1 year after diagnosis disclosing
no obvious abnormalities (A, top left); axial FLAIR image at the same level at 2 years showing
perisylvian hyperintense signal (A, top right); MRI findings at 3 years during acute focal
status epilepticus with impaired awareness: axial contrast-enhanced T1-weighted image
revealing mild subcortical frontal operculum enhancement (A, bottom left) and axial FLAIR
image showing mild progression of frontal operculum hyperintensity (A, bottom right). Axial
diffusion-weighted images (DWI) demonstrating restricted diffusion throughout the left
cerebral cortex (B) and axial T2-weighted images through cerebellum showing signal
abnormalities in the right cerebellum hemisphere consistent with crossed cerebellar
diaschisis (C) when the patient was in status epilepticus (at the same time as the bottom
images in panel A). D, Follow-up images at 3 months after status epilepticus showing
persistent atrophy and gliosis of the left perisylvian region on coronal FLAIR images.
Modified with permission from Irislimane M, et al, Can J Neurol Sci.22 © 2011 Canadian Neurological
Sciences Federation.

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NEUROIMAGING OF EPILEPSY

KEY POINTS less specific, MRI findings

include T2 hyperintensities in
● Autoimmune glial
fibrillary acidic protein
white matter and leptomeningeal
(GFAP) astrocytopathy is an enhancement. This entity
inflammatory cause of responds well to corticosteroids.
meningoencephalitis with
seizures. It has a typical
Infectious Causes
imaging pattern of diffuse
perivascular enhancement CNS infections may cause
radiating out from the seizures acutely, during a
lateral ventricles on chronic infection, or through
contrast-enhanced MRI.
sequelae that persist long after
● CT imaging may be the infectious organism is no
necessary as a complement longer living in the CNS. A more
to MRI images for the complete list is provided in
imaging diagnosis of TABLE 3-4.
neurocysticercosis.

NEUROCYSTICERCOSIS.
Neurocysticercosis is a leading
cause of focal epilepsy in many
FIGURE 3-15
low- and middle-income regions
Axial postcontrast T1-weighted MRI of autoimmune and can cause epilepsy
glial fibrillary acidic protein (GFAP) astrocytopathy. throughout the several-year life
Patterns of enhancement include radial cycle of its causative parasite,
periventricular (A), leptomeningeal and punctate
Taenia solium, or long after its
(B), serpiginous (C), and periependymal (D).
Reprinted with permission from Kunchok A, et al, Curr Opin death. The parasite is ingested
Neurol.24 © 2019 The Authors. through fecal-oral contamination
and can release larvae into the
human bloodstream, and from
there, some can reach the brain. The larvae then proceed through four stages of
development, each with unique imaging characteristics (TABLE 3-5).25 When the
parasite dies, it progresses to the nodular calcified stage, remaining within the
brain for the rest of the patient’s life as a fibro-calcified nodule.
On CT imaging, the chronic lesions appear as single or multiple small
nodular hyperdense masses, without perilesional edema or enhancement.
These lesions appear hypointense on T1-weighted and T2-weighted MRI
sequences. T2* sequences reveal a strongly hypointense blooming artifact
(FIGURE 3-16).

IMAGING IN PRESURGICAL EVALUATION

Although most patients with epilepsy can achieve control of seizures with
antiseizure medications alone, a substantial proportion of patients have drug-
resistant epilepsy. Where resources are available, all such patients should be
referred to a comprehensive epilepsy center for a presurgical evaluation; for
more information about this, refer to the article “Surgical Treatments for
Epilepsy” by George W. Culler IV, MD, and Barbara C. Jobst, MD, PhD, FAAN,26
in this issue of Continuum. In simple terms, epilepsy surgery consists of carefully
identifying the seizure focus within the brain and surgically removing it when
safe to do so.
The decision to remove a region of the brain is not taken lightly and requires
an intensive and detailed evaluation of the patient’s seizures. On one hand, the

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Chronic Central Nervous System Infections or Infection Sequelae TABLE 3-4
Associated With Epilepsy That Can Be Seen on Imaging

◆ Cerebral malaria
◆ Cryptococcosis
◆ Herpes simplex virus encephalitis
◆ Neurocysticercosis
◆ Toxoplasmosis
◆ Paragonimiasis
◆ Subacute sclerosing panencephalitis
◆ Syphilis
◆ Tuberculosis

Stages of Neurocysticercosis Evolution and Their Radiologic Findingsa TABLE 3-5

Stage MRI findings CT findings

Stage 1: vesicular (living parasite) A scolex may be seen a within cyst of Cyst appears as a hypodense
approximately 1-2 cm; when visible, the lesion isodense to CSF
scolex may enhance and is best seen on
fluid-attenuated inversion recovery (FLAIR)
images; minimal or absent enhancement of
the cyst wall; cyst fluid isointense to CSF

Stage 2: colloidal vesicular (early Scolex is no longer visualized; a fluid-fluid Cyst appears as a hypodense
degeneration and host inflammatory level may be seen within the cyst, lesion with ring enhancement
response) suggesting internal debris; cyst fluid with contrast
hyperintense on T1-weighted sequences;
gadolinium ring enhancement surrounds the
cyst; T2-weighted sequences may show
perilesional edema; absence of diffusion-
weighted imaging (DWI) restricted diffusion

Stage 3: granular nodular (further Morphology evolved to a smaller nodular Contrast images may show
degeneration) lesion; gadolinium enhancement of lesion enhancement within the lesion
with possible small ring enhancement; or small ring enhancement
T2-weighted sequences may show mild
perilesional edema

Stage 4: nodular calcified (end stage as a Hypodense nodule on T1- and T2-weighted Hyperdense nodule;
nonviable calcified granulomatous lesion sequences; usually no edema or nonenhancing
without host inflammatory response) enhancement

CSF = cerebrospinal fluid; CT = computed tomography; MRI = magnetic resonance imaging.

a
Data from Lerner A, et al, Neuroimaging Clin N Am.25

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NEUROIMAGING OF EPILEPSY

FIGURE 3-16
Imaging from a patient with anterior temporal neurocysticercosis causing left temporal onset
seizures. Two other lesions were seen in other regions of the brain (not shown). On axial
T1-weighted (A) and fluid-attenuated inversion recovery (FLAIR) (B) images, the lesion
(arrows) was seen as a small nodular hypointensity, with prominent hypointense “blooming”
artifact (arrow) on axial susceptibility-weighted imaging (SWI) (C). MRI could not distinguish
whether the lesion represented calcification or hemosiderin deposit, so CT was performed
(D), confirming highly dense calcifications (arrow) and the diagnosis of chronic
neurocysticercosis lesions.

seizure focus must be established with maximal confidence. On the other hand,
the function of any region of cortex under consideration for removal must be
established to avoid a permanent disabling functional deficit from the surgery.
The presurgical evaluation is therefore highly individualized, and imaging data
are essential to focus both identification and surgical planning for preservation of
neurologic function.

Focus Identification
Identifying the seizure focus for resection is a simple endeavor in some
patients but highly complex in others. A general principle of focus
identification is to collect different types of data, which may include the
details of seizure symptomatology, neuropsychological profile, interictal EEG,
video-EEG recordings of seizures, structural imaging, and, when necessary,
different methods of functional imaging or intracranial EEG data, each of
which may suggest a particular seizure focus. When these different methods
of evaluation are concordant, the seizure focus can be predicted with higher
confidence, and the likelihood of surgical success is increased. When they are
inconclusive or discordant, surgical planning becomes more challenging.
In the evaluation of a patient with focal epilepsy, the presence or absence of an
epileptogenic lesion that can be visualized on structural imaging is usually the
most important factor predicting the eventual success of surgery. For many
lesion types such as mesial temporal sclerosis, DNETs, or cavernous
malformations, rates of seizure freedom after surgery can exceed 70%.27 Simply
put, a lesion that can be seen can more easily be identified and removed. This
concept is so basic that focal epilepsy was traditionally divided as “lesional” or
“nonlesional,” referring to whether patients have a visible lesion on MRI. Without
a visible lesion, intracranial EEG monitoring is often necessary before focus
resection. The lower rates of postoperative seizure freedom attest to the difficulty
of correctly identifying the seizure focus in patients with so-called
“nonlesional” epilepsies.28

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 In fact, however, it is understood that all focal epilepsy must be “lesional,” KEY POINTS
given that a lesion of some type must be responsible for the seizures, even if not
● In the course of a
visible on MRI. Therefore, the term MRI-negative is now preferred to describe the presurgical evaluation for
situation previously referred to as nonlesional. With improvements in MRI drug-resistant epilepsy,
scanners, imaging protocols, and special techniques, lesions are now found that imaging results are essential
in the past would have gone unnoticed, converting MRI-negative patients to for seizure focus
identification and surgical
MRI-positive patients.
planning for the
Functional imaging technologies can assist with focus identification, preservation of neurologic
particularly when structural imaging is negative. Functional imaging takes function.
advantage of different physiologic characteristics of epileptogenic brain regions,
such as altered glucose metabolism, to identify the region of abnormal function. ● In the presurgical
evaluation of a patient with
Although lacking the anatomic precision and etiologic detail of structural imaging, focal epilepsy, the presence
when successful, functional imaging can help lateralize or even localize the seizure or absence of an
focus. When concordant with other types of data, the images obtained assist with epileptogenic lesion on
the formation of a hypothesis for the putative seizure focus, which may guide structural imaging has a
major impact on surgical
intracranial EEG investigation or, in some cases, direct resective surgery. planning and seizure-free
outcomes.
STRUCTURAL IMAGING. Structural neuroimaging allows neurologists to visualize
the anatomy of the brain and adjacent structures, as well as pathologic lesions
that can be responsible for seizures.

3-TESLA MRI AND POSTPROCESSING TECHNIQUES. As discussed in previous sections,

MRI provides unparalleled anatomic detail for identifying and characterizing
potentially epileptogenic lesions. An important task for the neurologist and
neuroradiologist is to ensure that any potential lesion is not missed. Often,
this requires reexamination of the images as more clinical detail is obtained; for
example, if the region of seizure onset is confirmed during EEG monitoring in an
apparently MRI-negative patient, that region should be carefully reviewed to look
for subtle abnormalities that might have passed unnoticed on previous screening
examinations. A major focus of research in this area is the use of postprocessing
techniques that can visually accentuate potentially epileptogenic lesions.
Techniques highlighted by the ILAE Neuroimaging Task Force include volumetry
of mesiotemporal lobe structures, hippocampal T2 relaxometry, and texture
analysis.

Volumetry of mesiotemporal lobe structures. Atrophy of mesiotemporal structures

is an important imaging correlate of mesial temporal epilepsy, but it may be
subtle and escape routine visual inspection. Either through the use of manual
volumetry or automated algorithms, evaluation with T1-weighted MRI of the size
of structures associated with the mesiotemporal lobe, including the hippocampus,
amygdala, entorhinal cortex, and temporal pole, either in comparison with
normal controls or the patient’s contralateral mesiotemporal structures, can
help lateralize the seizure focus and implicate the temporal lobe in epilepsy
patients.

Hippocampal T2 relaxometry. In addition to atrophy, T2/FLAIR hyperintensity of

the hippocampus is an important finding in the visual inspection of mesial
temporal sclerosis, but various technical difficulties are involved in trying to
identify a subtle abnormality or asymmetry of signal intensity on a computer
screen. T2 relaxometry offers a quantitative estimate of the intensity of the T2

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NEUROIMAGING OF EPILEPSY

signal, which increases the sensitivity of MRI for identifying mesiotemporal

gliosis, in particular when hippocampal volumes are normal.

Texture analysis. Focal cortical dysplasia is a common cause of MRI-negative

epilepsy and may be extremely subtle or frankly undetectable with standard MRI
sequences. Various methods of automated texture analysis may be used to
quantitatively evaluate and visually enhance the MRI correlates of focal cortical
dysplasia, such as blurring of the gray-white matter or alterations in the intensity
of gray matter signal. Depending on the sensitivity of the algorithm, multiple
areas of potential abnormality can be expressed visually and correlated with the
patient’s other clinical data to evaluate potential targets of intracranial EEG
evaluation (FIGURE 3-17).

FIGURE 3-17
Imaging from a patient with nocturnal seizures. Axial 3-Tesla MRI shows an area of focal
atrophy in the left orbitofrontal region (purple cursor in all images) in axial (top row),
sagittal (middle row), and coronal (bottom row) images (note that, contrary to the usual
orientation, the patient’s left side is shown on the left in the axial and coronal images).
The sulcogyral pattern is abnormal and includes many small gyri. On T1-weighted (first
column) and fluid-attenuated inversion recovery (FLAIR) (second column) images, a blurring
of the gray-white matter junction can be seen. The FLAIR signal is also increased. These
anomalies were confirmed by image processing (third and fourth columns) with texture
analysis showing hyperintensity and decrease of gradient, with a large darkened area.
This anomaly is suggestive of focal cortical dysplasia type IIa.
Image courtesy of Andrea Bernasconi, MD, Montreal Neurological Hospital.

330 APRIL 2022

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7-TESLA MRI. Compared with 3T MRI, 7T MRI offers a higher field strength, KEY POINTS
which can be translated to superior image quality and susceptibility contrast,
● MRI postprocessing
as well as a greater spatial resolution. The introduction of 7T MRI into techniques such as
epilepsy clinical practice offers the hope of translating these advantages to a volumetry of mesiotemporal
higher sensitivity for epileptogenic lesions in patients for whom no lesion was lobe structures,
detected on MRI with lower magnetic field strength. Research has shown it to hippocampal T2
relaxometry, and automated
be more sensitive in detecting malformations of cortical development including
texture analysis may be
focal cortical dysplasia, hippocampal sclerosis, and vascular malformations.29 helpful in identifying lesions
Other potential uses include better characterization and delineation of known that were not detectable on
lesions, more precise planning of electrode positioning for intracranial EEG simple visual inspection.
monitoring, and better mapping of eloquent regions of the brain before
● Functional imaging
resection.29 However, 7T MRI presents several technical and logistic challenges, evaluates physiologic
as well, and its high cost has limited its adoption in many epilepsy centers. characteristics of
epileptogenic brain regions
FUNCTIONAL IMAGING. Especially when structural imaging fails to identify a clear to identify regions of
abnormal function, helping
epileptogenic lesion or when investigations reveal multiple potential epileptic to lateralize or localize the
foci, functional imaging may assist in restricting the areas of the brain under seizure focus.
investigation, often in the context of planning a subsequent intracranial EEG
study. Different types of functional imaging take advantage of the fact that
epileptogenic brain tissue has different metabolic and electrophysiologic
characteristics from normal tissue. These regions of difference are then
expressed visually and projected onto existing structural images, usually
MRI. The resulting images, when concordant with other data, allow neurologists to
lateralize or localize the seizure focus, therefore assisting with surgical planning.

POSITRON EMISSION TOMOGRAPHY. The epileptic focus and the region surrounding it
may have reduced metabolism during the interictal period. This region with
interictal hypometabolism consumes differentially less fludeoxyglucose (FDG)
than regions of healthy tissue, a phenomenon that can be detected and expressed
with FDG–positron emission tomography (PET) imaging. A glucose analogue
radiotracer (18F-FDG) is injected into the patient. Brain cells, which rely primarily
on glucose for energy, avidly take in the tracer, where it remains trapped
unmetabolized. The patient is scanned no less than 30 minutes later, and the PET
images display the regions of the brain that contain relatively more or less of the
radiotracer. Areas that light up less than expected, either through visual
inspection in comparison with the contralateral side or by using quantitative
algorithms, can be considered hypometabolic. PET images can also be exported to
existing MRI images of the same patient, adding anatomic detail to the regions of
altered metabolism.
In temporal lobe epilepsy, unilateral temporal hypometabolism is correlated
with the side of seizure focus, allowing lateralization in such cases. Even in
MRI-negative epilepsy, patients with temporal hypometabolism on FDG-PET
have more favorable postsurgical outcomes. It should be noted, however, that the
region of hypometabolism often extends well beyond the true epileptic focus,
such that PET imaging cannot be used to guide delineation during surgical
planning (CASE 3-5). Recent research suggests that for patients with mesial
temporal epilepsy, a more widespread region of hypometabolism portends a
lesser likelihood of postsurgical seizure freedom, especially when extending into
extratemporal or contralateral regions, with the best outcomes found when the
hypometabolism is restricted to the anteromesial region.31 Although FDG-PET

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NEUROIMAGING OF EPILEPSY

can also be used to detect extratemporal epileptic foci, the reported sensitivity in
such patients is much lower.
Compared with many other functional imaging techniques, the logistic
barriers to obtaining PET imaging are significantly fewer because this technique
can be obtained routinely on an outpatient basis. As a result, it can sometimes be
used as an adjunctive technique in the diagnosis and classification of epilepsy,
even in patients who are not presently candidates for epilepsy surgery.

SINGLE-PHOTON EMISSION COMPUTED TOMOGRAPHY. Like FDG-PET imaging, single-

photon emission computed tomography (SPECT) detects altered metabolism in
epileptic brain tissues; however, these techniques have two fundamental differences
between them. The first is that the surrogate for metabolism is not glucose

CASE 3-5 A 14-year-old boy presented with left

temporal seizures that were refractory
to antiseizure medications. Seizures
were characterized by alteration of
consciousness accompanied by
swallowing and left-arm automatisms.
EEG showed left temporal spikes and
seizures originating from the left
anterior temporal head region. MRI
showed a left temporal anteroinferior
encephalocele with an adjacent skull
defect on skull-base CT (FIGURE 3-3).
FDG-PET coregistered with MRI
showed an area of hypometabolism
in the left temporal lobe, extending FIGURE 3-18
well posterior to the encephalocele Axial fludeoxyglucose positron
emission tomography (FDG-PET) MRI
(FIGURE 3-18). After resection of showing both the left temporal
the encephalocele and anteroinferior encephalocele (arrow)
temporal pole, seizure frequency was and region of hypometabolism,
reduced by more than 90%.30 indicated by the blue-shaded area of
the left temporal lobe, much larger
than on the right. Note that the blue-
shaded region extends well posterior
of the encephalocele.
Image courtesy of Lily C. Wong-Kisiel, MD, and
Robert J. Witte, MD, Mayo Clinic, Rochester,
Minnesota.

COMMENT The FDG-PET shows a region of hypometabolism that extends well beyond
the epileptogenic lesion. In such cases, the region of hypometabolism
should not be used to delineate the surgical margins, as this phenomenon
is well described. The larger region of hypometabolism does suggest a
lesser probability of postsurgical freedom from seizures, even when the
presumptive seizure focus is fully resected, but should not be a
contraindication to surgery.

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consumption but rather altered blood flow. The second is that, in common clinical
practice, SPECT seeks evidence of increased metabolism at the time of a seizure,
rather than decreased metabolism in the interictal period. Seizures are, by
definition, transient events of excessive or synchronous neuronal activity in the
brain, which by their nature require increased metabolism if an energy crisis is to be
avoided. The brain vasculature, therefore, diverts blood flow toward seizing tissue.
SPECT exploits this change in blood flow by the injection, at the moment of a
seizure, of a radiotracer such as technetium 99m–hexamethylpropyleneamine
oxime (99mTc-HMPAO) that is rapidly taken up within the brain and then
remains for several hours, providing an image of cerebral blood flow at the
moment of injection when the patient is scanned within 4 hours of the seizure.
The images obtained are then compared with images taken after an injection in
the same patient during an interictal period, allowing a statistical analysis of the
differences in regional blood flow between the ictal and interictal periods.
Regions of hyperperfusion during the ictal period compared with the interictal
period are considered candidate regions of seizure focus. By using statistical
parametric analysis, the data can also be normalized and compared with a control
group, and the result can be coregistered to MRI to allow visualization of the
areas of ictal hyperperfusion on the patient’s anatomy for hypothesis building or
surgical planning (FIGURE 3-19).
The logistic challenges to obtaining an ictal SPECT are significant. In practice,
SPECT is almost always obtained during an inpatient epilepsy monitoring unit
admission. While the patient is being monitored continuously by EEG and watched
carefully by medical personnel, antiseizure medications are frequently reduced to
provoke seizures. The radiotracer must be continuously replenished at the bedside
given its short half-life, and it is usually unavailable outside of normal work hours.
Immediately on the onset of a seizure, as identified by patient notification, EEG
changes, or clinical symptoms, a nurse or EEG technician near the bedside must
inject the radiotracer as quickly as possible. Given the tendency of focal seizures to
spread to adjacent regions or to become bilateral tonic-clonic seizures, a late
injection may indicate the region of spread rather than the initial focus. Therefore,
the sooner the tracer is injected after seizure onset, the better the yield.

FIGURE 3-19
Ictal-interictal subtracted single-photon emission computed tomography (SPECT)
coregistered to axial MRI showing activation centered on the right mesial temporal
structures during seizure onset, suggesting a right temporal seizure focus.

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NEUROIMAGING OF EPILEPSY

FIGURE 3-20
EEG–functional MRI (fMRI) showing activation clusters superimposed on axial (A), sagittal (B),
and coronal (C) T1-weighted fMRI correlated with interictal spikes and slow waves diffusely
maximal over the right temporal and parietal head regions on EEG. These discharges were
correlated with maximal activation of the right supramarginal and angular gyri.

FIGURE 3-21
Magnetic source imaging showing the location of magnetoencephalography dipoles
coregistered to MRI, superimposed on coronal (A), sagittal (B), and axial (C) T1-weighted
images. The images show that the biggest clusters of magnetic dipoles are located in the
left opercular and anterior insular regions. Note that, contrary to the usual orientation, the
patient’s left side is shown on the left in the coronal and axial images.

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 Despite these hurdles, SPECT is a well-established technique for identifying a KEY POINTS
temporal or extratemporal seizure focus in patients with MRI-negative focal
● Fludeoxyglucose positron
epilepsy. In MRI-negative extratemporal cases, SPECT is an important test that emission tomography (FDG-
can establish a putative surgical target for intracranial EEG monitoring and is PET) imaging identifies
predictive of seizure-free outcomes.32 regions of interictal glucose
hypometabolism. In
temporal lobe epilepsy,
EEG–FUNCTIONAL MRI. EEG–functional MRI (fMRI) is a functional imaging
unilateral temporal
technique focused on correlating changes in focal oxygen levels with interictal hypometabolism is
EEG discharges, allowing more precise localization of the discharges within the correlated with the side of
brain. Interictal scalp-surface EEG spikes are often generated at the seizure seizure focus. FDG-PET is
less sensitive in
focus, but for various technical and theoretical reasons, it is not possible to
extratemporal epilepsy.
precisely extrapolate their location inside the skull. fMRI allows the visualization
of changes in blood oxygen levels within the brain (see the later section on ● Single-photon emission
other uses of fMRI). When EEG discharges are seen to be correlated in time computed tomography
with a focal change in blood oxygen levels, the region of metabolic change (SPECT) uses a radiotracer to
detect increased blood flow
can be delineated as the generator of the discharges (FIGURE 3-20). The during the ictal period to
information obtained can be correlated with other clinical data in the identify the seizure focus.
planning of epilepsy surgery in patients with complex epilepsy who have The tracer must be injected
interictal discharges.33 immediately on seizure
onset, creating logistic
challenges.
MAGNETIC SOURCE IMAGING. Similar to EEG-fMRI, magnetic source imaging (MSI)
is a method used to detect the source of interictal discharges within the brain to ● Functional MRI (fMRI) and
identify a potential seizure focus. Instead of correlating them with brain oxygen diffusion tensor imaging
(DTI) are imaging modalities
levels, however, magnetic source imaging records magnetic fields that are
that can help identify the
generated by neuronal currents at the moment of interictal spikes, recording them location of critical brain
at the surface of the head (magnetoencephalography). Unlike EEG electric tissue and assist with the
potentials, which are distorted by the tissues of the brain, skull, and scalp, safe resection of the
magnetic fields are not altered by these structures, allowing for more effective seizure focus.

modeling of the spike sources. The magnetoencephalographic data are then

coregistered with MRI data to display the posited location of the magnetic dipoles
within the patient’s brain anatomy, providing another method to localize the
seizure focus in MRI-negative
patients (FIGURE 3-21).34

Surgical Planning
Once the seizure focus has been identified, it must be removed or destroyed
surgically to achieve seizure freedom. Patients are often surprised to learn that a
piece of the brain can be taken out without causing serious neurologic injury. But
given the specialization of different regions of the brain, it is essential to ensure
that the region to be removed is not responsible for some critical function such as
speech or motor activity. Knowledge of brain anatomy is essential but not
sufficient to avoid neurologic impairment, given the variability in functional
topography among patients, especially in regions affected by a lesion that may
have been present since birth and influenced brain development from a young
age. fMRI and diffusion tensor imaging (DTI) are imaging methods that can
predict the location of critical brain tissue.

FUNCTIONAL MRI. fMRI is an imaging modality primarily used to identify the

regions within the brain associated with different neurologic functions. The
technique detects changes in blood oxygen levels that indicate which regions of

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NEUROIMAGING OF EPILEPSY

the brain are more active when a patient performs a specific standardized task
using the function under review compared with a rest or control condition.
Although fMRI can be used to evaluate the localization of sensory or motor
function, it is most frequently used in epilepsy surgery planning to lateralize
and localize language areas. Different language functions (eg, naming,
comprehension) can be tested individually by using protocols and mapped onto
the patient’s brain anatomy. This information can be used to estimate the risk
of language impairment after surgical resection, especially when considering a
left temporal lobectomy, or to help define surgical margins. Being less invasive,
this technique has partially replaced the Wada test for language lateralization
(FIGURE 3-22). When a surgery is considered high risk for loss of function,
however, intracranial cortical stimulation mapping may be necessary
before resection.

DIFFUSION TENSOR IMAGING. Whereas fMRI examines cortical function, DTI is

primarily used to map critical white matter tracts, damage to which might leave

FIGURE 3-22
Functional MRI (fMRI) used to evaluate lateralization of language function in a right-handed
patient with left mesial temporal sclerosis and drug-resistant epilepsy before lobectomy.
A, Statistical representation of changes in blood oxygen level–dependent (BOLD) activation
on a normalized brain during a language completion task to evaluate expressive speech;
darker areas show greater activation. The patient read an incomplete written sentence and
spoke out the missing words. This task showed bilateral activation in the frontal regions,
near the Broca area, left greater than right. B, Areas of higher BOLD activation (yellow) are
superimposed onto left sagittal, coronal, and axial T1-weighted MRI images of the patient’s
brain. Bilateral occipital activation was also seen due to the visual nature of the task. Note
that, contrary to the usual orientation, the patient’s left side is shown on the left in the axial
and coronal images. C, Areas of higher BOLD activation (see the yellow-red scale) are
superimposed onto a three-dimensional reconstruction of the patient’s brain MRI, shown
from different perspectives. Other language tasks (not shown) also mostly showed bilateral
activation, suggesting bilateral language function. A left temporal amygdalohippocampectomy
and anterior temporal lobectomy was performed without impact on the patient’s language
function.

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the patient with permanent
neurologic impairment. DTI is a
magnetic resonance technique
that measures the random
movements of water molecules
in three dimensions within the
brain tissue, which have
different characteristics
according to the nature of
the tissue within which the
water is contained. Modeling
of the information obtained
allows the graphic
representation of white
matter tracts such as the FIGURE 3-23
corticospinal tract or Meyer Diffusion-tensor imaging (DTI) coregistered to
coronal T1-weighted MRI showing the locations of
loop, allowing prediction of a the corticospinal tract (blue) relative to a large left
postsurgical deficit risk or frontal oligodendroma (red mass) causing seizures
assisting in surgical planning before a partial resection.
(FIGURE 3-23).

CONCLUSION
It is the neurologist’s task to understand each patient’s epilepsy well enough to better
explain and treat their disease. In this endeavor, the importance of neuroimaging
cannot be underestimated, especially for more challenging cases. For neurologists
who treat patients with epilepsy, understanding the advantages and limitations of
each modality is essential and will lead directly to better care and a higher likelihood of
seizure freedom in their patients. As imaging technology improves, the judicious
selection and interpretation of imaging modalities will become all the more critical.

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