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Neuroimaging in Epilepsy Surgery

Erasmo A Passaro, MD, Director, Comprehensive Epilepsy Program/Clinical Neurophysiology Lab, Bayfront Medical Center Florida Center for
Neurology
Ramon Diaz-Arrastia, MD, PhD, Assistant Professor, Department of Neurology, Comprehensive Epilepsy Center, University of Texas
Southwestern
Updated: Jan 26, 2010

Introduction
The imaging of epilepsy has vastly changed in the last 15 years. Prior imaging with computed axial tomography (CT) infrequently
revealed the pathologic substrate for epilepsy. Although early low field strength MRI increased the diagnostic yield, it could only
identify obvious pathology such has neoplasms, encephalomalacia, and vascular malformations. The advent of high-resolution
magnetic resonance imaging with a dedicated epilepsy protocol has significantly increased the frequency that a pathologic
substrate for epilepsy is identified. This has had a dramatic clinical impact on the evaluation and management of epilepsy since
MRI findings can assist with classification, determine prognosis for remission, predict long-term intractability to antiepileptic
medications, and identify potential surgical candidates.

The International League Against Epilepsy Guidelines for Neuro-imaging in the Epilepsy Patient (1997) recommends a dedicated
epilepsy protocol MRI for all patients with a new-onset seizure or newly diagnosed epilepsy in a nonemergent setting.
Unfortunately, in most clinical practice settings, a nonepilepsy protocol MRI is performed. While a routine MRI will exclude
ominous structural substrates that require urgent treatment in themselves such as high-grade gliomas and arteriovenous
malformations, subtle structural substrates such as hippocampal sclerosis and malformations of cortical development (MCDs)
will be missed. Identification of these substrates has long-term therapeutic and prognostic implications for remission versus
intractability.

Approximately one third of patients with partial-onset epilepsy are medically intractable defined as failing at least 2 first-line
antiepileptic medications. The chance of being considered an epilepsy surgery candidate is greatly enhanced when a structural
substrate is found on MRI. In a recent cross-sectional study of 495 patients in an epilepsy clinic, 51% had an abnormal scan (CT
or MRI). In those patients with focal epilepsy who had a standard MRI, an abnormality was found in 49%, and in those who had
an epilepsy protocol MRI an abnormality was found in 72%. An earlier study by Li et al found similar findings.[1 ]

Another study compared standard MRI interpreted by nonexpert neuroradiologists to the interpretation by an expert
neuroradiologist. The same patients then had a follow-up epilepsy protocol MRI interpreted by an expert neuroradiologist. The
nonexpert reports of standard MRI identified 39% as abnormal, the expert reports of the same MRI identified 50% as abnormal.
Epilepsy protocol MRI interpreted by an expert identified a focal lesion in 85% of those with a normal standard MRI. The most
commonly missed finding was hippocampal sclerosis followed by tumor and other findings. Less commonly missed findings
included vascular malformations and malformations of cortical development. The ILAE Commission on Neuroimaging also
recommends an epilepsy protocol MRI in all patients with intractable epilepsy.

A study by Kwan and Brodie in 2000 found that, in patients with newly diagnosed epilepsy, only 47% became seizure free with
the first AED and only 14% with the second AED.[2 ]Further AED trials achieved seizure freedom in only 5% of patients. This
study showed that intractable epilepsy is more common than generally believed, and can be identified early. However, referral
for epilepsy surgery is delayed in half of intractable epilepsy patients who are referred greater than 10 years from the onset of
intractability. This further underscores the importance of epilepsy protocol MRI which has a high yield for identifying a structural
substrate that would enable these patients to be referred early for an epilepsy surgery evaluation thus, providing them with an
optimal chance of attaining seizure freedom.

Epilepsy protocol MRI

Conventional MRI imaging is inadequate for epilepsy patients since many of the findings are subtle and easily missed. Routine
MRI consists of a short scan time, 3-to 5-mm thick slices with an interslice gap of 2-3 mm. These studies do not include SPGR or
MPRAGE T1-weighted images that enhance gray white matter differentiation, which is crucial to analyze the cortical architecture.

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These images are also not acquired in a coronal oblique plane perpendicular to the long axis of the hippocampus, which is
particularly important when evaluating temporal lobe epilepsy (TLE).

Epilepsy protocol MRI, on the other hand, includes the entire brain from nasion to inion, T1-weighted MPRAGE or SPGR images
1.5-mm slice thickness with no intervening gap obtained in the coronal oblique plane (if temporal lobe epilepsy is suspected).
These images are acquired as a 3-D volume thereby allowing postprocessing to correct for head misalignment and for
reformatting images into multiple planes to confirm a subtle malformation of cortical development. An epilepsy protocol MRI also
includes coronal and axial FLAIR sequences with 3-mm slice thickness and 0- to 1-mm interslice gap. A conventional thin slice
(3 mm) T2-weighted axial and coronal sequence is also obtained. Gadolinium is not required, unless a tumor or a vascular
malformation is identified and in some neurocutaneous syndromes such as Sturge-Weber syndrome in order to visual
leptomeningeal angiomatosis.

Functional neuroimaging techniques, including positron emission tomography (PET), single-photon emission computerized
tomography (SPECT), magnetic resonance spectroscopy (MRS), magnetic source imaging (MSI), and functional MRI (fMRI) are
not universally available, but can be very helpful in the localization of the epileptogenic zone and for mapping functional areas of
the brain such as language and motor function. The clinical utility of each imaging modality will be reviewed, with an emphasis
on MRI structural imaging.

MRI of the Temporal Lobe

Hippocampal sclerosis

Hippocampal sclerosis (HS) is characterized by neuronal loss and gliosis. HS is the most common pathologic substrate of
surgically treated epilepsy in adults seen in 67% of patients. In patients with newly diagnosed epilepsy, it has been reported in
1.5-3% of adults. When evaluating the medial temporal structures (hippocampus, amygdala, entorhinal cortex, and
parahippocampal gyrus), one should evaluate the size, signal, shape, and dual pathology (SSSD). The typical MRI findings of
HS include atrophy of the hippocampus on T1-weighted SPGR that is typically seen in 90-95% of cases. The atrophy is most
prominent in the hippocampal body.

On FLAIR imaging, increased signal is observed within the hippocampus. FLAIR is ideally suited to identify signal changes within
the hippocampus since gliotic changes have increased water content appearing as increased signal on T2 weighted MRI. The
FLAIR sequence nulls the increased signal intensity of the CSF in the temporal horn of the lateral ventricle and the choroidal
fissure that can dwarf the increased signal in the hippocampus on a conventional thin-slice T2-weighted spin echo image. One
must also be aware that the baseline signal of the hippocampus on FLAIR MRI is greater than of the cortex, and can be
mistakenly interpreted as bilateral HS. In these cases, thin-slice coronal T2-weighted images should be reviewed for
confirmation.

Hippocampal atrophy and increased signal are not always seen together in the same patient. For example, some patients have
increased FLAIR signal or T2 signal without accompanying atrophy. The increased T2 signal is felt to reflect gliosis rather than
neuronal cell loss. Occasionally, secondary findings of hippocampal sclerosis will be observed such as (1) enlargement of the
ipsilateral temporal horn, (2) thinning of the fornix, (3) mamillary body atrophy, (4) loss of normal interdigitations of the
hippocampal head, and (5) atrophy of the collateral white matter between the hippocampus and the collateral sulcus.

High-resolution MRI is 80-90% sensitive for identifying hippocampal sclerosis by qualitative interpretation. Bilateral hippocampal
atrophy is seen in 10-20% of patients, but it may be difficult to visualize unless quantitative measures are done. In children with
intractable epilepsy, HS is also seen on MRI in children. For example, HS is observed in 21% of children with newly diagnosed
TLE and up to 57% of children with intractable TLE. More common findings in children with intractable TLE include
malformations of cortical development and developmental tumors.

Entorhinal cortex atrophy

While quantitative assessment of the entorhinal cortex (ERC) is ideal, ERC size can be evaluated by visual assessment. ERC
atrophy is often seen concomitantly with hippocampal atrophy, but it can also be seen independently. It is characterized by
thinning of the collateral white matter of the ERC.

Hippocampal sclerosis and dual pathology

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Approximately 15-20% of patients with HS have dual pathology, that is, another pathologic substrate within or outside the
temporal lobe in addition to HS. Dual pathology is more commonly observed with malformations of cortical development and
developmental lesions such as porencephaly. It is less commonly seen with vascular malformations (7%) and neoplasms (2%).
With vascular malformations, HS is more likely to be present if the lesion is in close proximity to the hippocampus.

Pearls and pitfalls in the evaluation of hippocampal sclerosis

One must also be vigilant not to attribute all cases of increased signal within the hippocampus to HS. While increased signal on
FLAIR indicative of HS is not always accompanied by hippocampal atrophy, the hippocampus should never be abnormally
enlarged since this indicates a low-grade neoplasm, hamartoma, or hippocampal dysplasia and not HS.

Amygdala atrophy and dysplasia

The amygdala should be evaluated for symmetry. Occasionally, the amygdala may be reduced in size along with hippocampal
atrophy. However, this is difficult to observe visually. Amygdala atrophy accompanying HS has been identified with volumetric
analysis in 12% of pathologically confirmed patients with HS. Another study identified ipsilateral amygdala atrophy by volumetry
accompanied HS in 20% of patients. However, they also found that amygdala atrophy was also frequently seen contralateral to
HS in 15%.

Sometimes, the amygdala is pathologically enlarged consistent with amygdala dysplasia, hamartoma, or a low-grade neoplasm.
This enlargement may or not be associated with increased signal on FLAIR MRI. Usually, in the setting of a low-grade glioma or
a developmental tumor, accompanying T2 signal changes are present. Amygdala enlargement is not associated with
hippocampal atrophy and is seen in imaging-negative TLE. However, sometimes amygdala enlargement is accompanied by
hippocampal enlargement and likely represents hamartomatous enlargement of the hippocampus and the amygdala.

Viewing the images in the axial plane may also increase the yield of identifying enlargement of the amygdala. One group
recommended that abnormal amygdala enlargement may be visually assessed by evaluating for prominent amygdala gray
matter extending medially, anterior to the sylvian fissure.

MRI of Malformations of Cortical Development and Neoplasms

Classification of malformations of cortical development

Malformations of cortical development (MCD) are classified into 3 different categories based on the stage the MCD occurred: (1)
cortical dysplasia (neuronal and glial proliferation or apoptosis <10 wk), (2) heterotopias (abnormal neuronal migration 10-20
wk), (3) polymicrogyria (abnormal late cortical migration and organization >20 wk). Some degree of cortical organization also
occurs postnatally. For a detailed developmental and genetic classification of MCD, please refer to Barkovich et al, 2005.

[3 ]
Imaging of malformations of cortical development
Malformations due to abnormal neuronal and glial proliferation or apoptosis

Microlissencephaly and microcephaly with simplified gyral pattern has been described in patients with profound congenital
microcephaly (head circumference that is more than 3 standard deviations below normal at birth). These conditions are felt to
result from abnormally decreased cellular proliferation or pathologically increased apoptosis. The sulcal pattern is similar to the
sulcal pattern in normal patients; however, there are too few sulci. If the cortex is of normal thickness (3 mm), a diagnosis of
microcephaly with simplified gyral pattern can be made. If the cortex is abnormally thick, then a diagnosis of microlissencephaly
is made.

Hemimegalencephaly is characterized by abnormal enlargement of a lobe, multiple lobes, or a hemisphere due to marked
dysplasia. This condition can be an isolated finding or can be seen with neurocutaneous syndromes such as (1) epidermal nevus
syndrome, (2) hypomelanosis of Ito, (3) neurofibromatosis type 1, (4) Klippel-Trenaunay-Weber syndrome, and (5) tuberous
sclerosis. Imaging findings include large clumps of grey matter that extend from the pial surface to the ventricle. The affected
lobe or hemisphere is enlarged, the white matter shows increased signal on T2-weighted images, and usually the lateral
ventricle is enlarged in the dysplastic region.

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Focal cortical dysplasia with balloon cells is also known as Taylor-type cortical dysplasia. Theses lesions are nearly identical to
those seen in Tuberous Sclerosis. Usually, a small focal region is involved. Sometimes, the cortical dysplasia extends from the
pia to the ventricle (transmantle dysplasia). MR imaging findings include (1) cortical thickening that is observed on at least 3 or
more contiguous slices; (2) blurring of the grey-white matter junction; (3) increased signal of the underlying white matter on T2-
weighted images; and (4) often times, a linear, curvilinear, or funnel-shaped abnormal signal intensity is seen extending from the
cortical white matter junction to the surface of the lateral ventricle.

Malformation due to abnormal neuronal migration

Classic lissencephaly (smooth brain) is defined as reduced sulcation, and the cortical surface shows reduced number and depth
of sulci. In some cases, there is complete absence of sulcation, whereas in others, there is a reduction. This condition is due to a
mutation of either the LIS1 gene at chromosome 17p13.3 or the DCX gene at Xq22. Both mutations are believed to cause
lissencephaly by interfering with translocation of migrating neurons as they advance along radial glial cells. With the LIS1
mutation, the abnormality is most severe in the parieto-occipital lobes, and with the DCX mutation, the gyral abnormality is most
severe in the middle and anterior half of the frontal lobes.

Subcortical band heterotopia (SBH) represents a milder form of the LIS1 or DCX mutation. On MRI imaging, either a thick or a
thin band of cortex is seen in the white matter underlying and running parallel to the normal-appearing cortex. If the SBH is
mainly frontal, the DCX mutation is the likely cause, whereas if it is observed in the parieto-occipital region, the LIS1 mutation is
more likely. Other mutations have also been described, and the reader is referred to a recent review by Barkovich and
colleagues (2005). SBH can easily be missed when it consists of a thin band of cortex. Clinically, some of these patients appear
to have localization-related epilepsy from another region. However, surgical outcome in this group is poor since the SBH is a
marker of diffuse epileptogenicity.

Heterotopia refers to a collection of neurons in an abnormal location. They can be located in the subcortical white matter,
subependymal region (periventricular), or underlying the normal-appearing cortex in a laminar pattern (SBH). They are round to
ovoid nodules that consist of both neuronal and glial cells. On MRI imaging, they are grey matter isointense on both T1 weighted
and T2 weighted imaging. Subcortical heterotopias can range from single to multiple grey matter nodules that may extend from
the ventricular wall to the cortical mantle. Occasionally, there may be dimpling of the cortex overlying the region of the
heterotopia. They are usually unilateral but can be bilateral in which case they are associated with cognitive delay.

Periventricular nodular heterotopias (PVN) are most commonly seen in the lateral ventricles, with the trigones and the frontal
horns the most frequent location. They are round or oval and can lie in the wall of the ventricle and protrude into the ventricular
space or sometimes are present in the periventricular white matter. In mild cases, only a few nodules are seen, whereas, in more
severe cases, a continuous layer can be seen lining the ventricular wall. These nodules are grey matter isointense on all MR
imaging sequences. While many cases are sporadic, some cases are due to a mutation of the FLNA gene that codes for filamin
1, which is involved in the migration of the neuron from the germinal zone onto the radial glial fibers, and is located on band
Xq28.

Identification of PVN is clinically important in that seizure-free outcome after anteromedial temporal is poor in patients with PVN
with clinical and EEG features of temporal lobe epilepsy. The reason for this is that these nodules are epileptogenic, and recent
small series have demonstrated that a good surgical outcome can be obtained when the PVN are unilateral, seizures localize to
the nodule(s) and are resected.

Malformations secondary to abnormal late migration and organization

Polymicrogyria (PMG) consists of an excessive number of small gyri with shallow sulci. PMG can be (1) focal and limited, (2)
focal unilateral and extensive, (3) bilateral and symmetrical, (4) bilateral and asymmetrical, (5) multifocal, or (6) diffuse. On MR
imaging, numerous small gyri with shallow sulci are seen. Sometimes, the gyri appear cortex has an irregular, bumpy inner and
outer cortical surface with broad gyri and shallow sulci. The cortical-subcortical junction is often irregular.

Schizencephaly consists of a CSF cleft extending from the subarachnoid space to the lateral ventricle. The wall of the cleft is line
with dysplastic cortex and/or polymicrogyria. The lips of the cleft can be closed (type 1) or open (type 2). The most common
location is posterior peri-sylvian cortex. Two thirds of cases are unilateral, and one third are bilateral. Schizencephaly is
commonly associated with polymicrogyria, optic nerve hypoplasia, and absence of the septum pellucidum. Although both PMG
and schizencephaly are strikingly abnormal on MR imaging, they often contain primary motor, sensory, or visual function.

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Focal cortical dysplasia (FCD) without balloon cells consists of a focal abnormality of cortical lamination of the cerebral cortex
and the underlying white matter with abnormal cortical neurons but without the presence of balloon cells or cells extending from
the pial surface to the ventricular surface. MR imaging findings include cortical thickening on at least 3 or more contiguous slices,
blurring of the grey white matter junction, and focal cortical thinning with volume loss of the underlying white matter. Increased
signal on T2-weighted imaging may be seen; however, the signal does not extend to the ventricular surface.

An occasional helpful finding is the "cleft-dimple" complex where the size of the subarachnoid space overlying the FCD is
enlarged and the cortex appears to "buckle" away from the subarachnoid space. The neuroimager must be aware that normal
cortex may appear thickened when sliced obliquely cross a sulcus. In this regard, it is imperative to make sure that the findings
seen on numerous contiguous slices are still present when reformatted into multiple planes and correlated with clinical, EEG,
and functional imaging data. One must also be aware that the mildest forms of FCD characterized by dyslamination alone may
not show any abnormality on even high-resolution MR imaging.

MRI of neoplasms associated with epilepsy

Neoplasms are the structural substrate in 3-4% of patients with epilepsy in the general population. In patients with intractable
epilepsy treated with epilepsy surgery, neoplasms account for approximately 20% of cases. Neoplasms associated with chronic
epilepsy are usually located in the cortex and are not usually associated with mass effect or vasogenic edema. The temporal
lobe is the most common location (68%). Neoplasms found in patients with chronic epilepsy include (1) low-grade astrocytic
tumors, (2) oligodendroglioma, (3) gangliogliomas, (4) dysembryoplastic neuroepithelial tumor (DNET), and (5) a pleomorphic
xanthoastrocytoma (PXA). On MR imaging, most neoplasms are hypointense on T1-weighted images and hyperintense on T2-
weighted images. However, it is often difficult to distinguish these neoplasms, unless specific imaging characteristics for each
tumor are present on MR imaging (see below).

Astrocytomas, fibrillary subtype, (WHO grade 2) are usually ill-defined infiltrative tumors that usually do not enhance with
gadolinium. Pilocytic astrocytomas, on the other hand, are well defined though not encapsulated, and a mural nodule is seen
after gadolinium enhancement. Oligodendrogliomas are usually peripherally located and may appear cortically based with
gyriform calcifications and adjacent changes in the calvaria. They are commonly seen in the frontal or temporal lobe. Gadolinium
enhancement is variable.

Gangliogliomas are most commonly seen in the temporal lobe of patients younger than 30 years. They are mixed solid and
cystic lesions that are cortically based with minimal or no mass effect. Calcification is often present. Gadolinium enhancement is
variable. The finding of calcification and cystic changes in a cortically based lesion raises the possibility of this neoplasm. These
lesions can be associated with concomitant cortical dysplasia.

Dysembryoplastic neuroepithelial tumors (DNET) are benign low-grade, multicystic, and multinodular cortical-based tumors
mostly seen in children and young adults. A cortically based hypointense nodule can be seen on T1-weighted images. Calvarial
remodeling may be seen. Cortical dysplasia can be seen in 20-30% of these tumors. Gadolinium enhancement is variable. If a
cortically based, multicystic tumor is seen on MR imaging, a DNET should be considered.

Pleomorphic xanthoastrocytoma (PXA) are superficially located tumors adjacent to the leptomeninges with an enhancing mural
nodule. Leptomeningeal involvement is characteristic of this tumor. Local recurrence and malignant transformation can occur
with this tumor in 50% of patients.

Positron Emission Tomography

Fluoro-deoxyglucose positron emission tomography

Fluoro-deoxyglucose positron emission tomography (FDG-PET) reveals interictal hypometabolism of the epileptogenic temporal
lobe in more than 85% of cases. This zone of hypometabolism is much larger than the ictal-onset zone defined
electrophysiologically and the epileptogenic region defined pathologically. This test is more sensitive when an asymmetry index
is calculated comparing the quantitative metabolism of each temporal lobe and prevents misinterpretation due to partial volume
averaging artifact. The degree of hypometabolism does not correlate with the degree of cell loss or the degree of hippocampal
atrophy identified by MRI. In patients with TLE, unilateral hippocampal atrophy, and concordant EEG data, FDG-PET provides
redundant data. However, it may provide additional information in patients whose MRI and EEG findings are discordant and in
patients whose MRI findings are normal.

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Visual analysis of FDG-PET is less sensitive in frontal lobe epilepsy, with fewer than 50% of cases showing localized
abnormalities. In these cases, quantitative normalized analysis may improve sensitivity of this test. Newer techniques, such as
statistical parametric mapping (SPM) and 3-D stereotactic surface projection (3-DSSP) images, may be more sensitive than
conventional FDG-PET analysis. With the SPM technique, the subject's PET scan is subtracted on a pixel-by-pixel basis from a
normal database of control subjects. This technique may provide localizing information in patients with either extratemporal
epilepsy or TLE with a normal MRI. Coregistration with MRI may improve the sensitivity and specificity of FDG-PET by correcting
for partial volume effects.

11
C-flumazenil PET

Preliminary evidence suggests that radioligand PET scans with the benzodiazepine antagonist11 C-flumazenil (FMZ) may have
greater sensitivity in identifying the epileptogenic region than FDG-PET. FMZ labels central GABA receptors. Early studies at the
University of Michigan showed a reduction in FMZ binding in the temporal lobe of patients with intractable TLE, which is more
restricted than the region of hypometabolism seen with FDG-PET. This reduction in FMZ binding correlates with neuron loss in
the hippocampus.

Newer techniques, using SPM and an MRI-based method for partial-volume effect correction, have shown that the reduction in
FMZ binding is greater than what would be expected from volume loss alone. This finding suggests that, in addition to neuronal
loss, GABA binding in the epileptogenic hippocampus is reduced. FMZ-PET also shows enhanced sensitivity in patients with
malformations of cortical development (MCD). More recent studies have shown either increases or decreases in benzodiazepine
receptor density in regions of MCD. However, surgical outcome in patients with a localized abnormality on FMZ-PET and normal
MRI findings is not yet known.

Alpha methyl L-tryptophan and serotonin receptor PET imaging

In view of basic science, evidence that serotonin plays a role in epilepsy, PET imaging with serotonin precursors or serotonin
agonists has been recently used with the hope of improving the detection of the epileptogenic zone. For example, reduced
concentrations of brain serotonin are found in the brains of the genetically epilepsy-prone rat (GEPR). In addition, treatment with
agents that facilitate serotonergic transmission inhibit seizures in many animal models of epilepsy. Reduction of brain serotonin
concentrations, on the other hand, increases seizure susceptibility in animal models of epilepsy. Furthermore, in human epileptic
brain tissue resected for the treatment of epilepsy, increased serotonin was found.

Alpha methyl L-tryptophan PET (AMT-PET), like L-tryptophan, is a serotonin precursor that can help measure brain serotonin
synthesis rates. Like tryptophan, AMT is metabolized into serotonin, but unlike tryptophan, it is not converted into protein. AMT is
converted to alpha methyl serotonin, but unlike serotonin, it is not metabolized by monoamine oxidase. Chugani and colleagues
used AMT in patients with tuberous sclerosis and found reduced AMT uptake in cortical tubers as compared to normal cortex.
However, epileptogenic tubers confirmed by ictal onset region demonstrated increased uptake.[4 ]

Another study by Fedi and colleagues evaluated patients with either cortical dysplasia on MRI or a normal MRI. Increased AMT
uptake was identified in 60% of patients with cortical dysplasia and 30% of patients with normal MRI. Juhasz et al reported
similar findings. AMT has also been studied in patients who failed epilepsy surgery and was able to identify increased AMT
uptake in residual epileptogenic cortex as identified by intracranial EEG. However, it could only identify the epileptogenic region
in 43% of patients.

Serotonin 5-HT1A receptor binding has also been studied with the PET ligands (18F)FCWAY and (11C)WAY. Toczek et al found
reduced 5-HT1A binding in the medial and lateral temporal regions ipsilateral to the epileptogenic temporal lobe.[5 ]Savic and
colleagues reported similar findings, but they also reported reduced binding in limbic connections such as the cingulate cortex
and the insula.[6 ]

Single-photon Emission Computerized Tomography

Despite great progress in structural neuroimaging, in most specialized epilepsy centers, the epileptogenic zone remains
unlocalized by MRI scanning in approximately 20-50% of patients with medically intractable epilepsy. This problem has
stimulated efforts to develop functional neuroimaging techniques that can demonstrate transient physiologic disturbances, not
just static structural ones.

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Single-photon emission computerized tomography (SPECT) scanning, after the administration of technetium Tc 99m
hexamethylpropyleneamine oxime (99m Tc-HMPAO, Ceretec) or (99m Tc-ECD, Neurolite), is a readily available and relatively
inexpensive method of measuring regional cerebral blood flow. These radiotracers are taken up rapidly by the brain during the
first pass and, after entering neural cells, are converted rapidly to hydrophilic compounds that are trapped intracellularly and are
stable for several hours. Thus, SPECT scanning can provide a semiquantitative image of cerebral blood flow 30-60 seconds
after intravenous injection.

SPECT is performed during the ictal period to help delineate the epileptogenic zone. It is particularly helpful in patients with
normal MRI findings, as well as in patients with abnormal MRI findings and a nonlocalizing EEG. Since seizures are associated
with increased glucose metabolism (metabolism is closely coupled to cerebral blood flow), ictal SPECT scans show increased
perfusion in the region of seizure onset. However, obtaining a true ictal injection is important, particularly for extratemporal lobe
seizures, since with late injections, the areas of increased perfusion may represent seizure spread rather than seizure onset.

Obtaining a snapshot of cerebral blood flow during the epileptic seizure ("ictal SPECT") and comparing that to the results of an
injection when the patient is free of seizures ("interictal SPECT") is relatively convenient. An area of increased blood flow during
the seizure that demonstrates decreased blood flow during the interictal period is more likely to be the site of seizure onset and
correlates highly (approximately 90% sensitivity) with MRI abnormalities.

In TLE, ictal SPECT has 90% sensitivity in localizing seizures, with good interobserver reliability. Ictal increased perfusion is
seen in both the medial and the lateral temporal lobe. In the immediate postictal period (60 seconds), hyperperfusion of the
medial temporal lobe with hypoperfusion of the lateral temporal lobe are noted. In the late postictal period (up to 20 minutes
postictally), perfusion in both the medial and lateral temporal lobes may be decreased.

From a practical point of view, however, SPECT scanning adds little useful information in patients who have lesions detected by
MRI and localizing or lateralized EEG findings. Ictal SPECT is not helpful in localizing seizures in patients with bilaterally
independent temporal lobe seizures, since the procedure samples only one seizure at a time. Moreover, false lateralization with
ictal SPECT may occur if the seizure ceases in the temporal lobe of origin while continuing in the contralateral temporal lobe at
the time of tracer injection. For extratemporal lobe seizure, such as frontal and parietal lobe seizures, ictal SPECT has sensitivity
as high as 90% in localizing seizures if ictal injection occurs shortly after ictal onset (ie, within 20 seconds).

Subtraction ictal SPECT co-registered to MRI

The sensitivity of ictal SPECT is increased significantly when ictal and interictal images are subtracted. This subtracted image is
then superimposed on high-resolution MRI, which further increases the sensitivity and specificity of the interpretation. Surgical
outcomes in patients whose seizure focus is localized with this technique are under study. More recently, postictal subtraction
SPECT coregistered to MRI has been studied as a method of localizing the epileptogenic zone. Newer methods include
statistical parametric mapping where a control database of inter-ictal SPECT scans are subtracted from the patient's ictal
SPECT scan and a z score is generated. This subtraction image is subsequently coregistered to MRI.

A study by Kazemi et al determined that statistical ictal SPECT coregistered to MRI was superior to subtraction ictal SPECT
coregistered to MRI for seizure localization before temporal lobe epilepsy surgery.[7 ]

Magnetic Source Imaging

Magnetoencephalography (MEG) detects the magnetic fields produced by the electrical currents of neuronal activity. Unlike the
electrical currents of neuronal activity, which are extracellular, magnetic fields are produced by the intracellular currents of apical
dendrites, which are recorded from the scalp by MEG. Unlike conventional EEG that detects radially oriented electrical activity
that is attenuated in strength and spatially distorted by tissues between brain and scalp surface, magnetic fields are minimally
affected by intervening tissue layers. Furthermore, MEG measures a subset of neuronal activity that is tangential to the scalp.

These magnetic dipoles generated by MEG are then superimposed on structural MR images creating magnetic source imaging
(MSI). Numerous studies have shown that this technique is helpful in patients with neocortical epilepsies to map interictal
epileptiform activity, which in conjunction with other noninvasive structural and imaging data, guide intracranial subdural grid
placement to improve surgical outcome.

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A large series of 455 patients showed that MSI identified the lobe to be treated in 89% of patients. In all extratemporal cases,
MSI correctly identified the correct lobe. One might argue that MSI provides redundant data. However, in this study, MSI
provided additional information about the epileptogenic zone in 35%, and it provided crucial information for surgical decision
making in 11%.

Thus, MSI is a promising modality for seizure localization in that it can confirm the epileptogenic zone along with other functional
imaging data, aid in the identification of a subtle cortical abnormality on MRI, and provide localizing information not obtainable
from other imaging modalities. In this regard, it can either obviate the need for invasive monitoring in cases with a structural
lesion without localizing or lateralizing ictal EEG data or guide intracranial subdural electrode placement to improve localization
of the epileptogenic zone and improve seizure-free outcome.

The disadvantage to MSI is that it is limited to a few centers; it is performed in the outpatient setting in the United States where
AEDs cannot always be tapered or discontinued safely; and recording time is limited, which reduces the chance of obtaining
sufficient interictal data with the exception of patients who have frequent inter-ictal activity. Furthermore, although ictal MSI has
been recorded and is highly localizing, the chance of capturing a seizure during a study is small. Some centers partially taper
AEDs and/or give clonidine to enhance the yield of identifying interictal epileptiform activity.

MRS, Functional MRI, And Novel Structural MRI Technique

Proton magnetic resonance spectroscopic imaging

This technique is based on the principle that N -acetyl aspartate (NAA) is found primarily within neurons and precursor cells; a
reduction in NAA usually is regarded as indicating loss or dysfunction of neurons. Creatinine (CR) and choline (Cho) are present
in much higher concentrations in glia than in neurons. Patients with TLE have reductions in the NAA/(Cho + CR) ratio. This
reduction has been shown to correlate with the presence of hippocampal sclerosis and to correctly lateralize the side of seizure
onset in 97% of patients. About 20-40% of patients have bilateral metabolic disturbances, and preliminary evidence suggests
that this finding is associated with a higher probability of surgical failure.

Recent developments in multivoxel Proton magnetic resonance spectroscopic imaging may be of further value.

Whether this technique is useful in patients with no lesions on MRI, particularly those with extratemporal epilepsy, is less clear.
MRS also has been used to measure lactate levels postictally, although its clinical utility has yet to be established.

Functional MRI

Functional MRI (fMRI) evaluates cerebral blood flow by looking at the difference between venous oxyhemoglobin and
deoxyhemoglobin; this is called the blood oxygen level–dependent (BOLD) contrast technique. During cortical activation,
cerebral blood flow to the eloquent cortex increases focally as a response to the stimulus, but oxygen extraction changes little.
This causes a relative increased concentration of oxyhemoglobin and a relatively decreased concentration of deoxyhemoglobin
draining the activated cortex. Deoxyhemoglobin is paramagnetic; it exerts magnetic susceptibility effects on local tissue, which
are detected by T2-weighted imaging as decreased signal intensity. Oxyhemoglobin, on the other hand, is diamagnetic and has
little effect on T2-weighted images.

Thus, cortical activation results in a relative decrease of the lowered signal intensity produced by the decreased concentration of
deoxyhemoglobin, which leads to a relative increase in signal in the activated cortex relative to contiguous cortex. fMRI has been
used to map language, motor function, and interictal spikes. It also may be useful for seizure localization and has successfully
mapped simple partial seizures. However, capturing seizures with fMRI is difficult, because seizures are unpredictable and
complex partial seizures usually are associated with movement that obscures the fMRI image.

A study by Moeller et al provided support that EEG-fMRI may help to delineate the epileptic focus in patients with nonlesional
frontal lobe epilepsy.[8 ]

Novel structural MRI techniques

Surface-coil MRI and 3-D surface rendering may increase the yield in identifying focal areas of cortical thickening. The use of
multichannel phased array head coils is preferred over conventional quadrature coils. Other techniques, such as T1-weighted

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and T2-weighted inversion recovery, also may increase the sensitivity to identify subtle cortical malformations. 3T-phased array
(PA) MRI can further increase the signal to noise ratio 6-8 fold as compared to nonphase array coil 1.5T MRI. A recent study
found improved lesion detection with 3T PA MRI in patients with intractable epilepsy.

Preliminary data suggest that 3-D preoperative maps of hippocampi can help predict surgical outcome. However, future studies
are needed to determine whether this will be an independent predictor of surgical outcome. In novel techniques such as voxel-
based morphometry (VBM), a whole brain gray matter voxel-based comparison is made of the patient and the control group. A z
score map is then generated for the patient. This method demonstrates enhanced sensitivity in identifying subtle gray matter
abnormalities and for identifying additional areas of gray matter abnormalities in patients with focal cortical dysplasia.

Summary And Conclusions

The care of patients with epilepsy, as that of most other patients with neurological diseases, has been revolutionized by
developments in neuroimaging over the past 15 years. This has led to a far more accurate diagnosis of the pathologic substrate
of epilepsy, which is essential for accurate classification, determination of prognosis, and surgical candidacy. Structural MRI has
greatly reduced the need for invasive EEG evaluation of patients with intractable epilepsy and has therefore reduced morbidity.
Although general consensus exists among neurologists specializing in epilepsy as to when and what type of neuroimaging
studies should be performed in patients with epilepsy, these views have not yet been accepted completely by general neurologic
and medical practitioners despite the recommendations of the International League Against Epilepsy (1997).

Evaluation of a first seizure

The author's practice is that all patients presenting with a first seizure in adulthood be evaluated with high-resolution epilepsy
protocol MRI. In one study of 300 consecutive patients presenting with a first seizure, an epileptogenic lesion was identified by
MRI in 14%. In another study, MRI detected etiologically relevant structural abnormalities in 12.7%. Thus, even in patients with a
single seizure, a significant number of patients had an abnormal MRI that correlated with their epilepsy.

In intractable epilepsy, on the other hand, MRI identifies the pathologic substrate in 82-86% of patients. Children presenting with
focal seizures also should be evaluated by MRI scanning. Children or adults with clinically evident idiopathic generalized
epilepsies (eg, childhood absence epilepsy, juvenile myoclonic epilepsy) probably can forgo MRI scanning, although in clinical
practice being confident of the diagnosis at the time of presentation is often difficult. The presence of MRI abnormalities in
patients with new-onset epilepsy is predictive of seizure recurrence and also predicts lack of seizure control with medical
therapy.

Most importantly, MRI scanning in this setting will detect abnormalities, such as brain tumors, arteriovenous malformations, or
cryptogenic infarctions that may require further diagnostic and therapeutic interventions to prevent neurological deterioration. CT
scanning is used widely in patients presenting with a first seizure, usually because it is more readily available than MRI in most
emergency departments. However, patients should be referred for an epilepsy protocol MRI scanning as an outpatient.

Evaluation of medically intractable epilepsy

All patients with medically intractable partial epilepsy (defined as continued seizures despite therapy with therapeutic doses of
appropriate antiepileptic drugs) should be referred for MRI scanning using an epilepsy protocol. A significant number of these
patients will have hippocampal sclerosis, malformations of cortical development, developmental or glial tumors, or other
abnormalities such as vascular malformations and encephalomalacia, which are predictive of continued failure of medical
therapy.

Further, if ictal EEG recordings establish that these lesions correlate with the site of seizure onset, surgical resection of the
lesion and associated epileptogenic cortex is often curative. Thus, patients with intractable epilepsy defined as having failed at
least two antiepileptic drugs with persistent disabling seizures and MRI lesions should be put on a "fast track" for referral to a
specialized epilepsy center for consideration of surgical management. If the an epilepsy protocol MRI is normal, further trials of
medical therapy may be indicated, although persistence of medically intractable seizures for 2 years or more is also an indication
for referral to a specialized epilepsy center, regardless of MRI findings. These patients can also be surgical candidates if
seizures are well localized and functional imaging data (see below) are concordant with the seizure semiology and EEG findings.

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Functional neuroimaging (ie, SPECT, PET, MRS, MSI) should be reserved for use by specialized epilepsy centers in the
evaluation of the subset of patients with medically intractable epilepsy. These studies are helpful in the following cases: (1)
abnormal MRI with nonlocalizing EEG or discordant clinical semiology and/or EEG findings, (2) multifocal MRI (ie, tuberous
sclerosis), (3) normal MRI with lateralized or localized EEG findings, and (4) normal MRI with nonlocalizing EEG findings.

In summary, high-resolution dedicated epilepsy protocol imaging has revolutionized the evaluation, classification, and
management of epilepsy. It has allowed the determination of the structural substrate for epilepsy in many cases and helps to
determine prognosis for remission or intractability. Furthermore, structural neuroimaging and functional neuroimaging have
enabled a greater number of medically intractable epilepsy patients to become surgery candidates with an increased chance for
seizure freedom and improved quality of life.

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Keywords
medically refractory epilepsy, epilepsy surgery, epilepsy treatment, focal epilepsy, neuroimaging in epilepsy surgery, MRI in
epilepsy surgery, epilepsy management

Contributor Information and Disclosures

Author

Erasmo A Passaro, MD, Director, Comprehensive Epilepsy Program/Clinical Neurophysiology Lab, Bayfront Medical Center
Florida Center for Neurology
Erasmo A Passaro, MD is a member of the following medical societies: American Academy of Neurology, American Academy of
Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, American Medical Association, and
American Society of Neuroimaging
Disclosure: Glaxo Smith Kline Honoraria Speaking and teaching; UCB Honoraria Speaking and
teaching; Pfizer Honoraria Speaking and teaching; Takeda Honoraria Speaking and teaching

Coauthor(s)

Ramon Diaz-Arrastia, MD, PhD, Assistant Professor, Department of Neurology, Comprehensive Epilepsy Center, University of
Texas Southwestern
Ramon Diaz-Arrastia, MD, PhD is a member of the following medical societies: Alpha Omega Alpha, American Academy of
Neurology, New York Academy of Sciences, and Phi Beta Kappa
Disclosure: Nothing to disclose.

http://emedicine.medscape.com/article/1155295-print 22/05/2010
Neuroimaging in Epilepsy Surgery: [Print] - eMedicine Neurology Page 16 of 16

Medical Editor

Claude G Wasterlain, MD, Chair, Department of Neurology, VA Greater Los Angeles Health Care System; Distinguished
Professor and Vice-Chair, Department of Neurology, University of California, Los Angeles, David Geffen School of Medicine
Claude G Wasterlain, MD is a member of the following medical societies: American Academy of Neurology, American Epilepsy
Society, American Federation for Medical Research, American Neurological Association, Royal Society of Medicine, and Society
for Neuroscience
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine

Disclosure: eMedicine Salary Employment

Managing Editor

Jose E Cavazos, MD, PhD, FAAN, Associate Professor with Tenure, Departments of Neurology, Pharmacology, and
Physiology, University of Texas Health Science Center at San Antonio; Co-Director, South Texas Comprehensive Epilepsy
Center; Director of the Epilepsy Center, Audie L Murphy Veterans Affairs Medical Center
Jose E Cavazos, MD, PhD, FAAN is a member of the following medical societies: American Academy of Neurology, American
Clinical Neurophysiology Society, American Epilepsy Society, American Neurological Association, and Society for Neuroscience
Disclosure: Nothing to disclose.

CME Editor

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery,
University of South Florida School of Medicine, Tampa General Hospital
Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of
Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association
Disclosure: Nothing to disclose.

Chief Editor

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery,
University of South Florida School of Medicine, Tampa General Hospital
Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of
Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association
Disclosure: Nothing to disclose.

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