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[Frontiers in Bioscience, Elite, 7, 48-65, January 1, 2015]
48
1. ABSTRACT
Identification and localization of
epileptogenic zone (EZ) is vital in patients with
medically-intractable focal epilepsy, who may
be candidates for potentially curative resective
epilepsy surgery. Presence of a lesion on
magnetic resonance imaging (MRI) influences
both diagnostic classification and selection for
surgery. However, the implications for MRI-
negative cases are not well-defined for such
patients. Most of these patients undergo invasive
long-term Electroencephalography recordings
before a final decision regarding resection is
possible. Recent developments in structural and
functional neuroimaging which include quali-
quantitative MRI, Positron Emission Tomography,
Single Photon Emission Computed Tomography,
and functional MRI have significantly changed
presurgical epilepsy evaluation. Source analysis
based on electrophysiological information, using
either EEG or magnetoencephalography are also
promising in order to noninvasively localize the EZ
and to guide surgery in medically-intractable focal
epilepsy patients that exhibit nonlesional MRI. This
chapter aims to review the value of the combined
use of structural and functional imaging techniques,
and how this multimodal approach improves both
selection of surgical candidates and post-operative
outcomes in medically-intractable nonlesional focal
epilepsy.
Multimodal imaging in nonlesional medically intractable focal epilepsy
Lilia Maria Morales Chaco, Carlos Alfredo Sanchez Catasus1, Margarita Minou Baez Martin1,
Rafael Rodriguez Rojas1, Lourdes Lorigados Pedre, Barbara Estupiñan Diaz1
1Epilepsy Surgery Program, International Center for Neurological Restoration (CIREN), Ave 25 #
15805% 158 and 160, Playa 11300, Havana Cuba
TABLE OF CONTENTS
1. Abstract
2. Introduction
3. Multimodal imaging in presurgical evaluation of nonlesional medically intractable focal epilepsy
3.1. SPECT and PET as multimodal neuroimaging
3.2. Electromagnetic source localization and functional neuroimaging
4. Multimodal neuroimaging and epilepsy surgery outcome
5. Conclusions
6. Acknowledgments
7. References
2. INTRODUCTION
At least 30% of patients with epilepsy
will fail to respond to antiepileptic drug (AED)
treatment (1). For those, the best approach
is surgical treatment with resection of the
epileptogenic zone (EZ) (2, 3). Identification and
accurate localization of EZ is vital in patients with
medically-intractable focal epilepsy, who may
be candidates for potentially curative resective
epilepsy surgery. Precise localization of this region
should be ideally done using several methods
based on different pathophysiological principles.
Localization accuracy is a pre-requisite for seizure-
free outcome and for minimizing the side effects
of the operation, though it remains a challenge,
especially for nonlesional epilepsy (4, 5).
Magnetic Resonance Imaging (MRI)
is one of the most important diagnostic tools
in presurgical evaluation of epileptic patients.
However, the proportion of MRI-negative patients
in reported epilepsy surgery cohorts ranges from
16 to 47%. Most of these patients undergo invasive
long-term EEG recordings before a final decision
regarding the possibility of resection. In addition,
post-operative seizure freedom rates, with few
exceptions, range from 40 to 50% (6-11). There is
also evidence that the connotations of normal MRI
may be applied more to extratemporal epilepsy than
to temporal lobe epilepsy (TLE) surgery (12-19).
Multimodal imaging in focal epilepsy
49 © 1996-2015
Moreover, a satisfactory postsurgical outcome is
commonly correlated with positive (MRI) findings, in
which focal lesions or cortical abnormalities may be
disclosed (7, 20-22).
The ability to localize seizure origin is
even more challenging in children with nonlesional
epilepsy in whom widespread and extratemporal
epileptogenicity related to malformations of cortical
development (MCDs) is common. In the pediatric
population there is a higher frequency of cortical
dysplasia (23), a type of lesion that often shows
negative on MRI scans (8, 24, 25). Thus the
absence of a MRI lesion weighs heavily against
surgical candidacy. That is why, pediatric epilepsy
centers typically defer surgical consideration in this
population (26).
Structural neuroimaging such as quali-
quantitative MRI and functional neuroimaging
like Perfusion single photon emission computed
tomography (SPECT), using both 99mTc-HMPAO
or 99mTc-ECD, and 18F-FDG positron emission
tomography (18F-FDG PET) and functional MRI
(fMRI) have significantly changed presurgical
epilepsy evaluation. Source analysis based on
electrophysiological information, using either EEG or
magnetoencephalography (MEG) have significantly
changed presurgical epilepsy evaluation, particularly
in nonlesional cases (5, 27-40). Furthermore,
multimodal post-processing and coregistration
increase the diagnostic value of all imaging data, and
help overcome the intrinsic limitations of individual
modalities.
The idea of a poor prognostic implication
of normal MRI has been exhaustively stressed.
However, relatively little work has focused on
identifying the factors that do characterize
‘‘favorable’’ epilepsy surgery candidates within this
group (41-43). On the other hand, few studies have
proposed that MRI-negative cases, which present
challenges in terms of presurgical evaluation
and surgery, are indeed surgically treatable with
satisfactory outcomes (17, 41-44). Moreover, there
is a lack of studies showing the utility of a multimodal
approach use in the same patients on individual
basis and the value of multimodal imaging in the
nonlesional epilepsy population (33, 45-47).
In this chapter we aim to review the value
of the combined use of multiple anatomical and
functional brain imaging modalities in presurgical
evaluation for precise localization of the EZ in
epileptic patients with normal MRI. It also reviews
the prediction of epilepsy surgery outcome regarding
this multimodal imaging approach.
3. MULTIMODAL IMAGING IN
PRESURGICAL EVALUATION OF
NONLESIONAL MEDICALLY INTRACTABLE
FOCAL EPILEPSY
Conventional noninvasive presurgical
epilepsy evaluations include ictal and interictal scalp
EEG and MRI in practically all patients. Functional
imaging is also commonly used, and it plays an
important role in localization of seizure onset in
patients with nonlesional MRI or multiple potentially
epileptogenic lesions. On the other hand, MEG
and fMRI are increasingly utilized to localize the
EZ and to delineate proximity to eloquent cortex.
Each modality has weaknesses and strengths with
respect to temporal or spatial resolution, and to
functional or anatomical relevance. On the basis of
recent research in the field of neuroimaging, several
novel imaging modalities have been improved
and developed to provide information about the
localization of EZ during presurgical evaluation of
patients with medically intractable epilepsy (48).
Additionally, the concordance of coregistered
data from multiple imaging modalities serves as a
predictor of seizure-free outcome (49-51).
Several studies, mainly focused on TLE,
have described the utility of these techniques
including the diagnostic sensitivity and specificity
when used separately in various epilepsy
groups (47, 52-61). There is also a growing
agreement that the combined use of these imaging
techniques increases the accuracy of EZ localization
(62-64). In other words, a multimodal imaging
approach could use concordant imaging findings to
achieve better EZ localization.
3.1. SPECT and PET as multimodal
neuroimaging
Multimodal post-processing is defined
as the simultaneous presentation of two or more
modalities which have been spatially coregistered.
Although most investigations have focused on
the use of single modalities (i.e. SPECT or PET)
coregistered to MRI or Computerized Tomography
(CT), in practice, combinations of additional
postprocessing techniques and imaging modalities
are used to improve EZ localization, grid placement,
and ultimately outcome (65).
Multimodal imaging in focal epilepsy
50 © 1996-2015
The indications for Subtraction of the
interictal SPECT from the ictal SPECT coregistered
to MRI (SISCOM) in patients undergoing a
presurgical evaluation include nonlesional focal
epilepsy, multilobar pathology and conflicting
results in the noninvasive evaluation (9). SISCOM
may result in better delineation of epileptogenic
zone, which may sometimes be missed even
on ictal SPECT (66). In patients with normal MRI
and refractory epilepsy, SISCOM may also help to
detect subtle focal cortical dysplasia, and has been
described as particularly useful in identifying the
seizure-onset zone in these lesions (56, 67, 68).
The presence of a SISCOM alteration
may obviate the need for intracranial EEG (icEEG)
recordings in selected patients (69, 70). A prospective
study in patients with nonlesional MRI, discordant
data in standard presurgical assessment, or
widespread MRI lesion showed that SISCOM results
altered the electrode implantation scheme in the
majority of patients. The concordance of these results
with other tests such as EEG, MRI and semiology,
were predictive for good seizure outcome (71).
In summary, SISCOM significantly improves the
results in sensitivity and specificity, particularly in
extratemporal lobe epilepsies (54, 55, 72, 73).
Another study that reported the influence
of various techniques showed that SISCOM was
localizing in 66.7.% of temporal and 84.6.% of
extratemporal cases in a selected group of pediatric
epileptic patients with excellent surgical outcome
(74). Similar results were found by Barba et al,
showing that SISCOM had a high localizing value
and good surgical outcome in this difficult patient
group (75). Figure 1 presents SISCOM analysis
in one of our patients with nonlesional TLE and
postoperative seizure-free outcome.
The use of multimodal coregistration using
SPECT and MR spectroscopy in patients with
TLE were examined by Doelken, et al. This study
demonstrated that the combination of modalities
increased sensitivity of focus lateralization to 100%
and was especially valuable in MRI-negative cases.
They also found that combining modalities allowed
recognition of bilateral pathology which generally
predicts unfavorable postoperative outcome, though
it was not examined in their cohort (49).
On the other hand, 18F-FDG PET has
higher spatial resolution and lower background
activity than perfusion SPECT (29). However, one of
the limitations of 18F-FDG PET for the evaluation of
epilepsy during the ictal phase is its low temporal
resolution. This is due to the fact that 18F-FDG uptake
period (30–45 minutes) is significantly longer than
the average seizure duration (1-2 minutes) which
leads to a mixture of interictal, ictal and postictal
phases (76). So, interictal 18F-FDG PET has an
established role in the noninvasive localization of
EZ (29). Consequently, interictal 18F-FDG PET/MRI
coregistration where PET images are fused onto the
structural MRI of the same patient provided more
sensitivity than PEt alone in the detection of cortical
lesions (77).
It has been shown that 18F-FDG PET/MRI
has a high sensitivity (up to 98%) to detect focal
cortical dysplasia (FCD), especially in patients
with mild FCD type I and normal MRI (78). FCDs
are highly epileptogenic brain lesions and are
one of the most important causes of intractable
epilepsy (79, 80). Although the precise mechanisms
of epileptogenesis in these lesions are not known,
some studies suggest that the over-expression
of the multidrug efflux transporter proteins such
as P-glyprotein (Pgp) in both malformative and
neoplastic glioneuronal tissue from patients with
refractory epilepsy may explain one possible
mechanism for drug resistance in these pathologies
(81-84). A recent result has supported the notion
that brain Pgp overexpression contributes
to a progressive seizure-related membranes
depolarization in hippocampus and neocortex (85).
In this context functional neuroimaging techniques
such as MR spectroscopy, FDG-PET, or new PET
tracers, may infer the presence of abnormality and
could help to better localization of pharmacoresistant
brain areas (86). (11C)-verapamil (VPM) is the best
validated PET tracer to image Pgp function in vivo to
date. A reduced VPM uptake in refractory compared
to seizure-free patients with TLE was reported
using (11C)-verapamil. This result supports the
hypothesis of Pgp overexpression in refractory
epilepsy (87). It is important to highlight that 18F-
FDG may be an in vivo and in vitro marker for
multidrug resistant (88, 89).
18F-FDG PET/MRI in nonlesional
childhood epilepsy (90, 91) has been also validated.
Rubi S et al. prospectively evaluated PET and PET/
MRI results of 31 nonlesional pediatric patients (92).
They demonstrated the ability of this tool to guide
a second look at MRI studies previously reported
as nonlesional, turning a meaningful percentage
of these into subtle-lesional. As a result, 18F-FDG
Multimodal imaging in focal epilepsy
51 © 1996-2015
PET/MRI has become a useful tool for preoperative
EZ detection in patients with drug resistant epilepsy
and normal or less specific findings on MRI.
Interictal FDG-PET and ictal SPECT
have similar sensitivity to localize the EZ, but
complementary when the other modality is not
localizing in a given patient (93). Both ictal SPECT
and interictal PET are sensitive methods for the
lateralization of TLE. However, ictal subtraction
SPECT is more sensitive when MRI is normal and it
is especially useful in frontal epilepsy (31).
In a group of eighteen TLE patients
with normal appearing MRI, we found that ictal
video-EEG (V-EEG) has the highest percentage
of correct lateralization (100%), followed by ictal
SPECT/SISCOM and choline/creatine and N acetyl
aspartate/creatine metabolic ratios measured by
magnetic resonance spectroscopy (94). This study
confirmed that localizing data provided by V-EEG
and complemented by functional neuroimaging
studies can be used to perform successful temporal
lobectomies on patients with drug-resistant
nonlesional TLE or bilateral structural abnormalities.
Despite the demonstrated utility of nuclear
medicine neuroimaging in nonlesional medically
intractable focal epilepsy, recent studies combing
SPECT and/or PET with electromagnetic source
localization data have shown incremental validity to
determine EZ for surgical purpose without invasive
electrodes or for planning intracranial electrode
placement in patients with nonlesional medically
intractable epilepsy.
3.2. Electromagnetic source localization
and functional neuroimaging
Source analysis based on
electrophysiological information, using either EEG
or MEG, and neuroanatomical data (e.g. MRI)
Figure 1. A. Ictal scalp Video- EEG pattern during a habitual complex partial seizure of a 52-year-old patient with nonlesional temporal lobe
epilepsy and postoperative seizure-free outcome. Note rhythmic activity at seizure onset in channels containing the temporal leads, F7, T3,
Cg3, T1. B. SISCOM study (threshold, + 2 SD) of the patient. SISCOM showed a focal cerebral hyperperfusion in the left temporal lobe,
concordant with ictal EEG and clinical data in a region apparently normal by MRI. C. Magnetic resonance imaging of the patient. T1 and
T2-weighted sequences did not clearly reveal structural abnormalities.
Multimodal imaging in focal epilepsy
52 © 1996-2015
allow revealing the source localization of interictal/
ictal epileptic discharges (IEDs) in patients with
focal epilepsy (36-39). These methods include low
resolution electromagnetic tomography analysis
(LORETA), dipole brain electric source analysis
(BESA) and brain distributed variable resolution
electromagnetic tomography (VARETA) (5, 34, 95).
Recently a bayesian spatio-temporal model for source
reconstruction of MEG/EEG data has been also
proposed (96). The complementary strengths and
weaknesses of established functional brain imaging
methods and EEG/MEG-based techniques make
their combined use a promising avenue for studying
brain processes at a more fine-grained level (97).
Anatomical MRI/CT can also be fused
in 3D arrangement with data obtained with other
functional neuroimaging such as PET, SPECT,
fMRI, near-infrared spectroscopy (NIRS) and optical
imaging of intrinsic signals (98). These techniques
highlight information on the functional correlates of
anatomical or space-occupying lesions and their role
in focal epilepsy (98, 99).
During the last decade several studies
that compare diagnostic modalities with different
underlying mechanisms were published (100-102).
A study carried out by Santiago-Rodríguez
et al. (2006) evaluated the concordance of
hypoperfusion zones measured by interictal
SPECT with BESA and VARETA in patients with
complex partial seizures. They concluded that the
concordance of hypoperfusion zones was better
with BESA than with VARETA (103). Previous
studies had found lower concordance rates of
magnetic source imaging (MSI), SISCOM and
icEEG in neocortical epilepsies compared to
mesial TLE cases (33, 47).
In our study we compared LORETA vs
Bayesian Methods Analysis (BMA), average brain
vs individual brain in patients with nonlesional focal
epilepsy. We found that the methods based on time-
frequency decompositions of EEG are useful tools
to determine ictal EEG onset and the subsequent
estimation of their generators. Besides, BMA
solutions estimated on individual brains are less
distributed than LORETA (Figure 2).
Figure 2. A. LORETA calculated on the average brain space (ab-LORETA) and BMA and LORETA calculated on the individual brain space
(ib-LORETA and ib-BMA respectively) in a patient with non lesional right temporal lobe epilepsy. LORETA and BMA solution (time-domain
analysis of ictal activity) demonstrated a right temporal source. LORETA solution showed bilateral temporal sources. Note that ib approach
introduces a much higher accuracy and precision levels. B. Ictal scalp EEG onset pattern of the patient presented in A. Note rhythmic activity
at seizure onset in channels containing the temporal leads, F8, T4, and Cg2.
Multimodal imaging in focal epilepsy
53 © 1996-2015
We also found that morphometric
measurements (volumetry and voxel based
morphometry) are able to localize small signs of
structural alteration in the brain when quantitative
MRI information is combined with inverse solution
estimation. In many cases they can be consistent with
functional estimation by inverse solution of the EZ
(unpublished data) (Figure 3).
Jayakar P et al. (2008) reported that a
multimodal integrative approach can minimize the
size of resection and alleviate the need for invasive
EEG monitoring in a cohort predominantly of children
with nonlesional drug-resistant focal epilepsy
undergoing successful resective surgery (104).
Various reports on MSI, SPECT, and icEEG in
patients with focal epilepsy have been written focused
on nonlesional neocortical and mesiotemporal
lobe epilepsies (37, 39, 100, 105). One of them,
which did not specifically focus on nonlesional
neocortical epilepsies, showed that MSI had the
highest concordance rate with icEEG compared to
SPECT and PET (105).
Not long ago, Schneider F et al. conducted
the largest retrospective study to examine and
compare icEEG with MSI and SISCOM in patients
with nonlesional neocortical epilepsy. The most
important finding from this study was that sublobar
concordance of ictal icEEG with either MSI or
SISCOM was superior to ictal icEEG alone in
localizing the EZ. Another result was that specificity
and positive predictive value of ictal icEEG were
higher combined with MSI and SISCOM (102). With
regard to the diagnostic values of each modality
alone, they did not observe significant differences
between icEEG, MSI, and SISCOM. Like previous
studies, their findings showed that icEEG had the
highest sensitivity for localizing the EZ based on
epilepsy surgery outcome (71, 101).
Certainly, few studies have directly
compared SISCOM, MEG, and FDG-PET with iEEG
in the same patient. One of these studies focused
on children with nonlesional epilepsy demonstrated
that both SISCOM and MEG had better lobar
concordance with icEEG than statistical parametric
mapping (SPM) analysis of 18F-FDG-PET (106).
These findings suggest that nonlesional neocortical
epilepsy with both positive MSI and SISCOM may
indicate a higher chance of a localized icEEG
result. Therefore, both diagnostic modalities provide
additional and not redundant localizing information
over the one provided by icEEG alone, even if icEEG
is localizing. In a previous study these authors had
already suggested that multimodality approach may
improve surgical outcome (43).
In recent years, studies have shown that
localization accuracy of MEG might be closer to that
of the “gold standard” icEEG (100, 101, 107, 108).
Knowlton et al. observed that MSI had the highest
concordance rate with icEEG compared to ictal
SPECT and 18F-FDG PET (101). However, MEG is
less available and requires more IEDs (38, 64, 109).
Figure 3. A. Morphometric measurements (volumetric and voxel based morfometry using MRI) in a patient with non lesional qualitative
MRI showed in Figure 2. Quantitative RMN localized small signs of structural alteration in the brain medial and inferior temporal girus,
consistent with fuctional estimation by inverse solution (BMA and LORETA). B. Focal cortical dysplasia observed in the inferior temporal gyrus
resected during epilepsy surgery in the patient with non lesional right temporal lobe epilepsy showed in Figures 2 and 3A. Histopathological
features of focal cortical dysplasia type- 1B, (dyslamination associated with giant and immature neurons). Hematoxylin-eosin; bar: 100 µm).
Histopathological findings confirmed a diagnosis of neocortical temporal mild Palmini type-IB FCD.
Multimodal imaging in focal epilepsy
54 © 1996-2015
Since MEG covers the whole head
(e.g., cortices) while icEEG is sample-limited,
MEG might be more advantageous in detecting the
seizure focus than icEEG in patients with normal
MRI. Some reports indicate that MEG may also
allow differenti ating focal cortical dysplasia (FCD)
type I and II (110, 111).
When Leijten, F.S et al compared MEG
and simultaneous EEG using high-resolution source
imaging in mesiotemporal lobe epilepsy, it was found
that MEG localized sources were more superficial,
whereas EEG localized sources were deeper. They
demonstrated that the yield of spikes was too low,
and EEG/MEG equivalent current dipoles modeling
showed partial correlation with ECoG findings (112).
Further, Kaiboriboon et al. (2010)
demonstrated that when MRI, and/or ictal scalp EEG
is not localizing, MEG/MSI can detect medial temporal
spikes and it may provide important localizing
information in patients with mesial TLE (113).
High-density EEG and EEG-fMRI are also
noninvasive imaging techniques which separately
considered are widely used to investigate electrical
activity and abnormal neural activity in relation
to blood oxygen dependent level (BOLD) activity
respectively (114). These imaging techniques can
be combined to map noninvasively abnormal brain
activation elicited by epileptic processes. Zhang et al
observed in EEG-fMRI exams that hemodynamic
changes related to IEDs in patients with MRI-negative
TLE are often localized in extratemporal regions. This
might be noninvasive evidence that the ictal onset
zone of these patients are not localized in the temporal
region (115). Thornton R et al. also suggested that
EEG-fMRI may provide useful additional information
about the seizure onset zone in epileptic patients
with FCD. Widely distributed discordant regions of
IED-related hemodynamic change appear to be
associated with a widespread seizure onset zone and
poor postsurgical outcome (114).
In practice, a multimodal imaging approach
for presurgical evaluation has been taken by
various epilepsy centers in which concordant
neuroimaging findings often reduce the need for
icEEG in presurgical planning. For example, in
the protocol of drug-resistant epilepsy presurgical
evaluation in our center, if the findings of noninvasive
techniques such as long-term video-EEG, ESI (EEG
Source Imaging), MRI, ictal SPECT/SISCOM are
convergent, then presurgical icEEG monitoring is
unnecessary and surgical treatment with ECoG
(electro-corticography) is performed; otherwise,
presurgical icEEG monitoring is suggested (5, 94).
It is important to point out that promising
noninvasive neuroimaging such as MEG/MSI, PET
and ictal SPECT alone or in combination; so far
still cannot replace invasive icEEG in localizing EZ
especially in nonlesional extratemporal epilepsies.
However, these neuroimaging techniques could
minimize the need for invasive presurgical monitoring
in certain cases. On the other hand fMRI, MEG/MSI
and EEG/ESI have reduced the need for ECoG in
mapping the eloquent cortex, and also fMRI might
replace invasive Wada test in language lateralization.
Lastly, accurate anatomic models using
noninvasive presurgical imaging data combined with
post-implantation electrode maps can be of immense
value after a failed epilepsy surgery, providing
important data regarding localization of functional
cortex in relation to ictal abnormalities and potentially
avoiding duplication of previous invasive studies.
4. MULTIMODAL NEUROIMAGING AND
EPILEPSY SURGERY OUTCOME
Multimodal neuroimaging is needed not
only in presurgical evaluation, but also during
functional navigation in epilepsy surgery (116).
Assessment of clinical validity of multimodal imaging
in epilepsy surgery requires post-surgical outcome.
Up to the present, most studies, have been limited
to case reports of correlation with icEEG. However,
test concordance in presurgical evaluation is
also essential for predicting the epilepsy surgery
outcome (77).
Previous studies have found lower
concordance rates of MSI, SISCOM and icEEG
in neocortical epilepsies compared to mesial
TLE cases (32; 33). On the other hand, another
investigation had demonstrated that positivity of all
tests including MSI, 18F-FDG PET and ictal SPECT
predicted increased odds for seizure free outcome
after surgery (117).
Correlations to surgical outcome suggest
that SISCOM also provides complementary
information to MRI or neurophysiological
findings (70, 71, 118-122). O’Brien et al. reported an
excellent outcome when SISCOM localization was
concordant with surgical-resection site in patients
with medically intractable focal epilepsy and normal
Multimodal imaging in focal epilepsy
55 © 1996-2015
MRI (55). That is to say, resection of the area of
increased perfusion is associated with better surgical
outcome.
In a multicenter study, Matsuda et al. (2009)
compared SISCOM with regular ictal SPECT and
found that SISCOM provides higher predictive value
of good surgical outcome and more reliability on
the diagnosis of the epileptogenic focus than side-
by-side comparison in medically intractable partial
epilepsy (123).
SISCOM has also shown to have high
localizing and predictive value for seizure-free
outcome in extratemporal lobe epilepsy (74, 101).
In 2013, Kurd et al. showed that complete resection
of the dysplastic cortex localized by SISCOM,
FDG-PET or icEEG was a reliable predictor of
favorable postoperative seizure outcome in patients
with nonlesional extratemporal epilepsy (124).
Lee et al. showed that seizure-free outcome
could be achieved in 47% and that up to 90% seizure
reduction could be achieved in 80% of the patients
with refractory epilepsy and normal MRI evaluated
with ictal SPECT and 18F-FDG PET (125).
In an interesting study, Knowlton et al.
(2008b) investigated the prediction of epilepsy
surgery outcome regarding ictal SPECT, MSI,
and 18F-FDG PET (105). Most of the 34 SISCOM
patients in this study had extratemporal lobe
epilepsy with no localizing MRI or EEG. SISCOM
had the highest predictive value (odds ratio= 9.9.) for
excellent surgical outcome. Further, it was found that
MEG/MSI, PET and ictal SPECT had clinical value
in predicting good surgical outcome for patients with
nonlocalized MRI or video-EEG, and MEG/MSI was
close to ictal icEEG in predicting a good surgical
outcome (105).
Schneider´s investigation also clearly
shows that a multimodal approach can significantly
contribute to predict surgical outcome (102). They
found that specificity and positive predictive value
of ictal icEEG were higher combined with MSI and
SISCOM. Interestingly, they observed that MSI
was more advantageous compared to SISCOM in
predicting seizure-free epilepsy surgery outcome,
when sublobar concordance of MSI with ictal
icEEG was present whereas a positive SISCOM
concordant with ictal icEEG and complete resection
may have prognostic implications, forecasting a
more advantageous epilepsy surgery outcome.
Two recent studies reported that
concordance of icEEG with MEG results increased
the predictive value for a seizure-free surgical
outcome in patients with nonlesional neocortical
epilepsy (102, 126). Seo´s et al. investigation also
compared SISCOM, MEG, and FDG-PET with icEEG
and surgical outcome in children with nonlesional
epilepsy, and concluded that multimodality approach
may improve surgical outcome (106).
The role of fMRI in the prediction of surgical
outcome in epilepsy has also been investigated in
some studies. For example, the use fMRI triggered by
IEDs (EEG-fMRI) can identify not only hemodynamic
abnormalities in the seizure onset zone of patients
with epilepsy but also detect abnormal networks
that may have implications in surgical outcome. In
addition, EEG-fMRI has the advantage of single
subject analysis that can add patient-specific
information for clinical decisions. These studies have
demonstrated that the concordance of IED-triggered
hemodynamic abnormalities with the localization of
surgical resection is associated with better surgical
outcome (114, 127).
In spite of the increasing number of
multimodal studies showing the utility of this
approach in patients with medically intractable
nonlesional focal epilepsy, it would be useful to
randomize patients to neuroimaging or invasive
techniques in order to assess the clinical utility of
neuroimaging more accurately. Besides, there is
no meta-analysis clarifying the importance of this
approach neither cost-effectiveness studies to
identify the most cost-effective method. Accordingly,
carefully designed multi-center prospective trials can
clarify the usefulness of the combined use of these
imaging techniques in epilepsy surgery process.
Notwithstanding that appropriate clinical
trials are still needed to provide more evidence,
the multimodal approach may play a greater role
in presurgical evaluation of nonlesional medically
intractable neocortical focal epilepsy patients, or those
with multiple potentially epileptogenic abnormalities
on MRI. This approach could reduce the costs and
risks of epilepsy surgery and provide surgical options
for more patients with medically intractable epilepsy.
5. CONCLUSION
Selection of surgical candidates and post-
operative outcomes may be improved by recent
developments in multimodal analysis that combines
Multimodal imaging in focal epilepsy
56 © 1996-2015
structural and functional neuroimaging techniques.
In our view, a multimodality approach is needed to
identify subtle abnormalities in presurgical evaluation
which may reduce invasive EEG monitoring and
surgical failure.
Future prospective multicenter studies and
ramdomized randomized placebo-controlled trials
are required in order to clarify how the multimodal
imaging analysis may contribute both to presurgical
evaluation and prediction of surgical outcome in
nonlesional epilepsy patients. These studies are
also needed to determine how each technique can
be optimized, not only economically, but also for
individual benefit.
6. ACKNOWLEDGMENTS
We thank Odalys Morales Chacón for
her English assistance. We would also like to thank
Maria Luisa Rodriguez and Abel Sanchez for their
useful cooperation.
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Abbreviations: EZ, epileptogenic zone;
MRI, Magnetic resonance imaging; EEG,
Electroencephalography; icEEG, intracranial
EEG; PET, Positron Emission Tomography;
SPECT, Single Photon Emission Computed
Tomography; SISCOM, Subtraction of the
interictal SPECT from the ictal SPECT
coregistered to MRI; fMRI, functional MRI; MEG,
magnetoencephalography; TLE, temporal lobe
epilepsy; MSI, Magnetic Source imaging; ESI,
EEG Source Imaging
Key Words: EEG, epilepsy surgery, MEG, MRI,
multimodal imaging, nonlesional medically
intractable epilepsy, SPECT, PET, Review
Send correspondence to: Lilia Maria Morales
Chacon, International Center for Neurological
Restoration (CIREN), Clinical Neurophysiology
Service, Ave 25 #15805 % 158 and 160, Playa
11300, Havana, Cuba, Tel: 537- 2735379,
Fax: 537-2732420, E-mail: lilia.morales@
infomed.sld.cu
