MRI-Negative Epilepsy Evaluation and Surgical Management

MRI-Negative
Epilepsy
Evaluation and Surgical Management
MRI-Negative Epilepsy
Evaluation and Surgical Management
Edited by
Elson L. So, MD
Professor of Neurology, Epilepsy and EEG, Mayo Clinic College of Medicine, Rochester,
MN, USA
and
Philippe Ryvlin, MD, PhD
Professor of Neurology, and Head of the Department of Clinical Neurosciences, CHUV,
Lausanne, Switzerland
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Library of Congress Cataloging in Publication data
MRI-negative epilepsy : evaluation and surgical management / edited by
Elson L. So, Philippe Ryvlin.
p. ; cm.
Magnetic resonance imaging-negative epilepsy
Includes bibliographical references and index.
ISBN 978-1-107-03423-5 (Hardback)
I. So, Elson, editor. II. Ryvlin, Philippe, editor. III. Title: Magnetic
resonance imaging-negative epilepsy.
[DNLM: 1. Epilepsypathology. 2. Epilepsysurgery. 3. Magnetic
Resonance Imagingmethods. 4. Neuroimagingmethods.
5. Treatment Outcome. WL 385]
RC373
616.85307548dc23 2014017472
ISBN 978-1-107-03423-5 Hardback
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Every effort has been made in preparing this book to provide accurate and up-to-date
information which is in accord with accepted standards and practice at the time of
publication. Although case histories are drawn from actual cases, every effort has been
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To my parents
Elson.
To my beloved wife and children
Philippe.
Contents
List of contributors
Preface
1. Scope and implications of MRI-negative refractory focal epilepsy
Elson L. So and Philippe Ryvlin
2. Seizure semiology and scalp EEG in MRI-negative refractory focal epilepsy
Soheyl Noachtar and Elisabeth Hartl
3. Clinical and advanced techniques for optimizing MRI in refractory focal
epilepsy
Neda Bernasconi and Andrea Bernasconi
4. PET in MRI-negative refractory focal epilepsy
Alexander Hammers
5. Advanced SPECT image processing in MRI-negative refractory focal
epilepsy
Elson L. So, Terence J. OBrien, and Benjamin H. Brinkmann
6. MEG and magnetic source imaging in MRI-negative refractory focal
epilepsy
Koji Iida, Akira Hashizume, and Hiroshi Otsubo
7. Electric source imaging in MRI-negative refractory focal epilepsy
Christoph M. Michel and Margitta Seeck
8. Functional MRI in MRI-negative refractory focal epilepsy
Friederike Mller and Stephan Ulmer
9. Multimodality image coregistration for MRI-negative epilepsy surgery
Benjamin H. Brinkmann and Vlastimil Sulc
10. Subdural electrode implantation and recording in MRI-negative epilepsy
surgery
Michael R. Sperling and Christopher T. Skidmore
11. Depth electrode and stereoelectroencephalography in MRI-negative
epilepsy
Philippe Ryvlin, Alexandra Montavont, Karine Ostrowsky-Coste, and Marc
Gunot
12. Ultraslow and high-frequency recordings in MRI-negative refractory focal
epilepsy
Vlastimil Sulc and Gregory A. Worrell
13. Cortical mapping in MRI-negative epilepsy surgery

Gonzalo Alarcn and Antonio Valentn
14. Localization and surgery for MRI-negative temporal lobe and temporal-plus
epilepsies
Sang Kun Lee and Hye-Jin Moon
15. Localization and surgery in MRI-negative frontal lobe epilepsies
Chaturbhuj Rathore and Kurupath Radhakrishnan
16. Localization and surgery in MRI-negative posterior cortex epilepsies
Christoph Baumgartner and Susanne Pirker
17. MRI-negative refractory focal epilepsy in childhood
Prasanna Jayakar and Michael Duchowny
18. Surgical approaches and techniques in MRI-negative focal epilepsy
Sumeet Vadera and William Bingaman
19. Histopathology findings in MRI-negative focal epilepsy
Ingmar Blmcke and Roland Coras
20. Neuropsychological issues in MRI-negative focal epilepsy surgery:
evaluation and outcomes
Rosana Esteller, Daniel L. Drane, Kimford J. Meador, and David W. Loring
21. Conclusion
Philippe Ryvlin and Elson L. So
Index
Contributors
Gonzalo Alarcn MD, PhD
Department of Clinical Neuroscience, Kings College London; Department of
Clinical Neurophysiology, Kings College Hospital, London, UK
Christoph Baumgartner MD
Karl Landsteiner Institute for Clinical Epilepsy Research & Cognitive Neurology,
2nd Neurological Department, General Hospital Hietzing with Neurological Center
Rosenhgel, Vienna, Austria
Andrea Bernasconi MD
Neuroimaging of Epilepsy Laboratory, Department of Neurology and McConnell
Brain Imaging Center, Montreal Neurological Institute, McGill University, Montreal,
Quebec, Canada
Neda Bernasconi MD, PhD
Neuroimaging of Epilepsy Laboratory, Department of Neurology and McConnell
Brain Imaging Center, Montreal Neurological Institute, McGill University, Montreal,
Quebec, Canada
William Bingaman MD
Section of Epilepsy Surgery, Neurologic Institute, Cleveland Clinic, Cleveland, OH,
USA
Ingmar Blmcke MD
Department of Neuropathology, University Hospital Erlangen, Erlangen, Germany
Benjamin H. Brinkmann PhD
Mayo Systems Electrophysiology Laboratory, Mayo Clinic, Rochester, MN, USA
Roland Coras MD
Department of Neuropathology, University Hospital Erlangen, Erlangen, Germany
Daniel L. Drane PhD
Departments of Neurology and Pediatrics, Emory University School of Medicine,
Atlanta, GA, USA
Michael Duchowny MD
Department of Neurology and the Brain Institute, Miami Childrens Hospital and the
Department of Neurology, Florida International University College of Medicine,
Miami, FL, USA
Rosana Esteller PhD, EE
NeuroPace Inc., Mountain View, CA, USA
Marc Gunot
Department of Functional Neurosurgery, Neurological Hospital, Lyon, France

Alexander Hammers MD, PhD
Neurodis Foundation, c/o CERMEP Imagerie du Vivant, Lyon, France; PET
Imaging Centre, Division of Imaging Sciences & Biomedical Engineering, Kings
College London, London, UK
Elisabeth Hartl, MD
Epilepsy Center, Department of Neurology, University of Munich, Munich, Germany
Akira Hashizume MD, PhD
Epilepsy Center, Department of Neurosurgery, Hiroshima University Hospital,
Hiroshima, Japan
Koji Iida MD, PhD
Epilepsy Center, Department of Neurosurgery, Hiroshima University Hospital,
Hiroshima, Japan
Prasanna Jayakar MD, PhD
Department of Neurology and the Brain Institute, Miami Childrens Hospital and the
Department of Neurology, Florida International University College of Medicine,
Miami, FL, USA
Sang Kun Lee MD
Department of Neurology, Seoul National University Hospital, Seoul, Korea
David W. Loring PhD
Departments of Neurology and Pediatrics, Emory University School of Medicine,
Atlanta, GA, USA
Kimford J. Meador, MD
Stanford Comprehensive Epilepsy Center, Department of Neurology & Neurological
Sciences, Stanford University School of Medicine, Stanford, CA, USA
Christoph M. Michel PhD
Department of Fundamental Neurosciences, University of Geneva, Geneva,
Switzerland
Friederike Mller MD
University Hospital of Pediatric Neurology, Christian Albrechts University of Kiel,
Kiel, Germany
Alexandra Montavont
Department of Functional Neurology & Epilepsy, Neurological Hospital, Lyon,
France
Hye-Jin Moon
Department of Neurology, Keimyung University Hospital, Daegu, Korea
Soheyl Noachtar MD
Epilepsy Center, Department of Neurology, University of Munich, Munich, Germany
Terence J. OBrien MD, FRACP
Department of Medicine, Royal Melbourne Hospital, University of Melbourne,
Parkville, Victoria, Australia
Karine Ostrowsky-Coste MD
Department of Epilepsy, Sleep, and Pediatric Neurophysiology, Femme-Mre-Enfant
Hospital, Lyon, France
Hiroshi Otsubo MD
Neurophysiology Laboratory, Division of Neurology, Hospital for Sick Children,
Toronto, Ontario, Canada
Susanne Pirker MD
Karl Landsteiner Institute for Clinical Epilepsy Research & Cognitive Neurology,
2nd Neurological Department, General Hospital Hietzing with Neurological Center
Rosenhgel, Vienna, Austria
Kurupath Radhakrishnan MD, DM
R. Madhavan Nayar Center for Comprehensive Epilepsy Care, Sree Chitra Tirunal
Institute for Medical Sciences and Technology, Trivandrum, Kerala, India
Chaturbhuj Rathore MD, DM
R. Madhavan Nayar Center for Comprehensive Epilepsy Care, Sree Chitra Tirunal
Institute for Medical Sciences and Technology, Trivandrum, Kerala, India
Philippe Ryvlin MD, PhD
Department of Clinical Neurosciences, CHUV, Lausanne, Switzerland
Margitta Seeck MD
EEG & Epilepsy Unit, Department of Clinical Neurosciences, University Hospital
Geneva, Geneva, Switzerland
Christopher T. Skidmore MD
Jefferson Comprehensive Epilepsy Center, Department of Neurology, Thomas
Jefferson University, Philadelphia, PA, USA
Elson L. So MD
Section of Electroencephalography, Department of Neurology, Mayo Clinic College
of Medicine, Rochester, MN, USA
Michael R. Sperling MD
Jefferson Comprehensive Epilepsy Center, Department of Neurology, Thomas
Jefferson University, Philadelphia, PA, USA
Vlastimil Sulc MD
Mayo Systems Electrophysiology Laboratory, Mayo Clinic, Rochester, MN, USA;

International Clinical Research Center, St. Annes University Hospital, Brno, Czech
Republic
Stephan Ulmer MD
Medical Radiological Institute, Zrich, Switzerland; Institute of Neuroradiology,
University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany
Sumeet Vadera MD
Department of Neurosurgery, University of California Irvine, CA, USA
Antonio Valentn MD, PhD
Department of Clinical Neuroscience, Kings College London; Department of
Clinical Neurophysiology, Kings College Hospital, London, UK
Gregory A. Worrell MD, PhD
Mayo Systems Electrophysiology Laboratory, Divisions of Epilepsy & Clinical
Neurophysiology, Department of Neurology, Mayo Clinic, Rochester, MN, USA
Preface
MRI-negative refractory focal epilepsy is well known to present major challenges in
seizure localization and surgical treatment. Many epilepsy centers around the world are
encountering increasing numbers of patients with MRI-negative refractory epilepsy. As a
result, there has been a growing number of publications on the topic of presurgical
evaluation and postsurgical outcome of MRI-negative surgery. A great proportion of these
publications emanate from advances in imaging techniques. The MRI is one of the
historically most versatile diagnostic tools, with new techniques still developing decades
after its advent. However, other imaging modalities are keeping pace in their development
for detecting functional alterations that can serve as surrogates or markers of the
epileptogenic focus. At the same time, data have been accruing from electrophysiological
and histopathological investigations in MRI-negative patients who have undergone
presurgical evaluation and surgical management.
MRI-negative epilepsy is not a single disease entity or epilepsy type, and the global
experience with its evaluation and surgery has been varied. No one epilepsy center has all
the most advanced presurgical diagnostic or surgical techniques at its disposal. Experience
or skills in the techniques are expected to vary between centers. Perhaps for these reasons,
outcomes of MRI-negative epilepsy surgery are not uniform between centers. Therefore,
in developing diagnostic and therapeutic approaches for MRI-negative epilepsy surgery,
there is a need for critically assessing surgical outcomes in terms of factors that contribute
to postsurgical seizure control and neuropsychological impact.
The editors and authors have developed this book so that clinicians and researchers in
epilepsy would find it to be useful because of the following features:
The book collates and integrates in one medium the fast-evolving state of the art and
the science in the evaluation and surgical management of MRI-negative focal
epilepsy.
Content of the book is clearly organized by diagnostic and treatment options and
approaches, and by the type of refractory epilepsy.
Contributors to this book are experts in their respective areas, with recognized
research investigations and clinical experience in the areas.
Each diagnostic technique and surgical approach discussed is critically appraised for
its value and limitations.
Clinical relevance of the materials in this book is enhanced by patient cases, with
many images provided to illustrate salient points in each chapter.
Elson L. So
Philippe Ryvlin
Chapter 1 Scope and implications of MRI-negative

refractory focal epilepsy
Elson L. So and Philippe Ryvlin
MRI-Negative Epilepsy, ed. Elson L. So and Philippe Ryvlin. Published by Cambridge University Press.
Cambridge University Press 2015.
Definition of MRI-negative epilepsy

In the absence of a demonstrable epileptogenic lesion, epilepsy is often referred to as
nonlesional epilepsy. In this book, we preferentially use the term MRI-negative
epilepsy instead of nonlesional epilepsy. Our reason for this preference is that MRI of
patients with refractory epilepsy not infrequently shows structural lesions or alterations
which are not the immediate cause of the epilepsy. Some of these lesions or abnormalities
that are noncausative for epilepsy are cerebral atrophy, nonspecific white matter signal
changes, and slight asymmetry in size or shape of regions in the brain. In these situations,
the MRI cannot be said to be normal. Therefore, we avoided the use of the term epilepsy
with normal MRI.
Another reason for our preferential use of the term MRI-negative epilepsy is that
histopathological examination of resected tissues has revealed lesions in as many as 50%
of nonlesional MRI patients, especially neuronal migrational abnormalities such as
microdysgenesis and focal cortical dysplasias [1]. Conversely, histopathologically proven
cortical dysplasia lesions are undetectable by MRI in 30% of the patients [2]. For these
reasons, the term nonlesional epilepsy would be literally and technically incorrect. The
term MRI-negative epilepsy better conveys the context in which it is used, in that the
presurgical MRI is devoid of a structural abnormality as the probable cause of the
epilepsy, and for which epilepsy surgery evaluation could be considered.
The term cryptogenic epilepsy has also been used in reference to MRI-negative
epilepsy [3]. Whereas there is some overlap between the population of patients with
cryptogenic epilepsy and the population with MRI-negative epilepsy, the two conditions
do not always coexist in patients. The term cryptogenic epilepsy arose from the concept
of classifying different types of epilepsy according to etiology [4]. An example of the
complex interface between epilepsy etiology and MRI findings is in familial focal
epilepsies. Unless clinical and laboratory investigations are conducted to establish the
heredo-familial basis of the epilepsy, familial temporal or frontal lobe epilepsy could be
classified as cryptogenic epilepsy. Some members in affected families have negative MRI,
whereas others have epileptogenic lesions such as mesial temporal atrophy [5]. Yet,
epilepsy surgery has been effective in some MRI-positive and some MRI-negative familial
focal epilepsies. Nonetheless, MRI findings have overall been consistently a more
important factor than epilepsy etiology in identifying patients for epilepsy surgery, and in
prognosticating the outcome of the surgery.
Implications of MRI-negative epilepsy
Despite the use of optimal conventional MR-imaging techniques, the proportion of

epilepsy surgery candidates with MRI-negative epilepsy still ranges from 20% to 40%
among epilepsy centers. Moreover, data from the USA show a trend of declining
hospitalizations in large epilepsy centers over about 20 years [6]. Some large epilepsy
centers have verbally reported increasing proportions of MRI-negative patients, and
declining volumes of resective surgeries. A study is underway to verify these observations.
Epilepsy surgery is less likely to be considered in MRI-negative epilepsy patients than
in MRI-positive patients. Up to 30% of patients prospectively evaluated in experienced
epilepsy surgery centers were not deemed to be surgical candidates, and a major factor for
not undergoing surgery is the absence of an MRI lesion and other localizing evidence [7].
In a single-center study of both temporal and extratemporal epilepsy patients who had
modern MRI imaging, only 15% of MRI-negative patients were offered surgery vs. 73%
of MRI-positive patients [8].
One reason why only a minority of MRI-negative refractory epilepsy patients proceed
to surgery is that seizure localization evidence in MRI-negative patients is often lacking.
Localization to the epileptogenic zone by seizure semiology was correct in only about
34% of the patients, 14% by interictal scalp EEG, 28% by ictal scalp EEG, 29% by PET,
and 15% by SISCOM. The rate of discordance between the results of these tests is also
high in MRI-negative patients. This overall deficiency in concordant seizure-localizing
findings often necessitates intracranial electrode implantation to identify the ictal onset
zone. A retrospective study of patients who underwent epilepsy surgery evaluation shows
that all MRI-negative patients, compared with 50% of MRI-positive patients, had
undergone intracranial electrode implantation [9]. The extent and complexity of
intracranial electrode implantation are often greater in MRI-negative than in MRI-positive
patients, in whom the cerebral lesion would have guided the extent of intracranial
electrode coverage. The risk of complications with intracranial electrode implantation is
associated with the extent of the implantation. The risk has been reported to increase by
40% for every additional 20 subdural electrodes implanted [10]. Yet, extensive intracranial
electrode implantation may not assure higher probability of postsurgical seizure control. It
has been reported that neither the extent nor the type of intracranial ictal EEG discharge
predicts postsurgical seizure freedom in MRI-negative epilepsy surgery [11].
The presence of an epileptogenic lesion in a surgically safe and accessible location is
the single most favorable factor in determining outcome of epilepsy surgery. Numerous
studies have consistently contrasted the prognosis between MRI-positive and MRInegative epilepsy surgery. Meta-analysis of studies on the subject shows that, compared
with MRI-negative patients, MRI-positive or histopathology-positive patients have a 2.5
times higher chance for seizure freedom following epilepsy surgery. Selected groups of
lesional temporal lobe epilepsy surgeries are associated with a 90% chance of excellent
postsurgical seizure control, whereas the rate is only 65% in MRI-negative temporal lobe
surgeries [12]. Similarly, lesional frontal lobe epilepsy surgeries have a 72% probability of
excellent postsurgical seizure control, whereas the rate is only 41% in MRI-negative
frontal lobe surgery [13]. In one study of both temporal and extratemporal refractory
epilepsy, surgery resulted in seizure freedom in only 38% of the MRI-negative patients vs.
76% of the MRI-positive patients [8]. However, many studies have shown that the
outcome of MRI-negative epilepsy can be improved with the use of modern diagnostic
measures, with instances of excellent surgical outcome rates approximating those in MRIpositive epilepsy [14]. Therefore, a major objective of this book is to critically assess and
identify measures that can improve the surgical outcome of MRI-negative epilepsy
surgery.
MRI-negative epilepsy surgeries also carry a higher risk for postoperative functional
deficits than surgeries involving an MRI lesion. MRI-demonstrated lesions such as tumors
or encephalomalacias are generally expected to be devoid of intrinsic cortical function;
thus, their borders provide good, though imperfect, demarcation between nonfunctioning
and functioning tissues. Such anatomical guidance is lacking in MRI-negative epilepsy.
Additionally, a greater degree of intrinsic cortical function resides in epileptogenic tissues
that are MRI-negative than in MRI-demonstrated lesions. Helmstaedter and colleagues
have observed that MRI-negative patients experience more prominent memory loss after
temporal lobectomy than MRI-positive patients [15].
MRI-negative refractory epilepsy patients could still benefit from surgery [16, 17],
especially if a more modest postsurgical prognosis than seizure freedom is acceptable to
the patient. Alarcon and colleagues found that postsurgical seizure frequency of three
seizures or less per year is as likely to be achieved in MRI-negative surgeries as in MRIpositive surgeries (74% vs. 73%) [9]. Nonetheless, in their subgroup of extratemporal
epilepsy, MRI-negative patients had a much lower rate of achieving seizure freedom than
MRI-positive patients (16.7% vs. 39.1%). The putative goal of surgery for medically
refractory epilepsy should be seizure freedom, given that improvement in quality of life
after surgery is best associated with the achievement of complete seizure control [18].
The less favorable outcome of MRI-negative epilepsy surgery may be due to a number
of factors. Without a visible potentially epileptogenic lesion, the epileptogenic zone may
be missed or underestimated. In some MRI-negative patients with extratemporal epilepsy
as proven by intracranial EEG and favorable postsurgical outcome, presurgical videoscalp EEG recordings had wrongly localized seizure onset to the temporal lobe [19]. The
pathology underlying MRI-negative epilepsy is also poorly understood and possibly
widespread or multifocal. Although cortical dysgenesis is increasingly found in resected
tissues from patients with MRI-negative epilepsy, the histopathology in as many as 50%
shows only nonspecific changes such as gliosis. In fact, the absence of a clear-cut
epileptogenic lesion in the histopathology and the persistence of seizures after surgery in
many MRI-negative patients may be consequences of misguided resection which failed to
include the epileptogenic histopathological lesion, or the absence of a well-delineated
epileptogenic lesion for resection. In the latter situation, the pathophysiology of
epileptogenesis might involve molecular or cellular abnormalities affecting large portions
of the brain, which constitutes a more widespread epileptogenic network than that of
epilepsy with a definite MRI-detectable or histopathology-proven lesion. Examples of this
concept include focal epilepsies associated with mutations of the nicotinic acetyl-choline
receptor subunit (autosomal dominant nocturnal frontal lobe epilepsy) or of the leucinerich glioma-inactivated 1 gene (autosomal dominant focal epilepsy with auditory features),
or multifocal type 1 cortical dysplasia.
Therefore, the critical issue in the presurgical evaluation of refractory MRI-negative
epilepsy is the development and validation of diagnostic strategies for localizing the
epileptogenic zone and surgical approaches for resecting the zone. Accordingly,
biomarkers could be developed to identify subgroups of MRI-negative patients with
favorable surgical prognosis, such as those with MRI-occult focal cortical dysplasia
(FCD). When used alone or in combination, clinical information, scalp EEG, MEG,
SPECT, or PET may in the future presurgically distinguish between MRI-occult type II
FCD where surgical prognosis is favorable, and type I multifocal/extensive cortical
dysplasia where the prognosis is poorer. It is also conceivable that advances in current and
future diagnostic techniques may prove that a comprehensive understanding of the
pathophysiology underlying each case of MRI-negative epilepsy is more important for
postsurgical outcome than the current strategy of identifying the seizure onset zone.
Scope of the issues

Our terminology of MRI-negative epilepsy includes instances when MRI shows a subtle
focal finding that is suspected or disputed to be the cause of the refractory epilepsy [20,
21] (Figure 1.1) The reason is that evaluation for epilepsy surgery is just as complex and
rigorous whether or not a subtle or disputable finding is present on the MRI. The tests and
strategies available for localizing and resecting the ictal onset zone are applicable in either
case.
Figure 1.1 Examples of subtle abnormalities appreciated on MRI re-review. Upper panel
shows FLAIR (left) and T1-SPGR (right) images of subtle left hippocampal signal
abnormality without atrophy. Lower panel shows FLAIR (left) and T1-SPGR (right)
images of subtle left hippocampal atrophy without signal abnormality. (From reference
[20]; reproduced with permission of publisher John Wiley and Sons.)
There are also instances when the histopathological examination of resected tissues
disclosed lesional pathology, which then prompted reassessment of the presurgical MRI
that was perviously pronounced to be negative [20]. With reassessment of the presurgical
MRI, a subtle lesion or alteration at the location of the surgery was then recognized.
Visual reassessment of the MRI combined with morphometric analysis have

retrospectively identified a subtle lesion in eight of nine patients whose presurgical MRI
was deemed negative, but postsurgical tissue examination showed lesional pathology [8].
These situations should still be considered as MRI-negative epilepsy, because the
presurgical knowledge of the MRI result had been the basis for developing the strategies
in identifying and resecting the ictal onset zone, and also in prognosticating the surgical
outcome.
Both presurgically and postsurgically detected subtle MRI alterations should be further
scientifically investigated, because studies have suggested that subtle focal alterations in
otherwise MRI-negative epilepsy could be associated with excellent postsurgical seizure
control [8, 20]. With continuing advancements in MRI imaging, MRI findings that are
currently negative, subtle, or disputable for epilepsy surgery consideration may eventually
be detected and recognized as definite anatomical lesions with potential epileptogenicity.
Even before then, advancements in functional imaging and electrophysiology may
establish subtle alterations to be highly probable ictal onset zones, which may be targeted
for further seizure localization studies and subsequent surgical resection. Accumulation of
experience in surgery of patients with subtle MRI alterations will lead to better
understanding of their histopathological nature [3].
There are many types of MRI-negative epilepsies that are of generalized or
indeterminate onset, but this book concentrates on the surgical evaluation and treatments
of refractory focal epilepsy. Nonetheless, much of the methods and approaches in
searching for the seizure onset zone for focal resective surgery are also applicable in
evaluating patients with suspected generalized or indeterminate seizure onset. When the
evaluation process has more confidently excluded focal refractory epilepsy, and the
generalized-onset nature of the epilepsy is affirmed, the appropriate pharmacologic or
surgical treatments for the nonfocal epilepsy may then be considered.
In concentrating the treatise of this book on refractory focal epilepsy, the authors make
no presumptive restriction regarding the size or extent of the seizure focus for inclusion in
this book. The extent of the seizure focus or foci, and their relationship to eloquent cortex,
is at the crux of the complexities and nuances of MRI-negative epilepsy surgery
evaluation. We have also specifically included in this book the discussion of temporal-plus
epilepsy and posterior cortical epilepsy, in which the clinical and scalp EEG findings
appear to involve the parietal, occipital, or temporal lobe, or a combination of these lobes,
and the intracranial recording subsequently confirming either a unilobar or multilobar
region of seizure onset.
References
1. Siegel, A., et al., Medically intractable localization-related epilepsy with normal MRI:
Presurgical evaluation and surgical outcome in 43 patients. Epilepsia, 2001. 42: 883
888.
2. Hauptman, J. and G. Mathern, Surgical treatment of epilepsy associated with cortical
dysplasia: 2012 update. Epilepsia, 2012. 53(Suppl 4): 98104.
3. Bernasconi, A., et al., Advances in MRI for cryptogenic epilepsies. Nature Reviews,
2011. 7: 99108.
4. Commission on Classification and Terminology of the International League Against
Epilepsy. Proposal for Classification of Epilepsies and Epileptic Syndromes. Epilepsia,
1985. 26: 268278.
5. Kobayashi, E., et al., Outcome of surgical treatment in familial mesial temporal lobe
epilepsy. Epilepsia, 2003. 44(8): 10801084.
6. Englot, D.J., et al., Epilepsy surgery trends in the United States, 19902008.
Neurology, 2012. 78(16): 12001206.
7. Berg, A., et al., The multicenter study of epilepsy surgery: Recuitment and selection of
patients for surgery. Epilepsia, 2003. 44(1): 14251433.
8. Bien, C., et al., Characteristics and surgical outcome of patients with refractory
magnetic resonance imaging-negative epilepsies. Archives of Neurology, 2009. 66(12):
14911499.
9. Alarcon, G., et al., Is it worth pursuing surgery for epilepsy in patients with normal
neuroimaging? Journal of Neurology, Neurosurgery & Psychiatry, 2006. 77(4): 474
480.
10. Hamer, H., et al., Complications of invasive video-EEG monitoring with subdural
grids. Neurology, 2002. 58: 98103.
11. Lee, S.K., et al., Surgical outcome and prognostic factors of cryptogenic neocortical
epilepsy.[see comment]. Annals of Neurology, 2005. 58(4): 525532.
12. Radahkrishnan, K., et al., Predictors of outcome of anterior temporal lobectomy for
intractable epilepsy. A multivariate study. Neurology, 1998. 51: 465471.
13. Mosewich, R., et al., Factors predictive of the outcome of frontal lobe epilepsy
surgery. Epilepsia, 2000. 41: 843849.
14. Carne, R.P., et al., MRI-negative PET-positive temporal lobe epilepsy: a distinct
surgically remediable syndrome. Brain, 2004. 127(Pt 10): 22762285.
15. Helmstaedter, C., I. Petzold, and C. Bien, The cognitive consequence of resecting
nonlesional tissues in epilepsy surgery: Results from MRI-negative and histopathologynegative patients with temporal lobe epilepsy. Epilepsia, 2011. 52(8): 14021408.
16. Wetjen, N., et al., Intracranial electroencephalography seizure onset patterns and
surgical outcomes in nonlesional extratemporal epilepsy. Journal of Neurosurgery,
2009. 110(6): 11471152.
17. Fong, J., et al., Seizure outcome and its predictors after temporal lobe epilepsy
surgery in patients with normal MRI. Epilepsia, 2011. 52(8): 13931401.
18. Seiam, A., H. Dhaliwal, and S. Wiebe, Determinants of quality of life after epilepsy
surgery: Systematic review and evidence summary. Epilepsy and Behaviour, 2011. 21:
441445.
19. Lee, S., et al., Intracranial ictal onset zone in nonlesional lateral temporal lobe
epilepsy on scalp ictal EEG. Neruology, 2003. 61: 757764.
20. Bell, M., et al., Epilepsy surgery outcomes in temporal lobe epilepsy with a normal
MRI. Epilepsia, 2009. 50(9): 20532060.
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negative partial epilepsy. Epilepsia, 2009. 50(12): 26112618.
Chapter 2 Seizure semiology and scalp EEG in MRInegative refractory focal epilepsy
Soheyl Noachtar and Elisabeth Hartl
The rationale of epilepsy surgical intervention depends on the localization of the

epileptogenic zone and its complete removal [1]. The following methods were used to
delineate the epileptogenic zone [2]:
seizure description and patient history
MRI
interictal EEG
ictal EEGvideo monitoring
ictal (and interictal) SPECT
interictal PET
neuropsychological evaluation
Several studies have shown that it is more difficult to identify the epileptogenic zone if
MRI does not reveal any abnormality [2, 3]. In general, the chance of a postoperative
seizure freedom outcome from epilepsy surgery is less favorable in nonlesional MRInegative patients as compared to patients with MRI-documented lesions [3]. However,
thanks to advances in MRI technology, the sensitivity in detecting epileptogenic lesions
improved dramatically over the last two decades [4]. It is, therefore, mandatory to perform
state of the art epilepsy-oriented MRIs before stating that a given patient has MRInegative epilepsy.
Concordance of noninvasive results implicating a resectable focus is usually considered
the prerequisite to proceed to epilepsy surgery based on noninvasive studies only. This is
mostly true in temporal lobe epilepsy, which is the most common focal epilepsy that is
referred to epilepsy surgery centers. However, in a large series of unselected patients with
extratemporal lesions, discrepancy of EEG and MRI localization was more common than
congruence [5]. Discrepancy did not necessarily imply that resective epilepsy surgery was
associated with poor postsurgical outcome [5].
Invasive evaluation may be used in patients in whom noninvasive studies are
inconclusive or reveal discrepant results, but still support a testable hypothesis of a
resectable focus. Under these circumstances, properly placed invasive electrodes
frequently provide useful additional information about the localization and extent of the
epileptogenic zone. If MRI is negative, the defintion of the epileptogenic zone has to rely
on localization information derived from methods such as seizure semiology and EEG,
which then become more important. Frequently, in MRI-negative patients, invasive studies
are required to define the localization of the epileptogenic zone.
Interictal EEG
Electroencephalography is the most specific method to define the epileptogenic cortex.

Interictal epileptiform discharges, particularly if consistent over time, can provide useful
information [6]. In temporal lobe epilepsy, consistently unitemporal interictal epileptiform
discharges (IED) have a better prognosis for seizure freedom than bilateral IEDs. Focal,
particularly extratemporal, epilepsies in which the EEG shows active regional polyspikes
are more likely associated with cortical dysplasia as etiology of the epilepsy than patients
with other IEDs [7]. Rhythmic midline theta activity, which is distinct from patterns of
drowsiness of mental activation, is highly signficant for frontal lobe epilepsy and rarely
seen in temporal lobe epilepsy [8]. This is particularly interesting since one out of four of
these frontal lobe epilepsy patients did not show any interictal epileptiform discharges on
noninvasive long-term EEG-monitoring and the rhythmic midline theta was the only
interictal EEG abnormality [8].
Ictal EEGvideo monitoring

Ictal EEGvideo recording is critical in localizing the epileptogenic zone. A careful
analysis of the first clinical signs and symptoms of a seizure and of the evolution of the
seizure symptomatology can provide important clues on the epileptogenic zone [911].
One must keep in mind, however, that often an epileptic seizure arises from a silent
region of cortex and would remain asymptomatic unless it spreads to eloquent cortex
such as primary motor, primary sensory, or supplementary sensorimotor areas (Figure 2.1).
Unfortunately, ictal EEG frequently documents discrepant results in extratemporal
epilepsies [5]. Good concordance to MRI lesions and interictal EEG is only typical for
temporal lobe epilepsy [5].
Figure 2.1 Illustration of the relation of the seizure onset and symptomatogenic zones.
Seizure onset in the prefrontal region is likely to stay unnoticed unless the epileptic
activity spreads into symptomatogenic cortex:
1. Spread into the supplementary sensorimotor area leads to bilateral asymmetric
tonic seizure
2. Spread into the somatosensory hand area leads to right face clonic seizure
3. Spread into the frontal eye field leads to right versive seizure
4. Spread into frontal speech area leads to aphasic seizure
Seizure onset in the left occipital lobe leads to the following seizure evolution:
5. Right visual aura right versive seizure
Seizure onset in the temporal lobe leads to the following seizure evolution:
6. Acoustic aura/abdominal aura automotor seiure right face clonic seizure.
Seizure semiology
Careful clinical observations and detailed reports of seizure semiology by the patient or
observers have been used since the 18th century to classify epileptic seizures and epileptic
syndromes. A detailed analysis of seizure semiology is still essential for the proper
management of epileptic patients. A clear definition of the seizure type is important for
classifying the epilepsy syndrome of the patient. The syndrome, together with the etiology
of the epilepsy, are the essential factors determining the prognosis as well as the most
effective pharmacological treatment. Seizure semiology plays an important role in the
presurgical work-up, particularly when analyzed independently of other presurgical tests
(EEG monitoring, neuroradiology, etc.). In addition, seizure semiology can be used

effectively to differentiate between epileptic and nonepileptic seizures.
It is very important to emphasize that as a rule epileptic discharges limited to the
seizure onset zone do not cause clinical symptoms unless located in an eloquent area
(Figure 2.1). This is because the epileptogenic zone does not necessarily overlap with the
symptomatogenic zone [1]. The term symptomatogenic zone refers to the area of the
cortex that produces certain clinical symptoms as a result of epileptic activation. For
example, seizures that originate in the frontal convexity remain asymptomatic as long as
they do not spread into the symptomatogenic zones. If the epileptic activation reaches the
primary motor area, versive or focal clonic seizures result (Figure 2.1). If the
supplementary sensorimotor area is activated, focal tonic or hypermotor seizures occur;
and if the activation spreads into the limbic system (cingulate gyrus), features of the
seizure possibly become those of automotor seizures [12] (Figure 2.1). There is some
association of specific seizure types with brain regions: seizures characterized by oral and
manual automatisms (automotor seizures) [13, 14] are more common in temporal lobe
epilepsy than in extratemporal epilepsy [15]. However, the specificity to temporal lobe
epilepsy is much higher if automotor seizures are preceded by epigastric (abdominal)
auras [15]. Similarly, unilateral clonic seizures of the face are frequently seen in patients
with paracentral epilepsies. However, the same seizure type may occur in patients with
temporal lobe epilepsy but then is usually preceded by manual and oral automatisms
(automotor seizure. In fact, this evolution is more likely to occur in lateral than mesial
temporal lobe epilepsy [16]. Unilateral clonic seizures may be associated with both frontal
and temporal lobe epilepsies. However, the sequence of the seizure evolution makes a
major difference. In temporal lobe epilepsy, unilateral facial clonic seizures are typically
preceded by manual and oral automatisms, which are rarely the case in frontal lobe
epilepsy. Thus, the association of single-seizure types to particular localizations of the
epileptogenic zones is not as strong as the association of the evolution of seizure types to
specific brain regions. This may explain why several studies which neglected this fact
found poor localizing value of seizure semiology [17]. Another limitation is that many
studies relied on the description of seizures rather than investigating adequate videorecorded seizures [17]. Patients or witnessess descriptions of seizure are subject to bias
and not sufficiently reliable.
Table 2.1 summarizes studies on nonlesional epilepsy patients. A computerized online
search via MEDLINE (online PubMed from first available year to April 2013) using the
search term nonlesional epilepsy identified 121 studies, of which 78 were excluded for
being review articles (n = 16), meta-analysis (n = 1), or a commentary (n = 1). Animal
studies (n = 2), genetic studies (n = 4), as well as ten studies investigating symptomatic
epilepsy and 19 not clearly differentiating between nonlesional and lesional epilepsy
patients (n = 19) were excluded. Seven publications including patients with status or
generalized epilepsy syndromes were excluded, as they do not localize in early infancy. In
addition, studies were excluded if they did not use MR imaging (n = 6) or were written in
languages other than English or German (n = 9). Two publications were excluded, because
the full text was not available online. In total, 43 studies met our inclusion criteria.
Table 2.1 Characteristics of selected studies about nonlesional epilepsy
Author
(year)
Trial
Patient
number
(m/f)
EEG
Semiology
interictal
ictal
invasive
(n)
PET/SP
Helmstaedter
et al. (1993)
[23]
CCT
8 (5/3)
5 CPS, 3
GTC
n.a.
Blum (1994)
[24]
pUCT
57 (-/-)
n.a.
n.a.
n.a. (-)
Stanley et al.
(1998)[25]
pCCT
20
(10/10)
20 PS
n.a.
n.a.
n.a. (10)
Swearer et
al. (1999)
[26]
pUCT
23
(12/11)
23 PS
n.a.
n.a. (13)
Velasco et
al. (2000)
[19]
pUCT
22
(11/11)
22 CPS, 1
GTC, 12
SGC
a.
a.
a. (22)
Matheja et
al. (2001)
[18]
pCCT
62
(26/36)
a.
Mendona et
al. (2001)
[27]
pCCT
19 (10/9)
19 PS
n.a.
Hong et al.
(2002)[22]
rUCT
41
(27/14)
n.a.
a.
n.a. (-)
Hori et al.
(2001)[28]
pUCT
20 (-/-)
Wieshmann
et al. (2003)
[29]
pCCT
16 (7/9)
a.
a.
a. (16)
Leutmezer et
al. (2003)
[30]
pCCT
18 (-/-)
n.
n.a.
Merlet et al.
(2004)[31]
pCCT
5 (5/0)
n.a.
n.a.
a. (5)
Carne et al.
(2004)[32]
rCCT
30
(16/14)
30 CPS,
30 SGC
a.
a.
Oh et al.
(2004)[33]
pUCT
8 (6/2)
6 CPS, 3
SGC
n.a.
n.a.
Brzdil et al.
(2006)[34]
CR
1 (1/0)
1 SPS
a.
a.
a. (1)
Najm et al.
(2006)[35]
CR
1(1/0)
1 CPS, 1
SGC
a.
a.
a. (1)
Ito et al.
(2007)[36]
pCCT
13 (8/5)
4 SPS, 13
CPS, 5
SGC
a.
n.a.
a. (3)
Box et al.
(2007)[37]
pUCT
3 (2/1)
3 CPS, 1
GTC, 1
SGC
a.
a.
a. (3)
Shields et al.
(2007)[38]
CR
1 (1/0)
1 PS
a.
a.
a. (1)
Kaczmarek
et al. (2007)
[39]
pCCT
89 (-/-)
89 PS
Adams et al.
(2008)[40]
pUCT
91
(41/50)
91 PS
n.a.
n.a.
Concha et al.
(2009)[41]
pCCT
13 (5/8)
13 CPS
n.a.
n.a.
n.a. (4)
Nakayama et
al. (2009)
[42]
CR
1 (1/0)
1 CPS, 1
GTC
a.
Tanriverdi et
al. (2009)
[43]
rUCT
393
(191/202)
Velasco et
al. (2009)
[44]
CR
2 (1/1)
2 SPS, 2
SGC
a.
a.
a. (2)
Aubert et al.
(2009)[45]
rUCT
8 (3/5)
n.a.
n.a.
a. (8)
Poon et al.
(2010)[46]
CR
1 (0/1)
1 CPS
a.
a.
a. (1)
Lowe et al.
(2010)[47]
rUCT
76 (-/-)
n.a.
n.a. (24)
Oliva et al.
(2010)[48]
pUCT
12 (4/8)
a.
Mankinen et
al. (2011)
[49]
pCCT
21
(10/11)
a.
Box et al.
(2011)[50]
rUCT
6 (3/3)
6 CPS
a.
a.
a. (5)
Kim et al.
(2011)[51]
rUCT
55
(31/24)
4 SPS, 7
CPS, 16
GTC, 28
SGC
n.a.
n.a.
n.a. (55)
Hindi-Ling
et al. (2011)
[52]
rUCT
33 (-/-)
n.a.
n.a.
n.a. (-)
Au et al.
(2011)[20]
pUCT
4 (2/2)
2 SPS, 3
CPS, 2
GTC
n.a.
a.
a. (4)
Tyrand et al.
(2012)[53]
pUCT
4 (3/1)
4 CPS, 1
SGC
n.a.
n.a.
a. (4)
Wang et al.
(2012)[54]
CR
1 (1/0)
1 SPS
a.
a. (1)
Mankinen et
al. (2012)
[55]
pCCT
21
(10/11)
a.
Schneider et
al. (2012)
[56]
rUCT
14 (10/4)
n.a.
n.a.
a. (14)
Kovac et al.
(2012)[57]
CR
1 (0/1)
1 PS, 1
GTC
a.
a.
a. (1)
Sun et al.
(2012)[58]
CR
1 (1/0)
1 PS, 1
GTC,
reflex ep.
a.
a.
a. (1)
Chaudhary
et al. (2012)
[59]
pUCT
8 (6/2)
8 PS, 3
reflex ep.
a.
a.
Bien et al.
(2013)[60]
rUCT
567
(297/270)
n.a.
n.a.
n.a. (-)
Mueller et
al. (2013)
[61]
pCCT
36
(13/23)
n.a.
n.a.
n.a.(6)
n = number of subjects, m = male, f = female, bihem. = bihemispheric, histop. =

histopathology, r = retrospective, p = prospective, UCT = uncontrolled clinical trial,
CCT = controlled clinical trial, CR = case report, SPS = simple partial seizure, CPS =
complex partial seizure, GTC = generalized tonicclonic seizure, SGC = secondary
generalized seizure, n.a. = no data available, a. = data available, TL = temporal lobe,
FL = frontal lobe, PL = parietal lobe, OL = occipital lobe, CR = central region, Y =
yes, N = no.
Different terminologies were used to classify or label seizure semiology. It was mostly
labeled after the lobe, such as temporal lobe seizure or frontal lobe seizure, providing no
reliable clinical information on the seizure characteristics. Other studies used the seizure
classification system of the International League against Epilepsy with terms such as
complex partial seizures (CPS) or simple partial seizures (SPS). These terms only provide
the information whether consciousness is disturbed or not in patients with focal epilepsies
regardless of the actual seizure semiology. Only few publications of case series provide
detailed information on seizure semiology and EEG findings [1820]. We, therefore, use
the semiological seizure classification to provide clinically localizing information [13, 14].
With the help of EEGvideo-recorded seizures, several very reliable lateralizing signs
have been identified which have an accuracy of 80100% (Table 2.2) [12, 21].
Table 2.2 Lateralizing seizure phenomena
Lateralizing seizure phenomena
Hemisphere of seizure
onset
Authors
Head and eye deviation
Contralateral
[6264]
Dystonic hand posturing
Contralateral
[63, 65]
Figure 4 sign
Contralateral to extended
arm
[66]
Automatisms with preserved

responsiveness
Nondominant
[67, 68]
Ictal speech
Nondominant
[69]
Postictal aphasia
Dominant
[69]
Ictal vomiting
Nondominant
[70]
Ictal spitting
Nondominant
[71]
Peri-ictal urinary urge
Nondominant
[72]
Postictal nose rubbing
Ipsilateral
[73]
Postictal coughing
Nondominant
[74]
Unilateral clonic seizure
Contralateral
[75]
Unilateral tonic seizure
Contralateral
[76]
Unilateral eye blinking
Ipsilateral
[7779]
Asymmetric ending
Ipsilateral to clonia
[80]
The EEG data were mostly reported as being concordant or discordant with the other
diagnostic findings (Table 2.1). Highest diagnostic sensitivity in the localization of
epileptogenic foci and seizure lateralization was demonstrated for ictal scalp EEG.
Concordance rate was higher in the good than in the poor surgical outcome group [22].
The lateralizing and localization value of seizure semiology, and their role in MRInegative surgery, are further discussed elsewhere in this book according to the brain
regions affected by epilepsy (Chapters 14, 15, 16, and 18), in children (Chapter 17), and
with relevance to cortical mapping (Chapter 13).
Illustrative patients
How seizure semiology and EEG help to develop a hypothesis on the epileptogenic zone
in patients with negative MRI is illustrated by the following two patients:
Patient 1: This 27-year-old, right-handed female bank clerk has had epileptic seizures
since the age of 8 years. She had frequent predominantly nocturnal hypermotor and
asymmetric bilateral tonic seizures which were sometimes preceded by an aura of
fear. Her MRI was normal. Interictal EEG revealed evenly distributed right and left
mesial temporal interictal epileptiform discharges and slowing. Ictal EEG showed
frontal, nonlateralized seizure patterns. Postictally, the patient was at times aphasic
and her generalized tonicclonic seizures were preceded by right versive seizures.
Her medical history was unremarkable. Antiepileptic medications in monotherapy
and several combinations did not control the seizures.
In summary, MRI was negative, ictal EEG showed nonlateralized frontal
abnormalities, and interictal EEG demonstrated bitemporal discharges. However,
semiology was pointing to a left hemisphere and a likely frontal onset (sleep
predominance, hypermotor seizure, bilateral asymmetric tonic seizures, right versive
seizure, postictal aphasia). Based on these noninvasive findings, an invasive
evaluation was performed with subdural grid electrodes covering the left frontal
convexity, and strip electrodes over the left mesial frontal and right lateral frontal
region. Seizure onset could be identified over wide areas of the mesial and lateral left
frontal lobe sparing the speech areas and the motor strip. After speech area and motor
strip were identified by electrical stimulation of the cortex, an extensive left frontal
lobe resection sparing only the precentral gyrus, the inferior frontal gyrus, and parts
of the orbitofrontal region, was performed. Histology revealed widespread cortical
dysplasia type I. The patient is seizure-free for 5 years with antiepileptic medication.
Neuropsychological performance improved postoperatively.
Patient 2: This 34-year-old, right-handed accountant has had epileptic seizures since
the age of 24 years. He had acoustic auras which would evolve into automotor
seizures consisting of oral and manual automatisms. Rarely, he also had abdominal
auras. Before seizures further evolved into generalized tonicclonic seizures,
sometimes right face clonic seizures occurred. The MRI was normal. Interictal EEG
showed left temporal (85%) and rare right mesial temporal (15%) epileptiform
discharges, mostly in sleep. Ictal EEG showed consistently left temporal seizure
patterns. Interictal FDG-PET showed left lateral temporal and less severe mesial
temporal hypometabolism. Ictal SPECT revealed left lateral and mesial temporal
hyperperfusion. Subtraction of interictal PET and ictal SPECT showed lateral
predominance of the left ictal hyperperfusion. His verbal memory was above average
but subjectively declining over the last few years. Several antiepileptic drugs failed to
control the seizures. His medical history was remarkable for a febrile illness with
confusion and headache at age 22 which was not further diagnosed at that time. No
family history of epilepsy.
In summary, MRI was normal but EEG, PET, and SPECT point to a left temporal
seizure onset. However, seizure semiology with acoustic auras is suggestive of a
lateral neocortical temporal seizure onset. This is supported by the fact that MRI did
not reveal a left mesial temporal sclerosis, PET and SPECT showed a lateral temporal
predominance, and his verbal memory was still above average (though markedly
declining subjectively). An invasive evaluation with stereotactically implanted depth
electrodes covering the left mesial and lateral temporal region revealed seizure onset
in the superior and middle temporal gyrus, which were resected. The mesial temporal
structures were spared. Histology revealed mild gliosis. The patient is seizure-free
postoperatively for 8 years with medication. Postoperatively, he developed some
minor verbal memory deficit, which improved over several months but did not reach
baseline level.
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6.
Chapter 3 Clinical and advanced techniques for optimizing

MRI in refractory focal epilepsy
Neda Bernasconi and Andrea Bernasconi
Introduction
Temporal lobe epilepsy secondary to mesiotemporal sclerosis, and extratemporal lobe
neocortical epilepsy secondary to dysplasias are the two most common drug-resistant
epilepsies amenable to surgery. In both syndromes, early identification of these anomalies
allows timely resective surgery, limits the long-term effects of recurrent seizures and
medication, and has been shown to have positive consequences on cognitive outcome and
brain development.
Magnetic resonance imaging (MRI) is a pivotal component in the investigation of any
form of epilepsy because of its unmatched ability in visualizing brain pathology. In
particular, MRI has transformed the evaluation and management of patients with drugresistant epilepsy by allowing reliable detection of the structural lesion associated with the
epileptogenic zone, thus leading to increased rates of successful resective surgery [1].
Despite technical improvements in MRI hardware and sequences, however, best-practice
MRI is unremarkable, and thus unable to reveal the potential surgical target in about 50%
of patients [2]. Notably, however, in many centers, despite the high efficiency in providing
good EEG interpretation, MRI is still fully outsourced to the radiology department and
usually includes only basic imaging. It can be argued that epileptology must include
responsibility for good-quality and advanced imaging optimized for the patients particular
problem.
It is becoming increasingly clear that both hippocampal sclerosis and neocortical
dysplasias constitute a spectrum of histopathology, clinical, and radiological presentations
broader than originally suspected [39]. Indeed, epilepsies initially considered MRInegative are not necessarily nonlesional since in 30% to 50% of those patients who
undergo surgery, histological examination of the resected specimens reveals dysplasias [2,
3], mild hippocampal sclerosis [1012], or subtle isolated neocortical or hippocampal
gliosis [13, 14]. Importantly, retrospective assessment of preoperative MRI scans, guided
by quantitative structural image analysis, can frequently identify a lesion. These findings
reinforce the importance of obtaining high-quality, if needed, multiple-image datasets
interpreted by MRI experts to evaluate and treat patients with so-called MRI-negative
epilepsy.
The definition of epilepsies with negative MRI is a moving target that changes with
advances in diagnostic technology. While a consensus exists that the primary
histopathological substrates are subtle hippocampal sclerosis and dysplasias, the MRI
signature of these entities is not yet fully defined, mainly because of the lack of a unified
methodology to evaluate their underlying structural changes. The purpose of this chapter
is to give an overview of methods that have significantly improved the detection of subtle
brain lesions in drug-resistant epilepsy. After presenting clinical protocols aimed at
optimizing visualization, we will discuss advanced protocols including quantitative image
acquisitions and processing methods.
Optimizing conventional structural MRI

Broadly speaking, as the field strength increases, the signal-to-noise ratio (SNR) in an
image increases approximately linearly. Consequently, the advent of high-field magnets at
3 Tesla, combined with the use of phased arrays instead of a conventional quadrature coil,
has resulted in accelerated image acquisition, and improved signal- and contrast-to-noise
ratios for a more detailed and complete characterization of structural changes in the
hippocampus or the neocortex than those obtained at 1.5 Tesla. While these systems are
becoming the new high-field standard, their clinical value strongly depends on the
expertise of the individual who interprets the images. Importantly, evidence suggests the
highest sensitivity for detecting subtle epileptogenic lesions is achieved when using
epilepsy protocols that are evaluated by an experienced reader with proper clinical
information [15, 16].
The ideal sequence should provide high spatial resolution, high contrast, and complete
brain coverage. An increase in voxel resolution is an empirical choice based on acceptable
image quality parameters and clinically reasonable acquisition time. However, there is a
cost in terms of SNR that is paid for such increase. Recently commercialized 32-channel
phased-array head coils provide an elegant solution to this challenge leading to significant
signal-to-noise increase and obviating the use of small single surface coils. Although
sensitivity of these multiple arrays is higher at the neocortex, up to 30% increase can be
achieved in the mesial temporal lobes compared to an 8-channel head coil, and up to 60%
with respect to a conventional quadrature coil. Consequently, a number of sequences
implemented on 3 Tesla scanners currently offer superb anatomical images at
submillimeter resolution (Figure 3.1).
Figure 3.1 High-resolution submillimetric MRI at 3 Tesla with 32-channel phased-array

coils. Compared to the 1 mm isotropic T1-weighted images (left panels), T1- and T2weighted images at micrometric resolution (middle and right panels) unveil anatomical
details of the mesiotemporal lobe that are essential for reliable quantitative studies, such as
volumetry.
In our experience, high-resolution magnetization prepared rapid acquisitions with
gradient echo (MPRAGE) sequences provide excellent contrast and significantly reduced
partial voluming effects; they have been documented to be superior for digital image
processing. The T1-weighted inversion recovery (IR) also offers a high GM/WM contrast,
which improves the visual distinction between gliotic changes and normal tissue, and the
visualization of medullary veins and enlarged perivascular spaces. The T2-weighted
images are useful for detecting signal changes, usually hyperintensity, associated with
gliosis. As current 3 Tesla systems offer flexibility in parallel imaging performance, such
as generalized autocalibrating partially parallel acquisitions (GRAPPA), it is now possible
to acquire multispectral volumetric images (T1, IR, T2, and FLAIR) with isotropic
resolution equal or below 1mm3 voxels in about 30 minutes, obviating the need for
dedicated epilepsy protocols as the rater can manipulate and reformat the image in any
plane without losing resolution. Nevertheless, when evaluating the temporal lobe,
particularly mesiotemporal structures, in addition to the above-mentioned volumetric
sequences, it is advisable to acquire 2D T2-weighted images perpendicular to the long axis
of the hippocampus with an in-plane resolution of 0.4 to 0.5 mm3 and a slice thickness of
2 to 3 mm, which many systems allow to achieve in about 5 minutes. The practical
implication of high-field scanners becoming increasingly available for clinical imaging is
that patients with normal-appearing 1.5 Tesla MRI should be re-examined at 3 Tesla.
Unfortunately, however, clinical radiologists may choose to evaluate lower-resolution
images that have been reconstructed into thicker slabs instead of the original highresolution volumetric acquisition as a means to decrease the number of sections to inspect.
For example, T1 or FLAIR images acquired originally at 1 mm3 isotropic resolution are
resampled at 3 mm, at times with the addition of interslice gaps. This procedure is
obviously detrimental, as in patients with drug-resistant epilepsy the highest resolution is
associated with lesser partial volume effects, thus favoring the detection of subtle
anomalies (Figure 3.2).
Figure 3.2 Image resampling vs. original resolution. Axial 3 Tesla FLAIR images of a
patient with histologically proven focal cortical dysplasia ILAE type IIb. The radiological
evaluation was initially performed on images reconstructed from the original 3D highresolution 1 mm acquisition into thick 3 mm slabs (upper panels), and has been reported
as unremarkable. The repeated inspection of the original 1 mm isotropic images (lower
panels), however, revealed a subtle dysplasia, mainly characterized by blurring of the
lesional boundaries (seen on all the slices, arrows) and a minute transmantle sign (arrow
head). Slice numbers for each dataset are shown.
While 7 Tesla systems appear quite promising for an even more detailed
characterization of epileptogenic lesions [17], it is currently unclear if they will replace
optimized 3 Tesla systems to become the new clinical standard for structural MRI.
Challenging disadvantages of ultra-high field imaging include far greater radiofrequency
signal inhomogeneities, higher energy deposition in tissue, as quantified by specific
absorption rate (SAR), and more pronounced imaging artifacts from static field
inhomogeneities at soft tissueair and soft tissuebone interfaces. To remain within the
SAR limits, the number of slices per measurement often has to be decreased, especially in
spin-echo T2- and FLAIR-weighted sequences. Thus, coverage of the entire brain at high
in-plane resolutions cannot currently be achieved at 7 Tesla within a single spin-echo
sequence. With appropriate coils, pulse sequence modifications, and imaging protocol
optimizations, however, it is likely that 7 Tesla scanners will be used without losing key
information obtained at lower field strengths.
Image processing of structural MRI

In many patients, routine visual MRI inspection does not permit diagnosis of epileptogenic
lesions with a sufficient degree of confidence or it is simply unremarkable. This clinical
difficulty has motivated the development of computer-aided methods aimed at analyzing
brain morphology and signal intensities. These procedures provide distinct information
through quantitative assessment without the cost of additional scanning time or exposure
to ionizing radiation. Whereas the general tendency is to automate analyses generating
results that are both replicable and rater independent, it is advisable that the fundamental
image preprocessing steps (e.g., intensity nonuniformities correction, registration, and
tissue segmentation) remain accessible to the user for purposes of quality control.
Temporal lobe epilepsy

Hippocampal sclerosis is the histopathological term used to describe neuronal loss and
astrogliosis in the hippocampus proper, particularly CA1 and CA4, and the dentate gyrus
[4, 18]. Although these features are commonly examined at the level of the midbody of the
hippocampus, there is significant variability in their extent and severity. In addition, as
tissue obtained from surgical resections may be incomplete due to partial resections or
fragmented as a result of subpial aspiration, a comprehensive evaluation of the
mesiotemporal lobe structures is limited; a neuropathological assessment of the entire
hippocampus, the amygdala, and entorhinal cortex in the same patients is thus rarely done.
Nevertheless, when available, surgical specimens and postmortem data have shown
evidence for extended pathology involving also the entorhinal cortex and amygdala [19].
Human pathological data on neocortical abnormalities outside the temporal lobes has also
been infrequent due to difficulties in obtaining postmortem specimens. In their seminal
study, Margerison and Corsellis [20] described neuronal loss and gliosis in frontal and
occipital cortices in 22% of patients. In a single patient who underwent temporal lobe
surgery, another autopsy report showed varying degrees of architectural abnormalities
involving virtually all lobes [21].
Quantitative analysis of the mesiotemporal lobe

For the last two decades, MRI volumetry has been the most commonly employed
quantitative technique to assess mesiotemporal lobe pathology as it is more sensitive than
visual evaluation. In TLE, hippocampal atrophy is considered a surrogate marker of
hippocampal sclerosis; the degree of atrophy correlates with the severity of neuronal loss
in the cornu ammonis, particularly CA1 [22]. The utility of hippocampal volumetry stems
from its ability to lateralize the seizure focus in about 70% of cases at the individual
patient level [23]. Yet, in clinical settings, manual volumetry of mesiotemporal lobe
structures, often restricted to the hippocampus, is largely underutilized as it is considered
prohibitively time consuming and requires an anatomy expert to perform the task.
Automatic hippocampal segmentation studies in TLE have been sparse and many have
provided up until now rather unsatisfactory results [2426]. We developed a robust and
reliable algorithm that integrates deformable parametric surfaces and multiple templates in
a unified framework [27]. Our method showed excellent overlap with manual labels,
achieving submillimetric accuracy in patients, regardless of the degree of atrophy, that was
virtually identical to that obtained in healthy controls. Importantly, the produced labels of
the various structures may be used for more advanced processing, as detailed below.
Since volumetry provides a global estimate of atrophy, its sensitivity to detect subtle
diffuse or focal anomalies is limited. This may explain why in 3040% of patients with
unambiguous electroclinical features of drug-resistant TLE, hippocampal volumetry is
unremarkable even though histopathology reveals subtle sclerosis. Indeed, surgical
specimens in MRI-negative TLE have clearly demonstrated 20% cell loss in the
hippocampal CA1 subfield [4, 12] or isolated gliosis. Neuronal loss may predominate in
the entorhinal cortex or the amygdala [19]. In light of these observations, entorhinal cortex
volumetry provides a valuable alternative, lateralizing the focus in 25% of cases with
normal hippocampal volume [11]. Shape analysis has the potential to further refine the
MRI correlates of hippocampal pathology [28]. We have developed and validated a 3D
surface-based method relying on spherical harmonic shape descriptors that localizes
submillimetric variations of volume between a given structure and a template while
guaranteeing anatomical correspondence across subjects [29], a requisite for reliable
statistics. In our experience, this technique is effective in detecting subtle atrophy in
patients with normal whole hippocampal volume (Figure 3.3).
Figure 3.3 Hippocampal shape analysis. Coronal 3 Tesla T1- and T2-weighted MRI and
hippocampal surface maps of atrophy normalized with respect to healthy controls (z-score,
shown by the color bar) for two patients with right TLE. In the first patient (A), the right
hippocampus is clearly atrophic and shows T1 hypo- and T2 hyperintensity. Surface-based
analysis confirms and localizes areas of atrophy along the rostrocaudal extent of the right
hippocampus. In case (B), the inspection of conventional MRI was reported as normal.
Conversely, the surface-based maps reveal subtle atrophy, at the level of the right
hippocampal head and the body. Histology confirmed the presence of subtle hippocampal
sclerosis. Dotted lines on the surface maps indicate the level of the coronal MRI cuts.
Right is right on the panels.
Compared to the visual analysis of T2-weighted MRI, T2-relaxometry, which provides
a quantitative estimate of T2-weighted signal, has been shown to yield an increased
sensitivity in detecting mesiotemporal gliosis [3032]. We demonstrated that hippocampal
T2-relaxometry correctly lateralizes the seizure focus in 82% of patients with normal
hippocampal volume [31]. We also showed that prolongation of white matter T2 signal in
the temporal stem occurs in about 70% of these patients; in half of them the increase was
bilateral and symmetric. However, white matter T2-relaxometry provided a correct
lateralization of the seizure focus in a third of patients, demonstrating that such
measurement may provide complementary information [32].
Quantitative analysis of the neocortex

Since the early 2000s, the technique of voxel-based morphometry (VBM) has been
extensively used to assess structural abnormalities in TLE as it permits an automated
whole-brain structural analysis without prior anatomical segmentation. However, for
detecting focal pathology within the mesiotemporal lobe, voxel-based measurements are
insufficiently sensitive, especially when pathomorphological changes are relatively subtle,
as is the case in hippocampal sclerosis [33]. On the other hand, VBM [34] and
measurement of cortical thickness [35, 36] offer a sensitive means for assessing wholebrain structural integrity. In drug-resistant TLE, they have shown widespread atrophy and
evidence for disease progression, particularly in the frontocentral areas [37]. Notably, we
demonstrated that patients with obvious hippocampal atrophy and those with normal
hippocampal volume have similar patterns of static and dynamic pathology in neocortical
regions remote from the seizure focus [35]. Equivalent neocortical dynamics occurring
despite different degrees of mesiotemporal lobe pathology supports the concept that these
two TLE entities are part of the same spectrum and that longitudinal changes are most
likely reflective of secondary effects of seizures. In light of functional data showing
progressive cognitive decline and extension of the epileptogenic network in relation to
recurrent epileptic discharges, these results provide compelling evidence that drugresistant TLE, regardless of the degree of hippocampal atrophy, is a progressive disorder
that warrants early surgery.
The majority of studies dedicated to the assessment of the neocortex have been group
based. Preliminary data suggest, however, that machine-learning techniques applied to
whole-brain automated segmentation may aid lateralizing the presumed seizure focus in
single subjects with visually normal MRI [38]. Nevertheless, as features selected by the
classifier may challenge biologically plausible interpretations, the clinical use of these
techniques warrants cross-validation through independent studies.
Focal cortical dysplasia

Neocortical epilepsy related to focal cortical dysplasia (FCD) accounts for more than half
of pediatric and a quarter of adult patients [3]. Main FCD features on structural MRI
include abnormally thick cortical gray matter (5092% of cases) and blurring of the gray
white matter interface (6080% of cases) [3, 39]. Analysis of T2-weighted images reveals
gray matter hyperintensity in 4692% of lesions and sensitivity of FLAIR images is even
higher (71100%). The typical transmantle sign, a footprint of disrupted cell migration
along radial glial processes, presents as a funnel-shaped hyperintensity extending from the
ventricle to the lesion and is seen in the majority of FCD type II cases [7, 39, 40].
The in vivo visibility of dysplastic changes on MRI generally parallels the degree of
histopathological derangement [3]. Even in patients with FCD type II, however, as the
radiological spectrum on MRI encompasses variable degrees and patterns of gray and
white matter changes, visual identification can be challenging, particularly when
inspecting the convoluted neocortex in two-dimensional images. Indeed, recent surgical
series indicate that up to 33% FCD type II and 87% of FCD type I [7, 8, 39] present with
unremarkable routine MRI, underlining the limited power of conventional imaging to
resolve subtle cortical dysplasia.
Gyral anomalies may be the only visible MRI sign of cortical dysgenesis. Using
automated sulcogyral morphometry, we demonstrated that 85% of small FCD lesions,
primarily those overlooked during conventional radiological inspection, are located at the
bottom of an abnormally deep sulcus [41]. Importantly, such evidence can guide the
search for migrational anomalies in patients in whom large-scale MRI features are only
mildly abnormal or absent.
Several groups have applied VBM to detect structural abnormalities related to MRIvisible FCD in single patients [16]. This fully automated image processing method, which
identifies differences in tissue density at a voxel level, detects increases in gray matter
concentration colocalizing with the lesion in 6386% of cases. Histopathological
confirmation of lesions that eluded visual inspection (despite their relatively large size)
[42] suggests that VBM may be applied to investigate patients with MRI-negative
epilepsy. Importantly, however, a threshold of 2SDs above the mean gray matter
concentration in healthy controls does not guarantee specificity of findings since, at this
threshold, false positives may occur in control subjects. Voxel-based comparison has also
been used to analyze intensities derived from quantitative MRI contrasts such as T2relaxometry, double inversion recovery, and magnetization transfer imaging. These
approaches have shown high sensitivity (87100%) in detecting obvious malformations of
cortical development [4345]. Nevertheless, these techniques may identify areas
concordant with clinical and EEG findings in less than a third of MRI-negative cases and
have low specificity [44, 46].
The relatively unspecific nature of VBM with respect to pathological characteristics of
FCD has motivated the search for computer-based models of morphological imaging
features distinctive of dysplasias. Using models of cortical thickness, blurring, and tissue
intensity derived from 3 T1-weighted images [47] and combined into a single composite
map, the sensitivity of visual identification of histologically proven FCD may be increased
up to 40% relative to conventional MRI, while maintaining high specificity [48].
Furthermore, blending these models with the quantification of high-order image texture
features that cannot be discriminated by the human eye, we were able to detect
automatically about 80% of dysplastic anomalies [49, 50]. One limitation of voxel-based
approaches is that they do not fully take into account the complex topology and are
therefore prone to volume averaging of nonadjacent cortical regions across sulci,
potentially increasing the false-positive rates. In our experience, a surface-based approach
preserving topographic anatomy is effective in detecting small lesions (Figure 3.4).
Figure 3.4 Surface-based computational models of focal cortical dysplasia. In this

patient with frontal lobe epilepsy, high-resolution 3 Tesla MRI was reported as normal,
likely because of the subtle nature of the dysplasia, as demonstrated by the coronal T1weighted MRI section (right lower corner). The upper panels display the T1-weighted
derived computational models normalized with respect to controls (z-score). The cortical
thickness map is unremarkable. Conversely, the gray matter intensity map and the gradient
map (modeling graywhite matter blurring) show significant anomalies. The composite
map identifies the lesional area as the only anomaly compared to controls. Histopathology
of the surgical specimen confirmed the presence of focal cortical dysplasia ILAE type IIb.
We have adopted this framework also for fully automated lesion detection based on
neural networks that successfully identified 89% of small FCD lesions overlooked by
experts [41].
Overall, the most relevant clinical impact of post-processing is that cases considered
MRI negative at first have been increasingly recognized as secondary to FCD type II,
particularly FCD type IIa.
Diffusion tensor imaging

Diffusion tensor imaging (DTI) makes inferences about the integrity of axon and myelin
sheaths through the analysis of passive water diffusion relative to white matter tracts [51].
In TLE, fractional anisotropy (an index of deviation of water diffusion from a random
spherical displacement) is consistently decreased in temporolimbic tracts [5254].
Nevertheless, the ability of DTI to lateralize the focus has been disappointing [55].
Notably, the conventional whole-tract approach yielding a single value per diffusion
parameter per tract reduces sensitivity for the detection of subtle focal changes. Relative to
the widespread pattern of anisotropy changes, mean diffusivity anomalies (a marker of
bulk diffusion) follow a more restricted distribution [52]. To overcome this limitation, we
measured the spatial distribution of diffusion indices along tracts carrying temporal lobe
connections and showed that the effect size of diffusivity alterations decreases as a
function of anatomical distance to the temporal lobe, suggesting colocalization with the
focus [56]. Importantly, our segmental analysis allowed us to correctly lateralize 100% of
MRI-negative TLE patients (i.e., with normal hippocampal volumes). On the other hand,
whole-tract analysis identified the epileptogenic hemisphere in only 85% of cases.
In patients with MRI-visible FCD, regions of interest [57] and whole-brain voxel-based
analyses [58] have shown abnormalities in diffusion indices in the subcortical white matter
adjacent to the malformation. Nevertheless, in some patients with no visible MRI
anomaly, focal changes may colocalize with the EEG focus [5860] (Figure 3.5).
Figure 3.5 Surface-based diffusion tensor imaging in focal cortical dysplasia. The upper
panels show the outline (in yellow) of the gray matter portion of the lesion on the apparent
diffusion coefficient (ADC) map, and on the T1- and T2-weighted MRI. Lower panels
show the mean ADC map of the immediate subcortical white matter in ten healthy
controls. In the patient, both the mean and z-score ADC maps show abnormally increased
values in the white matter below the FCD lesion. These changes indicate microstructural
abnormalities extending beyond the visible lesion.
Yet, abnormalities often extend beyond the epileptogenic region and the visible FCD
[61], highlighting the need to balance sensitivity and specificity. Moreover, the underlying
nature of diffusion abnormalities needs to be clarified, as correlative studies have been so
far limited to a single patient [62].
Magnetic resonance spectroscopy

Magnetic resonance spectroscopy (MRS) measures in vivo the concentration of
metabolites, including N-acetylaspartate (NAA), choline (Ch) and creatine (Cr). Spatially
selective excitation and refocusing pulses allow acquiring a single volume (voxel),
typically 1 to 8 cc. Alternatively, spectroscopic imaging allows collecting data from
multiple locations simultaneously. Numerous factors contribute to the advantages of
performing spectroscopy at 3 Tesla. Primarily, the stronger chemical shift at higher fields
increases the spread of individual peaks, resulting in improved spectral resolution and
identification of metabolites that were obscured at 1.5 Tesla, such as GABA and
glutamate. Also, the improved SNR increases the signal derived from each metabolite, so
that their peaks are easier to differentiate from background noise.
Decreases in NAA, a compound specific to neurons, may lateralize the seizure focus
[23] and predict surgical outcome [63] in drug-resistant TLE, thus yielding potential
clinical value. Seizure focus lateralization in patients with no visible hippocampal
sclerosis, however, has been disappointing [64]. Moreover, patients with neocortical
epilepsy often have poorly defined epileptogenic regions, posing significant additional
demands with regard to the selection of the brain region to explore, and the type of data
acquisition (single voxel versus chemical spectroscopic imaging). Nevertheless, in frontal
lobe epilepsy, MRS has provided some encouraging results [65, 66]. Using proton
spectroscopy, it is also possible to measure both in vivo GABA and glutamate, the primary
excitatory neurotransmitter in human brain. Increases in glutamate, have been observed in
association with the ipsilateral hippocampus in MRI-negative TLE [67, 68]. Due to low
signal to noise, however, attempts to measure GABA within the putative seizure focus
have produced mixed results [69, 70].
Overall, spectroscopy in MRI-negative epilepsies should be regarded as a
complimentary investigation.
Conclusion
By revealing subtle lesions that previously eluded visual inspection, quantitative image
analysis, particularly image processing of structural MRI, has clearly demonstrated
increased sensitivity compared to conventional techniques. Importantly, as advanced
image post-processing can be performed on clinical MRI yielding 3D millimetric or
submillimetric multicontrast images, they offer a substantial costbenefit. Based on our
experience and mounting evidence from the literature, we propose the term MRI-negative
be used in patients in whom both the visual inspection and quantitative image processing
analyses at 3 Tesla interpreted by an epileptologist with expertise in neuroimaging are
unremarkable.
Importantly, to date, the MRI signature of FCD type I remain imprecise. Nevertheless,
as lesions in patients with MRI considered nondiagnostic may possibly differ only slightly
from normal tissue and present unanticipated traits, future methods applied to these
cohorts should entail the design of statistical models of morphology and signal in a
multivariate framework rather than be based on the current unimodal approaches. Such
efforts, ideally refined through correlative histopathology, will help clinicians devising
better criteria to perform timely interventions that achieve seizure control, turning these
challenges into opportunities for better patient care.
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Chapter 4 PET in MRI-negative refractory focal epilepsy

Alexander Hammers
General considerations
The main role of imaging in a patient with focal epilepsy is to explore its cause. The MRI
remains the mainstay examination in this situation and allows the distinction between a
patient with surgical lesions that are able to explain the patients seizures, and MRInegative patients who do not have lesions, or only show nonspecific or incidental findings
(see Chapters 1 and 3).
Despite the availability of guidelines for MRI neuroimaging in patients with focal
epilepsies (1, 2), in clinical practice patients may be referred to as MRI-negative when
in fact expert review or repeat MRI reveal epileptogenic lesions (3). Similarly, the imaging
features of hippocampal sclerosis and focal cortical dysplasia among the most frequent
epileptogenic lesions were not well characterized until the late 1990s, and earlier studies
may have missed relevant abnormalities. In this chapter, we will whenever possible try to
include only studies of MRI-negative patients that fulfill minimum MRI quality criteria (1,
2).
Positron emission tomography (PET) is a nuclear medicine technique. Substances
labeled with a radioactive isotope, usually 18F (half-life ~2h) or 11C (half-life ~20 min),
are injected intravenously and are taken up by neurons as an energy substrate
([18F]fluorodeoxyglucose, FDG) or are bound reversibly or irreversibly to receptors. The
isotopes emit positrons which annihilate on encountering an electron in tissue, emitting
two gamma rays at ~180 of each other, which can be detected by detector crystals
arranged as rings in the PET camera and used for reconstruction of quantified tomographic
images. Static or dynamic (time course) images of radioactivity distribution in the brain
are acquired after injection. In the case of FDG, static images are generally used; receptor
studies generally require dynamic acquisition of ~1530 images or frames over 6090
minutes. Arterial plasma concentration of radioactivity or radioactivity time courses in a
region devoid of specific binding can then be used in mathematical models to derive
binding parameters. Depending on which labeled substance has been injected, glucose
metabolism (via FDG) or various receptor systems can be assessed. The FDG is by far the
most widely used radiopharmaceutical. More detailed reviews are available elsewhere
(e.g., 46).
Whatever the MRI finding, it is important to assess the PET finding with reference to
the structural anatomy, i.e., coregister MRI and PET (7, 8). Otherwise, apparent
hypometabolism or reduced receptor binding can be caused by focal atrophy or a wide
sulcus; truly reduced signal, particularly at the bottom of a sulcus, can be missed as it may
be similar to surrounding white matter (Figure 4.1).
Figure 4.1 Added value and complementarity of combined FDG-PET and MR imaging.
Example of a focal pharmacoresistant epilepsy. The FDG-PET alone does not show a
clear-cut asymmetry. The MRI alone only shows unusual gyration (arrow). The
superposition of both images following posthoc coregistration reveals a focal area of
hypometabolism, restricted to a single sulcal bottom. The patient has remained free of
seizures for 3 years so far after a focal resection restricted to this gyrus. (Data kindly
provided by F. Chassoux; Figure reproduced from reference 58.)
Another important methodological advance of the past few years has been the addition
of statistical analyses to the standard visual analysis of PET, often in the form of the
widely used statistical parametric mapping software (SPM; www.fil.ion.ucl.ac.uk/spm) or
via cortical asymmetry analyses (e.g., 9).
Various methodological pitfalls include image artefacts and presence of even only a few
subjects with abnormalities in the control group (4), different ages between controls and
patients (10), and details of quantification (11).
Blood flow PET uses H2[15O]; the half-life of 15O is ~2 minutes. Interictal scans are
unreliable, and in contrast to SPECT, ictal scans are generally impossible to obtain in
practice due to the short half-life of 15O. For the assessment of brain function, H2[15O]
PET has been all but superseded by fMRI (see Chapter 8), even if some areas of
application remain in the research setting (e.g., interest in brain areas affected by
susceptibility artefact on MRI; requirement for noiseless scans).
FDG-PET
Hypometabolism is a hallmark of the epileptogenic zone as well as surrounding areas. The
FDG-PET method has been used in epilepsy since the 1980s (12, 13), i.e., since well
before routine availability of MRI. Areas of hypometabolism are often larger than a lesion
or the epileptogenic zone, but are generally related to seizure onset zones and/or areas of
seizure spread (14). Discrepancies between FDG-PET and other investigations are
generally associated with poorer prognosis in MRI-negative temporal lobe epilepsies (15).
Detailed recent reviews are available (16).
The FDG method, with its half-life of ~2 hours, is available commercially. Thanks to
the success of FDG-PET/CT in oncology, most university hospitals with epilepsy surgery
programs will have access to FDG-PET. While FDG uptake can be fully quantified with
an arterial input function and dynamic scanning, static scans are used in clinical practice,
usually acquired for about 1015 minutes, about 3050 minutes after injection. It is
important to supervise the patient during the uptake period to minimize the risk of seizures
leading to focal hypermetabolism (13) and possibly false lateralizations. Some
recommendations include EEG during this period. This may pose logistical problems, in
particular with modern PET/CT scanners where electrodes cannot be left in place during
scanning due to artefacts when measuring attenuation with CT. In our experience, patient
observation and direct questioning about possible seizures having occurred during the
uptake period eliminates much of the risk, all the more so as seizures may not always be
clinically obvious, but may also be silent on scalp EEG. As always, imaging results should
be considered critically, in the context of all available information, and the possibility of
false lateralizations due to ictal hypermetabolism (17) should be taken into account,
particularly when using measures of asymmetry (see below).
In the context of this book, one of the most important contributions of FDG-PET,
analysed in conjunction with coregistered MRI, is the detection of occult focal cortical
dysplasia (FCD). Detecting FCD through focal FDG hypometabolism represents a step
change in MRI, changing MRI-negative to post hoc MRI-positive patients with a good
surgical prognosis (7, 8). Several series have retrospectively evaluated the contribution of
FDG-PET in cases where FCD was detected on histology. In one such series of 14 MRInegative patients, FDG-PET had been unremarkable in only three, and the degree of
completeness of resection of the abnormalities (on FDG-PET, SISCOM or intracranial
EEG) was associated with a good postsurgical outcome (55). A larger series of 62 patients
with type II FCD contained 25 with normal or doubtful 1.5T MRI findings (56). Of those
25 MRI-negative patients, FDG-PET correctly identified the location of the FCD in 21
(84%), but was negative as well in two, and falsely localizing to the orbitofrontal cortex in
another two. Of note, two FCDs were only identified after PET/MRI coregistration. The
25 MRI-negative patients had an indistinguishably good postoperative outcome (88%
Engel class I and 56% entirely free of all seizures) compared with the 37 MRI-positive
ones (94%/75%).
The FDG-PET technique may also be useful in retrospectively revealing pathology on
MRI, or by increasing confidence in the relevance of subtle possible MRI abnormalities.
In a series of 31 children with 1.5T MRI that was initially thought to be noncontributive
(57), FDG-PET showed focal hypometabolism in 21. A second reading of the same initial
MRIs in the light of the PET findings, and with both modalities coregistered, changed the
conclusion from normal MRI to subtle MR abnormalities in seven, and from subtle
changes initially considered irrelevant to probably pathological in another two.
Histological verification was only available for five patients; all had FCD.
In the context of TLE, FDG-PET has also proven useful. For example, in TLE where no
decision for or against surgery could be made based on MRI and video-EEG, FDG-PET
led to a decision in 72/84 cases (18). Whereas negative or inconclusive MRI was more
prevalent in the subgroup where PET was useful, it is important to note that surgical
outcome (63% seizure-free) for MRI-negative patients was similar to that of the entire
cohort of 302 operated patients (64% seizure-free). Several studies have underlined the
good prognosis of MRI-negative, PET-positive TLE patients (19, 20).

A peculiarity of TLE to be taken into account in the organization of epilepsy surgery
programs is that the ipsilateral hypometabolism is often clearly detectable on appropriately
oriented images by visual analysis, yet remains invisible to more objective techniques
like SPM (21). The yield of voxel-based techniques may thus be higher in extratemporal
lobe epilepsies, with the possible exception of children (22).
In addition, the presence of focal hypometabolism may be a stronger predictor of
postoperative seizure freedom than the presence of a focal MRI lesion (16, 23),
reinforcing prior studies of the usefulness of FDG-PET for predicting postsurgical
outcome in patients headed for intracranial EEG (24).
Other radioligands used clinically

Many of these radioligands come from the research arena and are labeled with 11C. As by
definition all organic molecules contain carbon atoms, 11C is very versatile for labeling a
wide range of substances by replacing one of their carbon atoms, i.e., without changing
their biological properties. In addition, radiation burden tends to be a little bit lower.
However, with its half-life of ~20 minutes, use of substances labeled with 11C is restricted
to centres with a cyclotron to produce the isotope on site.
GABAA receptors
The ligand which has perhaps found the most widespread use is [11C] flumazenil (FMZ),
an antagonist at the benzodiazepine site of GABAA receptors containing the subunits
alpha 1, 2, 3, or 5 (for a review, see 5, 25); GABA is the most important inhibitory
neurotransmitter, and epileptogenic foci are often associated with reduced [11C]FMZ
binding. Such areas of reduced [11C]FMZ binding are, as a rule, much smaller than areas
of hypometabolism seen with FDG-PET (Figure 4.2).
Figure 4.2 FMZ (left) vs. FDG (right) decreases in the same patient: FMZ abnormalities
are smaller; FMZ more clearly indicates bilateral hippocampal damage. Note both show
the same parasagittal abnormality due to the patients brain structure.
In TLE, reduced [11C]FMZ binding is correlated with hippocampal volume loss due to
partial volume effects, but clinical utility in patients without MRI abnormalities was
suggested by the fact that decreases are over and above volume loss (e.g., 26). In a review
of the literature, 45 patients with TLE and negative MRI were identified (25). Of these,
38/45 had abnormal [11C]FMZ PET scans, confirming [11C]FMZ PETs higher sensitivity
compared to MRI, and in 21/45 these abnormalities were thought to be surgically useful.
Unsurprisingly, surgical series showing data on postoperative patients showed a higher
proportion of [11C]FMZ PET scans judged useful.
In the same review, [11C]FMZ PET was also more sensitive than MRI in patients with
focal epilepsy of extratemporal origin and negative MRI (25). In total, 73/102 MRInegative patients with extratemporal seizure origin identified in the literature showed
abnormalities of FMZ binding. These were definitely surgically useful in 27/102 and
definitely or potentially useful (e.g., preventing potentially harmful further investigations)
in 54/102. Again, there was evidence of recruitment bias when comparing surgical with
nonsurgical series.
There are 18F labeled FMZ analogs which would allow more widespread use due to 18F
having a half-life of about 2 hours. However, only a handful of studies so far have used
them, albeit with generally promising results (reviewed by 16).
GABAA receptors are present on the majority of neurons. Hence, FMZ can also to an
extent serve as a neuronal marker, particularly in the white matter (see (27) and references
therein). There is a tight correlation between temporal lobe heterotopic white matter
neurons and white matter [11C]FMZ volume-of-distribution (VD). The presence of mainly
temporal white matter [11C]FMZ-VD increases in a sizeable proportion (11/18) of MRInegative TLE cases, and of mainly periventricular increases in 7/44 MRI-negative patients
with extratemporal seizure origin suggest that occult migration disturbances may be the
underlying basis for this observation in a number of these cases. The presence of
periventricular increases was associated with poorer outcome in two independent groups
of patients with hippocampal sclerosis (HS) (27, 28). Larger control groups have recently
increased the precision of surgical outcome predictions, which may now be useful for
individual preoperative counseling (28).
As [11C]FMZ binds to the benzodiazepine site of the GABAA receptor, benzodiazepines
given therapeutically will decrease the binding. The situation is less clear for other
antiepilepsy drugs having GABA-ergic mechanisms, but these considerations add an
additional constraint to using [11C]FMZ PET clinically.
Serotoninergic neurons
[11C]alpha-methyl-tryptophan (AMT), a marker of increased and/or aberrant serotonin (5HT) metabolism, has initially been used in children with tuberous sclerosis, where AMT
sometimes accumulates in the epileptogenic tuber. In a series of 27 children who
underwent FDG and AMT PET, 19 had negative MRI (29). Of those, nine had abnormal
AMT asymmetry, including two children with no or wrongly localizing abnormalities on
[18F]FDG-PET. As discussed in reference (30), all areas of increased [11C]AMT uptake
were close to the epileptogenic zone, and [11C]AMT PET was more specific, albeit less
sensitive than [18F]FDG-PET.
The Montreal group studied 18 patients, seven patients with cortical dysplasia and 11
with MRI-negative and also [18F]FDG-PET negative focal epilepsies (31); [11C]AMT PET
showed increased binding in the presumed epileptogenic zone in four of the seven patients
with cortical dysplasia, but also in three of the 11 patients with previously negative
imaging studies. Furthermore, [11C]AMT binding was positively correlated with the
number of interictal epileptiform discharges.
In another study that did not show individual patients data, at the group level, seven
unilateral TLE patients with normal hippocampal volumes showed increased [11C]AMT
binding in the ipsilateral hippocampus (32). No such group finding was seen in seven
unilateral TLE patients with hippocampal sclerosis. As stated previously (30), the lack of
correction for partial volume effects in this study means that hippocampal increases in the
sclerotic hippocampus may have been overlooked, and lack of data for individual patients
does not allow an estimation of the usefulness of the technique for presurgical evaluation.
Out of 33 mainly pediatric patients with previous unsuccessful cortectomies, ten had
focal [11C]AMT abnormalities concordant with ictal onset on EEG. Seven were
reoperated, of whom four had had negative MRI prior to the first operation. Five
(including three with previously negative MRI) became seizure-free and the other two
were improved (51).
Overall, these are promising findings in the difficult-to-treat imaging-negative group.
[11C]AMT PET may in principle have a wider clinical application. However, there are
several issues. First, whereas the specificity of increased binding for epileptogenic or
periepileptogenic cortex is high, the sensitivity in patients with negative MRI is rather
low (29, 31). Second, it is relatively hard to synthesize [11C]AMT in a reliable fashion.
Finally, the 11C isotope precludes wider distribution after centralized synthesis, meaning
that it is currently only available in three centers Detroit in the USA, Montreal in
Canada, and Lyon in France which seriously restricts its clinical use.
5-HT1A (serotonin) receptors

Receptors for serotonin (5-HT) can be visualized and quantified with several different
antagonist ligands; in epilepsy, [carbonyl-11C]WAY 100635, [18F]FCWAY, and
[18F]MPPF have been used (for an extensive review including discussion of
methodological issues, see 4]. The postsynaptic 5-HT1A receptors have a limbic
distribution. The cerebellum does not contain 5-HT1A receptors outside the vermis and is
often used as a reference region for quantification; however, the exact definition of the
reference region has an important influence on binding potential (BPND) values obtained
(33).
[18F]FCWAY may be the most difficult to use as a 5-HT1A tracer, due to defluorination,
requiring correction for spill-in from the bones, and the presence of a radioactive
metabolite which enters the brain. After correction for both, seizure onset zones in 12
patients with TLE were correctly lateralized if not localized [53]. The group included
three patients with normal hippocampal volumes. The [18F]FCWAY asymmetry indices
were greater than those for hippocampal volumes or FDG-PET (52).
[18F]MPPF was used in 53 controls and nine patients with TLE of various aetiologies
(34), who all underwent video-EEG with depth electrodes implanted because of atypical
features for mTLE. Areas of maximally reduced binding potential (BPND) corresponded to
or at least included the ictal onset zone in seven, and propagation areas in two. In all
three patients with negative MRI, [18F]MPPF PET lateralized correctly; when examined as
a group with SPM (35), the decrease in these three patients was confined to the (inferior)
temporal pole and did not include the hippocampus. Individually, SPM demonstrated
decreases in the ipsilateral temporal lobe in two of the three patients with negative MRI.
A much larger group of 42 patients with TLE of various subtypes was studied by the
same group with [18F]MPPF and parametric maps of BPND analyzed visually and with
SPM, compared with 18 controls (36). In the whole group, visual analysis was more
sensitive than SPM, but SPM detected some bilateral abnormalities or binding increases.
Insular decreases were frequently seen in addition to decreases in the epileptogenic zone.
A clustering of decreases involving only hippocampus, amygdala, and temporal pole was
seen in 16/18 patients who became seizure-free postoperatively. Only two of the seven
patients with negative MRI did not show [18F]MPPF BPND abnormalities on either visual
or SPM analysis. Visual analysis of MPPF BPND maps was concluded to contribute
surgically useful information in TLE.
Normalization by a within-subject measure typically the contralateral hemisphere
can yield very sensitive measures (e.g., 29, 37, 38). Accordingly, the voxel-based
asymmetry analyses were more sensitive than visual analysis in 24 TLE patients with
Engel class I postsurgical outcome, including in the eight with negative MRI (39).
A study using the 5-HT1A antagonist [carbonyl-11C]WAY 100635 analyzed with

regions of interest included 14 controls and 14 patients, eight with HS and six with
negative MRI (of whom four also had unremarkable FDG-PET) (40). All patients,
including those with negative MRI, had decreased ipsilateral mesial temporal binding
potential of [carbonyl-11C]WAY 100635. Again, decreases in the ipsilateral insula of
unclear clinical significance were frequently seen. These findings were replicated with
[carbonyl-11C]WAY 100635 in 13 controls and 13 patients, of whom five had negative
MRI (41).
Whereas the preceding studies generally found 5-HT1A PET useful in MRI-negative
patients, there were just two studies aimed at including MRI-negative patients only. In
one, individual data were not shown (see 4 for review). Another study included 12 patients
with TLE and negative MRI on visual inspection (three HS and one cortical dysplasia
were found postoperatively), and 15 controls (42). The [18F]FCWAY was quantified
similar to the description above. Asymmetries correctly lateralized nine of 11 patients with
unilateral foci including one with normal FDG-PET; both patients without [18F]FCWAY
asymmetries were correctly lateralized via FDG-PET asymmetries; and one patient with
bitemporal seizure onset had nonlateralizing [18F]FCWAY PET but (falsely) lateralizing
FDG-PET.
Altogether, these studies suggest that 5-HT1A receptor PET may play a role in
lateralizing TLE, particularly when other imaging modalities are nonconclusive. A caveat
is the nearly exclusive limbic binding; if the differential diagnosis is between a temporal
or occipital focus with temporal spread, 5-HT1A receptor PET is unlikely to be useful.
Other targets have been explored but have not found clinical uses (e.g., monoamine
oxidase type B binding sites as markers of astrocytes, and cholinergic receptors). Labeled
amino acid or nucleotide tracers are used in the characterization of low-grade glioneuronal
tumours. They may show increased uptake in MRI-visible focal cortical dysplasia (e.g.,
53) and might therefore conceivably show relevant abnormalities in MRI-negative cases.
However, this has not been the experience of all groups (54), and further studies would be
needed to evaluate whether these tracers have any use in MRI-negative epilepsy where the
yield would presumably be low.
Radioligands used in research

Using PET allows the pursuit of several interesting avenues in the research setting.
There are efforts to develop novel ligands, e.g., for glutamate NMDA receptors (43).
Ictal/postictal/interictal comparisons have elucidated the role of neurotransmitters in
stopping seizures, particularly the opioids (e.g., 44; review in 4), and are starting to show
differences between patients with normal MRI versus patients with hippocampal sclerosis.
Difference images were not, however, able to pinpoint the seizure onset zone in individual
patients. Cannabinoid type 1 (CB1) receptors have about a tenfold higher concentration
than opioid receptors. There is evidence that CB1 receptor availability increases focally
after seizures (45), and postictal/interictal comparisons could in principle be used similarly
to SISCOM for determining seizure onset zones (45).

There is a variety of ligands available to probe the dopamine system. Dopamine is
thought to have an anticonvulsant modulatory action (see references in 4). The
dopaminergic system has been studied in various syndromes, including some where MRI
is typically negative, e.g., autosomal dominant nocturnal frontal lobe epilepsy. Very few
patients with MRI-negative focal epilepsy in the sense of the focus of this book have
been studied, and if so, they have not been separately analyzed due to the small number of
patients in each study (46). However, recent morphological studies have uncovered that
the substantia nigra is smaller ipsilaterally to the seizure focus in TLE with and without
hippocampal sclerosis (47); so it is to be expected that MRI-negative patients would show
PET abnormalities of their dopamine system as well.
One of the major hypotheses to explain drug resistance in epilepsy is the transporter
hypothesis, postulating an increase of P-glycoprotein (P-GP) activity in the epileptogenic
focus. P-GP is a component of the bloodbrain barrier and actively removes a large
number of lipophilic molecules from the brain, including several antiseizure drugs. The
use of PET with labeled P-GP substrates has contributed to evidence for PGP action in the
epileptogenic focus (e.g., 48, 49).
Probing receptor subtypes with heterogenous distribution in the brain will not replace
the workhorse tracers with ubiquitous uptake that are able to probe the entire brain for
abnormalities during the presurgical work-up. However, such highly selective tracers offer
possibilities for investigating specific cerebral dysfunctions associated with epilepsy, such
as the possible molecular basis of memory impairment in epilepsy (4).
Case example (Figure 4.3)
Figure 4.3 Multimodal imaging in a child with pharmacoresistant epilepsy. Top: axial
slices. Top left, FDG-PET superimposed on MRI. Top middle, SPM analysis of FDG-PET.
Top right, MEG synthetic aperture magnetometry (SAM) analysis. Middle left, SPM
analysis result superimposed on to sagittal slice. Middle right, position of intracranial
depth electrodes; electrodes q and n highlighted. Bottom: extract from interictal and ictal
icEEG demonstrating seizure onset in q and n electrodes. (Data courtesy of Philippe
Ryvlin, IDEE, Lyon.)
Outlook and conclusions

The PET technique is only one of several useful techniques when MRI fails to reveal a
potentially epileptogenic lesion; FDG-PET remains the mainstay of PET investigations
and can be substantially enhanced by joint interpretation with anatomical MRI, and by
additional voxel-based analysis against a control group.
Of the other tracers, 5-HT1A tracers may be useful for lateralizing TLE, and, to a
degree, further describe the TLE syndrome. However, nonlimbic epileptogenic foci are
likely to be missed. FMZ may be useful in selected cases and has the advantage of a
widespread cortical signal, but is not widely available and performs best with invasive
quantification. AMT has low sensitivity in MRI-negative epilepsy, but may on occasion be
spectacularly useful.
Depending on the clinical situation, other investigations may be preferable over PET.
MEG is particularly useful when combined with spatial filtering techniques (50), but
requires the presence of frequent interictal spikes (see Chapter 6). Ictal SPECT or
interictalictal SPECT comparisons (e.g., SISCOM) depend on seizures that are frequent
enough (or can be provoked), tracer availability, and seizures that are long enough for
successful injection of the radioligand (see Chapter 5).
As pointed out throughout this chapter, PET requires interpretation alongside MRI
findings. This is an example of a joint indication for both imaging techniques for which
the novel technology of hybrid (simultaneous) MRI-PET may be extremely useful.
In addition, more quantitative analyses of MRI images and derived features like gray
white matter junction maps are becoming more widely available (see Chapter 3).
Combining such feature maps with PET, particularly when adding their respective
statistical comparison against control groups, should be useful and can be combined with
machine-learning techniques (e.g., 47) for automatic classification either of each voxel in
the image or of the patient into a certain category.
Acknowledgments
I am indebted to my clinical and nonclinical colleagues for the many discussions we had
over the years regarding the themes of this chapter.
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Chapter 5 Advanced SPECT image processing in MRInegative refractory focal epilepsy

Elson L. So, Terence J. OBrien and Benjamin H. Brinkmann
Introduction
The phenomenon of hyperemia at the region of the seizure focus has been known for
decades. Perfusion SPECT is utilized to image patterns of altered regional cerebral blood
flow (rCBF) for localizing the seizure onset zone. Thus far, perfusion SPECT is the only
test that could image the altered physiology of all peri-ictal states (i.e., interictal, ictal, and
postictal states).1 The alteration during the interictal state is typically one of baseline
hypoperfusion at the focus of seizure activity. In contrast, hyperperfusion transiently
characterizes ictal activity, at the longest probably for 2 to 3 minutes beyond seizure
termination. Ictal hyperperfusion switches to hypoperfusion during the early postictal
state, typically and transiently to a degree markedly less than that of interictal perfusion
(Figure 5.1).2
Figure 5.1 Graphic representation of the SPECT-detected perfusion changes

corresponding to the different states of activity at the seizure focus. (Adapted from,2 with
permission from Lippincott, Williams & Wilkins.)
The most frequently used SPECT radiotracers for peri-ictal perfusion imaging are
99mTc-hexamethylpropylene amine oxime (Tc-HMPAO), and 99mTc-Bicisate
(Tc-ECD).
Following injection of these 99mTc-linked radiotracers during a seizure for ictal studies,
they are quickly fixed to brain receptors because of their high first-pass brain extraction
rate. The SPECT images can be acquired up to 3 to 4 hours after the injection, because of
the relatively slow radioactivity decay of these 99mTc-linked radiotracers.
Compared to ictal SPECT, interictal SPECT used alone has been shown to have low
sensitivity in detecting the seizure focus. A major advancement in the use of SPECT in
epilepsy evaluation has been the development of computerized subtraction techniques for
detecting differences in perfusion patterns between the ictal state and the baseline
interictal state in the same patient,3, 4 or between the patients ictal perfusion pattern and
the pattern in normal subjects.5, 6 Both types of subtraction studies have been developed to
improve the yield of peri-ictal SPECT studies.
The purpose of this chapter is to discuss and demonstrate the role of modern SPECT
acquisition and analysis in the presurgical evaluation of patients with drug-resistant MRInegative epilepsy. Strategies for enhancing the yield of ictal SPECT studies will also be
discussed.
Subtraction SPECT techniques

Subtraction ictalinterictal SPECT coregistered to MRI
Injection of the SPECT radioisotope should be performed as soon as practically possible
following seizure onset to ensure the blood flow pattern observed represents the
characteristic increase at the seizure onset zone, rather than regions of propagated seizure
or postictal activity. For subtraction ictal SPECT coregistered to MRI (SISCOM), the
images are transferred to a workstation for processing after acquisition and reconstruction
of ictal and interictal SPECT image.4, 7 Cerebral activity is separated from extracerebral
activity by using thresholding to create a binary mask of the cerebral region and the mean
of the ictal and interictal cerebral pixel intensities are calculated. Ictal and interictal pixel
intensities are rescaled to a constant mean pixel intensity to normalize differences in tracer
uptake, retention, and decay. The interictal scan is coregistered to the coordinate space of
the ictal SPECT using a voxel intensity-based algorithm, and the interictal image is
transformed and resampled using a high-quality interpolation algorithm. The normalized
and transformed interictal SPECT images are subtracted from the normalized ictal SPECT
to produce a difference image, representing the differences in cerebral blood flow between
the two scans. The standard deviation of cerebral pixels in the difference image is
calculated, and a threshold based on the standard deviation is applied to identify the most
prominent areas of increased and decreased blood flow. Hyperperfusion (positive
difference) images are examined for ictal phenomena, while hypoperfusion (negative
difference) images are examined for perfusion decreases indicating the postictal change
from increased to decreased perfusion.
Following processing of the SPECT scans, the ictal SPECT is coregistered to a highresolution structural magnetic resonance image (MRI) of the patient, typically using an
algorithm maximizing the normalized mutual information between the two images. The
ictal SPECT image can be displayed as an overlay on the MRI to verify the accuracy of
registration. If the alignment is accurate, the thresholded hyperperfusion and
hypoperfusion images are displayed as an overlay on the MRI to identify areas of
increased and suppressed cerebral blood flow. This places a map of the physiological
changes related to the seizure in the context of the structural anatomy in the MRI. These
steps are diagrammed in Figure 5.2.
Figure 5.2. Diagram of steps in attaining subtraction ictal SPECT coregistered to MRI
(SISCOM) images.
SPM-based SPECT analysis

The SPECT images of cerebral blood flow can also be compared statistically in reference
to a population of paired scans of normal subjects. This approach has the advantage of
incorporating normal physiological variation in a statistical comparison of the ictal and
interictal SPECT scans,5, 6, 8, 9 and it has been shown to have better yield than SISCOM.
In these methods, a voxel-by-voxel estimate of normal interscan variation is constructed
from paired resting scans of normal volunteers by statistical parametric mapping (SPM).10
The differences between normalized voxel intensities in the paired ictal and interictal
scans of the patient are compared to the population of paired normal resting scans, thus
generating a three-dimensional volume of t-statistics. Positive (hyperperfusion) and
negative (hypoperfusion) thresholds are then applied to identify statistically significant
perfusion changes. Because of the limited spatial resolution of SPECT imaging, a voxel
cluster threshold corresponding to the spatial resolution of the imaging system is also
applied to remove activations due to noise.9 These steps are diagrammed in Figure 5.3.
Figure 5.3 Diagram of steps in attaining statistical ictal SPECT coregistered to MRI
(STATISCOM) images.
Yield of SISCOM in MRI-negative epilepsy

It is widely accepted that the greatest value of ictal SPECT in the presurgical evaluation of
patients with drug-resistant epilepsy is when the MRI is negative, or when it shows either
a large lesion or multifocal lesions.11 In such cases, identifying a focal region of ictal
perfusion abnormality, particularly with the use of subtraction techniques and MRI
coregistration, can localize the seizure onset zone and provide a target for implantation of
intracranial electrodes or surgical resection.12 However, only few studies have specifically
evaluated the yield of ictal SPECT in MRI-negative refractory epilepsy. In our initial study
of the clinical utility of SISCOM, 26 of the 51 patients with drug-resistant temporal or
extratemporal epilepsy had negative MRI. The SISCOM images in 92% (24/26) of the
patients were judged to be localizing by blinded reviewers.13
In our subsequent series of 44 patients who underwent surgery for MRI-negative
temporal lobe epilepsy, 33 had SISCOM studies, of which 82% (27/33) were localizing.
The presence of a SISCOM abnormality localized to the resection site was found to be
significantly associated with postsurgical seizure-free outcome. Other factors associated
with the outcome were the absence of contralateral or extratemporal interictal epileptiform
discharges, and the presence of subtle nonspecific MRI findings at site to the resection.14
We have also evaluated the usefulness of SISCOM in the presurgical evaluation of
patients with MRI-negative extratemporal epilepsy. The SISCOM images were
determined to be localizing by blinded reviewers in 77% (13/17) of the patients.15
Concordance of the SISCOM localization with the site of surgical resection was associated
with a significantly better chance of excellent postsurgical outcome with respect to
seizures, compared with those in whom the images were either nonconcordant or
nonlocalizing (55% vs. 0%, p < 0.05). Moreover, the extent of resection of the region of
primary cortical ictal hyperperfusion was predictive of postsurgical outcome. A
subsequent study from our center shows that SISCOM was localizing in 68% (58/85) of
the patients with MRI-negative extratemporal epilepsy.16 However, only 24 patients
eventually underwent resective surgery, and no presurgical clinical factor or test result was
found to be statistically associated with postsurgical outcome; 38% (9/24) were still
seizure-free after 10 or more years after their surgery.
A more recent study shows that in 58% (74/130) of drug-resistant temporal or
extratemporal epilepsy patients, SISCOM yielded results that permitted consideration for
surgical resection or intracranial electrode implantation.11 Half of these patients had
negative MRI. However, only 38% (28/74) of these patients eventually underwent
resective epilepsy surgery, ten of whom had negative MRI. Six of these ten patients had
postsurgical seizure freedom. In another study, SISCOM was localizing in 93% (13/14) of
the patients who had histologically proven cortical dysplasia but negative MRI.17
Yield of SPM-based subtraction SPECT in MRI-negative

epilepsy
The use of normative dataset, against which ictal SPECT data are analyzed by SPM to
discern seizure onset activity and location, could theoretically obviate the need for
interictal SPECT study. Using this method set at a high threshold of p < 0.001, Lee and
colleagues reported that hemispheric lateralization of the epileptogenic focus was correct
in approximately 60% of their 21 temporal lobe epilepsy patients.18 (Focal or regional
localization was not investigated.) The reason for the modest yield could be that when the
seizure onset zone is interictally hypoperfused, seizure activity at the zone may increase
perfusion only to a level at or near that of control subjects in the normative dataset. The
SPM analysis then detects little or no difference between the degree of ictal perfusion of
the patient and the degree of perfusion in the normal control dataset at the corresponding
zone. In the same study, Lee and colleagues also analyzed with SPM the difference data
from ictalinterictal subtraction. However, this method did not increase the sensitivity of
detecting the epileptogenic zone.
Amorim and colleagues conducted a study similar in principle to that of Lee and
colleagues study.19 Amorim and colleagues found that SPM comparison of ictal studies
with normal control data detected the ictal onset zone in 64% of their 22 patients, even
when the sensitivity threshold was set low at p value of < 0.05. The yield was improved to
77% when SPM analysis was applied to ictalinterictal subtraction data. However, either
method fared lower than their visual review of ictal and interictal scans, which observed
the epileptogenic focus in all patients.
The method of ictalinterictal SPECT analyzed by SPM (ISAS) was used to analyze
data from ictal or postictal Tc-HMPAO injections in 28 studies of mesial temporal
epilepsy and 19 studies of neocortical epilepsy.9 Analysis of the ictal injection studies had
a sensitivity of 93% and specificity of 87% in localizing the epileptogenic temporal lobe,
whereas the analysis for localizing the neocortical epileptogenic zone had a sensitivity of
77% and specificity of 93%. On the other hand, ISAS analysis of postictal injection
studies was poor for localizing the seizure onset zone, but lateralization to the hemisphere
of seizure onset was correct in approximately 80% of the studies. These favorable rates
should be appreciated in the context of well-localized epilepsy; because all mesial
temporal epilepsy patients in the report had lesional epilepsy (the proportion of lesional
epilepsy in the neocortical group is unreported). With few exceptions, patients in Lee and
colleagues and Amorim and colleagues reports also had lesional epilepsy.18, 19 A study
using a method similar to ISAS has already demonstrated high yields in lateralizing the
epileptogenic zone in epilepsy with mesial temporal sclerosis.20 In the study, ictal
interictal difference SPECT analysis of the hippocampus subregion by SPM achieved
correct lateralization in 91% of the patients, and 87% with analysis of the amygdala
subregion. These rates were comparable with the yield of MRI in these patients, which
was 89% for FLAIR and 78% for volumetric abnormalities. However, all foregoing
studies have not demonstrated the usefulness of SPM-based ictal SPECT in nonlesional
refractory epilepsy. Peri-ictal perfusion characteristics at lesional seizure onset foci should
not be presumed to be identical to those at nonlesional foci.
The foregoing SPM-based studies consisted mostly of patients who had responded to
epilepsy surgery. Patients who were not ideal surgical candidates were mostly excluded
from the reports, such as those with indeterminate or multifocal seizure onsets. In clinical
practice, patients undergoing epilepsy surgery evaluation include those who are good
surgical candidates such as the subjects in these studies, as well as those who are not.
Patients who had prior nonlocalizing or conflicting data are the ones who most need
functional imaging studies such as peri-ictal SPECT. It should also be noted that seizures
with secondary generalization were excluded from the ISAS study.9
Thus far, statistical ictal SPECT coregistered to MRI (STATISCOM) is the only SPMbased method of ictalinterictal subtraction SPECT using normative data that has been
shown to be useful in both MRI-positive and MRI-negative refractory epilepsies.6 Blinded
reviewers in a study compared STATISCOM with SISCOM in 87 consecutive temporal
lobe epilepsy surgery patients who were enrolled in the study regardless of their
postsurgical outcome. The agreement between reviewers was better with STATISCOM
than with SISCOM (kappa score of 0.81 vs. 0.36) A hyperperfusion focus was detected by
STATISCOM in 84% of the patients and in 66% by SISCOM (p < 0.05). The
STATISCOM correctly distinguished between mesial and lateral neocortical temporal
epilepsy in 68% of the patients, compared with only 24% by SISCOM (p = 0.02). The
superiority of STATISCOM over SISCOM in this regard was also demonstrated in the
subgroup of 35 patients with MRI-negative epilepsy (80% correct with STATISCOM
versus 47% with SISCOM; p = 0.04). Correct localization by STATISCOM within mesial
vs. lateral neocortical subregion was associated with 81% postsurgical seizure freedom,
whereas indeterminate subregional localization was associated with postsurgical seizurefree rate of 53% (p = 0.03). This association between subregional localization and surgical
outcome was not present in SISCOM studies. The findings indicate that the epileptogenic
zone is more accurately identified when a very focal subregional SPECT abnormality is
detected, than when an abnormality is regional or undetectable, and that STATISCOM is

better suited for detecting focal subregional temporal lobe abnormalities.
A subsequent study compared STATISCOM, ISAS, and SISCOM in 21 patients who
had standard anterior temporal lobectomy for refractory MRI-negative epilepsy.21 All
patients had no potentially epileptogenic lesions on their MRI studies that had been
optimized for detecting the lesions. Radiotracer used in this study was Tc-ECD, and all
injections were ictal with a mean latency of 26 seconds after seizure onset. Normative
perfusion data were derived from 30 control subjects who each had two SPECT studies
performed. The two scans on each control subject were performed on different days. Both
hyperperfusion and hypoperfusion maps were generated with threshold set at p value of <
0.001 for ISA, and < 0.027 for STATISCOM. Three reviewers of the studies were blinded
to all other clinical and laboratory data, and each type of SPECT study was assessed
without knowledge regarding the other types of studies. Localization was concordant with
the resected site in 71% of the patients with STATISCOM, 67% with ISAS, and only 38%
with SISCOM (Figure 5.4). The localization rates were not statistically different between
STATISCOM and ISAS, but either method was significantly better than SISCOM (both p
< 0.001). Kappa score for interrater agreement was 0.82 for STATISCOM, 0.70 for ISAS,
and 0.20 for SISCOM. Moreover, the reviewers mean confidence rating was also
significantly higher with either STATISCOM or ISAS than with SISCOM (2.94 and 2.92
respectively, vs. 1.89; p < 0.001).
Figure 5.4 (a) STATISCOM and (b) ISAS showing similar hyperperfusion (redorange)
temporal hyperperfusion focus, whereas (c) SISCOM does not show the abnormality.
(Blue foci are nonlocalizing hypoperfusion changes.)
The STATISCOM, ISAS, and SISCOM methods were also compared in a separate
study of MRI-negative refractory extratemporal epilepsy (personal communication).
Similar to findings in MRI-negative temporal epilepsy, interobserver agreement between
blinded reviewers was better for STATISCOM or ISAS than for SISCOM (0.66, 0.44 vs.
0.36). Rate of detecting a hyperperfusion focus was also higher with STATISCOM or
ISAS than with SISCOM (90%, 92% vs. 62%). In seizure-free patients, the rate of
concordance between the focus and resection was also superior for either STATISCOM or
ISAS than SISCOM (80%, 77% vs. 47%).
Techniques for optimizing yield of SPECT

The rapidity of SPECT radiotracer uptake is generally considered the advantage of SPECT
imaging over other functional imaging tests, because when the radiotracer is injected very
soon after seizure onset, the focus of maximal radiotracer uptake may represent the seizure
onset zone. However, if the radiotracer injection is delayed, the radiotracer uptake pattern
may represent seizure propagation pathways or destination, giving rise to false
localization. Prompt radiotracer injection is aided by presence of reliable epileptic auras,
obvious early clinical or EEG manifestations of seizures, and absence or delayed seizure
spread. Seizure generalization consistently diminishes the yield of peri-ictal SPECT for
seizure localization.22 Moreover, seizures in some patients have short duration, especially
extratemporal-onset seizures. In which case, the radiotracer may be injected postictally
rather than ictally.23 The yield of postictal SPECT is less than that of ictal SPECT.12 Table
5.1 shows the techniques for optimizing yield of ictal SPECT studies for seizure
localization.
Table 5.1 Techniques for optimizing yield of ictal SPECT studies
A. Preparation for radiotracer injection

1. Test for pregnancy
2. Place patient in room closest to the video-EEG or nurse
station
3. Allow family or friends who could recognize seizure onset to
stay in the room to help raise alarm with staff when seizure
begins
4. Establish indwelling intravenous access for injecting
radiotracer or rescue antiseizure medications
5. Taper antiepileptic drugs, unless seizures are daily
6. Record seizures, to assure that seizure-type of interest have
begun to occur
7. Review with staff the clinical and EEG features of recorded
seizures, to facilitate prompt recognition of seizure onset
8. For patients with nocturnal seizures, sleep deprive at night
and allow sleep in daytime
9. If seizure occurrence is frequent, have staff sit by patient,
with radiotracer ready, especially if seizures are brief
B. Postinjection measures
1. Confirm with patient and family that the seizure injected is
typical of habitual seizures
2. Consider giving antiseizure medication to control seizures
3. Continue video-EEG monitoring to establish that seizures
have not recurred for ideally 24 hours, before subsequent
interictal SPECT injection
C. Interpretation of results
1. Process and review data for both hyperperfusion and

hypoperfusion changes, regardless of timing of injection
2. Interpret SPECT images with consideration of timing of
injection relative to video-EEG evidence of seizure initiation
and progression
3. Localize seizure onset with integration of clinical information
and other test data
4. Coregister SPECT images with images of other tests on threedimensional MRI brain image for evaluation of their
concordance, and their relationship to eloquent cortex
Case example
A 21-year-old right-handed man had afebrile unprovoked seizures since 15 months of age.
Seizures in the first decade of life consisted of staring and unresponsiveness to verbal
communication occurring for a few seconds, but up to 50 times a day. Since 10 years of
age, seizure manifestations had been noted as preferentially nocturnal sleep-related brief
attacks of stiffening and jerking of the right extremities. However, these seizures have
later been described as tingling all over the body, followed by unresponsiveness and
observed pupillary dilatation, rocking motion of the torso, and flailing of all extremities.
Each seizure was reported to last only 15 seconds at the longest, with only 25% of the
seizures reported to occur at night. Multiple antiepileptic medications had failed to control
his seizures, including phenytoin, primidone, carbamazepine, and topiramate.
Neurological examination showed mild mental retardation but no other abnormalities.
Neuropsychological evaluation revealed full scale IQ of 80, verbal IQ of 88, and
performance IQ of 75. Relative compromise of phonemic fluency and complex problemsolving skill was thought to be consistent with left anterior brain dysfunction.
Epilepsy protocol brain MRI showed no lesion. Interictal EEG recording disclosed left
frontotemporal epileptiform discharges. Video-EEG monitoring recorded multiple
episodes of sudden arousal from sleep and violent rocking to-and-fro of the torso with
flailing of all extremities, each episode lasting about 20 seconds. There was mild postictal
confusion, which lasted for a little over 1 minute. The EEG during seizure onset showed
sudden appearance of muscle and movement artifacts from a background of sleep activity,
and no discernible seizure discharge.
A Tc-ECD was injected 7 seconds after the termination of a 19-second typical seizure.
The SISCOM analysis showed left lateral frontal convexity focus of hyperperfusion (see
Figures 5.5 a and b). The focus was subsequently confirmed, by a total of 44 contacts of
the subdural grid and strip recording, to be concordant with the EEG seizure onset zone.
Electrocortical stimulation of the contacts showed that the expressive speech area was
superior and posterior to the SISCOM focus and the ictal onset zone. Subsequent resection
of the SISCOM and ictal EEG onset regions was followed by seizure freedom while still
taking antiepileptic medications for more than 5 years.
Figure 5.5. (a) Coronal view of hyperperfusion focus detected by subtraction ictal
SPECT coregistered to MRI (SISCOM) in a 21-year-old patient with MRI-negative
refractory epilepsy. Subdural EEG recording confirmed the SISCOM focus to be the ictal
onset zone, resection of which rendered the patient long-term seizure freedom; (b) sagittal
view.
Role of ictal SPECT in delineating the surgical focus

The SISCOM technique, but not STATISCOM nor ISAS, has been compared with PET
and MEG. Few epilepsy centers have access to all three functional imaging modalities of
PET, SISCOM, and MEG for use in evaluating epilepsy surgery candidates. Comparison
of these three modalities by one such center in 27 temporal and extratemporal epilepsy
patients whose MRI had no potentially epileptogenic focal lesion revealed that SISCOM
had a predictive value for postsurgical seizure freedom, with an odds ratio of 9.1 (p =
0.05), vs. 4.9 for PET and 5.6 for MEG (both p > 0.05).24 Another study in children with
MRI-negative epilepsy showed that either SISCOM or MEG had better concordance with
the intracranial EEG findings than SPM PET (79% with either vs. 13% with SPM PET).25
Nonetheless, the complementary role of each imaging modality was emphasized, because
patients often had positive findings on one or some modalities, but not on others. In the
few patients who had concordant positive findings of all three modalities, the predictive
value for intracranial seizure localization and for postsurgical seizure control was
exceptionally high. Another study had demonstrated in MRI-negative patients that when
there was concordance among interictal scalp EEG, ictal scalp EEG, PET, and SISCOM,
80% of the patients gained postsurgical seizure freedom; whereas the rate was only 45%
when only two modalities were concordant.26 Postsurgical seizure freedom in children
was also associated with better concordance of the functional imaging study results than
those not seizure-free (concordance score of 4.7 vs. 3.9).25
Nonconcordance of the ictal SPECT findings with the epilepsy history, seizure
semiology, or with other laboratory modalities should suggest the possibility of false
localization, especially due to seizure propagation by the time the radiotracer was binding
to brain receptors. More frequently than not, intracranial EEG recording is needed in MRI-
negative epilepsy to confirm the ictal onset zone, even when ictal SPECT demonstrates an
abnormal focus. The ictal SPECT focus may underrepresent or overrepresent the ictal
onset zone that needs to be resected.27 Intracranial electrode implantation also permits
mapping for identifying eloquent cortex, especially in neocortical epilepsy. When safety
permits, complete resection of both the ictal EEG- onset zone and the SPECT abnormality
is associated with better postsurgical outcome. In few instances, intracranial electrode
implantation and recording may be obviated when the contemplated extent of safe
resection already includes the ictal SPECT abnormality, such as with standard temporal
lobectomy on the hemisphere nondominant for language and memory function.
Conclusion
Advanced subtraction SPECT imaging with statistical comparison against normative
control data improves the yield of ictal SPECT in MRI-negative refractory epilepsy. The
SISCOM, ISAS, and STATISCOM methods have been demonstrated to be useful for
evaluating either temporal or extratemporal MRI-negative refractory epilepsy, but both
STATISCOM and ISAS are superior to SISCOM by convincing margins.
The abnormal SPECT focus is relevant to the type of seizure during which the
radiotracer was injected. This principle is important in patients with multifocal seizures or
concomitant nonepileptic spells. Therefore, effort should be made to confirm that the
seizure corresponding to the SPECT study is representative of the patients habitually
disabling epileptic seizures.
Ictal SPECT study results should be applied in epilepsy surgery evaluation only in the
light of other data such as the clinical history, seizure semiology, electrophysiologic, and
functional imaging result. The concordance of multimodal evidence of seizure location is
especially important in MRI-negative epilepsy. More often than not, intracranial EEG
recording is needed to confirm and better delineate the focus for safe surgical resection.
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SPECT coregistered to MRI (SISCOM) in presurgical evaluation of epilepsy. Epilepsia
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16. Noe K, Sulc V, Wong-Kisiel L, et al. Long-term outcomes after nonlesional
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17. Kudr M, Krsek P, Marusic P, et al. SISCOM and FDG-PET in patients with nonlesional extratemporal epilepsy: correlation with intracranial EEG, histology, and
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Chapter 6 MEG and magnetic source imaging in MRInegative refractory focal epilepsy
Koji Iida, Akira Hashizume and Hiroshi Otsubo
Introduction
Magnetoencephalographic (MEG) data have been used in determining the location of
epileptic foci and eloquent brain function in patients with demonstrable lesion-related
focal epilepsies.1, 2 Magnetic source imaging (MSI) involves the superimposition of
locations of brain activity, measured by MEG, on to MR images;35 MSI can delineate the
somatosensory cortex for purposes of preoperative assessment.5 For presurgical epilepsy
evaluation, MSI can locate the source of an epileptic spike as an equivalent current dipole
(ECD) and predict the epileptic zone in patients with refractory epilepsy with lesions.1, 2,
6, 7 A single spike dipole from an MEG spike cannot determine the spatial extent of the
epileptic zone because the model represents the center of activation by a point source
rather than the area of activated cortex.8 Previous studies have characterized distributions
of MEG spike dipoles with respect to results from intraoperative electrocorticography
(ECoG) and intracranial EEG (icEEG) data.2, 7, 9 A single MEG cluster, the localization of
which was within and extended from areas of MRI-defined cortical dysplasia and at
margins of tumors or cystic lesions, correlated highly with that of the ictal onset zone.2, 7,
10 Further, failure to resect the brain region containing the MEG cluster (e.g., eloquent
cortex) leads to postoperative seizure recurrence.1
This chapter describes characterization of MEG spike dipoles and discusses the
combination of other modalities in patients with MRI-negative focal epilepsy, and various
types of algorithm for analyzing MEG data.
MEG predicts outcome following surgery for MRI-negative

refractory epilepsy
The outcome following epilepsy surgery in patients with normal brain MRI depends on
the case selection criteria and expertise of the epilepsy center. There is no accurate
estimate of the prevalence of normal MRI findings in patients with refractory epilepsy
who are potential surgical candidates. The probability of excellent postsurgical outcome
following nonlesional surgery is uniformly lower than lesional surgery across many
studies in the literature. In a recently published meta-analysis,11 only 3445% of patients
with nonlesional MRI were seizure-free after epilepsy surgery. In patients with temporal
lobe epilepsy, the odds of being seizure-free after surgery were 2.7 times higher in those
with lesions. In patients with extratemporal epilepsy the odds were 2.9 higher in those
with lesions.
Smith et al.12 reported the extent of the MSI focus resection associated with surgical
outcome in 20 patients with nonlesional extratemporal lobe epilepsy. Eight of ten patients
became seizure-free when their nonlesional extratemporal MSI focus was extensively
resected, versus one of ten when the focus was partially or totally unresected. Knowlton et
al.13 showed that the positive predictive value of MSI was 90% and the negative
predictive value was 44% for successful short-term surgical outcomes in patients with
extratemporal and mesial/lateral temporal lobe epilepsies. The subjects included those
with nonlocalizing MR abnormalities or ambiguous abnormalities, e.g., large, multiple,
subtle, or questionable lesions. In one series of 22 children with normal or nonfocal MRI
findings and resective surgery,14 17 (77%) children achieved a good postsurgical outcome
(defined as Engel class IIIA or better), which included eight (36%) seizure-free children.
All children with postsurgical seizure freedom had an MEG cluster in the final resection
area. Postsurgical seizure freedom was obtained in none of the children who had bilateral
MEG dipole clusters or only scattered dipoles. They concluded that the presence of a
MEG dipole cluster confined to the resection area was a prerequisite for postsurgical
seizure freedom, and the absence of the MEG dipole cluster, the presence of bilateral
MEG dipole clusters, or scatters may not indicate the precise epileptic network to resect.
The MEG was able to differentiate two epileptic foci as independent clusters of MEG
spike dipoles within the right frontocentral region in an MRI-negative adolescent with
simple partial seizure with secondary generalization.15 Distribution of MEG spike dipoles
have been classified according to their number and density in neocortical epilepsy.7
Clusters consisted of six or more spike dipoles with < = 1 cm between adjacent dipoles,
whereas scatters consisted of fewer than six spike dipoles regardless of the distance
between dipoles, or spike dipoles with > 1 cm between dipoles regardless of the number of
dipoles in a group (Figure 6.1). The extent of distribution of MEG dipoles can be
classified into focal, regional, hemispheric, or multifocal. The density of MEG spike
dipoles can be described as cluster or scatter. Both the distribution and the density of the
MEG spike dipoles play a role in understanding epileptic networks. Oishi et al.9 reported
similar results in 20 neocortical epilepsy patients, including four MRI-negative patients.
They found that a single MEG cluster is predictive of a seizure-free outcome. Ten of 14
patients with single clusters became seizure-free after the resection of the ictal onset zone
on icEEG, in comparison with one of six patients with multiple MEG spike clusters (p =
0.049). More single clusters (nine of 14) coincided with the ictal onset zone than multiple
clusters (none of six) (p = 0.014). Conversely, association between postsurgical outcome
and MRI findings was not significant; postsurgical seizure freedom occurred in eight of 13
patients with a single MRI lesion, one of four patients with no lesion, and two of three
patients with multifocal lesions. Although the MEG single cluster has been a predictive
factor for good postsurgical outcome, concordance between EEG and MEG localization is
also essential to accurately localize the epileptic focus;9,14 MEG data can also provide
critical information in the placement of intracranial electrodes.16
Figure 6.1 Three-dimensional rendering MRI with equivalent current dipoles (ECD). A
39-year-old female had daily seizures consisting of jitteriness-like movements in the
extremities and facial grimacing, lasting 510 seconds in duration. MRI did not show any
abnormality. The regional clustered MEG spike dipoles (red squares with tails) are
localized in the right frontotemporal regions. The regional scattered MEG spike dipoles
are localized in the posterior temporal and central head regions. Red squares indicate
locations of ECDs and tails represent moment of ECD. Yellow circle represents
somatosensory evoked field. Green circle represents auditory evoked field with 1 kHz tone
burst. After intracranial video-EEG monitoring, she underwent resection of frontal lobe
and anterior part of lateral temporal region including ictal onset zone and active interictal
zone. White line indicates the posterior border of the resection. The regional clustered
MEG spike dipoles were completely resected. She has been seizure-free while taking
antiepileptic medications for 15 months after surgery. Histopathological finding was
reported as normal.
In cases where MEG shows scattered dipoles in neocortical epilepsy, various
possibilities such as focal or multifocal epileptic networks may underlie this finding.
There are very few papers reporting patients with scattered MEG dipoles in surgical series
of neocortical epilepsy.7, 14 Postsurgical seizure freedom was obtained in no children who
had normal or nonfocal MRI findings and only scattered dipoles.14 In two children who
had a neocortical lesion and only scattered MEG dipoles, they achieved seizure freedom
after cortical excisions and multiple subpial transections over the entire scattered dipoles
area where icEEG colocalized the epileptic zones.7 When scattered MEG dipoles are
found in neocortical and MRI-negative epilepsy, repeat MEG studies may help to show
clustered MEG dipoles correlating with active epileptiform discharges on EEG. Further
studies are needed to to understand the implications of scattered dipoles in MRI-lesional
and MRI-negative epilepsy surgery patients.
Complementary use of MEG and other noninvasive

modalities for localizing an epileptogenic zone
The findings of MEG are often compared with neuroimaging modalities, rather than with
the electrophysiologic findings from scalp video-EEG recordings. In a subset of MRIpositive cases, MEG spike dipoles are expected to localize the epileptogenic zone, and the
dipoles may asymmetrically surround the epileptogenic lesion.2 In contrast, MEG spike
dipoles in MRI-negative cases have no landmark of a lesion with which to associate.
Therefore, peri-ictal SPECT and subsequent subtraction image coregistered to MRI
(SISCOM), and 2-deoxy-2-(18F)fluoro-D-glucose PET (FDG-PET) have been applied for
comparison with the MEG results in MRI-negative cases.
Seo et al.17 compared lobar localizing values among MEG, SISCOM, and statistical
parametric mapping (SPM) analysis of FDG-PET in MRI-negative pediatric epilepsy
patients. In 14 children with MRI-negative surgery, 7 (50%) were seizure-free after
surgery; MEG (79%, 11/14) and SISCOM (79%, 11/14) showed significantly greater lobar
concordance with icEEG than SPM-PET (13%, 3/14) (p < 0.05).
Schneider et al.18 compared the localization value of SISCOM and MEG in MRInegative focal epilepsy. They screened 54 MRI-negative surgical candidates and selected
14 consecutive patients (1053 years) to compare MEG and SISCOM data with the
icEEG-based resection area. Their determination of the MEG seizure localization was the
result of an equivalent current dipole model that required a minimum of five MEG spikes
for localization. The SISCOM data were transformed into a Z score using the mean and
standard deviation of the differences in all brain voxels.19 They used a Z score of 2 for
determining SISCOM-based seizure localization. The MSI and SISCOM data were
compared with icEEG results with respect to four regional concordance categories as
sublobar, lobar, multilobar, or nonlocalizing. Sublobar concordance of icEEG and
MEG, and complete focus resection was found in five (36%) of the 14 patients: four
(80%) became seizure-free. Sublobar icEEG-MSI concordance and complete focus
resection significantly increased the chance of postoperative seizure freedom (p = 0.038).
In contrast, only four of the six (67%) patients with sublobar concordant icEEG and
SISCOM and complete focus resection became seizure-free (p = 0.138). They concluded
that MEG was more advantageous compared to SISCOM in predicting seizure-free
epilepsy surgery outcome when sublobar concordance with icEEG was observed in MRInegative focal epilepsy.
Widjaja et al.20 reported complimentary use of FDG-PET and MEG to improve
detection of the epileptogenic zone in localization-related pediatric epilepsy with normal
or subtle changes on MRI. They evaluated the sensitivity, specificity, positive, and
negative predictive values of lobar localization of MEG, FDG-PET, FDG-PET+MEG
(defined as both of two tests concordant with the icEEG-based resection area), and FDGPET/MEG (defined as one or both tests concordant with the resection area) in 22 children
who underwent cortical resection. Fourteen of 16 patients with a MEG cluster concordant
with cortical resection achieved postoperative seizure freedom, whereas ten of 15 patients
with FDG-PET concordant with cortical resection were seizure-free postoperatively; MEG
had higher sensitivity and specificity (85.0% and 99.1%, respectively) relative to FDG-
PET (65.0% and 95.4%, respectively). FDG-PET+MEG had reduced sensitivity but
increased specificity (55.0% and 100%, respectively) relative to individual test. In
contrast, FDG-PET/MEG had increased sensitivity but reduced specificity (95.0% and
93.5%, respectively. In MRI-negative epilepsy, concordant results of MEG and FDG-PET
suggested the location of the discrete epileptogenic zone, with good probability of
excellent seizure outcome when both abnormal foci are resected (Figures 6.1 and 6.2). The
two investigations were complementary in the assessment of children with localizationrelated epilepsy, particularly when one test was nonlocalizing or nonconcordant.
Figure 6.2 FDG-PET coregistered on to axial MRI. FDG-PET shows hypometabolism

in the right frontal and temporal lobes, corresponding to the regional clustered MEG spike
dipoles in Figure 6.1.
In a subset of patients with MRI-negative focal epilepsy, results of MEG can prompt
the re-evaluation of the MRI review to improve the identification of structural brain
lesions on MRI. Funke and colleagues21 re-evaluated the MRI after MEG data became
available in 29 patients with suspected neocortical epilepsy. In 7 (24%) patients, MEGguided review of MRI led to recognition of clear, but previously unidentified, lesions;
MEG can be a useful adjunct to MRI for the identification of structural lesions in MRInegative focal epilepsy. Currently available advanced techniques and modalities of MRI
have become more relevant for detecting subtle lesions adjacent to the MEG spike dipoles
in cases with previously diagnosed MRI-negative epilepsy.
Who are the patients most likely to benefit from MEG?

The MEG studies in extratemporal neocortical epilepsy had higher yields than did studies
in patients with mesial temporal lobe epilepsy.14,22
In patients with frontal lobe epilepsy, the presurgical evaluation, and even the diagnosis,
may be compounded by poor electroclinical localization, due to the rapid propagation of
the EEG epileptiform and seizure discharges. Ossenblok and colleagues23 have analyzed
the epileptogenic localizing value of interictal MEG and simultaneous scalp EEG spikes
by systematically using automated analysis procedure in 24 patients with frontal lobe
epilepsy, including two patients with MRI-negative epilepsy. Interictal spikes were more
abundant in MEG than those in the EEG recordings. Cluster analysis of MEG spikes
followed by dipole localization was successful (n = 14) for twice as many patients as for
EEG source analysis (n = 7). They concluded that the localizability of interictal MEG
spikes in frontal lobe epilepsy was more robust than that of interictal EEG spikes. In a
case study with atonic seizures due to the MRI-negative frontal lobe epilepsy,24 MEG
identified the original and propagated sources of MEG spike despite bilaterally
synchronized EEG spikes. Akiyama and colleagues25 similarly reported that MEG
identified the leading spike dipole in a patient with cortical myoclonus and epileptic
spasms secondary to a left frontal lesion. There are several reasons for the spatial and
temporal resolution differences between EEG and MEG, and for explaining why MEG is
able to distinguish the original spike sources among synchronously projecting and/or
propagating discharges in neocortical epilepsy, especially in frontal lobe epilepsy: (1) a
standard international 1020 system EEG, with fewer sensors compared with the wholehead MEG sensor positions, may have insufficient spatial sensitivity to detect minor
activation at the onset of spike; (2) the spatial distribution of MEG sensitivity over a
minimum 3 cm2 across the fissure26 is estimated to be smaller than that of EEG, which
requires > 6 cm2;27 (3) temporal resolution of MEG is superior to conventional 19-channel
scalp EEG in detecting the beginning of an interictal spike in the fissural cortex. After an
interictal spike at a small area in the fissural cortex has spread to a wider area including
the crown of the gyrus, the EEG may remain negative, or bilateral frontal spikes may
sometimes appear, after the peak of the MEG spike.28
Otsubo and colleagues29 proposed the existence of a syndrome of malignant Rolandic
Sylvian epilepsy (MRSE), in contrast to benign Rolandic epilepsy (BRE). The MEG
differentiated the characteristics of spike discharges between MRSE and BRE; MRSE
features consisted of: (1) fronto-centro-temporal spikes on EEG; (2) refractory
sensorimotor seizures; (3) MRI-negative; (4) neurocognitive deterioration; (5) MEG spike
dipoles randomly oriented and located around the RolandicSylvian fissures. Resective
surgery based on MEG spike dipoles and icEEG can control the refractory epilepsy in
MRSE. The MEG localized another type of nonbenign RolandicSylvian spike dipoles in
18 patients with atypical benign focal epilepsy (ABPE). The ABPE showed bilateral
MEG spike dipoles around the RolandicSylvian fissures. These children may have
continuous spikes and waves during sleep. Also, these children may need to switch from
carbamazepine to ethosuximide to improve control of the multiple types of seizures which
may include drop attacks, motor seizures, epileptic negative myoclonus, absences, and
focal myoclonic seizures.
Paetau and colleagues31 observed that MEG is able to localize the epileptic discharges
from the deep sulci, such as the Sylvian fissure. The MEG method records perpendicularly
oriented magnetic fields generated by intracellular currents, whereas EEG preferentially
records radially oriented electrical fields of extracellular currents. The palisading neurons
in the wall of RolandicSylvian interhemispheric fissures and deep sulci tangentially
project the magnetic field to the brain surface and scalp to be detected by MEG.32, 33
Deep-seated neuronal activities in the deep sulci are not detected by scalp EEG. The
extracellular currents radially projected from the brain surface obscure the deep-seated
neuronal activities for EEG detection. The MEG signal, however, is reduced in inverse
proportion to the square of the distance between the sensor and the current source.
The MEG showed showed regional differences in the sensitivity for detecting epileptic
spikes: preferential regions with a high detection rate of electrocorticography-associated
MEG spikes were fronto-orbital (100%), interhemispheric (89%), temporolateral (73%),
frontal-superior (72%), and central (76%) regions, compared to the mesial temporal region
(28%).34 Occult peri-insular epilepsy in a small number of patients has been localized by
MEG identification of epileptogenic regions, even when multiple other diagnostic
methods had failed to do so.35 There was either no interictal spikes or nonlocalizable ictal
discharge on the scalp video-EEG in two of the three patients. The MEG localized the ictal
discharges in the deep anatomical structure of the fusiform gyrus in an MRI-negative
patient in whom scalp EEG failed to record ictal discharges.36 Wang and colleagues37
have also reported successful localization of seizures by MEG in a patient with subtle
FCD in the frontal operuculum. They simultaneously recorded interictal and ictal
discharges on MEG and stereotactic EEG, and these discharges were not detected on scalp
video-EEG recordings.
The role of MEG in MRI-negative temporal lobe epilepsy

There was no report in the literature about the use of MEG specifically for MRI-negative
temporal lobe epilepsy. For patients with mesial temporal lobe epilepsy (MTLE), MEG is
not a method to exactly localize the spike source, because of the structural and functional
configurations of the hippocampal formation38 and other networks in temporal lobe
epilepsy.39, 40 Therefore dipole modeling of MEG spikes has been applied to explain
MTLE. Three dipole models of MEG spike have been described in MTLE: (1) anterior
horizontal dipole, corresponding to mesial temporal discharges propagating to the anterior
temporal pole; (2) anterior vertical dipole, corresponding to mesial temporal discharges
propagating to the lateral temporal region; and (3) posterior vertical dipole, reflecting
extensive temporal epileptic networks.39, 40
Leijten and colleagues22 have compared whole-head MEG (151-channel) with highresolution (64-channel) EEG for source localization in MTLE with unilateral hippocampal
sclerosis. The sensitivity of MEG in detecting interictal spikes was only 32%, compared to
42% for EEG, and no patients showed MEG spikes only: MEG-localized sources were
more superficial and EEG-localized sources were deeper. Magnetic signals attenuate
according to the square of the distance from a source to a detector, and MEG prefers to
detect open circuit neurons in the cortex of temporal lobes rather than closed circuit
neurons in the amygdala and hippocampus. The MEG technique does not detect activities
from the hippocampus itself, but detects discharges spread over the lateral and anterior
part of neocortices including inferior, middle, and superior temporal gyri in most cases. In
the rare situations of epileptic discharges appearing at parahippocampal or fusiform gyrus,
MEG could detect the deep-seated cortical discharges.36, 38
In contrast with the above findings, Kaiboriboon et al.41 have reported a high rate of
MEG spike detection (85%) in 22 patients who underwent prospective MEG recording
(whole-head 275-channel) and anterior temporal lobectomy with or without hippocampal
atrophy on MRI. In 17 patients with unilateral hippocampal atrophy, MEG localized the
spike sources ipsilateral to the site of surgery in ten patients (58.8%), including one with
hippocampal atrophy contralateral to the side of a lobectomy. Two of four patients with
MRI-negative temporal lobe epilepsy had localized spike sources ipsilateral to the side of
surgery. The other two patients had bilateral or no spikes. The difference in sensor position
or types, and the reduction of antiepileptic medications, may have contributed to the
differences in the detection rates. Detection rates may also differ according to the types of
MEG pick-up coils. Magnetometer coil was thought to be superior in recording spikes
from deep regions including the mesial temporal lobe, and the planar gradiometer coil was
thought to be superior in detecting superficial spikes, such as in the temporal
neocortices.41, 42
New analysis method

The single ECD concept is based on the assumption that there is only one compact current
source in the brain. There are two mathematical steps: (1) forward problem, based on a
design of the approximate model of the brain conductor, (2) inverse problem, in seeking
the single ECD that can explain the measured magnetic fields with minimum error. When
multiple neurons discharge synchronously in convoluted cortices and the discharge rapidly
propagates to remote areas, there is a limitation for this ECD technique to delineate the
epileptic discharges. Recently, various new techniques have been introduced to MEG
analysis.
Synthetic aperture magnetometry (SAM) is a beamformer technique.43 The SAM
method is an adaptive spatial filter with the constraint that the variance of current
fluctuation is minimized; SAM can estimate the temporal course of electrical neural
activity at a particular site in the brain marked by 3D imaging voxels on MRI. Oishi et
al.44 applied this technique to MEG analysis to simulate intracerebral epileptiform
discharges in the region of interest in ten pediatric patients, including four patients with
MRI-negative epilepsy who underwent cortical resection based on icEEG. Oishi et al44
compared interictal spikes on SAM with nonsimultaneously recorded icEEG. They
demonstrated resemblance of the waveforms between virtual sensors on SAM and icEEG,
at the same neocortices.
Sugiyama and colleagues45 proposed an advanced version of SAM (SAM-g2) using
kurtosis of reconstructed waveforms at the virtual sensors. Distribution of the automated
high kurtosis voxels on MRI was consistent with the location of MEG spike dipoles from
multiple/generalized/diffuse spikes surrounding the tubers in patients with tuberous
sclerosis complex. The kurtosis reflects the combined effect of the amplitude and duration
of interictal paroxysmus.46 The SAM-g2 demonstrated the voxels with high kurtosis
values as an epileptic region, possibly the ictal onset zone.
Mohamed and colleagues47 applied the event-related beamformer method to estimate
the spatial distribution of source power in the individual MEG spikes by comparing the
MEG spike dipoles and the seizure onset zones on icEEG in 35 children with refractory
neocortical epilepsy. The localization of interictal spikes corresponds to the centroid of
MEG spike source cluster. The event-related beamformer localization was concordant
with the seizure onset zone on icEEG at the gyral level in 69% of patients. In a subset of
patients with unifocal event-related beamformer localization, beamformer results were
concordant with the ictal onset zone on intracranial EEG in 22 of 23 patients.
Guggisberg and colleagues48 applied short-time Fourier transformation to spike-locked
waveforms at the virtual sensors. They reported the distribution of the virtual sensors with
high beta and gamma activities is more suitably consistent with the epileptogenic zone
than the distribution of ECDs.
Shriaishi and colleagues have expanded the indication of MEG not only in focal
epileptiform discharges, but also in widespread epileptiform activities.49, 50 Dynamic
statistical parametric maps (dSPM) are a spatial filter with the constraint that total
weighted currents on the cortices are minimized. The dSPM reconstructed the propagation
of spike or slow waves on the virtual sensors of the brain surface in two epilepsy
patients.49 They also applied the well-known short-time Fourier transformation process
sensor by sensor to demonstrate the time evolution of the specific frequency bands during
spike propagations in two patients with MRI- demonstrable lesion-related focal
epilepsies.50
Bouet and colleagues51 proposed a new procedure to delineate spiking volume. The
volumetric imaging of epileptic spikes (VIES) with sorting of optimal high-frequency
activities over 20 Hz is reconstructed with a recent beamforming approach, dynamic
imaging of coherent neural sources, and statistical processing between spike periods and
static baseline periods. They found a good agreement between VIES and intracranial
stereotactic EEG (SEEG) in 21 patients with focal epilepsy.
Gradient magnetic-field topography (GMFT) is a method of inward projection of the
signals of planar gradiometers vertically on to brain surfaces without solution of the
forward or the inverse problem (Figure 6.3).52 Shizoru et al.53 compared MEG, icEEG,
and surgical outcomes and found that the distribution of the high-signal GMFT at the
spike onset overlapped the ictal onset zone and interictal zone on icEEG better than
focal/regional distributions of ECDs in neocortical epilepsy patients. The GMFT is less
affected than ECD by signal-to-noise ratio when detecting with minimum error the area of
spike onset.
Figure 6.3 Gradient magnetic-field topography (GMFT). Sequential GMFTs over the
right hemisphere during 40 ms section (10 ms each) demonstrate the dynamic changes of
the gradient magnetic field at one MEG spike. High gradients (red zones) represent the
location of current sources of the spike. The red zone shifts inferiorly from the right
frontal lobe towards the anterior temporal region during the single spike. Power bar at
right represents gradient magnetic field (femtotesla/cm).
Fischer et al.54 applied a novel technique designed to generate an ellipsoidal volume
from the scattering of single MEG dipole localizations in 33 adult patients who underwent
epilepsy surgery. The ellipsoidal volume analysis was compared with the resection volume
generated from pre- and postoperative MRI images. A high coverage of the MEG ellipsoid
volume by the resection volume and a low distance between the mass centers of both
volumes correlated to a favorable seizure outcome.
Conclusion
In MRI-negative epilepsy patients whose scalp video-EEG shows electroclinical
correlation that indicates focal-onset seizures, the colocalization of MEG spike dipoles
with interictal EEG discharges is very valuable for supporting the eventual delineation of
the epileptogenic zone by icEEG. Moreover, discrete epileptogenic networks could be
suggested by the colocalization of FDG-PET and SISCOM findings with MEG findings.
On the other hand, bilateral or scattered MEG spike dipoles in MRI-negative epilepsy
require further investigational studies, including repeat MEG studies in some cases.
Extensive or multiple epileptic networks are not infrequently encountered in MRInegative patients. This situation is a major challenge for MEG localization of the potential
epileptogenic zone, and also for the surgical resection of the zone.
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Chapter 7 Electric source imaging in MRI-negative

Christoph M. Michel and Margitta Seeck
Introduction
Presurgical evaluation of nonlesional epilepsies remains a major challenge. During the last
2025 years, a number of brain imaging techniques have been proposed and successfully
developed, validated first in lesional cases and then progressively applied to patients with
nonlesional epilepsy. Nevertheless, in a review of 2010, looking at reports on outcome in
lesional and nonlesional epilepsy between 1995 and 2007, only modest numbers of
seizure-free patients were retrieved: between 2646% of all nonlesional patients benefited
from surgery, with somewhat better results in temporal lobe epilepsy and in children (1).
Integrating other imaging modalities appears therefore vital to increase this success rate. A
good example is the study of PET-positive/MRI-negative patients with temporal lobe
epilepsy, providing evidence that the lack of a MRI lesion is not necessarily associated
with a worse surgical outcome (2).
While there has been major progress in MR-based and nuclear imaging, the use of EEG
as a possible imaging technique remains rarely considered, although it is the cornerstone
technique in the diagnosis of epilepsy. In fact, even today, most authorities in the field
wont contest that EEG is much valued, not only for the diagnosis of epilepsy, but also for
regionalizing the epileptogenic focus. Recent advances in EEG recording and analysis
techniques converted the EEG to a valuable imaging tool (3), but these methods have not
yet found their place in clinical routine. Plummer et al. (4) reviewed EEG source imaging
(ESI) studies up to 2007. They underline the value of ESI and the surprisingly still modest
utilization in the presurgical work-up of patients with focal epilepsy. Given that most
epileptic patients show epileptogenic discharges on scalp EEG and that EEG source
imaging can reliably identify the irritative zone even from standard clinical EEG
recordings, its use in clinical routine would be justified. However, similar to MRmachines, higher power is related to higher yield, i.e., larger electrode arrays, and full
use of EEG-localization algorithms are more likely to be more informative than small
arrays and simple approximations.
With the present chapter, we like to expose advantages but also some limits and
considerations of electric source imaging (ESI) in epileptology.
Basics of electric source imaging

Electrical source imaging (ESI) is based on the recording of multichannel EEG on the
scalp. It relies on mathematical algorithms that estimate the brain sources that give rise to
a certain scalp electric field. Since there are many possible solutions for the same electric
scalp field, known as the inverse problem, a priori assumptions are required to
determine a meaningful underlying source or maybe several sources that explain the scalp
field. This is true for the EEG as well as its homologous technique, the
magnetoencephalography (MEG). The more appropriate these assumptions are, the more
likely the inverse solutions are correct and precise.
Assumptions concern the head model as well as the model of the sources that are
supposed to generate the scalp fields. The latter gave rise to many studies; their review
would go beyond the scope of this chapter. The interested reader is referred to detailed
reviews elsewhere (58). Other relevant technical aspects of ESI are briefly summarized
below.
Head models
The head volume conductor model refers to the shape of the tissue that is supposed to
generate the scalp fields, the orientation of the sources in this tissue, and the conductivity
properties of the different layers between the active neurons and the scalp electrodes. The
most simple head volume conductor model consists of a homogeneous single sphere. By
including several concentric homogeneous spherical shells, the different conductivity
properties of the tissues (brain, CSF, skull, and scalp) can be imitated and included in
the calculations. Spherical head models have been used in many source localization
studies, particularly in those using equivalent dipole localization methods. They are still
very often applied in MEG source imaging studies, including applications to epilepsy
(e.g., (9)). Because of their simplicity, spherical head models are computationally
efficient. However, the real human head is not a sphere and spherical head models can
lead to serious mislocalizations when the solutions are coregistered with the real MRI of
the patient (10). Realistic head models that take the real geometry of the individual brain
into account lead to improved source reconstructions, particularly in basal brain areas such
as the occipital cortex and the mediobasal temporal lobe (11). Realistic head models are
more complex and computation-intense, but they allow the direct incorporation of the
anatomical structure of the individual patients brain from the magnetic resonance images,
an aspect that is particularly important in patients with large brain lesions (12). This is
particularly important in the context of epilepsy surgery. Realistic head models are based
on boundary or finite element methods with the latter being able to incorporate also
inhomogeneous conductivities of the head such as the anisotropic conductivity distribution
of the white matter (13). Realistic head models also allow the delineation of the sulci and
gyri in the brain, and thus allow the restriction of the local orientations of the dipoles (14),
thereby reducing the number of possible solutions.
Source models
The source model refers to the assumptions about the current sources in the brain that are
responsible for the scalp potentials. It is generally assumed that the primary sources of the
EEG are the postsynaptic currents of a large number of pyramidal cells that are
simultaneously active. Since the EEG electrodes on the scalp are far away (far field) from
these neurons, electrical activity can be modeled as an equivalent current dipole. If only
one or a very few current dipoles are assumed, their most probable location for a given
momentary scalp field can be determined by iterative procedures. Such simplified

equivalent dipole models have been most commonly used in the initial EEG source
imaging studies and is still the method of choice in MEG source imaging in epilepsy (15).
However, equivalent dipole models are only valid if the neuronal sources are confined to a
few focal regions and if the number of these regions are known a priori. If multiple
sources distributed over the entire brain volume are simultaneously active, the equivalent
current dipole model may lead to erroneous results.
Distributed current source models have been developed that can account for the wholebrain bioelectric activity without a priori assumptions on the number of sources.
Distributed current source models parcel the whole brain in small regions and position a
current dipole in each of these regions (solution point). These solution points can be
restricted to the gray matter of the brain, if realistic head models are used. Since the
number of solution points is generally much larger than the number of measurement
points, additional constraints have to be imposed in order to obtain unique and well-posed
linear inverse solutions. The first proposal to solve this inverse problem was termed the
minimum norm least-squares (MNLS) inverse that minimizes the least-square error of the
estimated inverse solution (16). Variations of the MNLS were developed by including the
dependencies of a local point on the activity of its neighbors. In other words, neighboring
neurons behave most likely more similar than neurons in remote regions. Such additional
a priori information is included in algorithms known as low-resolution brain
electromagnetic tomography (LORETA) (17), variable resolution electromagnetic
tomography (VARETA) (18), local autoregressive average (LAURA) (19), and others.
Also, methods to assess the statistical significance of the inverse solutions have been
developed such as dynamic statistical parametric mapping (dSPM) (20) and standardized
LORETA (sLORETA) (21). Most of the recent applications of EEG source imaging in
epilepsy use these linear distributed inverse solutions.
Number and position of electrodes

It is evident that the precision of EEG source imaging not only depends on the proper head
and source model, but also on the proper sampling of the electric field over the whole
scalp, including basal brain areas to better estimate the activity of the inferior temporal or
orbital frontal cortex (22) (Figure 7.1). Electrodes also have to be spaced properly to avoid
spatial undersampling (23). The spatial frequency, intimately associated with the precision
of ESI, is limited by the blurring induced by the low conductivity of the skull (24). Early
simulation studies estimated the maximal spatial frequency or the distance between
electrodes to 12 cm (25), requiring more than 100 electrodes to cover the whole head.
Downsampling approaches on data sampled with high density confirmed this number,
showing severe localization errors of known epileptic foci when the electric field was
sampled with 64 electrodes or less (26). Moreover, simulation studies by Ryynnen et al.
(27) showed that by using more realistic conductivity values for the skull, the number of
electrodes should be rather above 200. While the application of these high number of
sensors is obviously more challenging for EEG than MEG, recent advances in EEG
technology make it possible to record from high-density EEG with reasonable efforts (28,
29).
Figure 7.1 Illustration of the electrode positions of a high-density EEG (in this case a
Geodesic Net from EGI Inc.) in comparison to the position of electrodes in the standard
1020 system. Left: electrodes position revealed by measuring the subjects MRI with the
net in the scanner. Middle and right: electrodes position with respect to the underlying
segmented brain MRI. The lower rows show zoomed-in regions. Note the large areas of
the brain on temporal and medial brain areas not covered by the 1020 system (Figure
made by L. Spinelli.)
Electric source imaging in focal epilepsy

In recent years several studies demonstrated that ESI could be a very useful tool in the
clinical work-up of patients with focal epilepsy, not only to localize the epileptogenic
zone, but also to visualize the propagation of ictal and interictal discharges within the
epileptic network (for reviews see (4, 6)). Even when applied to standard EEG recordings
performed in the clinical settings, i.e., with only 2535 electrodes, it can provide
important hints with respect to the focus localization at a lobar level and guide the
positioning on intracranial electrodes (22), if an invasive procedure is felt necessary. The
advantage of ESI coupled with clinical long-term EEG is that it allows recording and
analysing interictal activity in patients with rare spikes or spikes only appearing during
sleep.
However, for the reasons explained above, ESI is most powerful when the EEG is
recorded from a high number of electrodes. In this case, the clinical yield of ESI exceeds
or equals that of conventional presurgical imaging methods PET, SPECT, and MRI as
demonstrated in a recent prospective study of 152 operated patients (30). All patients had
a sufficiently long (> 1 year) postsurgical follow-up to reliably assess the postoperative
seizure outcome, allowing the evaluation of the sensitivity and specificity of ESI. If the
EEG was recorded with a large number of electrodes (128256 channels) and if the
individual magnetic resonance image was used as head model, a sensitivity of 84% and a
specificity of 87% of ESI were obtained. These values were superior to those of structural
MRI (73% sensitivity, 50% specificity), PET (65% sensitivity, 37% specificity), and ictal
interictal SPECT (54% sensitivity, 62% specificity). The sensitivity and specificity of ESI
decreased to 73% and 75%, respectively, with a low number of electrodes (2129
channels). Lowest values were found when low-resolution EEG was combined with a
template head model (59 and 62%, respectively) (Figure 7.2).
Figure 7.2 Sensitivity and specificity of localization of the epileptogenic focus with
different imaging methods. Data from 52 out of the 152 operated patients who underwent
all investigations. Sensitivity is defined as percentage of patients with the maximum
abnormality being located within the operated area when the patient became seizure-free
after surgery. Specificity is defined as percentage of patients with maximum abnormality
lying outside the operated area when the patient did not become seizure-free. HR ESI =
high-resolution ESI (128256 channels), LR ESI = ESI with clinical EEG (< 29 channels),
i-MRI = individual head model for ESI, t-MRI = template head model for ESI, MRI =
structural magnetic resonance imaging, PET = positron emission tomography, SPECT =
single photon emission computed tomography. Data from Brodbeck et al., 2011.
Electric source imaging in nonlesional focal epilepsy: impact

on surgery
It is evident that ESI is an excellent imaging tool for patients with nonlesional epilepsy,
given that MRI, the other cornerstone exam, is negative. In a recent study of our group, we
looked at yield of ESI in ten patients with normal MRI (31). Ictal EEG data and seizure
semiology pointed to an epileptogenic zone located in the temporal lobe in five patients, in
the frontal lobe in two, and in the temporo-occipital, parieto-occipital and frontotemporal
regions in the remaining three. Presurgical evaluation included long-term video-EEG,
PET, interictal, and ictal SPECT in all patients, and invasive recordings in eight of them.
In five of the ten patients ESI was performed on their standard clinical EEG consisting
of 2931 electrodes. In the other five patients high-density EEG with 128 or 256 channels
was recorded, and ESI was based on the spikes detected in these recordings. A simplified
individual head model based on the patients MRI was used in all cases. In order to define
the accuracy of the ESI, the results were coregistered with the postoperative MRI and the
ESI was considered correct when the maximum fell within the resected area.
The analysis revealed a localization of the ESI maximum within the resected zone in
eight of the ten patients (Figure 7.3). All of these patients benefited from the surgery: six
were seizure-free, two had an Engel class II outcome. In contrast PET and SPECT
provided localizing results in only half of the patients. One of the two patients with
presumably incorrect ESI localization suffered from persistent seizures after surgery. The
ESI maximum in this case was localized adjacent to the resected zone (see also below,
case 3).
Figure 7.3 Epileptic focus localization with ESI in patients with nonlesional focal
epilepsy. The yellow-green area indicates the ESI maximum superimposed on the postoperative MRI when available or on the preoperative MRI with the approximated operated
zone marked by the red dashed line. The source maximum laid within the resected area in
eight patients and outside in two [1 and 7]. One of them [1] was not seizure-free after
operation. Copyright Brodbeck et al., 2009.
The second patient with incorrect ESI localization was seizure-free after surgery. In this
case, the scalp EEG only recorded spikes from the inferior parietal lobe, while the
intracranial recordings found interictal spikes in two regions, the inferior parietal and
interhemispheric parietal cortex. Thus, ESI correctly localized the inferior parietal spikes.
These spikes persisted in the postoperative scalp EEG, but this focus fortunately did not
provoke seizures (follow-up: 3 years).
It is interesting to note that the histopathological examination of the resected tissue
showed abnormalities in all cases: diffuse gliosis in five patients, cortical dysplasia in
three, microheterotopies in one, and a combination of these abnormalities in the remaining
patient. This indicates that patients with MRI-negative results are not entirely nonlesional.
It might be that in some of these patients a re-evaluation of the MRI, guided by the ESI
result, would have identified small lesions. Such findings have been reported in an
interesting recent MEG study of 29 nonlesional epileptic patients (32). They showed that
in seven of these 29 patients MEG-guided re-evaluation led to the identification of clear
lesions that were previously unidentified (see also case 4).
Localization of ESI, or dipole orientation of the source, could have also an impact on
the precise focus localization or even on the postoperative prognosis. For example,
nonlesional temporal lobe epilepsy might be related to different generators compared to
TLE associated to hippocampal sclerosis (HS). It was hypothesized that patients with HS
have spikes with oblique equivalent dipoles while patients with discrete cortical lesions
have spikes with radial dipoles (33). This has been questioned by other reports, which
found no differences in a group of patients with mesial TLE (34, 35). In a more recent
study (36), the dipoles of 12 nonlesional cases and 22 patients with hippocampal sclerosis
were compared using 29 scalp electrode recordings and realistic head models. No
difference was found, with around 25% of each patient group showing localization in the
mesial temporal structures. Furthermore, no difference between patients with good and
poor outcome was found (HS+ and HS- patients were distributed equally in both groups).
Thus, measuring the orientation of the dipole does not seem to provide additional relevant
information, at least if based on an EEG with < 60 electrodes.
Is ESI reliably localizing deep structures?

There is still ongoing discussion if noninvasive electromagnetic tools are able to depict
deep foci, e.g., in mesial temporal or extratemporal structures. Temporal deep structures
probably behave differently than extratemporal deep sources, given that the electric field
is generated predominantly by tightly packed parallel oriented pyramidal cells in the
hippocampal layers. This creates a relatively clear dipole or electrical field, which should
be picked up by scalp electrodes 34 cm away. Some authors claim that mesial temporal
structures are only seen if they recruit simultaneously lateral temporal neocortex and
that neither EEG nor MEG is able to detect spikes confined to the mesial temporal
structures (37, 38), whereas others showed data that suggest the possibility to localize
deep temporal foci from scalp recordings, particularly if the activity (spikes or evoked
responses) is averaged (3942). The demonstration of disappearance of spikes on the scalp
EEG after selective mesial resections indicates that mesial spikes can be localized by ESI
(43). However, the controversy might never be settled given that it is difficult to record
simultaneously with high spatial sampling from inside the hippocampus, the lateroanterior
temporal cortex and from the scalp. Combined recordings of EEG-fMRI or simultaneous
high-density EEG/MEG could provide further insights on this issue (4446).
Do we need spikes to localize the epileptogenic source?

Spikes, sharp waves with or without consecutive slow waves, are the hallmark of the
diagnosis of epilepsy. Fortunately, in most patients, they are present and allow determining
if a focal disorder is at stake and which lobe or region is most likely affected. However, in
some cases, no epileptiform discharges are detected. Even in intracranial recordings, there
might be no clearly identifiable ictal EEG onset, especially if originating in the
interhemispheric region. Thus not even invasive monitoring can be considered as the gold
standard (47). Personal observations also showed that intracranial electrodes might not
pick up epileptiform activity if displaced 12 cm from the epileptogenic zone, underlying
again the need for powerful preimplantation localization procedures.
One way to overcome spike-free recordings is the acquisition of combined highresolution EEG and fMRI. In a recent study, scalp voltage maps were computed from
previous epileptogenic discharges, then retrieved in the 64- or 128-channel EEG obtained
during the fMRI, which then allowed the identification of BOLD changes in relation to the
epileptogenic maps. This led to the correct localization in 14/18 patients (78%) with EEGnegative fMRIs (46). However, this requires the recording of spikes at some point. If
spikes or other epileptogenic discharges were never obtained, but an epileptic focus is
strongly suspected, template maps of the presumed focus and the calculation of their
presence, as indicated above, could be a solution. However, the reliability of this approach
remains to be demonstrated.
Illustrative case studies

Mixed studies, i.e., studies including patients with temporal and extratemporal epilepsy,
report equally good localization performance of ESI in both groups. Here we present
several cases, which show the advantages but also the limits of ESI in the individual
patient.
Patient 1 is a left-handed 18-year-old male patient, otherwise healthy and cognitively
unimpaired, who suffered from drug-resistant seizures since the age of 8. Clinically, the
seizures were characterized by loss of contact, grunting, and automatisms of the mouth
and hands lasting 30 to 60 seconds, followed by amnesia for the event. There was possible
postictal aphasia. The MRI was normal but PET was suggestive of a left anterior temporal
hypometabolism. In the 32-channel video-EEG monitoring, interictal discharges were
most often found over the anterior left temporal lobe (50%), with less frequent posterior
temporal (25%) and right-sided temporal epileptic discharges (25%). Ictal onset appeared
to be left hemispheric, probably temporal, but unambiguous localization or lateralization
could not be obtained in this patient, who also presented evidence of right-sided language
lateralization.
An ESI was performed using the predominant left anterior temporal spikes, which
localized the source precisely to the anterior aspect of the mesial temporal lobe structures.
Invasive video-EEG monitoring was performed with subdural grid and strip electrodes
on the left hemisphere, targeting mainly the left temporal lobe, with depth electrodes
inserted in both hippocampi. The seizure onset zone coincided with the contacts
superposing with the ESI zone (Figure 7.4). This case illustrates the capacity of ESI to
localize mesial temporal foci. Furthermore, an ESI of interictal spikes provides valuable
information of the ictal onset zone, since it often coincides with the contacts of intracranial
ictal onset (> 60%, personal unpublished data).
Figure 7.4 Case 1 (left temporal nonlesional epilepsy). ESI of the most frequent
interictal epileptogenic discharges found the source maximum in the left hippocampus
(red cross). The purple contacts of the left hippocampal depth electrode were involved in
generating the interictal spikes (irritative zone) and seizure onset and coincided with the
ESI source. This case shows the capability of ESI to identify deep temporal sources.
Resective surgery was carried out 2 years ago and the patient is since seizure-free.
Patient 2: The fact that ESI performs equally well in extratemporal nonlesional epilepsy
is illustrated by this case (48). This is a 6.5-year-old girl suffering from focal epilepsy
since the age of 4.5 years. She presented an undefined, unpleasant feeling, followed by
hypersalivation, left arm elevation and right arm extension evolving to a fencing position
or tonic abduction of arms with postictal aphasia. Secondary generalization was frequent.
The seizures were almost exclusively nocturnal, up to 20 per day. The interictal EEG
showed a very active left frontotemporal lobe focus. An ESI was performed on these
interictal discharges, indicating a left opercular source, concordant with PET and SPECT
findings (Figure 7.5).
Figure 7.5 Case 2, a 6.5-year-old girl with extratemporal nonlesional epilepsy. MRI was
normal, but ESI (green), ictal SPECT (blue) and PET (focal hypometabolism, not visible
due to superimposition of ESI and ictal SPECT) pointed to the left frontal opercular
insular region. Due to the high convergence of data, and despite the proximity of Brocas
area, the child was successfully operated without intracranial monitoring (for details see
Chiosa, et al., 2013).
The question was arising if intracranial monitoring should be performed. However, we
decided to proceed directly to resective surgery for several reasons: (1) there was no other
candidate region for the origin of seizures, (2) there was a high likelihood for incomplete
electrode coverage of this region, (3) language mapping was not necessary, since we knew
already that language was nearby (postictal aphasia), and also not possible because she
spoke only Albanese, (4) she would most likely recover from postoperative aphasia given
her young age.
The resection was performed using intraoperative monitoring. She suffered from
postoperative Brocas aphasia and right brachiofacial paresis, from which she recovered
within 6 months. She is seizure-free since 3 years. Histopathological examination revealed
cortical dysplasia.
This case illustrates that good results from ESI are not confined to temporal lobe
epilepsy. Noninvasive imaging in extratemporal nonlesional epilepsy could lead directly to
surgery, without intracranial monitoring, provided that all image modalities including ESI
are concordant.
Patient 3: The seizure disorder of this 9-year-old girl started at the age of 3.5 years. The
semiology was stereotypic, i.e., a sensory aura with painful features of the right foot,
followed by a Jacksonian march towards the upper limb, and hypermotor seizures with
extension of all four limbs. The interictal EEG showed intermittent slowing, occasionally
with sharp features, over the left superior parietal region; the ictal EEG had diffuse onset
or delayed left centroparietal slowing. The PET and MRI were normal and ictal SPECT
showed hyperperfusion in the left basal ganglia. Taking the semiology and all examination
findings together, it appeared that the girl suffers from left hemispheric extratemporal lobe
epilepsy, either close to the primary sensory foot cortex or, to the posterior opercularinsular region, given the pain component of her aura.
An ESI was obtained based on the suspicious left superior parietal EEG features but
without clear epileptogenicity. The results indicated a source in this region, postcentrally
and simultaneously a weaker activity in the temporal neocortex (reflecting the posterior
opercular region) (Figure 7.6).
Figure 7.6 9-year-old girl who underwent extensive evaluation for her MRI- and PETnegative left hemispheric epilepsy with sensory, somewhat painful foot auras. ESI
solutions (green) and resected volume (red) superimposed on the MRI with the positions
of the subdural electrodes (blue dots). The yellow star indicates the interictal and
(delayed) ictal onset. The ESI identified two sources: a strong superior parietal and a
weaker left deep temporal source. The patient continued to present seizure postoperatively,
either because of insufficient resection leaving the ESI in place, or because the ictal onset
zone was in fact remote in the deep opercular cortex.
Intracranial recording was performed consisting solely of subdural electrodes covering
the central and posterior left hemisphere. Additional depth electrodes targeting the deep
opercular or insular regions was strongly suggested, but considered too dangerous by the
neurosurgical team at that time. Sixteen habitual seizures were recorded with delayed EEG
onset after clinical onset in the superior parietal cortex, probably reflecting secondary
recruitment of the symptomatogenic zone.
Consequently, resective surgery was not proposed. However, due to insistence of the
family, and in the context of a severe epilepsy with up to 30 seizures per day, surgery was
carried out as palliative treatment, i.e., a very circumscribed resection of superior
postcentral cortex, next to but not including the ESI site. A few weeks after the
intervention, the seizure recurred with a similar frequency. The histopathological exam
was unrevealing.
This case shows that ESI can map any EEG feature, but only the clinical review of all
data will finally determine if a source makes sense. The ESI localized correctly the
origin of the sharp slow waves, but several aspects in her history made a primary superior
parietal focus unlikely. We do not know at this point if the resection was too small,
because it left the ESI maximum outside, or if ESI on slow waves, even if it has sharp
features, is inadequate for accurate presurgical localization of the epileptogenic zone.
Patient 4: The 10-year-old boy, right-handed, started at the age of 4 with nocturnal
nonlateralized hypermotor nocturnal seizures, sometimes preceded by paresthesias in the
left hand or face. Noninvasive monitoring showed a very active interictal focus with
rhythmic spikes or sharp waves of right central maximum. The ictal EEG did not show
focal or lateralized changes, but with a delay of 10 seconds, right frontal discharges. The
MRI was normal, ictal SPECT, ESI, and PET identified a right inferior postcentral focus.
Given the proximity to primary sensory cortex, we carried out an ESI of somatosensory
evoked potentials (SEPs, air puffs of the thumb).
Invasive monitoring confirmed the hypothesis of right postcentral epilepsy.
Interestingly, SEPs from the intracranial electrodes and corticography showed excellent
concordance with preoperative SEP ESI (Figure 7.7).
Figure 7.7 10-year-old boy with right postcentral epilepsy. Retrospective MR review
identified a suspicious cortical area in the deep basal postcentral structures. Upper row:
PET (yellow) showed a suspicious area of hypometabolism despite presence of cortex. 1
cm above ESI maximum (red). Lower row: results of corticography allowing the
identification of sensory hand cortex (blue rectangle) and hand motor cortex (red
rectangle). These findings coincide with ESI of somatosensory evoked potentials obtained
preoperatively (green) and with evoked potential recordings from intracranial electrodes
(blue dots). The epileptogenic zone is depicted by the light blue dashed circle, close to the
vital cortex but not superimposing it.
The child underwent a right inferior postcentral cortical resection, sparing the hand
sensory cortex. No more seizures occurred for 2 years since surgery.
This case illustrates again that concordant noninvasive imaging, including ESI, is able
to localize precisely extratemporal lobe foci. Moreover, ESI of evoked potentials, obtained
with large electrode arrays, identifies relevant cortex, which helps to shorten the cortical
stimulation sessions, particularly important in children and patients with limited
collaboration.
Electric source imaging in MRI-negative focal epilepsy:

impact on identification of relevant pathological networks
While the major application of ESI is in the field of epilepsy surgery, it is also used in
patients who are not candidate for surgery, but suffer from focal epilepsy, or presumably
focal epilepsy. Epileptic encephalopathy with continuous spikes and waves during slow
wave sleep (CSWS) is an age-related epileptic disorder characterized by acquired
neuropsychological impairment or even mental retardation, heterogeneous seizure types,
and subcontinuous interictal spike-wave activity in the EEG during slow wave sleep.
There are different etiologies, which have in common that they include focal pathologies,
symptomatic or nonlesional. However, since they are characterized by a nonfocal EEG
pattern, lateralized or generalized, network alteration needs to play a role to explain this
discordance.
A combined EEG-fMRI and ESI study was done in 12 children with CSWS, all with
negative MRI or subcortical abnormalities such as periventricular leukomalacia (49).
Interestingly, an ESI of the initial activity points to the perisylvianinsular region in all
patients who showed a focal onset of their spike sources (8/12). These were right-sided in
two and left-sided in six patients, indicating that there is a focal component despite the
rather diffuse and generalized EEG pattern. In comparison, the simultaneously acquired
fMRI provided less focal results, due to poorer temporal resolution, but in all patients
some of the BOLD changes were also found near or in the perisylvian cortex.
Patients with genetic mutations are usually not considered for epilepsy surgery, except
those with tuberous sclerosis who are lesional in essence. An example of successfully
operated nonlesional genetic epilepsy is provided by Weckhuysen et al (50). In the context
of a larger genetic study of patients with early-onset epileptic encephalopathy, they
described a 2-year-old girl with a STXBP1 mutation and focal seizures originating in the
right posterior cortex. Intracranial recordings showed multifocal onset but confined to the
right temporo-occipital cortex, subsequently leading to occipital lobe disconnection and
subpial transections of the temporal lobe. Histopathology showed dysplasia type 1a. The
girl enjoyed a 95% seizure reduction. An ESI was not performed in this patient. This case
underlines indications of resective surgery beyond the classical MRI-negative epilepsy,
i.e., with a known genetic mutation. Larger studies in the field of epilepsy surgery in
genetically determined epilepsy syndromes are needed. Furthermore, the potential for ESI
to help in localizing the surgical focus and in improving surgical outcome also needs to be
studied in such cases.
Conclusion
Electric source imaging (ESI) is an elegant tool to localize the epileptogenic cortex in the
individual patient. If combined with realistic head models, i.e., of the patients own MRI,
and high count channel numbers (> 100), the precision is quite high with a sensitivity and
specificity of > 80%. However, it requires the identification of clearly epileptogenic EEG
pattern in a given patient, i.e., it does not make knowledgeable EEG readers obsolete!
Combined with good-quality PET or ictal SPECT studies, careful patients history taking
and examination, the rather poor prognosis of MRI-negative epilepsy can be significantly
improved, in particular if all results are coconcordant.
As shown with the third case report, it is not sufficient to localize an ambiguous
epileptogenic EEG pattern. An ESI can localize any EEG component, so clear guidelines
are required to avoid mislocalization. The EEG pattern might not be always spikes or
spike-wave complexes, but could include rhythmic slowing or sharp slow waves if it is felt
that they reflect directly the patients epileptogenic focus. However, it is mandatory to
capture enough epileptogenic discharges. In that respect, ESI is probably superior to EEGfMRI or MEG, which are usually more time restricted. Newer high-resolution EEG
machines also allow long-term monitoring for several hours or days, so discharges can be
recorded more easily and more frequently. More prospective studies are needed to
determine if other aspects of ESI, e.g., propagation pattern, frequency of the presence of
epileptogenic focus sources, or ictal ESI studies, combined with noninvasive vital cortex
localization, will decrease the need for invasive monitoring, and improve the postsurgical
seizure outcome of nonlesional focal epilepsy to a level similar to that of lesional epilepsy.
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Chapter 8 Functional MRI in MRI-negative refractory focal

epilepsy
Friederike Mller and Stephan Ulmer
Abbreviations
BOLD blood oxygenation level dependent; EPI echo planar imaging; EEG
Electroencephalography; fMRI functional magnetic resonance imaging; HRF
hemodynamic response function; IED interictal epileptiform discharge; SOZ seizure
onset zone; icEEG intracranial EEG; MREG magnetic resonance encephalography.
Mapping of eloquent areas

Presurgical evaluation of eloquent areas is essential in patients with MRI-negative, drugrefractory epilepsy. Especially in children, craniotomy and wake cortical mapping might
not be an option to preserve language and memory function, which are at risk in dominant
hemisphere surgeries. Therefore, additional tools are needed to reliably depict eloquent
brain areas prior to surgery to avoid postoperative deficits.
Wada testing
To avoid such deficits, the intracarotid amobarbital (Wada) test has been used for decades
(1). However, this procedure comes with a risk of stroke or other adverse consequences of
sedation due to the amobarbital itself. The sensitivity can be reduced, if there is cross-flow
of blood to the opposite hemisphere via the circle of Willis, which is why the catheter has
to be advanced further into more distal vessels.
fMRI
Functional MRI (fMRI) was introduced two decades ago, in order to noninvasively depict
functional areas of the brain (2). Activated areas need more oxygen during task
performance, which results in increased blood flow in these areas. This leads to a local
signal drop in T2*-weighted images in activated areas, which can be measured as blood
oxygenation level dependent (BOLD) signal changes. In order to map such BOLD
changes, at least two conditions are necessary in a classic block design to differentiate
between activation and resting state. Usually, several periods of activation are performed
using echo planar imaging (EPI) in order to enhance sensitivity. More advanced methods
include event-related designs (see the EEG-fMRI section in this chapter). The BOLD
signal changes are statistically analyzed, color-coded, and overlaid on to the anatomical
MR images. Jack and colleagues applied fMRI clinically for the first time: fMRI of the
sensorimotor cortex prior to surgery was validated intraoperatively with
electrophysiological techniques and has since then become state-of-the-art mapping in

many centres prior to surgery of tumors in or adjacent to the motor strip (3).
fMRI reliability
The distance of BOLD signal activation and the edge of planned resection seems to be
crucial with respect to possible postoperative neurological deficits. Haberg et al. found
that there were fewer postoperative deficits, if this distance was more than 10 mm in brain
tumor surgery (4). This was further underlined by Krishnan et al., who demonstrated that a
lesion-to-activation distance less than 5 mm resulted in new postoperative neurological
deficits; he therefore recommended direct cortical stimulation below a distance of 10 mm
from the tumor border (5). One downside to this approach, however, is that the size of the
activation cluster depends on thresholding the data; therefore, the determination of a safe
resection can not be made based only on fMRI. The same holds true for laterality in
language so that any laterality index should be independent of thresholds (68).
Furthermore, a problem in language mapping only using fMRI is that fMRI activation
patterns depend on the language tasks. Thus areas not activated by a specific task might be
resected, which might result in a postoperative decline. On the other hand, less dominant
language areas might not be removed based on fMRI results, which may result in
inadequate seizure control (9). Further limitations of fMRI are that cooperation of the
patients is needed and that the patients need to be able to perform the required tasks. Also,
fMRI does not measure neural activation but merely a vascular response of the capillary
bed and draining veins (10), even if a close topographical correlation was found in the
macaque (11).
The fMRI and Wada for language and memory mapping

The reliability of fMRI compared to the Wada test has been investigated in a large number
of studies showing good concordance (12). However, fMRI depicts areas of the language
network which can involve both hemispheres (7). Binder and coworkers presented a
method to define language dominance based on a laterality index by counting activated
voxels in each hemisphere (13). Lateralization of language seems to be more reliable
when using tasks like sentence or word generation (14). Even if fMRI for the purpose of
language lateralization is widely accepted for presurgical evaluation of language function,
there is still doubt about its reliability (see above). Sabsevitz and colleagues were able to
show that preoperative fMRI can predict naming outcome in patients who were to undergo
left anterior temporal lobectomy (15). The laterality index based on fMRI tends to be a
stronger predictor for postoperative outcome (poor naming) than the Wada testing
laterality index. This is in line with several studies that have demonstrated limitations of
the Wada test in predicting verbal memory decline after anterior temporal lobectomy (16
18). Using a scene-encoding paradigm that leads to bilateral activation, Binder and
colleagues analyzed activation in the hippocampus and adjacent areas and found an
asymmetry depending on the side of seizure focus: especially the anterior hippocampus
laterality index which showed clear evidence of functional lateralization away from the
side of the seizure focus, as expected in chronic temporal lobe epilepsy. However, unlike
language lateralization, the hippocampal activation asymmetry was unrelated to

postsurgical verbal memory outcome (19). A recent study presented data from language
lateralization by fMRI and Wada testing in 229 patients with epilepsy. It again showed a
good concordance between fMRI language lateralization and Wada testing. The degree of
rightward shift of language dominance on fMRI testing was strongly correlated with
Wada/fMRI discordance, suggesting that fMRI may be more sensitive to right hemisphere
language processing than Wada testing is (20).
Studying memory in functional MRI is challenging. Using different paradigms, many
aspects of memory can be investigated (e.g., encoding and retrieval of patterns, words,
faces), which show activation in different areas. Studies investigating the retrieval of items
demonstrated medial temporal lobe activation with slight variations (2123). Left-sided
activation was found with verbal stimuli, and bilateral activation was detected with
pictorial stimuli (2426). Studies on memory and language fMRI studies performed to
predict postoperative decline in verbal memory following temporal lobectomy indicate
that individuals with greater ipsilateral activation compared to contralateral mesial
temporal activation have a greater decline in memory following temporal lobectomy (16,
27, 28). Dupont and colleagues demonstrated that fMRI activation during a delayedrecognition task seems to be a better predictor of postoperative verbal memory outcome
than the Wada test (29).
fMRI in children
fMRI in children faces further challenges. Some studies suggest that the hemodynamic
pattern of fMRI differs in children (30). Tasks have to be adapted to the cognitive abilities,
and a passive stimulation paradigm not requiring any particular response may be needed in
younger children (31). In a younger age, there is more widespread activation (32) with
age-related changes in different regions (33). The childrens attention needs to be focused
on the task and monitored during the experiment, especially when cognitive tasks are
involved. A rest condition during fMRI is even more problematic in children than in
adults, as it is hard to verify in children. Furthermore, the brain scan environment is
perceived by many children as frightening, especially because of the required
immobilization of the head. Therefore children should become accustomed to the scanner
prior to any experiment and the study itself. Yuan et al. showed that introducing visual
inputs to the patient reduce head motion (34).
Plasticity of eloquent areas

The developing brain is characterized by a large degree of plasticity. Dehaene-Lambertz et
al. demonstrated a left-dominant activation of language networks in children at as early as
3 months of age before any language development seems to begin (35). There is an
ongoing discussion about whether language-related areas are shifted to the right
hemisphere in early left-sided brain injury or epilepsy (36, 37), or whether there is an
intrahemispheric shift (38). The pattern or reorganization might depend on various factors,
such as handedness, type of the lesion, age at onset, or duration of the symptoms. Subtle
deficits in language performance in children with lesions in the left hemisphere might
suggest a left-sided dominance of language (39). Lesions acquired before the age of 5
years might lead to reorganization but it has been shown that language areas often remain
in their determined location even in early-onset seizure patients. However, a complete
shift of language can also occur when the lesion occurs very early in life (37, 40). Studies
have demonstrated that patients with early onset of epilepsy undergoing anterior temporal
lobectomy have a lower risk of experiencing a decline in postoperative language (41),
which again underlines the idea of a contralateral shift of these regions (42).
EEG-fMRI
Scalp EEG is an important clinical tool for the investigation of patients with epilepsy as it
can help localize the source of epileptic activity. However, EEG is characterized by low
spatial resolution, and epileptic activity arising from deep brain structures cannot be
detected. These limitations can be overcome by combining EEG with fMRI, since fMRI
shows good spatial resolution and sensitivity to signals of both deep and superficial brain
structures. Combined EEG-fMRI recordings allow mapping of BOLD signal changes
associated with interictal epileptiform discharges (IED) detected on the scalp EEG. In the
past years, EEG-fMRI studies have been used to noninvasively delineate the epileptogenic
zone. This section gives an overview of the methodology of EEG-fMRI. We discuss the
role of EEG-fMRI in presurgical evaluation (including MRI-negative cases) and the yield
of EEG-fMRI based on postsurgical evaluation studies. Novel techniques in the field will
be demonstrated
Background of EEG-fMRI
It is not trivial to record an EEG in an MRI environment. During scanning, the rapidly
changing magnetic field induces a strong current which results in a high-amplitude
gradient artefact in simultaneous EEG recordings. The development of gradient artefact
correction algorithms has made it possible to record the EEG continuously during the
fMRI investigation (43). An MRI-compatible EEG system with a high sampling rate
(several kHz) is needed for the recording, in order to fully capture the shape of the
gradient artefact for successful artefact correction. Online correction of gradient artefacts
can be applied to enable visual inspection of the EEG during the EEG-fMRI recording. In
addition to gradient artefacts, many EEG data sets are affected by heartbeat-synchronous
artefacts. These so-called pulse or ballistocardiographic artefacts are caused by subtle
pulse-synchronous movements of the head and can be removed by different artefact
correction methods (44, 45). For a more detailed description of the EEG-fMRI setup and
artefact correction algorithms please see recent review articles (46, 47).
Statistical analysis
The preprocessing of fMRI images does not differ from standard fMRI analysis and
includes realignment, smoothing, and normalization in the case of group analyses.
Standard analysis uses the event-related general linear model-based approach in which the
timing of events (e.g., IED) is used to build time series for the statistical analysis. In the
standard analysis, the timing of the events is convolved with the standard hemodynamic
response function which peaks approximately 5 seconds after the event. Statistical maps
show voxels significantly correlated with the marked event in the EEG. However, the
shape and latency of the hemodynamic response function (HRF) might vary with age or
different brain regions, or show altered response in epilepsy. If a more flexible HRF is
applied, the sensitivity of EEG-fMRI results can be improved. In addition to the standard
HRF, a more variable shape of the HRF can be achieved by including the derivative of the
HRF (48) by estimating noncanonical HRFs (49, 50) or using a set of different HRFs (51).
EEG-fMRI in focal epilepsy

The EEG-fMRI was developed as a tool which might have clinical implications in
presurgical evaluation by helping to localize the brain areas presumably generating IED.
Early studies showed IED-associated BOLD signal changes concordant with
electroclinical data in approximately 50% of the patients (52, 53). Improvements of the
statistical model by using multiple HRFs or fitting individual HRFs could increase the
sensitivity of BOLD signal detection (5154). The shape of the HRF might differ,
especially in children; and deactivations seem to occur more frequently in children with
focal lesional epilepsy than activations in the epileptogenic zone compared to adults (55,
56). Modeling spike-related BOLD signal changes in children might be even more
complex, since BOLD signal changes which precede the spike can be found in pediatric
patients (57). Increasing the field strength (3 Tesla versus 1.5 Tesla) also improves the
sensitivity of BOLD signal detection (58, 59). Patients selected for EEG-fMRI studies
should have frequent IED to capture a sufficient number of IED during the EEG-fMRI
investigation. However, often none or very few IED is recorded which leads to insufficient
statistical power in the analysis and consequently to inconclusive results. To overcome this
problem, Grouiller and coworkers applied a voltage map-based analysis in which they
built scalp voltage maps of averaged IED recorded during long-term clinical monitoring
and computed the correlation of this map with the EEG recorded inside the scanner. In
patients with previously inconclusive studies, BOLD changes concordant with intracranial
EEG or the resection area were detected. Even in patients in whom no clear IED in the
scanner EEG were detected, this voltage map-based analysis yielded conclusive results
(60). The sensitivity of the detection of IED-related BOLD signal changes can be further
increased, if additional EEG features, such as sleep specific activity, are modeled (61).
IED-associated BOLD signal and the epileptogenic zone

The relationship between IED-associated BOLD signal and the epileptogenic zone was
investigated by comparing BOLD signal changes to intracranial EEG recordings
performed after the EEG-fMRI investigation: Bnar and colleagues were able to show that
active electrodes in the intracranial EEG recordings were close to the areas of IEDassociated BOLD response (62). Good concordance between IED-associated BOLD signal
changes and seizure onset determined by intracranial EEG after the EEG-fMRI
investigation was also demonstrated in several cases in EEG-fMRI studies of focal
epilepsy (51, 63, 64). The studies mentioned above compared EEG-fMRI results with
intracranial EEG recorded on different days. Recently, safety studies made it possible to
perform an EEG-fMRI recording in patients with intracranial electrodes simultaneously
(icEEG-fMRI) (65, 66). In two patients investigated by Vulliemoz and colleagues no IED
was detected in scalp EEG-fMRI recordings performed prior to the implantation, while
icEEG-fMRI revealed clear IED in these patients. Until now, only few patients with
icEEG-fMRI have been reported. These studies showed BOLD response close to the
electrodes from which IED were recorded (67, 68). However, BOLD signal changes, not
only in the presumed epileptogenic zone but also in distant areas, were frequently detected
in both icEEG-fMRI and scalp EEG-fMRI studies (6771). These distant BOLD signal
changes may reflect remote effects of the epileptic IED and could be explained in part by
propagated epileptic activity (72, 73).
Most EEG-fMRI studies show both positive and negative BOLD responses. Positive
BOLD responses result from increased neuronal activity compared to baseline (74), while
negative BOLD responses might reflect suppressed neuronal activity (75). The IEDrelated negative BOLD signal changes might be caused by remote inhibition (76).
EEG-fMRI as a nonivasive tool in presurgical evaluation

Zijlmans and colleagues evaluated the role of EEG-fMRI in the preoperative work-up of
patients with medically refractory epilepsy (77). The authors investigated 29 patients with
EEG-fMRI who were denied surgery due to an unclear seizure focus. Only positive BOLD
signal changes that were topographically related to the IED field were considered. Eight
patients fulfilled this criterion and were re-evaluated for surgery based on the EEG-fMRI
results. Four of these patients did not show any structural abnormalities. In four patients,
including one MRI-negative case, EEG-fMRI improved identification of the seizure focus,
whereas EEG-fMRI showed either mulitfocality or widespread BOLD response in the
remaining four patients.
Most EEG-fMRI studies included both lesional and MRI-negative cases. We
specifically addressed the yield of EEG-fMRI in patients with MRI-negative frontal lobe
epilepsy. These patients are usually not considered good candidates for surgery, since
delineation of the epileptogenic zone is difficult due to widespread interictal discharges,
rapid spreading of ictal EEG changes, large areas which are inaccessible to scalp EEG, a
large variety of seizure semiology, and low sensitivity of PET and SPECT studies. The
aim of this study was to investigate whether EEG-fMRI can add meaningful information
about the epileptic focus in the presurgical evaluation of patients with MRI-negative
frontal lobe epilepsy. Good concordance between positive BOLD signal changes and
postoperative pathological analysis or other imaging modalities was found in eight out of
nine patients (78). An example of the comparison between EEG-fMRI results and methods
of the presurgical evaluation in a patient with focal epilepsy is depicted in Figure 8.1. A
postsurgical study showed that surgical resection which included the areas of positive
BOLD response was associated with a good postsurgical outcome (79). The EEG-fMRI
was recorded in ten patients undergoing presurgical evaluation; the locations of
preoperative, IED-associated BOLD signal changes were compared with the resected area
and postoperative outcome. Seven of ten patients were seizure-free following surgery and
the area of maximum BOLD signal change was found within the resected area in six of
seven patients. In the remaining three patients with only reduced postsurgical seizure
frequency, areas of significant IED-correlated BOLD signal change lay outside the
resection. Another study by Thornton and colleagues investigated patients with focal
cortical dysplasia and compared IED-associated BOLD signal changes with the seizure
onset zone (SOZ) based on icEEG recording and postoperative outcome 1 year after
surgery (80). Eleven of 12 patients had significant IED-related hemodynamic changes.
The fMRI results were concordant with the SOZ in five of 11 patients, all of whom had a
solitary SOZ on icEEG. Four of five had > 50% reduction in seizure frequency following
resective surgery. Two of these patients showed normal structural MRI. Another patient
with normal structural MRI, who had a solitary SOZ on icEEG and concordant BOLD
signal changes, was treated with gamma knife surgery and had a poor outcome. The
remaining six of 11 patients had widespread or discordant regions of IED-related fMRI
signal change. Five of six had either a poor surgical outcome (< 50% reduction in seizure
frequency) or widespread SOZ precluding surgery. The authors concluded that EEG-fMRI
provides useful additional information about the SOZ in patients with focal cortical
dysplasia: widely distributed discordant regions of IED-related hemodynamic change
appear to be associated with a broad SOZ and poor postsurgical outcome.
Figure 8.1 Comparison between EEG-fMRI and methods of the presurgical evaluation
in a patient with MRI-negative frontal lobe epilepsy. (A) interictal EEG (average
montage): focus F4; (B) interictal fMRI: positive BOLD response frontopolar; no negative
BOLD response; (C) ictal EEG: rhythmic spike and wave F4; (D) ictal fMRI: positive
BOLD response frontopolar, negative BOLD response frontal and posterior cingulated;
(E) MRI: suspicious, deep right-middle frontal sulcus; (F) ictal SPECT: hyperperfusion
frontal right; (G) FDG-PET hypometabolism frontal right; (H): postoperative MRI. (Taken
from Moeller F, Tyvaert L, Nguyen DK, LeVan P, Bouthillier A, Kobayashi E, et al. EEGfMRI: adding to standard evaluations of patients with nonlesional frontal lobe epilepsy.
Neurology 2009: 73:202330.)
If a method is used for clinical purposes, it has to show good reproducibility. Gholipour
and colleagues demonstrated reproducible EEG-fMRI results, supporting that this
technique might be used for clinical purposes. Their findings indicate that the sensitivity
of EEG-fMRI scans could be increased by scanning at 3T rather than at 1.5T (58).
However, what can EEG-fMRI tell us that EEG cannot? Pittau and coworkers evaluated
the new localizing information generated by EEG-fMRI compared to traditional EEG and
demonstrated additional information in many patients. Eleven of 33 patients studied were
MRI-negative cases. In nine of these cases the BOLD signal changes were concordant
with the spike EEG field; in six of these cases the BOLD signal changes provided
additional information to the scalp EEG (59). An example of a patient with MRI-negative
epilepsy is depicted in Figure 8.2. It is important that results are interpreted carefully,
since EEG-fMRI does not only show areas of the presumed epileptogenic zone, but also
areas (also distant areas) that might be indirectly influenced by the IED. If EEG-fMRI
results are considered in the context of other investigations of presurgical evaluation, they
can contribute to a better understanding of the epileptic zone in a specific patient.
Figure 8.2 Patient with MRI-negative frontal lobe epilepsy. The marked events were
Fp2F8 spikes. The BOLD response showed limited activation in the lateral right
orbitofrontal region. The patient underwent a depth electrode study. Five electrodes were
inserted into the right hemisphere: one in the orbitofrontal region (OF), one aiming for the
amygdala (A), one in the anterior hippocampus (H), one in the mid-insula (IM), and one in
the posterior hippocampus and parahippocampus (PH). The black points and lines indicate
the electrodes visible in these views and are obtained by coregistration with the BOLD
map. The intracranial study revealed a very active epileptic generator in the lateral portion
of the right orbitofrontal lobe (ROF6 ROF10). A limited right frontal corticectomy was
performed, and histology showed focal cortical dysplasia type I. Top: scalp EEG, bipolar
montage, Fp2F8 spikes. Bottom: intracerebral stereo EEG. Arrow indicates the interictal
event thought to correspond to the scalp spike. (Taken from Pittau F, Dubeau F, Gotman J.
Contribution of EEG/fMRI to the definition of the epileptic focus. Neurology 2012;
78(19):147987.)
Seizures
Seizures cannot be predicted and are only rarely recorded during the short time of an
EEG-fMRI. Analyzing a seizure is even more difficult, as it is often accompanied by
extensive movements which can make the analysis of the data impossible. To avoid
seizure-induced motion problems, Federico and colleagues analyzed the BOLD signal
prior to the beginning of a clinical seizure in three patients with focal epilepsy and found
BOLD signal changes in the preictal state (81). Studies in short seizures without seizureinduced movements showed extensive seizure-associated BOLD signal changes, which
also included the presumed SOZ (82, 83). A study by Tyvaert and colleagues on
malformations of cortical development demonstrated different BOLD signal changes for
interictal and ictal events (64). While the above-mentioned studies were analyzed in a
block design, new analysis techniques allow investigation of the dynamics of seizureassociated BOLD signal. The dynamic analysis of seizures can reveal regions of seizure
onset and propagation (8486). Tyvaert and colleagues studied ten patients with seizures
inside the scanner; three of the patients did not show structural abnormalities in the MRI.
In nine patients, including all MRI-negative cases, the location of the first activation of the
dynamical analysis coincided with the estimated focus based on seizure semiology,
interictal and scalp EEG, and intracranial EEG (if available).
Novel techniques
The EEG-fMRI localizes epileptic foci by detecting BOLD signal changes associated with
epileptic events visible in the EEG. However, scalp EEG is insensitive to activity
restricted to deep structures, and recording the EEG in the scanner is complex. A recent
study showed that it might be possible to detect epileptic activity from the fMRI data
without the help of an EEG. Based on a wavelet model of the fMRI data (2D-temporal
cluster analysis), Lopes and colleagues were able to detect similar results compared to an
EEG-based fMRI analysis (87). The method is based on the assumption that the resting
brain does not show significant BOLD variations in the HRF other than those associated
with IED in the epileptic brain. The method could provide results in patients in whom IED
on the scalp are not visible, and could allow the identification of IED epileptic networks in
fMRI without EEG. The sensitivity of EEG-fMRI studies could be further increased by
new fast MRI sequences. In such fMRI sequences, called magnetic resonance
encephalography (MREG), fMRI images are acquired with a temporal resolution of 100
ms (88). Since 2030 times more images after each IED are recorded than during a
classical fMRI sequence, the statistical power of the study increases. In a first study of 13
patients with focal epilepsy the average t-value of BOLD responses was significantly
higher in the MREG than in the standard fMRI sequence with a temporal resolution of 2.6
s. Moreover, BOLD responses with MREG were found in patients in whom the standard
fMRI did not show any BOLD changes. The BOLD signal changes were even detected in
single spike analyses (8990). The high temporal resolution might allow the
differentiation between onset and propagation of epileptic activity.
However, not only IED-associated EEG-fMRI might play a role in the presurgical
evaluation. Functional connectivity studies measure how different brain areas are
connected during the resting state of the brain. Negishi and colleagues proposed functional
connectivity as a predictor of epilepsy surgery outcome (91). The IED-related EEG-fMRI
was performed for each patient. An activation cluster that overlapped most with the
planned resection area was chosen, in order to perform a functional connectivity analysis.
Patients who had a poor postsurgical outcome showed less lateralized functional
connectivity than patients who were seizure-free after the surgery.
Conclusions on EEG-fMRI
There are few studies that specifically address the value of EEG-fMRI in MRI-negative
refractory epilepsy. Most studies investigated both lesional and nonlesional cases. These
studies show that IED and seizure-related EEG-fMRI can be used to noninvasively detect
the epileptogenic zone. It is of note that EEG-fMRI is only an additional tool in the
presurgical work-up, and the results have to be considered in the context of other
investigations of the presurgical evaluation. Postsurgical studies suggest that surgical
resection that includes the areas of positive BOLD response, and a lateralized functional
connectivity, is associated with a good postsurgical outcome. Novel techniques such as
fast MRI sequences may further increase the value of EEG-fMRI.
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91. Negishi M, Martuzzi R, Novotny EJ, Spencer DD, Constable RT. Functional MR
connectivity as a predictor of the surgical outcome of epilepsy. Epilepsia 2011;
52:17331740.
Chapter 9 Multimodality image coregistration for MRInegative epilepsy surgery

Benjamin H. Brinkmann and Vlastimil Sulc
Introduction
Resective surgery in MRI-negative epilepsy results in poorer outcomes and a higher rate
of recurrence compared to cases with a structural lesion visible on magnetic resonance
imaging (MRI). As many as 26% overall and 46% of extratemporal (1) patients
undergoing epilepsy surgery have negative MRI, and in these cases functional studies,
including positron emission tomography (PET), ictal and interictal single photon emission
computed tomography (SPECT), diffusion-weighted MRI (DWI), functional MRI (fMRI),
and chronic intracranial EEG (icEEG) monitoring are often essential for localization of the
epileptogenic zone. In order to coalesce the results from these disparate modalities around
a coherent epileptogenic hypothesis to guide resective surgery, the functional data must be
spatially aligned into a single coordinate system, typically corresponding to the patients
high-resolution T1-weighted MRI, to ultimately guide the resection plan.
In addition, improvements to the sensitivity and specificity of functional modalities are
often achievable by comparison of patient scans to spatially varying statistical metrics of
normality derived from measurements of normal, or nonepileptic, subjects. For a group
analysis, it is necessary to transform all data to one common template space. Recent
results in cerebral blood flow mapping with ictalinterictal subtraction SPECT show
significant improvement in localization when patient scans are evaluated in the context of
paired resting scans of normal individuals (2,3). Statistical parametric mapping of [18F]
fluorodeoxyglucose (FDG) PET scans in comparison to normals has been shown to
improve the localizing capability of PET in epilepsy (4,5). The development of novel
receptor PET tracers has also furthered the study of epilepsy via PET, and SPM will likely
prove useful as normal scans become available.
Preprocessing for coregistration

Image coregistration is predicated upon the assumption that voxel intensities or features in
one image correspond directly to intensities or features in the image to be coregistered. In
some cases, especially cross-modality registration, that assumption requires images to be
preprocessed before registration can proceed.
For accurate registration of functional imaging modalities to high-resolution MRI it is
often beneficial to separate brain voxels from the entire head image. Elimination of
nonbrain signals such as skull, orbits, and muscles generally improves the robustness of
the registration, as functional images usually contain little extra-brain tissue, and structural
images may contain changes in extracerebral morphology (e.g., a craniotomy in CT
images of electrode placement). There are three commonly used methods for achieving
brain/nonbrain segmentation: manual tracing, intensity thresholding with morphological
processing, and model-based approach. Manual thresholding is arduous and time
consuming, but does offer the user the opportunity to adjust appropriately to anomalies
(tumor, prior resection, surgical intervention, etc.) during the segmentation process. Semiautomated intensity thresholding with morphological processing is much less arduous and
may allow the user to retain some control over characterization of anatomical anomalies.
Model-based cerebral segmentation typically nonlinearly maps an anatomical model to the
brain either using surface or voxel-based criteria. The procedure requires very little user
intervention and offers the added benefit of providing standardized atlas labels and regions
of interest to the brain volume, but the procedure may inappropriately label anatomical
features that do not correspond clearly to standard brain regions. For functional imaging
modalities such as PET and SPECT, simple thresholding is usually sufficient to remove
extracerebral activity.
Some intensity normalization or filtering may be necessary as well to facilitate image
coregistration. The PET and SPECT images suffer from attenuation of emitted photons
passing through brain and skull tissue and commensurate reduction in counting statistics
proportional to depth from the skin surface. Most SPECT and PET acquisition systems
apply attenuation correction as part of the image reconstruction process, and while the
typical user would not need to correct for this effect explicitly, it does result in reduction
of signal-to-noise ratio near the center of the brain. The MRI images may suffer from
intensity nonuniformities due to uneven receiver coil coverage or an inhomogeneous main
magnetic field, resulting in a bias field across the image. A number of techniques have
been proposed for correcting this class of artifact (6,7), including filtering methods,
histogram correction, and template-based methods. Other types of artifacts in the image
due to patient motion, magnetic susceptibility, fluid flow, and other factors may distort the
relationships between voxel intensities or features to be coregistered, and they would be
expected to reduce the accuracy of image registration.
Image registration algorithms

The goodness of the match is based on a cost function (Figure 9.1), which is calculated
using some optimization algorithm. The cost function may involve relationships between
features (points, lines, surfaces, or anatomical features) in the images or a mathematical
computation involving intensity values of corresponding image voxels. The cost function
is designed such that when the two image sets are in perfect alignment the cost calculation
reaches an unambiguous globally minimal1 value. Normally, there are many parameters,
and it is not feasible to search through the whole parameter space. The usual approach is
to make an initial parameter estimate, and begin iteratively searching from there. A
judgment is then made about how the parameter estimates should be modified, before
continuing on to the next iteration. The optimization is terminated when some
convergence criterion is achieved (usually when chi2 stops decreasing or a fixed number
of iterations is reached).
Figure 9.1 Normalized mutual information rigid body registration of a PET image to a
T1-weighted MRI. The joint grayscale probability distributions are shown before and after
registration.
Numerical minimization is the process by which the parameter space of rotations and
translations is searched efficiently in order to find the optimal value of the registration cost
function. A number of published strategies exist for cost function minimization, and the
reader is directed to the literature for further detail (8,9). To speed up the optimization
process and to avoid local minima, most currently used registration methods employ some
form of multiresolution optimization. The images at larger scales are subsampled versions
(often with preblurring) of the original high-resolution images, and so contain fewer
voxels, which means that evaluating the cost function requires less computation. In
addition, as only gross features of the images remain at these large scales, it is hoped that
there will be fewer local minima for the optimization to be trapped in.
Interpolation, though often not considered part of the image registration algorithm
itself, is an important step in the coregistration process and can be viewed as
reconstructing a full continuous image from the set of discrete transformed points.
Interpolation methods can significantly affect the quality of the registered image, and
some precision has to be sacrificed in order to lower computational efforts. Nearest
neighbor (zero-order hold resampling) provides very fast interpolation that maps to the
value of the closest neighboring voxel without correcting for intensities at subvoxel
displacement. This algorithm is very fast, but the resulting image quality is degraded quite
considerably resulting in the resampled image having a blocky appearance. Bi- and
trilinear interpolation (first-order hold) is slower than nearest neighbor, but the resulting
images are of higher quality. These interpolation methods provide visually appealing
output images, but do suffer from loss of high-frequency information due to averaging of
neighboring pixel values in the interpolation process. Higher-degree interpolation
algorithms (polynomial interpolation), including quadratic, cubic, spline, and Gaussian,
provide more precise interpolation but are computationally slower because of more
neighboring voxels used in the algorithm. Windowed sinc (sin(x)/x) interpolation can be
used to apply image transformations and may offer the nearest approximation to true
Fourier interpolation given appropriate choice of window (10).
Linear registration
Linear registration is an important component of medical image analysis as it enables in a
single patient comparison of different imaging sequences, or multiple imaging modalities
that can provide additional information not available in a single image modality. With
intermodal coregistration, one image (usually a high-resolution structural MRI scan)
remains stationary and other images are spatially transformed to match it. Linear rigid
body registration is used routinely to correct movement between sequential scans in an
acquisition, as some degree of subject motion within the scanner is usually present,
especially when the scanning takes a long time. Once images are in the same space they
can be averaged in order to increase signal to noise, or subtracted to emphasize
differences between the images. Since the shape of the human brain changes very little
with head movement, rigid body transformation can be used to correct for different head
positions of the same subject. This is an important task as images from different imaging
modalities can have different orientation, field of view size, contrast, and noise
distribution.
Linear transformations are the most basic class of transformations, where all voxels are
constrained to move according to a global, linear relationship. A rigid body transformation
in three dimensions is defined by six parameters: three translations and three rotations.
Scale terms are computed from the voxel dimensions of the images to account for global
scale differences between images. Affine registration is similar to rigid body registration
but scale and linear shear terms are calculated from the registration metric. While still a
linear operation, affine registration can be thought of as a low-order, limited version of
nonlinear registration or spatial normalization.
Feature and surface metrics

Feature-based techniques identify homologous features (labels) in the source and
reference images and find the transformation for the best match. The features can be
homologous points, lines, or surfaces. Corresponding features can be identified manually,

but this makes this process subjective and time demanding. Anatomical landmark-based
matching of corresponding points is the simplest form of registration. The user chooses
homologous points in the base and transforming images, and a least-squares error
minimization is performed to compute the best transformation between the sets of points.
This procedure is user intensive, and accuracy can be poor unless a large number of
homologous points are used, due to the imprecision of landmark identification (11), but it
may be necessary in cases where homologous surfaces or voxel intensity correlations
cannot be established. However, point-based registration with invasively fixed fiducial
markers is used in neurosurgical systems with exceptional accuracy, and represents the
gold standard for accurate image-guided surgical navigation (12).
Surface-based registration has been commonly used with good results. Surface
registration algorithms require the user to identify analogous surfaces in the reference and
transformation images, and a best fit between surfaces is calculated. The brain surface is
typically used, although this may prove unreliable if significant shift has occurred with a
craniotomy (13,14). Surface matching algorithms minimize the mean squared distance or
some variant thereof between homologous surfaces in the two images, producing a hat on
head best fit (15,16). Surface-based registrations lend themselves particularly well to
applications where one of the data sets to be registered is inherently a surface, for example
matching scalp EEG electrode positions to a subjects MRI (17,18), or laser surface
scanning for intraoperative image-guided navigation (19). However, for most highresolution volumetric image registration applications, voxel-based cost functions have
been shown to provide more accurate results than surface-based algorithms (20).
Voxel intensity metrics

Voxel-based algorithms assume certain relationship between voxel values between two
images. This relationship can be a simple correspondence in the same modality
registration (e.g., SPECT to SPECT) or a more complex relationship when one tissue
voxel value corresponds to two or more tissues in other modality (e.g., CT to PET).
Woods et al. (21) developed one of the earliest successful voxel intensity-based
algorithms for image registration. The algorithms cost measure of registration between
MR and PET is based on the assumption that when registered the range of PET values
associated with a particular value of MR should be minimized. The overall measure is a
sum of the standard deviations of the ratios of corresponding image values, with an
iterative NewtonRaphson method employed to minimize the cost function. While the
algorithm has been used successfully in a variety of applications (22,23), there is a
concern that Woods technique can break down when there is a bimodal or multimodal
distribution of test volume values (24), which is often the case when matching CT and
MRI, where CT voxel intensities of brain parenchyma show little grayscale variation.
Mutual information (24,25), and normalized mutual information (26,27), is a measure
of dependence of one image on the other, and can be considered as the distance between
the joint grayscale probability distribution (P(f; g)) and the grayscale probability
distributions assuming complete independence (P(f)P(g)). When the two distributions are
identical, this distance (and the mutual information) is zero. Mutual information-based
registration does not assume a specific intensity relationship between different images and
is a measure of statistical dependency between two data sets. The most widely adopted
scheme for maximizing mutual information is Powells method, which involves a series of
successive line searches for each dimension until convergence is reached. Mutual
information registration can handle data that are conditionally multimodal.
While Woods algorithm and mutual information represent the most widely used voxel
intensity-based image registration techniques, other cost functions are also used, and they
include entropy correlation coefficient, and normalized cross-correlation (28). Cost
function and interpolation are usually shipped in a registration package. These include
AIR (21), SPM (29), UMDS (27), MRITOTAL (30), and FSL (31).
Nonlinear spatial normalization (warping)

Nonlinear spatial normalization involves transforming the subjects data into a normalized
stereotactic space by a given matching criterion. Definition of normalized space is the
same for all imaging modalities, so no further coregistration is needed once images are
normalized. Spatial normalization may be achieved using many of the same cost functions
underlying rigid body registration, but with higher-order polynomials or spatial frequency
components modeling the transformation. A common reference frame enables data
comparisons across subjects and time. The first step in registering images from different
subjects involves determining the optimum 12 parameter affine transformation used to
account for gross differences in head position and shape.
Lower-order scaling and skew terms

The rationale for adopting a low-dimensional approach is that it allows rapid and general
modeling of global brain shape. With more registration parameters used, a more precise fit
is usually achieved, but this relationship is not linear. Depending on the analysis design,
most of the variability can be accounted for using only nine or 12 degrees of freedom,
eliminating major differences in brain shape. With the exception of major sulci, there is a
high interindividual variance in cortical shape and features; and to achieve a perfect
match, it would be necessary to create sulci and gyri that do not exist in the original brain.
There is also no guarantee that spatially normalized gray matter loci are functionally
equivalent, particularly in patients with chronic epilepsy (32). Spatial smoothing,
commonly used in spatial normalization, improves the signal-to-noise ratio and is able to
compensate for small anatomical and functional interindividual variability with the cost of
losing some high-frequency information.
Higher-order complex deformations

High-dimensional registration can involve thousands to millions of match parameters, and
so is potentially able to match images very precisely. Additional registration parameters
used require more computing power; so for speed, a relatively low number of parameters
is usually used initially, with more complex parameters added progressively. Generally,
the algorithms work by minimizing the sum of squared difference between the image
which is to be normalized and a linear combination of one or more template images. For
optimal estimation, contrast in the template and registered image should be similar.
The set of sulci that are consistently present in normal subject is quite limited, and it
includes the interhemispheric fissure, the Sylvian fissure, the parietaloccipital fissure,
and the central sulcus. The differences in sulcal pattern appear even in monozygotic twins
(33). Additional functional and cytoarchitectonic differences can make definition of
homologous areas problematic (34).
Visually, the registered images appear very similar following spatial normalization.
This is not an adequate indication of the quality of the registration, but it does confirm that
the optimization algorithm has reduced the likelihood potentials. It is possible for the
wrong structures to be registered together, but distorted so that they look identical (35).
Validation of warping methods is a complex area. Klein (36) evaluated 14 registration
algorithms based on overlap measures of manually labeled anatomical regions and found
only a modest correlation between the number of degrees of freedom of the deformation
and registration accuracy.
For population studies, mapping to a standardized template space is often beneficial
because it enables reporting various activations or brain changes in reference coordinates.
These changes can then be compared across different studies. Furthermore, for a group
analysis, it is necessary to have all brains in the same space. This template stereotactic
space is usually defined by ICBM or MNI brain template and an approximate of the space
described in the atlas of Talairach and Tournoux (1988). An assumption is made that
functionally equivalent regions from different subjects lie in approximately the same part
of the brain. This is usually only partially true, and some smoothing is necessary for
statistical analysis. Because there is usually no perfect match for every voxel registered to
normalized space, some regions are compressed while others are dilated, which in
statistical analysis affects the contribution of a resized region.
Applications and examples

MRI-PET
The epileptogenic zone frequently exhibits decreased glucose metabolism interictally,
which often extends beyond the seizure focus (5). Correlation of PET hypometabolism
with the underlying cortical anatomy (typically via a high-resolution MRI) is an important
step in planning resective epilepsy surgery with concordant FDG-PET hypometabolism, as
this metabolic anomaly can significantly influence the location and amount of tissue
resected. The FDG-PET coregistred with MRI was shown to be highly sensitive to detect
focal cortical dysplasias type II and was also predictive for seizure freedom (37). Figure
9.2 illustrates a patient with right temporal lobe epilepsy confirmed by hypometabolism in
the right mesial temporal lobe. The patients FDG-PET was registered to a high-resolution
seizure protocol MRI via a rigid body mutual information algorithm.
Figure 9.2 F-18 fluorodeoxyglucose PET imaging registered to a high-resolution

postoperative T1-weighted MRI for a patient with right temporal lobe epilepsy. The
hypometabolic defect identifies the anterior temporal lobe as abnormal despite the absence
of a structural lesion in the original preoperative MRI.
MRI-SISCOM and comparison to STATISCOM

Subtraction ictal SPECT coregistered to MRI (SISCOM) (38) uses voxel-based rigid body
registration to register a patients interictal SPECT image to the ictal SPECT; and
following normalization, subtraction, and thresholding, to register the activation map to
the patients high-resolution MRI. Statistical comparison of the difference image to paired
sequential SPECT images from neurologically normal volunteers is possible once the
normal SPECT images have been nonlinearly registered to the patients brain. This
process has been shown to improve the sensitivity and specificity of ictal SPECT studies
(2,3). Figure 9.3 illustrates Tc-99m ethyl cysteine dimer SISCOM images (top) and the
same ictal and interictal SPECT images analyzed statistically against a group of 30 paired
SPECT images of normal volunteers for a patient with left temporal lobe epilepsy.
Statistical mapping was performed in MATLAB (Mathworks Inc., Natick, MA) using
custom software and SPM (Wellcome Trust Centre for Neuroimaging).
Figure 9.3 Subtraction ictal SPECT (top) and statistical mapping (bottom) of the SPECT
activations in a patient with left temporal lobe epilepsy.
Electrode coregistration and seizure mapping

Intracranial EEG recordings of seizure activity represent the current gold standard of
epileptogenic localization for resective surgery. It is often useful to visualize electrode
contact positions in conjunction with the underlying cortical anatomy, and it is possible to
create visualizations of neuronal activity interpolated on to the cortical surface, providing
a spatial context for electrophysiological activity. Electrode positions are typically
identified in X-ray CT images taken immediately following electrode implantation. In
Figure 9.4, registration of the CT (B) into the space of the patients high-resolution MRI
(A) was accomplished using a normalized mutual information algorithm implemented in
Analyze (Biomedical Imaging Resource, Mayo Foundation, Rochester, MN). Averaging
the two images is shown in (C). The cortical surface in the MRI was identified using a
semi-automated threshold-morphology algorithm, and three-dimensional renderings were
created using a volume compositing algorithm. Electrode positions are identified by the
red spheres, with the resected cortical tissue, identified by registering and subtracting the
patients postresection MRI, shown in yellow. Time-frequency analysis of one of the
patients recorded habitual seizures was performed, and the electrophysiological activity at
40 Hz midway through the seizure was color-coded and mapped on to the cortical surface.
This electrophysiological mapping can be an important step for accurate clinical diagnosis
and treatment as well as for scientific electrophysiological research.
Figure 9.4 Registration of a patients high-resolution structural MRI (A) with electrode
implant CT (B) allows the fused cortical surface and electrodes (C) to be rendered in three
dimensions, illustrating the relative locations of electrode contacts with the cortical
anatomy and eventual resection site, shown in yellow (D). The electrode registration also
permits mapping of recorded electrophysiology (activity at 40 Hz during a seizure) on to
the cortical surface (E).
Neuroimaging tools
Most of the previously mentioned software packages are freely available via the internet
and are able to run on various operating systems (36) depending on preference of the user.
A moderately powerful workstation is recommended, although for single-case analysis the
difference in computing time between a high-end and mid-tier workstation is usually
negligible. In a large data set, total computing time starts to play a more important role and
use of distributed computing and/or general-purpose computing on graphical processing
units (GPGPU) significantly shorten the analysis. For further imaging examples and
sources the reader is directed to the website of Neuroimaging Informatics Tools and
Resources Clearinghouse (NITRC, www.nitrc.org) funded by the National Institutes of
Health Blueprint for Neuroscience Research.
Conclusion
Image registration is an important tool for correlating functional measurements with their
underlying anatomical substrate in preoperative planning for resective epilepsy surgery.
Successful surgical management of focal epilepsy depends on accurate identification and
delineation of the seizure onset zone for resection. In the absence of an MRI-visible
structural lesion, epileptogenic localization depends on functional information from
imaging modalities including PET, SPECT, and functional MRI, as well as scalp and
intracranial electroencephalographic recordings of epileptiform discharges. In developing
the clinical localization hypothesis that will guide surgical resection, information from
these different modalities images must be compared and analyzed with respect to one
another and the patients underlying cerebral anatomy, and this integration mandates
coregistration of these functional modalities into a common physical coordinate system.
Dysfunctional patterns not otherwise apparent may be highlighted by statistical
comparison of a patients functional scans with a population of normal subjects, if the
patients scans and control scans are nonlinearly transformed into a common anatomical
reference space.
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1
While cost functions can be formulated to reach a maximal value at perfect
coregistration, it is traditional to refer to cost function minimization, and any calculation

can be inverted to fit this convention.
Chapter 10 Subdural electrode implantation and recording

in MRI-negative epilepsy surgery
Michael R. Sperling and Christopher T. Skidmore
Introduction
Noninvasive evaluation is often sufficient when planning epilepsy surgery, and improved
characterization of seizures, better understanding of epilepsy syndromes, and advances in
neuroimaging in particular have made the use of intracranial electrodes less necessary than
in the past. However, noninvasive testing at times fails to provide adequate information to
plan surgery, and intracranial video-EEG monitoring remains a valuable tool. The view
that intracranial EEG is a gold standard ascribes greater reliability and accuracy than it
deserves, but the data provided by the EEG enable surgery to be performed when surgery
would otherwise not be possible. The intracranial EEG can identify the zone in which
interictal abnormalities predominate, and delineate areas in which seizures arise. When
these regions are considered in light of the clinical history, examination, and other
laboratory features, surgery is often successful. Intracranial EEG must delimit the margins
of the epileptogenic zone (defined as the cortex necessary and sufficient to generate
seizures) and the function of cortex within the bounds of that zone may need to be defined.
Hence, the anatomy and physiology of the epileptic zone dictate how the EEG is best
obtained. Different types of intracranial electrodes may be used to define the cortical areas
that must be excised. When buried cortex, such as hippocampus, amygdala, and gyral
depths, are suspect, depth electrodes are best suited, since they penetrate the brain and
record directly from these areas. When superficial neocortex is believed to contain the
zone of interest, and particularly when functional mapping is required, then subdural
electrodes play an essential role. Depth electrodes are discussed elsewhere in this text. The
present chapter will review how subdural electrodes are used to define the extent of
resection in patients with negative MRI scans. The reader should be reminded that many
patients are evaluated with simultaneous use of both subdural and depth electrodes to
achieve optimal sampling of cortex. We will review the strategy used when planning
subdural investigations, effective use of subdural electrodes, results of subdural electrode
recording, and the complications associated with their use.
Subdural electrodes
Subdural electrodes are constructed by embedding platinum discs in an inert flexible
material, such as silastic. The contacts usually have an exposed diameter of 1.52.5 cm,
though this can be customized. Commercial electrodes are often spaced 1 cm apart, but
inter-electrode distances can also be customized if closer spacing is required. The contacts
can be arrayed in a variety of geometric configurations though they are most commonly
placed in linear arrays, known as strip electrodes, or rectangular arrangements, known
as grid electrodes. For ordinary clinical purposes, subdural strip electrodes are
fabricated in linear arrays of four to eight contacts, while grid electrodes come in a variety
of configurations, ranging from including 2 x 2 to 8 x 8 (Figure 10.1). The number of grid
electrode contacts can far exceed this, however, and is limited only by technical limits in
the number of recording channels and practical size constraints. Hence, grids containing
hundreds of contacts can be fabricated for research (or clinical) purposes, placing
electrode contacts at small intervals. Portions of the grid can be removed if needed in the
operating room to adapt the grid to local brain anatomy. In addition, the contacts need not
be placed in straight lines, but can be curved to account for gyral anatomy (most often
used when recording from interhemispheric cortex, i.e., pericallosal or cingulate gyri).
Figure 10.1 (a) Subdural strip electrode with connecting cable. A linear array of contacts
is spaced 1 cm apart, with wires running from each contact through the silastic matrix to a
cable that attaches to a connecting cable that can plug into a jackbox. (b) Subdural grid
electrode in an 8 by 8 contact array. Contacts are spaced 1 cm apart, with wires running
from each contact to cables that will attach to a connecting cable that plugs into the
jackbox.
Figure 10.2 shows an intracranial implantation of strip and grid electrodes. Strip
electrodes can be inserted via a burr hole or a craniotomy; their narrow width allows for
easy insertion, whereas grid electrodes must be placed through a craniotomy because of
their size. There are advantages and disadvantages to placing electrodes through a burr
hole instead of a craniotomy and these differences often help decide which type of
implantation is performed. Placing electrodes though a burr hole is less invasive than
inserting them via a craniotomy and is associated with lower infection rates (1), probably
because this method does not produce avascular segments of the skull. However, the
surgeon cannot directly visualize the cortex when placing subdural strips through a burr
hole to ensure that contacts are placed precisely where desired. Adhesions, veins,
variations in gyral anatomy, and bony protrusions can all misdirect the subdural electrode
strip, sometimes far from its desired location. Precise targeting and homotopic sampling is
therefore rarely possible. When sliding along the pial surface, subdural strip electrodes can
occasionally pierce the brain, if misdirected by a bony prominence or by accidentally
detouring into a sulcus. Subdural electrodes are easily removed either at the bedside or in
the operating room, much more easily than a subdural grid. Because strips have a lower
volume than grids, they have less potential for producing mass effect and are less apt to
cause herniation of the brain. Because subdural strip electrodes consist of a single row of
electrode contacts, their value in defining the spatial extent of interictal and ictal EEG
discharges is limited. However, this limitation can be overcome by placing several strips
approximately parallel to each other. In some locations, e.g., recording from the temporal
or frontal pole, one can readily ascertain the posterior extent of the resection line with a
single strip electrode; a single strip directed from lateral to mesial temporal or frontal lobe
cortex is adequate to determine whether seizures start in basal or lateral cortex (though the
anterior to posterior extent of the discharge might not be apparent).
Figure 10.2 Skull X-ray showing an 8 x 8 cm subdural grid spanning the right frontal,
parietal, and temporal lobes. Subdural strip electrodes have also been placed over occipital
and posterior temporal cortex, basal, and anterior temporal cortex, and frontal lobe. This
exemplifies a focused implantation with the grid, with added sampling of more distant
regions to ensure that an unexpected ictal onset is not also present.
Subdural grid electrodes are placed through a craniotomy, inserted under direct
visualization. They can therefore be accurately placed without the ambiguities or
limitations of inserting a subdural strip electrode through a burr hole. The larger size of
grid electrodes allows more comprehensive coverage of a cortical region and enhanced
spatial resolution. Helpful for defining interictal and ictal discharges, subdural grids are
particularly valuable for mapping eloquent cortex with electrical stimulation. As noted
above, morbidity of grids is greater than subdural strips (particularly with regard to
infection risk), patient discomfort is inherently greater because of the need for a
craniotomy, and risk of herniation is greater (2). While electrodes can be left in place for
many weeks if necessary, it is desirable to complete intracranial EEG recording quickly to
reduce infection risk. Most centers leave subdural electrodes in place from 414 days,
removing electrodes once the clinical question has been answered, and physicians should
hasten the process when employing grids to minimize risk of infection.

Subdural electrodes are subject to limitations. As noted above, they are not well suited
to record EEG from buried cortex, such as the hippocampus. The extensive array can
restrict the placement of depth electrodes, and a remarkable amount of cortex beneath the
grid lies between electrode contacts and is not sampled, particularly within the depths of
sulci. A neurosurgical procedure is needed to place the electrodes, and if seizures first
appear at the edge of a grid or in many contacts at once, moving the grid or adding
electrodes is not a trivial matter. It requires a second operation. It is possible that the mass
effect and trauma of grid insertion alters the electrophysiology of adjacent cortex, thereby
affecting interictal and ictal discharges. Lastly, interpretation of the intracranial EEG is
challenging, and it is often difficult to precisely determine when and where seizures start.
Ictal discharges might gradually intrude into the EEG background, and be masked by
changes in normal background frequencies caused by arousal. Improvements in recording
techniques have revealed intracranial EEG patterns not visible in the past (e.g., highfrequency oscillations), and our understanding of EEG interpretation continues to improve
as more knowledge is gained.
Recording the EEG

Commercial EEG equipment is designed to record from intracranial electrodes. Most
systems will allow the neurophysiologist to record from as many channels as desired, and
it is not uncommon to record from hundreds of contacts at once. We routinely record 196
channels of intracranial EEG in our institution, though properly examining so many
channels can pose practical problems because of limits in the human visual system and
display screens. The EEG should be sampled at 1000 Hz or 2000 Hz for accurate
representation of fast frequencies and detection of high-frequency oscillations. If
microwires are used to record from individual neurons, then faster sampling rates, up to 20
000 Hz are required. Synchronized video helps relate specific behaviors to the EEG. When
recording intracranial EEG, it is critical to ensure that the ictal changes in the EEG
precede any alteration in behavior. Should the EEG lag behind behavior, the earliest EEG
discharges are certainly propagated from an area of the brain without EEG sampling;
additional electrodes then need to be inserted to define the ictal onset zone.
Indications for use of intracranial electrodes

Intracranial electrodes are used when noninvasively obtained data is insufficient to
recommend a safe therapeutic procedure, and it is reasonable to believe that further
information will likely lead to an operation. A variety of protocols are employed,
subscribing to the general principle that intracranial EEG must be performed when an
epileptogenic structural lesion has not been adequately identified with noninvasive testing
(Table 10.1). This situation may occur if: 1. the data are discordant, raising the possibility
that seizures emanate from more than one area, or; 2. the data are insufficiently localizing
to confidently define the location of the epileptogenic zone. In MRI-negative patients, any
conclusion about the presence of a structural lesion is inferential since the lesion cannot be
visualized, and these individuals are more likely to require intracranial EEG. An example
of an MRI-negative patient with discordant data would be the circumstance in which the
aura and seizure semiology suggested a left frontal lesion, but the interictal spikes
emanated from the left frontal and anterior temporal regions, and positron emission
tomography (PET) showed right temporal hypometabolism. An example of an MRInegative patient with inadequate data would be one whose aura was nonspecific, interictal
EEG showed left anterior temporal spikes, but seizures were nonlocalized, and PET and
other noninvasive tests were normal. In contrast, the MRI-negative patient with an
epigastic aura, interictal right anterior temporal spikes, right anterior temporal seizures,
and right temporal hypometabolism with PET scanning with no conflicting data does not
require intracranial EEG; a right anterior temporal resection can be offered with a high
probability of success (3).
Table 10.1 Intracranial EEG rationale
Define the cortical area to be resected when noninvasive methods are
inadequate
Conflicting data, possibility of multifocal seizures
Inadequate concordance of data and doubt regarding the location of
epileptogenic zone
Define the function of cortex in areas where surgery is contemplated
Localize motor, sensory, language function
A reasonable hypothesis regarding localization is required
Fishing expeditions should be discouraged
Intracranial electrodes, especially subdural electrodes may be implanted when the
epileptogenic region has been established with reasonable certainty, but surgery poses risk
of causing a neurological deficit. For example, a patient whose seizures begin with tonic
posturing of the right hand and whose scalp EEG shows left frontal spikes in the interictal
state, left frontal seizure onset, and focal, restricted left frontal hyperperfusion with ictal
single photon emission computed tomography (SPECT or SISCOM) does not have a
cryptic epileptogenic zone. It is undoubtedly located in the left frontal lobe, anterior to the
primary motor cortex. However, the proximity of that zone to vital primary motor cortex
means that surgery could produce a lasting paresis of the hand. In this circumstance, two
options could be used. One could proceed directly to surgery, map primary motor cortex,
and then excise cortex immediately anterior to motor cortex, perhaps using
electrocorticography to search for interictal disturbances that might better define the
epileptogenic zone. Alternatively, one might prefer to use chronic intracranial video-EEG
with subdural electrodes, to better characterize the area responsible for both interictal and
ictal EEG abnormalities, and then map motor function in a less pressured environment
than the operating room. In the absence of a structural lesion in the MRI to help guide the
resection, the latter choice chronic intracranial EEG might afford more confidence and
reduce the risk of a lasting deficit.
Strategies for using subdural electrodes
How does one decide where to place intracranial electrodes? Positioning electrodes relies
on developing a reasonable hypothesis regarding the location of the epileptogenic zone.
The objective of the intracranial study is to define the epileptogenic zone as best as
possible and identify eloquent cortex. An intracranial study should determine whether
surgery can be performed, and if so, define the margins of the cortex to be removed and
locate relevant eloquent cortex. Proper planning can occur only after acquiring a careful
and detailed history, performing a neurological examination, obtaining scalp interictal and
ictal EEG, MRI scan, positron emission tomography (PET), neuropsychological testing,
and various other tests such as functional MRI (fMRI) or diffusion tensor imaging (DTI),
single photon emission computed tomography (SPECT), and magnetoencephalography
(MEG). Once these assessments are complete, plans can be made to place intracranial
electrodes over or within suspect cortex to finalize a surgical plan. Electrodes cannot be
placed everywhere in the brain, so it is important to have a high pretest probability of the
possible location(s) of the epileptogenic zone to guide implantation of the electrodes.
Where to place electrodes is determined by the presumed location of the epileptogenic
zone and the location of alternative areas that might be responsible for seizures. It is often
necessary to record EEG from cortical areas that are not part of the ictal onset zone but
might be involved early in the course of seizure propagation since removal of this cortex
might be necessary to abolish seizures in some individuals (it is part of the epileptogenic
zone). Sampling from cortex outside the epileptogenic zone is also critical for defining
that zone; after all, one cannot know that a particular area or lobe comprises the entirety of
the epileptogenic zone unless one also records EEG from other areas in the brain and
demonstrates that seizures do not start in those regions. For example, if a
neurophysiologist only records intracranial EEG from the right frontal lobe, all seizures
will appear to originate there irrespective of the actual location of the epileptogenic zone;
seizures might have begun elsewhere and appeared in the right frontal lobe electrode
contacts only after propagating there from the primary site. In addition, assessing the
routes and timing of seizure propagation can aid in determining whether the presumed
ictal onset zone is a plausible one. For example, if ictal onset appears in a frontal lobe and
the earliest site of seizure propagation is located in the contralateral occipital lobe, one can
be reasonably confident that the presumed frontal localization is incorrect, given the lack
of direct connections between these lobes; patterns of seizure spread should comport with
established brain anatomic connections. Lastly, if the epileptogenic zone is presumed to be
located near functional cortex, then electrode contacts will need to be placed over a broad
enough area to ensure that eloquent cortex can be defined.
In MRI-negative epilepsy, how might one proceed in planning an intracranial
investigation? The key steps are summarized in Table 10.2. The history is particularly
important. While many auras or early signs are not well localizing, others can be quite
specific and suggest the location of the epileptogenic zone (4, 5). For example, a seizure
beginning with bilateral proximal limb movements and preserved consciousness suggests
supplementary motor cortex localization, throat tightening might suggest frontal opercular
localization, a formed visual or auditory hallucination may indicate occipital or temporal
association cortex, an epigastric aura and early oral automatisms suggest mesial temporal
localization, and so forth. Lateralized motor features, such as versive head and eye
deviation, focal clonic or tonic movements, and the sign of four at secondary
generalization of complex partial seizures aid in identifying the hemisphere from which
seizures emanate. The symptoms may or may not contain lateralizing features, but these
symptoms and signs are nonetheless useful signposts on the road to localizing the epileptic
focus, and are particularly helpful when considered in concert with other diagnostic tests.
A particular constellation of clinical features might suggest that a patient has a specific
epilepsy syndrome, which may also aid in localization. Hence, the entire clinical picture
must be considered and taken in context to make an accurate diagnosis, which may lead to
specific anatomic localization. Although the MRI does not show a structural lesion, it may
be possible to infer the existence of such a lesion from clinical investigations. A focal
neurological deficit offers presumptive evidence for such a lesion. Focal hypometabolism
in a PET scan, lack of expected activation in a cortical region with fMRI, and DTI
abnormalities all suggest the presence of a lesion responsible for epilepsy and can convey
a good surgical prognosis (610). Detection of a focal abnormality in these tests can aid in
planning the location of intracranial electrodes. Other tests, such as the scalp EEG and
MEG, are often helpful in identifying areas that could be involved in seizure generation
and therefore guide the intracranial investigation. In contrast, the authors have not found
neuropsychological test results to be particularly useful in planning an intracranial
investigation (and the literature contains little evidence to support the localizing value of
these tests). People with refractory epilepsy typically have multifocal deficits, and when
epilepsy begins in childhood, reorganization of various functions further muddies the
waters.
Table 10.2 Approach to plan intracranial electrode placement in MRI-negative
epilepsy
1. Define symptoms and signs at start of seizure

2. Define epilepsy syndrome
3. Determine whether ancillary tests suggest presence of a structural
lesion
a. Neurological examination
b. PET
c. fMRI
d. DTI
e. Interictal SPECT
4. Determine whether tests suggest an epileptogenic lesion
a. Interictal scalp EEG
b. Ictal scalp EEG
c. MEG
d. Ictal SPECT
5. Synthesize data to form a hypothesis
6. Place electrodes in brain
a. Place electrodes in suspect areas

b. Place electrodes in adjacent eloquent cortex
c. Place electrodes in regions of expected early seizure
propagation
d. Ensure that some electrode contacts are placed beyond the
expected boundaries of the epileptogenic zone (need to
establish that seizures do not start in some places to be
confident they originate in suspect region, assessing routes of
propagation)
As noted above, it is critical to synthesize data from different sources to develop a

hypothesis to guide electrode implantation. Subdural electrodes can then be placed to
record EEG from suspect neocortex and define the boundaries of the area to be excised. If
buried cortex is implicated (e.g., hippocampus or the depth of a gyrus), then depth
electrodes might be used in concert with subdural electrodes for optimal sampling of
suspect brain areas. In an ideal circumstance, the noninvasively obtained information
provides a strong indication of the source of seizures, and a fairly restricted area of brain
needs intracranial EEG sampling. Sometimes, however, broad areas of neocortex are
suspect in one or both hemispheres, e.g., both frontal lobes, and a second intracranial
electrode study must be performed after the first intracranial EEG study narrows the focus
to a particular region of the brain. This region can then be intensively studied and mapped
to optimize outcome after surgery.
Types of electrode placement for different types of MRInegative epilepsy

Frontal lobe epilepsies: The frontal lobes contain several discrete cortical areas which
produce a variety of distinct types of seizures with different semiology. When clinical
suspicion is directed to particular areas, a suitable strategy for placing intracranial
electrodes can be suggested. One should always avoid focusing electrode placements in
too narrow an area, since the clinical hypothesis might be incorrect. Sampling from
adjacent areas or lobes often improves confidence in localization and helps prevents
surprises.
1. Supplementary motor or cingulate seizures: medial frontal cortex can be studied
with either subdural or depth electrodes. Subdural electrodes offer the advantage
of placing many contacts in one or both hemispheres, and allow for mapping of
the spatial extent of the seizure onset. Electrode strips or grids can be placed in
interhemispheric cortex in an anterior to posterior direction and parasagittal
electrodes can supplement these electrodes to define the lateral extent of
resection. In this region, the same electrodes can be used to electrically stimulate
the brain to define primary motor and sensory cortex, and somatosensory evoked
potentials can be recorded to aid in defining these same areas. Stereotactically
placed depth electrodes can also be placed in this region, but the amount of
cortex sampled may be more limited with these electrodes.
2. Orbitofrontal seizures: orbitofrontal cortex can be sampled with subdural grids or
strips. Placing grids has greater potential for morbidity because of the need to
mobilize the frontal lobe during grid placement. Defining the anteriorposterior
extent of an orbitofrontal epileptogenic zone can be challenging. The anterior
perforated space is a natural boundary for any resection and investigation in this
region. Rapid spread of orbitofrontal seizures to the amygdala and vice versa
poses challenges, and simultaneous recording from amygdala with depth
electrodes is usually advisable when an orbitofrontal focus is suspected.
3. Dorsolateral frontal lobe seizures: subdural grids are ideally suited for sampling
from large areas of dorsolateral frontal lobe, and mapping of eloquent cortex
with electrical stimulation and somatosensory evoked potentials.
4. Frontal pole seizures: subdural strips or grids can be used, with the former usually
adequate to define the posterior margins of any resection.
Parietal lobe epilepsies: Smaller than the frontal lobes, both medial and dorsolateral
parietal cortex can be studied with subdural electrodes. The parietal lobes are often
included in intracranial surveys when the frontal lobes are studied with intracranial EEG.
1. Medial parietal seizures: the technique is identical to that employed for medial
frontal seizures.
2. Dorsolateral parietal seizures: the technique is identical to that used for
dorsolateral frontal lobe seizures.
Occipital lobe epilepsies: The occipital lobes have anatomic connections with both
parietal and temporal lobes due to ontogeny, with superior occipital regions projecting
preferentially to the parietal lobe, while the inferior portions (below calcarine sulcus)
project to the temporal lobe. Hence, areas in these lobes should usually be evaluated when
occipital seizures are studied.
1. Lateral occipital lobe seizures: the technique is the same as for lateral cortical foci
in frontal and parietal lobes. Subdural grids or strips may be used.
2. Medial and basal occipital lobe seizures: interhemispheric and basal strips or
grids can be used. Seizure onsets can be more easily mapped with grids, but
surgeons infrequently excise striate cortex for epilepsy, so the intracranial EEG
technique should not be overly aggressive if resection will not be done in that
area.
Temporal lobe epilepsies:
1. Mesial temporal lobe seizures: Subdural electrodes can be used to record from
parahippocampal gyrus, but amygdala and hippocampus are buried and subdural
electrodes record at a distance from these structures. Hence, depth electrodes are
better suited for intracranial EEG recording from mesial temporal structures in
most circumstances (11).
2. Basal temporal lobe and temporal pole neocortical seizures: subdural electrode
strips are ideally suited to record from these regions. While one could use a
subdural grid, this is usually not necessary.
3. Posterior temporal lobe neocortical seizures: subdural grid electrodes are well
suited to map the seizure onset zone and define areas critical for language
(Wernickes area). Arrays of subdural strips can also be used, but intraoperative
language mapping is more often required due to gaps in sampling from cortex
with strip electrodes.
Pediatric considerations: Invasive monitoring is less often indicated in children than
adults because of the higher prevalence of lesions in the MRI. When necessary,
intracranial monitoring sessions tend to be briefer to enhance patient tolerance of the
procedure. Subdural electrodes are the preferred type of electrodes for most pediatric
studies. Mesial temporal epilepsy is uncommon in surgically treated young children, and
this constitutes a major reason to use depth electrodes. Stereotactic EEG can be used, but
there is insufficient published experience to compare it with subdural recording. Mapping
of cortical function can be accomplished in children, but developmental considerations
often limit the utility of this technique, and because of the inability of many children to
fully cooperate with testing. Fewer electrodes are placed in children than adults because of
small size of the skull, though this paradoxically permits more extensive sampling of
cortex. Management of fluid and electrolyte balance is more complex, bridging veins
more fragile, and anchoring of electrodes might be more challenging. Nonetheless, with a
well-focused question, subdural grids and strips can be used with good results in small
children (12).
Interpretation of subdural EEG

Several basic principles underlie interpretation of the intracranial EEG (Table 10.3).
Table 10.3 Intracranial EEG interpretation
Interictal EEG
Look for disruption of normal background rhythms
Loss of faster frequencies and normal sleep activity is significant
Delta activity is generally not significant
Amplitude of intracranial EEG signals is not important since can be
biased by the presence of blood and the solid angle of dipole of any
potential with respect to the recording electrode
Examine for interictal spikes sporadic spikes are usually not
significant, but periodic spikes, especially those in an area with
disruption of the background, may be meaningful
Ictal EEG
Determine area of earliest change in background activity
A variety of ictal onset patterns can be seen, ranging from increasing
rate of interictal spikes to focal appearance of rhythmic or
arrhythmic new frequencies
Frequencies can range from delta to gamma bands
Alerting/reticular activating system stimulation by seizures can

produce widespread alteration in background frequencies which
may be rhythmic and which must be distinguished from ictal
discharges
Determine the relationship between interictal abnormalities and the ictal
onset zone
Relate interictal and ictal findings to clinical symptoms, ictal behavior,
and tests implying underlying pathology (e.g., PET, fMRI, DTI)
One must carefully examine the interictal EEG. Underlying gliosis may be suspected
when observing disruption of normal background rhythms, with loss of faster frequencies.
Delta activity is generally not significant; a variety of temporary factors related to surgery
can cause delta. The amplitude of intracranial EEG signals also is not important.
Amplitude can be biased by the presence of blood beneath the electrode, and it depends
upon the relationship between the recording electrode and the solid angle of dipole being
recorded.
Interictal spikes can be meaningful and should be factored into surgical decisions. They
are more widespread in the intracranial EEG than scalp EEG, often seen in both
hemispheres and in multiple lobes. Interictal spike rates may not be higher in the region of
the epileptogenic zone, and they must be considered more carefully (Figure 10.3).
Sporadic spikes are usually not significant. Periodic, autonomous, repetitive spikes are
perhaps more often associated with pathologic cortex. Gamma bursts lasting 100
milliseconds to several seconds also may be present, and usually are pathologic, though
they are not always confined to the epileptogenic zone in our experience. When spikes are
located in the area of an underlying disturbance of background rhythms, they carry greater
significance as well. In certain conditions such as focal cortical dysplasia, intracranial
spikes help delineate the extent of the dysplasia (13). One must establish the relationship
between interictal spikes, the area of disrupted background activity, and the ictal onset
zone. The surgical resection should ideally include areas with pathological interictal
findings as well as the areas where seizures appear.
Figure 10.3 Interictal EEG showing sporadic spikes in both hemispheres. They are
present in right and left hippocampal contacts (RAP, RMP, RPP, LAP, LMP, LPP), and
right and left temporal lobe subdural contacts (RAT, LAT) (though not in the right
temporal subdural electrode RST).
The ictal EEG contains the most desirable data, since it presumably is a good indicator
of the epileptogenic zone the real source of seizures. Figure 10.4 shows an example of a
temporal lobe neocortical seizure recorded with subdural and depth electrodes.
Neocortical seizure onset most often manifests with frequency beta (> 13 Hz) or gamma
(> 30 Hz) activity, but occasionally slower frequency activity or an increased rate of
interictal spiking may be the first sign of a seizure. The subdural EEG may show a welllocalized, highly restricted area in which seizures first appear (Figure 10.5), or a broader
area contained within a single lobe, as in Figure 10.4, or even multilobar onset. Highly
focal gamma is probably the best indicator of the zone of seizure onset, but undue reliance
should not be placed on this zone as the definitive marker for resection. As discussed
below, only 50% of patients identified by intracranial EEG (meaning primarily ictal
recording) become seizure-free after surgery. The ictal EEG is far from the optimal tool.
Areas of early spread of ictal activity should be noted as well, since evidence suggests that
excision of secondarily activated areas can be associated with improved outcome (12). In
addition, the rate of propagation of seizures to the opposite hemisphere has been related to
surgical outcome. Longer interhemispheric propagation times are associated with better
outcome after temporal lobe (14) and extratemporal (15) resection. The EEG of seizures
may be relatively stereotyped in any one individual, although nearly all patients have
some degree of variability, however modest. In other patients, the EEG may display more
than one EEG onset pattern, particularly when more than one area generates seizures.
Patterns of spread can also vary, and termination patterns might differ somewhat from one
seizure to the next as well.
Figure 10.4 (a) EEG illustrating seizure onset (arrows) in a right anterior temporal
subdural strip electrode (RAT), followed within 50 milliseconds by onset in the right
hippocampal depth electrodes (RAP, RMP, RPP). Gamma frequency waves appear at the
start. The right subtemporal (RST) and right orbitofrontal electrodes (ROF) do not display
ictal activity at this time. Left-sided hippocampal depth electrodes (LMP, LPP) and a left
temporal subdural strip (LAT) show normal background activity at this time. In this
example, EEG onset is unambiguous and well defined, though not spatially restricted to a
single area, involving both hippocampus and basal temporal neocortex. (b) Approximately
30 seconds after the seizure has begun, ictal discharges appear in the left temporal depth
and subdural electrodes (arrow) with high-amplitude sharp waves followed by fast
activity. (c) Approximately 1 minute later, the seizure ends, first in the left temporal lobe
(bottom arrow) and later in the right temporal lobe (top arrow). Asynchronous termination
is quite common and of uncertain significance.
Figure 10.5 (a) EEG illustrating focal seizure onset with 7080 Hz activity (arrow) in a
single contact in left dorsolateral frontal cortex (at LFA). The other contacts in this page
record from adjacent left frontal lobe. The high filter setting is 300 Hz, and the signal was
recorded at a sample rate of 1000 Hz to detect this activity. (b) The seizure continues,
remaining restricted to the single left frontal subdural electrode, evolving in frequency and
spreading to adjacent contacts (arrow) in that electrode. Other electrodes do not yet show
the seizure. (c) Approximately 13 seconds after the seizure began, an ictal discharge
appears in the right frontal subdural contacts, first appearing as isolated sharp waves in a
single contact (RF1) (top arrow) and next appearing 4 cm away in another contact, RF5, in
the same subdural strip (bottom arrow). Over the next several seconds, the seizure spreads
throughout that subdural strip electrode. (d) This EEG segment, taken 13 seconds after
Figure 10.5C, contains a larger number of electrode contacts. The left frontal subdural
electrodes are shown at the top of the page (top arrow) and left temporal electrodes appear
at the bottom of the page (bottom arrows). This EEG shows only half of the channels
being recorded, and illustrates several points. First, one can note that the ictal discharges
are firing at different frequencies in temporal and frontal lobes; they are not synchronous.
Second, the large number of channels makes the EEG difficult to read, as fine detail
cannot be seen on the screen. Last, while ones eye may be drawn to the high-amplitude
activity, relevant ictal discharges may be less obvious; note the high-frequency, lowamplitude discharge in the bottom six channels on the page.
Lastly, one should not treat the intracranial EEG findings in isolation. They must be
related to other assessments. The seizure history, semiology, and other test results (e.g.,
PET, SPECT, fMRI, DTI) must be taken into account. For example, if the first symptom of
a seizure reliably consists of a formed auditory hallucination (e.g., hearing music), one
must conclude that an ictal EEG onset isolated to prefrontal cortex must be misleading and
should be ignored. The symptoms could represent propagation, but only if careful
behavioral analysis should prove that the auditory symptoms only occur after auditory
association cortex shows invasion of the ictal discharge (which represents an unlikely
scenario).
The yield of subdural EEG in MRI-negative patients is uncertain, and mainly depends
upon the criteria used to recommend an intracranial investigation. If criteria are quite
liberal, then only a small proportion of patients studied with intracranial EEG will be
candidates for surgery. If criteria are overly strict, then nearly all will be candidates for
surgery, but perhaps some patients who would have benefited from surgery will not be
offered intracranial EEG. Any percentage fixing the appropriate yield of a subdural EEG
investigation must be arbitrary. In the authors opinion, a majority of patients who have
intracranial EEG studies should ultimately prove to be surgical candidates, and if nearly
every patient has a therapeutic procedure after intracranial EEG, then the procedure is
probably overused, unnecessarily exposing some patients to risk.
Case discussions
We will review two cases that illustrate how subdural video-EEG monitoring may be used.
We will review the rationale underlying electrode placement and review results. These
cases will illustrate a hypothesis-driven approach to electrode implantation and synthesis
of the EEG data that is collected to render a final recommendation regarding epilepsy
surgery.
Case 1
A 34-year-old man developed seizures at age 16 which were never controlled with
medication. He experienced complex partial seizures with prominent early bilateral tonic
movement, occurring mainly while awake at a rate of 2040 seizures per month. He had
no warning preceding seizures, though he felt both arms and legs stiffening and shaking
for several seconds at the start of seizures before losing awareness. The remainder of his
history was unremarkable. His neurological examination was normal. The MRI and PET
were normal as were the interictal and ictal scalp EEG. Video showed bilateral proximal
arm and leg movement with head turning to the right at the start of the seizure.
Ictal behavior was consistent with a supplementary motor focus, and the preservation of
awareness at the start of the seizure was consistent with a lateralized source, though either
right or left supplementary motor cortex could be responsible. The lack of interictal or
ictal scalp EEG discharges was compatible with a medial frontal focus.
Plans were made for bilateral frontal and parietal lobe subdural placement, with two
strip electrodes placed anteriorly and two posteriorly in interhemispheric locations, and
dorsolateral frontal and parietal electrodes as well. It was anticipated that a medial frontal
ictal onset would be observed, and extra electrodes were placed to aid in identification of
this area. Figure 10.6a shows a diagram of the right-sided subdural strip implantation, and
a similar arrangement was used in the left hemisphere. Interhemispheric adhesions and
veins prevented placement of more subdural electrodes in the interhemispheric areas. The
interictal EEG showed frequent spikes in the anterior contacts of the right
interhemispheric electrode, and infrequent spikes scattered over both frontal lobes in
dorsolateral cortex. Figure 10.6b shows a seizure, with localized ictal onset anteriorly in
the distal four contacts of the right anterior interhemispheric subdural strip electrode. As a
result, a corticectomy was advised, resecting medial frontal cortex in the region of ictal
onset.
Figure 10.6 (a) Diagram of subdural strip placement. Shaded electrodes RAIH and
RPIH are placed over interhemispheric cortex. RAIH: right anterior interhemispheric
electrode. RPIH: right posterior interhemispheric electrode. (b) EEG illustrating ictal onset
with gamma frequency activity in RPIH contacts 14 with spread in 400 milliseconds to
adjacent right frontal subdural contacts.
Case 2
A 35-year-old right-handed man had nocturnal simple partial seizures starting at age 28.
He was awakened from sleep with a choking sensation, accompanied by the inability to
breathe or speak. He made gasping and choking sounds for 530 seconds with preserved
consciousness. Seizures occurred four times per night. He also had five secondarily
generalized seizures in the past, beginning with the choking sensation followed by rightsided facial numbness and then loss of consciousness with generalized tonic and then
clonic movements. He failed to respond to five antiepileptic drugs. He had no risk factors
for epilepsy. His neurological examination was normal. The interictal EEG and MRI were
normal. The PET scan showed subtle right temporal lobe and caudate hypometabolism,
and a subtraction ictal single photon emission computed tomography (SPECT)
coregistered to MRI (SISCOM) scan showed left medial frontal ictal hyperperfusion. The
ictal scalp EEG was largely obscured by artifact without an ictal discharge.
The history suggested a localized frontal lobe opercular focus because of the choking
sensation with preserved consciousness. The laboratory investigations were inconsistent
with his history and viewed as potentially misleading. An investigation with intracranial
electrodes was advised, sampling areas suggested by the history and tests. Subdural strip
electrodes were placed in both hemispheres, sampling from both frontal lobes inferiorly
and superiorly in dorsolateral frontal cortex, medial frontal cortex, and both temporal
lobes (the latter two sites studied because of the PET and SISCOM). With video-EEG
recording, the patient was noted to experience the choking sensation prior to earliest
appearance of an ictal discharge in the right dorsolateral frontal cortex during a
secondarily generalized seizure. Numerous simple partial seizures did not appear in the
intracranial EEG. A second intracranial implantation was then performed with attention to
the right frontal lobe. Two small subdural grids were placed over the right frontal lobe
along with a single strip electrode, sampling dorsolateral frontal and parietal cortex and
orbitofrontal cortex (Figure 10.7). The Sylvian fissure was dissected so that the
dorsolateral grid was inserted over frontal cortex buried within the fissure. Video-EEG
recording demonstrated frequent interictal spikes and well-localized seizures starting in a
single contact in right frontal opercular cortex (Figure 10.7b). Electrical stimulation was
next performed to map primary motor and sensory cortex. Resective surgery was then
performed, with a limited excision of cortex beneath the active contact and adjacent tissue;
cortex subserving facial movement was included in the resection. The patient had
temporary lower facial weakness which resolved over several months with no lasting
deficit, and seizures were abolished. This case illustrates the occasional need for a second
focused intracranial implantation once the localization becomes more apparent, and the
need to expose buried cortex (opercular) to obtain adequate EEG recording.
Figure 10.7 (a) Diagram of subdural grid placement over dorsolateral frontal and
parietal lobes. The posterior grid was placed in the Sylvian fissure after dissection (the
diagram cannot adequately display this feature). The skull X-ray shows electrodes as well.
RPFG: right posterior frontal grid. RSFG: right subfrontal grid. RSYL: right Sylvian
subdural strip. RF: right frontal subdural strip. (b) EEG illustrating focal seizure onset in a
single contact in the RPFG 18 with high-frequency activity that attenuated several seconds
after onset, later increasing in amplitude and evolving in frequency. The pattern of
apparent attenuation, called the start-stop-start phenomenon [21], is well characterized
with intracranial electrodes and probably reflects an increase in frequency with consequent
reduction in amplitude of the ictal discharge. The ictal discharge in the EEG preceded ictal
symptoms by several seconds. Each EEG segment (top and bottom) contains 12 seconds
of EEG, the bottom segment showing the immediate continuation of the seizure.
Case 3
A 47-year-old man had uncontrolled seizures beginning at age 16. The patient described
two different types of seizures, both occurring while asleep. The first type started with
arousal, followed by turning his head and body to the right, and he then pummeled the
headboard with his hands. These seizures lasted 3 minutes and occurred once every other
month. The second type of seizure began with a cry followed by bilateral tonic stiffening
of all four limbs. They lasted 35 minutes and occurred twice per month. He failed to
respond to lacosamide, zonisamide, carbamazepine, and phenytoin. His MRI and FDGPET scan were normal. The interictal scalp EEG revealed right frontotemporal (F8) sharp
waves, right prefrontal (Fp1) spikes, and left frontotemporal (F7) sharp waves. The ictal
EEG revealed paroxysmal fast activity (2030 Hz), maximal at the right frontotemporal
(F8) region, which then spread rapidly to the opposite hemisphere with bifrontal 5 Hz
rhythmic spiking.
The seizure semiology is consistent with either a temporal or frontal lobe localization,
and the prefrontal interictal spike and nocturnal pattern suggest frontal lobe epilepsy, with
origin perhaps in the orbitofrontal or frontal pole cortex. The right prefrontal spike
lateralization is consistent with seizure origin from either hemisphere; a right prefrontal
spike could arise in either left or right frontal pole, the angle of projection of the spike
dipole could lead to either an ipsilateral or contralateral scalp maximum. The ictal fast
activity suggests a neocortical focus, although this is not absolutely certain. The presence
of two distinct seizure types raises the possibility of two independent epileptogenic zones,
though variable seizure spread with all seizures starting in one cortical area could also
produce these phenomena. Hence, an intracranial investigation was planned, using
subdural electrodes to sample from right and left temporal and frontal lobes, including
orbitofrontal regions, and hippocampal depth electrodes were placed as well, though index
of suspicion was relatively low for a mesial temporal focus.
The map of electrode placements is shown in Figure 10.8a (the depth electrode
placement is not shown). The ictal EEG from one seizure starting in left orbitofrontal
subdural contacts appears in Figures 10.8b and 8c. The ictal EEG of another seizure
originating in right orbitofrontal subdural contacts is shown in Figures 10.8d and 8e. In
this patient, the existence of independent right and left frontal seizures was established,
and no resective surgical procedure was offered. The history of two distinct seizure types
indeed indicated the presence of two discrete foci, and this was proven by the intracranial
EEG.
Figure 10.8 (a) Diagram of subdural electrode strips placed over both temporal and
frontal lobes. Depth electrodes, not shown here, were placed via lateral approach through
the middle temporal gyrus into both hippocampi. L = left; R = right; OF: orbitofrontal;
AIH: anterior interhemispheric; PIH: posterior interhemispheric; FA: frontal A; FB:
frontal B; FC: frontal C; AT: anterior temporal; ST: subtemporal; PT: posterior
temporal (b) EEG illustrating focal seizure onset in left orbitofrontal subdural contacts
with ictal flattening followed by rhythmic sharp waves (bottom arrows). The top arrow
shows contralateral spread of the ictal discharge with rhythmic sharp waves in right
orbitofrontal contacts approximately 56 seconds after the seizure starts in the left frontal
lobe. C. (c) This page shows the continuation of the seizure beginning in Figure 10.8b.
Rhythmic sharp waves evolve in both frontal regions (arrows) and spread to other frontal
and temporal electrodes in both hemispheres. (d) EEG illustrating ictal onset in right
orbitofrontal subdural contacts (arrow) with rapid spiking. The left hemisphere contacts
(bottom half of the page, below the ECG) do not display an ictal discharge on this page.
The activity in the bottom five channels occurs interictally. (e) This page shows the
continuation of the seizure beginning in Figure 10.8d. The seizure remains confined to the
right hemisphere with no spread to the left side (bottom half of the EEG). This pattern is
quite different from the other seizure a different ictal onset pattern and different
evolution.
Surgical outcome
Studies of outcome after epilepsy surgery have consistently revealed that patients with
temporal lobe epilepsy fare better then patients with extratemporal lobe epilepsy, and
patients with lesions usually enter remission more often than patients without lesions in
the MRI. This appears to be true irrespective of use of intracranial EEG evaluation.
Seizure-free rates vary considerably between centers for extratemporal cases. In a metaanalysis that reviewed surgical outcomes for temporal and extratemporal lobe epilepsies
(9), 26% of cases were nonlesional. Nonlesional epilepsy was more common in
extratemporal lobe epilepsy, comprising 45% of cases. Overall, 46% of patients with
nonlesional epilepsy were seizure-free after surgery. Seizure-free rates were higher after
temporal lobe resection than in extratemporal resections, 51% versus 35%. Bulacio et al.
(16) reported on 135 non-lesional patients with temporal and extratemporal epilepsy who
underwent invasive EEG monitoring. These patients were implanted with either subdural
electrodes or depth electrodes placed into the mesial temporal structures, or both. They
found that 64% of their patients were seizure-free at 1 year and 48% at 3 years, but they
did not distinguish between temporal and extratemporal lobe epilepsies with regard to
seizure-free rates. Noe et al. (17) reported 31 patients with extratemporal epilepsy who
underwent chronic subdural recordings. In this study 24 patients were thought to have a
focal onset identified by the subdural electrodes, of whom 9 (38%) were seizure-free. In a
series reported by Siegel et al. (18) 8 of 14 patients (57%) with frontal lobe epilepsy were
seizure-free and MacDougall et al. (19) reported that 41% of the extratemporal epilepsy
patients in their series were seizure-free. In a study of 25 patients with frontal lobe
epilepsy who were studied with subdural electrodes, Holtkamp et al. (15) found that
patients with nonlesional epilepsy fared as well as those with lesions in the MRI. The
major factor in the intracranial EEG favoring seizure freedom was the presence of a highly
focal ictal onset (in one or two contacts) as opposed to more widespread ictal onset; 70%
of patients with restricted ictal onset were seizure-free after surgery; in contrast, only 13%
of patients with widespread onset were seizure-free. In addition, rapidity of seizure spread
to other lobes of the brain in the intracranial EEG independently predicted outcome.
Seizure-free patients had a mean latency of 5.8 6.1 seconds to spread to another lobe,
whereas patients with persistent seizures had a mean latency of 1.5 2.3 seconds (p =
0.016). These series demonstrate that many patients with MRI-negative epilepsy can gain
seizure relief after intracranial EEG with subdural electrodes, but, in general, patients with
MRI lesions fare better than those without such lesions (20).
Complications
Most patients who are implanted with subdural electrodes tolerate the procedure well.
These patients typically require an overnight admission to the intensive care unit and are
subsequently transferred to the epilepsy monitoring unit for chronic recordings. However,
even though complications rates are low, when they do occur they can lead to neurologic
injury; the intracranial monitoring may need to be terminated, and prolonged hospital
admissions/medical treatment may be required.
A recent meta-analysis regarding the safety of extraoperative invasive EEG monitoring
was completed and included 21 studies with 2542 patients (2). The length of implantation
in the various studies ranged from 140 days. The pooled prevalence rates for pyogenic
infections, superficial infections, and bone flap osteomyelitis were 2.3%, 3.0%, and 1.8%,
respectively. The pooled prevalence rate for intracranial hemorrhage was 4%. This
included 41 patients with a subdural hematoma, 13 patients with an extradural hematoma,
and 11 patients with an intraparenchymal hemorrhage. Thirty-four of these patients
required immediate surgical intervention secondary to the hemorrhage. The pooled
prevalence rate for increased intracranial pressure was 2.4% and for cerebrospinal fluid
leak was 12.1%. The pooled prevalence for developing acute focal neurologic deficits was
4.6% with hemiparesis being the most common symptom. The authors also found that
increased number of electrodes implanted was independently associated with increased
incidence of adverse events. Only five deaths were reported in this series of patients.
Conclusion
Subdural electrodes are a useful tool for evaluating patients with MRI-negative epilepsy.
However, subdural EEG is merely one of many methods used to examine the brain in
epilepsy. While often providing useful information, it also has the potential to be
misleading and the data obtained with subdural EEG must be considered in the context of
the entire clinical picture. Making a surgical decision based solely upon the intracranial
EEG, perhaps just the ictal EEG, while disregarding the history and other laboratory tests
should be avoided.
Finally, the advent of responsive neurostimulation technology has the potential to alter
the way intracranial EEG is regarded. Long-term outpatient intracranial EEG recording is
now feasible and we may not be limited to relying on brief sessions. The ability to monitor
the intracranial EEG over the course of many months or years may provide new insights
into the electrophysiology of epilepsy, and suggest new approaches to treatment.
References
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Chapter 11 Depth electrode and

stereoelectroencephalography in MRI-negative epilepsy
Philippe Ryvlin, Alexandra Montavont, Karine Ostrowsky-Coste and Marc Gunot
Introduction
Stereoelectroencephalograpy (stereo EEG or SEEG) primarily refers to the capacity of
recording intracerebral EEG from various cortical targets, for which precise anatomical
delineation and implantation requires a three-dimensional stereotaxic procedure. This
approach appears well adapted to the investigation of cerebral networks distributed over
several lobes or sublobar structures, including deeply located as well as more superficial
cortical areas. Such investigations are particularly useful in patients with MRI-negative
refractory focal epilepsy, whose main presurgical issues can be summarized as follows:
1. The lack of an identifiable epileptogenic lesion on MRI usually translates into
uncertainties regarding the sublobar region or even the lobe generating seizures,
justifying the need for intracerebral EEG (icEEG) investigations that enable
sampling of all suspected regions.
2. MRI-occult type II focal cortical dysplasia (FCD) represents the most common
pathology disclosed in successfully operated patients, and is often located in
deeply located brain regions that are best sampled with depth electrodes.
3. The possibility of very large or multifocal epileptogenic zones, often associated
with type I FCD, also needs to be considered, and further justifies icEEG
targeting complex distributed networks.
While SEEG offers many advantages when investigating patients with MRI-negative
refractory focal epilepsy, it also raises some issues: 1. SEEG does not represent a unified
approach, but rather encompasses a variety of concepts and methodologies which makes it
difficult to summarize its clinical effectiveness; 2. validation of the various forms of
SEEG investigation remains scarce, and primarily based on the success rate of SEEGguided epilepsy surgery in observational studies. This is even truer for MRI-negative
patients, for which no randomized trial is available for the comparison between subdural
grids and SEEG.
In this chapter, we will first present the historical and conceptual frameworks of SEEG,
together with their evolution over time and variation between centers, the underlying
surgical methods and associated complications, and the effectiveness of SEEG in patients
with MRI-negative refractory focal epilepsy. Low- and high-frequency stimulations, as
well as thermolesions will also be discussed.
Conceptual frameworks and disputed issues in SEEG
Historical perspective
The original SEEG method was developed in the late 1950s by Talairach and Bancaud at
St Anne hospital in Paris (1, 2, 3), taking advantage of their progress in the field of brain
stereotaxy (4). It should be stressed, however, that brain stereotaxy was also developed
since the mid-1940s by Spiegel and Wycis who performed thalamic EEG recordings in
patients with epilepsy (5, 6). In the very early stages of SEEG, intracerebral EEG was
recorded acutely in the operating room, while brain targets were primarily guided by
clinical and scalp EEG findings, long before CT scan and MRI were made available. The
fact that SEEG was developed when brain targets could not be guided by neuroimaging,
but rather by the electroclinical pattern demonstrated during scalp EEG recording of
seizures, might account for its specific relevance for investigating MRI-negative patients
(7).
The SEEG technique, as defined by Bancaud and Talairach, was selectively performed
at St Anne hospital in Paris for decades, while a few other centers were perfoming more
standardized depth electrode recordings focusing on the temporal lobes (8). During the last
25 years, SEEG has slowly disseminated to many French centers as well as to Italy
(Milano) (9). More recently, a dramatic worldwide development of SEEG has been
observed, triggered by the progress in frameless stereotaxy, and promoted by the
international SEEG course. The SEEG method is thus entering a new era, more than 50
years after its invention (10, 11).
The anatomo-electro-clinical correlation theory

While SEEG terminology primarily refers to the stereotaxic implantation of intracerebral
electrodes, the main conceptual framework underlying the SEEG method developed by
Bancaud and Talairach lies in the so-called anatomo-electro-clinical correlations,
whereby the ictal discharge is viewed as a spatiotemporal dynamic process, the
comprehensive understanding of which promotes an accurate delineation of the
epileptogenic zone (1215). Neuroimaging and EEG findings accumulated during the last
50 years have largely confirmed and enriched the anatomo-electro-clinical correlation
theory developed by SEEG founders. However, these data also stress that the
spatiotemporal dynamics of epileptic seizure is more variable and complex than initially
thought, to the point that a comprehensive understanding of the dynamics at the
individual level is often elusive. At best, SEEG will sample about 1% of the total brain
volume, hampering accurate extrapolation of seizure activity in all unexplored regions,
regardless of the thoughtful strategy used to optimally choose the SEEG targets. This
caveat is often neglected, promoted by the subjective impression that one can build a
mental representation of the propagating epileptic discharge that seemingly fits with the
recorded SEEG data. As for models of electrical or magnetic source imaging, where an
infinite number of solutions can account for the same EEG or MEG data set, interpretation
of SEEG findings might appear consistent with the recorded data and yet be inaccurate.
This issue is aggravated by the very limited cortical sampling of SEEG and the lack of
objective and appropriate mathematical models to display seizure propagation in clinical
practice. Recent attempts to provide three-dimensional representation of an
epileptogenicity index are thus of interest (16), but only partly address the above
limitations.
Disputed issues regarding seizure propagation areas

While the quest for a better understanding of seizure propagation is justified by the fact
that propagation patterns partly depend on, and thus can inform about, the seizure onset
zone, the extent to which this should influence individual SEEG plan ought to be disputed.
An illustrative example would be that of a patient with dialeptic seizures that would at
times progress towards clonic twitches of the right arm during the latest stage of the
attack. According to these observations, some SEEG centers would investigate the left
central region on top of those suspected to generate seizures, while others would consider
it useless to place an electrode in a brain region, the involvement of which during the late
phase of the ictal discharge, but not during its early phase, can be fully ascertained based
on ictal phenomenology alone.
Another disputed issue regarding the general concepts underlying SEEG is that of the
significance of early or rapid seizure spread. Some authors consider that brain regions
sustaining such early propagation need to be resected together with the seizure onset zone
(1720). Others would apply this statement only if a low-voltage, high-frequency
discharge is observed in these regions. These diverging views solely rely on personal
experience without any available validation study. Moreover, the empirical observation
that extending the surgical resection to brain structures involved in early seizure spread
might provide greater chance of postoperative seizure freedom could simply reflect the
fact that the larger the corticectomy, the more likely it is to include the entire epileptogenic
zone, regardless of the role of early propagation.
Overall, there is no consensus among SEEG centers on how to investigate and interpret
regions of seizure spread, translating into different implantation strategies.
Current SEEG framework in MRI-negative patients

As discussed in the introduction, patients with MRI-negative refractory focal epilepsies
raise specific issues that justify performing a SEEG investigation, but also determine its
overall strategy. These issues derive from the uncertain etiology, number, extension, and
localization(s) of the epileptogenic zone(s), together with the limited spatial sampling of
SEEG. As a rule, a fishing expedition, i.e., a largely distributed implantation without
any strong hypothesis, must be avoided, since the latter is very likely to either fail at
detecting a seizure onset zone or provide an erroneous localization of the latter. Thus,
SEEG should only be performed in patients where noninvasive data consistently point to a
sublobar region (11, 14). In some patients, noninvasive data are consistent and compelling
enough to obviate the consideration of an alternative hypothesis, in which case, SEEG will
only be performed to define the extent of the epileptogenic zone. In other patients,
uncertainties regarding the location of the epileptogenic zone lead to consideration of one
primary hypothesis together with one or several less likely alternatives. While SEEG
allows us to test several such hypotheses, it cannot offer optimal sampling of all tested
regions. Indeed, the investigation of the most suspected epileptogenic region will typically
require the implantation of five to ten electrodes within and around this region to precisely
identify its borders (depending on its anatomical configuration). According to the
maximum number of implanted electrodes (usually 15), it is difficult to use the same
design for alternative seizure onset zones, where only one or two sentinel electrodes will
be typically inserted (Figure 11.1).
Figure 11.1 Theoretical design of a SEEG investigation. Small circles (N = 14)

represent intracerebral electrodes, with the blue corresponding to those implanted in the
ictal onset zone, those in green placed in the surrounding propagation areas, and those in
brown testing alternative seizure onset zones. The configuration of blue and green
electrodes should allow for fine delineation of the borders of the ictal onset zone.
Two main clinical situations ought to be distinguished to further develop SEEG strategy
in MRI-negative patients:
a. Mesial temporal or temporolimbic epilepsies, usually associated with very
suggestive electroclinical and FDG-PET features, for which the main incentives
for performing SEEG are: 1. excluding bitemporal, pseudotemporal, or temporal
plus epilepsies (21, 22), all of which can mimic typical mesial temporal lobe
epilepsy (mTLE) (23); and 2. exploring the possibility of a selective
temporopolar (24), amygdala, or entorhinal (25, 26, seizure onset zone that will
allow sparing part or all of the nonatrophic hippocampus in order to reduce the
risk of postoperative memory decline, in particular when operating on the side
dominant for language (27). According to these objectives, depth electrodes are
required to selectively target the various mesial temporal structures of interest
(see above), as well as the insula, orbitofrontal cortex, or mesial temporooccipital or temporoparietal junction when judged necessary. Excellent seizure
outcome has been reported in well-selected groups of MRI-negative mTLE with
either end-folium sclerosis or negative as well as nonspecific pathology (2833).
b. All other epileptogenic zones, often quoted as neocortical, for which the main
hope and objective of SEEG is to disclose and delineate a MRI-occult FCD.
Indeed, the great majority of patients with MRI-negative neocortical epilepsy
who benefited from successful epilepsy surgery proved to suffer from such
pathology, usually FCD type II (7, 14, 34, 35). Conversely, less than a handful of
patients with normal pathology were reported to be cured from their epilepsy by
extratemporal lobe surgery. Thus, in contrast with cryptogenic mTLE where
presurgical investigations primarily aim at confirming the temporal origin of

seizures, the work-up of MRI-negative extratemporal epilepsies should equally
search for evidence of an underlying FCD as for their seizure localization. In
this context, the design of the SEEG plan also needs to consider the spatial
characteristics of MRI-occult type I and II FCD. The MRI-occult type II FCD
will typically be small-sized and located at the bottom of a single sulcus, with
some predilection for specific brain regions such as the superior frontal sulcus in
the frontal lobe (7, 3436). Conversely, MRI-occult type I FCD might be
extensive, involving several gyri and sometimes several lobes, and also
multifocal. Accordingly, SEEG strategy will differ as a function of the most
likely underlying pathology.
All noninvasive investigations are useful to elaborate the most relevant hypothesis and
related SEEG plan. Auras, when present, often have a high localizing value. Early ictal
signs and scalp EEG changes also prove instrumental. When available, ictal SPECT and
SISCOM bring additional useful information. Interictal EEG, MEG, and FDG-PET
abnormalities are important not only for localizing the epileptogenic region but also to
unravel its underlying pathology. In particular, FCD type II will often be characterized by
intense spiking activity and marked glucose hypometabolism with clear-cut borders (35,
37). Coregistration of electric source imaging or MEG clusters, together with SISCOM or
PET findings, helps in designing an optimal SEEG plan to precisely target the core and
borders of suspected type II FCD (38). Past history, including age of onset of epilepsy, can
also help inferring the underlying pathology (7, 34, 35, 39).
Figure 11.2 Typical placement of depth electrodes in the temporal lobe of patients with
MRI-negative mTLE (other electrodes might be placed outside the temporal lobe
according to patients characteristics). Electrodes anatomical targets: J = temporal pole, D
= entorhinal cortex and anterior portion of 3rd and 4th temporal gyri, L = posterior aspect
of 3rd and 4th temporal gyri, A = amygdala and anterior portion of second temporal gyrus,
B = anterior hippocampus and anterior portion of second temporal gyrus, C = posterior
hippocampus and posterior portion of second temporal gyrus, T = anterior/mid portions of
first temporal gyrus (reaching the anterior part of the long posterior gyrus of the insula), H
= posterior portion of first temporal gyrus (reaching the posterior part of the long posterior
gyrus of the insula).
Surgical aspects of SEEG methodology and their evolution

over time
The surgical methods used to perform SEEG have evolved over time in parallel with its
dissemination, according to three main stages. In the preMRI era, stereotaxic
ventriculography and angiography were performed and superimposed to delineate the
ACPC line, define atlas-guided anatomical targets, and ensure maximal vascular safety
of orthogonally implanted electrodes.
Figure 11.3 Advantage of SEEG in investigating MRI-occult type II focal cortical

dysplasia. The MRI on the left illustrates the typical location of a type II focal cortical
dysplasia at the bottom of sulcus. The image on the right shows the recording from an
electrode targeting a MRI-occult FCD in the anterior insula. High-amplitude spikes are
observed over the bipole P1P2 (i.e., insular leads), but not detectable 1 cm more
laterally within the frontal cortex.
When MRI became available, it rapidly replaced ventriculography and atlas-guided
implantation, by providing direct targeting of the brain structures to be investigated.
However, most SEEG centers have continued to use orthogonal implantations coupled
with stereotaxic angiographies with X-ray sources located 5 m away from the patients
head, to eliminate the linear enlargement due to X-ray divergence, offer optimal
stereotaxic registration, and minimize the risk of vascular injury. More recently,
digitization of angiography data has allowed the replacement of the cumbersome 5 mdistant X-ray sources by flat-panel X-ray detectors. The safety of this method, detailed
below, has enabled the expansion of the type and number of brain regions targeted by
SEEG, leading to the investigation of the insular cortex and implantation of up to 15
electrodes in the same individual. However, this approach remains limited by the
orthogonal trajectory of all implanted electrodes.
The third era is that of robot-assisted stereotaxy allowing for double-oblique
trajectories. This method, initiated in Grenoble (France) (40), and further developed in
Milano (Italy) and Marseille (France), is now rapidly expanding with the use of MR
angiography as a substitute for conventional angiograms.
Current methodology for orthogonal implantation using the

Talairachs grid
Under general anesthesia, the patients head is fixed in the stereotaxic frame (typically the
Talairachs frame, but the Leksells frame can be used as an alternative provided it is
adaptated to the Talairachs metallic grid) using transcutaneous metallic pins. Stereotaxic
digitalized angiography is then performed using flat-panel X-ray detectors attached to the
operating table (typically two, lateral and anteroposterior). Angiography should involve
the common carotid artery, in order to display both intracerebral and anterior meningeal
arteries, and provide arterial and venous views. The previously acquired frameless MRI is
then coregistered to the digitized angiogram, using anatomical landmarks of the corpus
callosum provided by the anterior cerebral artery and vein of Galen. Each MRI-based
brain target is then adjusted to allow an avascular trajectory of the corresponding
electrode, and transformed into coordinates of the Talairachs grid. A metallic landmark is
then inserted in the Talairachs grid at each of the calculated coordinates, in order to check
by means of a standard X-ray view, their appropriate placement with respect to the
original anatomical targets and vascular constraints. Percutaneous trephination is then
performed through the selected holes of the Talairachs grid. It should not include the dura,
which will then be carefully coagulated. A hollow peg is inserted in each trephination
hole, and its position checked by X-ray views. The distance between the internal extremity
of the peg and the desired depth of the tip of the electrode is then calculated, given a 5 mm
safety distance to any cisterna. Electrodes are then inserted according to these
calculations, with a fine adjustment of the penetration length being performed on the basis
of X-ray views obtained at the end of the procedure. Electrodes are then fixed to the peg
by means of a plastic cap. The precise anatomical location of each recording lead is later
provided by MRI scan (27).
Current methodology for robot-assisted oblique

implantation
Oblique trajectories offer several advantages over classic orthogonal electrodes, which
include targeting regions not attainable through the Talairach grid (e.g., rectus gyrus,
occipital pole), increased sampling of brain structures, the long axis of which is sagitally
oriented (insula, cingulate gyrus), and optimized placement of the recording leads within
the gray matter (41). However, it also has some drawbacks, including more complex 3D
representation for clinical interpretation of data. Furthermore, when investigating cortical
networks primarily connected through coronally disposed fibers, orthogonal electrodes
allow a more straightforward understanding of such network activity (e.g., the insuloopercular complex or mesiolateral parietal network, etc). Some oblique trajectories also
allow for implanting depth electrodes without angiography control.
Several methods of robot-guided SEEG have been developed, the technical
characteristics of which will not be detailed in this chapter. In any case, electrode
trajectories are determined on the patients MRI through the robot-dedicated software.
This procedure requires fiducials to be inserted in the patients skull, either at the time of
MRI, or during a perioperative additional scan, which is then merged with MRI.
Conventional digitized angiography or MR angiography can also be incorporated into the
robots software to minimize the risk of vascular insult. Similarly, other coregistered
information can be used for refining the implantation strategy, such as diffusion tensor
imaging and tractography, functional MRI, nuclear medicine data (SPECT or PET), or
electrical/magnetic source imaging. Combination with the Talairachs frame and grid is
possible, and can allow mixed procedures with both orthogonal and oblique electrodes.
Trephination and procedures to insert and secure the electrodes are not different from
those described for orthogonal implantations.
Cardinale and collaborators have evaluated the accuracy of traditional versus modern
robot-assisted procedures on 118 of their 500 SEEG procedures (42). The traditional
method was associated with a median entry point localization error of 1.43 mm
(interquartile range, 0.912.21 mm), and a median target point localization error of 2.69
mm (interquartile range, 1.893.67 mm), versus a median entry point localization error of
0.78 mm (interquartile range, 0.491.08 mm) and a median target point localization error
of 1.77 mm (interquartile range, 1.252.51 mm) for the current robot-guided procedure
(42).
SEEG complications
SEEG is usually considered a safer and better-tolerated investigation than subdural grids.
However, no randomized comparison of the two methods is available, and only a few
systematic evaluations of SEEG complications have been reported.
The Italian group of Milano have reported the largest series of 500 consecutive SEEG
with a total of 6496 implanted electrodes (42). Twelve major complications were
encountered (2.4%), including one death in a 3-year-old child whose autopsy showed
massive cerebral edema without intracranial hemorrhages, suggesting an impairment of
the hydroelectrolytic balance of unclear origin. Five intracranial hemorrhages were also
observed (1%), including one extradural during a preimplantation procedure, one
subdural, and three intraparenchymal, two of which resulted in permanent motor deficit.
Two patients developed intracranial infections. One obstructive hydrocephalus, caused by
a small clot in the aqueduct of Sylvius, required temporary external ventricular drain,
while one broken retained electrode had to be surgically extracted. Interestingly, all these
complications occurred during the first 215 procedures (18).
The second largest series was reported by the MNI group (Montreal, Canada), and
included 224 implantations with 3022 electrodes (43). Ten major complications were
reported (4.5%), including three hematomas (1.3%), three brain abscesses, one meningitis,
and one hypointense lesion found 1 week after electrode explantation. Scalp cellulitis was
observed in an additonal four patients, while two patients developed hemiparesis during
preoperative angiography in the early 1980s (43).
Our group reported SEEG complication rates in our first 100 patients in whom 1118
electrodes were implanted. There were three major complications (3%), including one
intracerebral hematoma (1%) which resulted in death, and two electrode breakages (27).
The death was indirectly related to the procedure since it occurred several days after the
electrodes were removed. The patient had developed brachial thrombophlebitis during the
late phase of SEEG recordings and was transferred to a cardiovascular surgery department
with a view to proceeding to surgical treatment of the venous clot. Eventually, vascular
surgeons decided to perform to intravenous thrombolysis, despite the contraindication of a
recent brain surgery, which resulted in the fatal hematoma. We have now updated our
complication rate to 460 SEEG procedures. In addition to the three above complications,
four hematomas were observed, including three asymptomatic subdural or extradural
hematomas, and one intracerebral that resulted in permanent language deficit. Another
four electrode breakages occurred, without neurological consequences, and two rapidly
controlled cases of meningitis. In total, SEEG-induced hematoma was observed in 0.9% of
our patients, with permanent deficit in 0.2%, figures that are very comparable to those
reported by the Milano group (1% hematoma, including 0.4% with permanent deficit).
In a more recent series of 100 patients in whom 1310 electrodes were implanted, the
rate of hemorrhagic complications was 3% without permanent deficit (10).
A fatal hematoma was also recently reported in a 10-year-old boy, 8 days after electrode
implantation, suggesting the rupture of a SEEG-induced growing pseudoaneurysm or the
tearing of a neighboring vessel by an electrode (44).
Overall, major complications occur in about 3% of SEEG procedures, including 1% to
3% of intracranial hematoma, some of which will result in permanent deficit or death (
0.6%).
SEEG recording and stimulation procedures

The SEEG technique offers the possibility of performing various types of electrical
stimulation in order to test the epileptogenicity and functionality of implanted brain
regions (45, 46).
Traditionally, high-frequency 50 Hz stimulations of 0.3 msec biphasic square pulses are
delivered using trains of 5 seconds maximal duration, and 3 mA maximal intensity (47
49). Such stimulation, when applied to brain regions involved in the epileptic network,
may generate: 1. ictal symptoms with or without associated EEG postdischarge (5052), 2.
subclinical postdischarge, and 3. full-blown seizure. In eloquent regions, high-frequency
stimulation can generate positive symptom or deficit reflecting the brain function at stake
(e.g., auditory hallucination, aphasia) (5356). Functional mapping of language or
sensorimotor areas is however less informative than that performed using subdural grids,
due to the less extensive coverage of those regions by SEEG.
Low-frequency 1 Hz stimulation, using 1 msec duration pulse, up to 30 second duration
and 5 mA intensity, appears more appropriate for testing the epileptogenicity or
functionality of brain regions that are highly sensitive to electrical stimulation, such as the
mesial temporal cortex or the central region (57, 58). In particular, hippocampal
discharges elicited by low-frequency stimulation are thought to more reliably indicate an
underlying epileptogenicity than those triggered by high-frequency stimulation (57, 59).
Epileptogenic zones located outside the mesial temporal regions are more rarely activated
by low-frequency stimulation (59). In the central region, low-frequency stimulation will
elicit brief repetitive motor signs or sensory symptoms with lower risk of uncomfortable
or painful sensations than those which might be triggered by high-frequency stimulation.
Very low-frequency stimulations at 0.2 Hz, also referred to as single pulse electrical
stimulation, do not usually trigger epileptic discharges nor ictal signs or symptoms.
However, they allow capturing of evoked potentials in other recorded regions. Some of
these potentials are physiological, especially those occurring during the first 100 msec
poststimulus, providing information on functional connectivity (6063). Others, usually
more delayed and polyphasic, are thought to reflect the epileptogenicity of either the
stimulated or the recorded brain region (64, 65).
Effectiveness of SEEG in patients with MRI-negative

There are only a few series reporting SEEG findings in populations of 20 or more MRInegative patients, most of which will also include patients with MRI abnormality (10, 14,
18, 35, 38) (Table 11.1). Most other series either were published before the MRI era or did
not provide any details regarding MRI-negative patients, reported less than 20 patients
with a normal MRI, or selected patients successfully operated to ensure the localization of
the epileptogenic zone and its association with other clinical parameters.
Table 11.1 Effectiveness of SEEG in MRI-negative refractory focal epilepsy
MRI-negative patients
No.
operated
%
class
I
% FCD type
II at
pathology
211
77
42
38%
Unknown
McGonigal et al. Brain

2007
100
43
29
55%
34%
Chassoux et al.
Epilepsia 2012
62
25
25
88%
100%
(inclusion
criteria)
Jung et al. Brain 2013
21
21
12
50%
33%
Gonzalez-Martinez et al.
Epilepsia 2013
100
28
28
57%
Unknown
TOTAL
494
194
136
51%
No.
SEEG
Cossu et al.
Neurosurgery 2005
Reference
The 2005 series from Milano is the first and largest study providing relevant
information on SEEG findings and its impact on epilepsy surgery in a large population of
MRI-negative patients (18). They reported 211 patients, 77 of whom (36%) had a normal
MRI; SEEG delineated the epileptogenic zone in 204 patients (97%). Epilepsy surgery
was proposed in 185 patients (88%), performed in 174 (82%), including 165 with a
postoperative follow-up of 1 year, and 46 (28%) with a normal MRI. In this latter
population, rates of complete seizure freedom and class I of Engel outcome (free of
disabling seizures) were 27% and 38%, respectively, compared with 52% and 62% for
MRI-positive patients. Pathology proved abnormal in 40 of the 46 (87%) MRI-negative
operated patients.
The Marseille group reported a series of 100 consecutive patients who underwent
SEEG, including 43 whose MRI was normal (14, 66). The epileptogenic zone could be
delineated in 96%, while surgery was offered in 84%, with no difference in operability
between patients with and without MRI abnormality. Complete seizure freedom was
achieved in 53% of the 60 operated patients with a postoperative follow-up 12 months,
including 55% of the 20 patients whose MRI was normal, and 53% of those showing MRI
abnormality. Pathology in MRI-negative patients included focal cortical dysplasia (n = 7/9
seizure-free), gliosis (n = 4/7 seizure-free), hippocampal sclerosis (n = 1/2 seizure-free),
and lack of available data in two (none seizure-free).
The Cleveland Clinic recently reported a similar series of 100 consecutive patients who
underwent SEEG, including 61 whose MRI was either normal or showed extensive
bilateral abnormalities, without details about each subgroup, however (10). Localization of
the epileptogenic zone(s) could be achieved in 96% of cases, with 16% showing
multifocal or bilateral foci which contraindicated surgery. These figures are remarkably
similar to those reported above in the Marseille series. A total of 75 patients had surgery,
53 of whom had a postoperative follow-up 12 months. In this latter population, 28
patients (53%) had a normal MRI, with a 57% seizure freedom rate, versus 68% in those
with an abnormal MRI. Pathology disclosed type I or II focal cortical dysplasia in most
patients, and proved normal in seven (25%), only one of whom was seizure-free.
The St Anne hospital reported a series of 62 histologically proven type II FCD, 37
(60%) of which underwent SEEG prior to surgery, including 21 of the 25 MRI-negative
(84%), and 16 of the 37 MRI-positive patients (43%, all before 2006) (35). The overall
surgical outcome was 68% with complete seizure freedom (n = 42/62), and 92% with class
I of Engel outcome (n = 57/62). Nonsignificantly greater seizure-free rate was observed in
MRI-positive (75%) as compared to MRI-negative patients (56%), whereas the proportion
of class I of Engel outcome was comparable in both groups (94% and 88% in MRIpositive and negative patients, respectively). The outcome data in the subgroup of patients
who underwent SEEG were not provided.
Our group recently reported a series of 21 MRI-negative patients who underwent SEEG
and MEG (38). A seizure onset zone was defined in all patients, but they were thought to
be well localized in only 65%. Eleven patients had surgery, six of whom achieved a class I
of Engel (55%). Pathology disclosed FCD in three patients, a mild form of malformation
of cortical development not otherwise specified in another two, and proved normal in six
patients.
Overall, less than 250 MRI-negative patients have been reported in large SEEG series;
SEEG appears to enable a definite conclusion regarding operability in most patients
(96%), about 80% of whom are subsequently operated. Complete seizure freedom rate in
this challenging population varies between 27% and 56%, with most series providing
figures > 50%. Class I of Engel outcome, when available, is substantially higher. The
presence of an underlying FCD, demonstrated at pathology, is associated with greater
chance of seizure freedom, whereas normal pathology is consistently associated with
surgical failure.
SEEG-guided radiofrequency thermocoagulation

One specific advantage of SEEG over subdural grids, is the possibility to perform
radiofrequency thermocoagulation (RFTC) lesions once the recording procedure is over, a
technique developed by our group (67, 68). The RFTC is performed without anesthesia by
using a radiofrequency generator connected to the electrode contacts. Lesions are
produced between two contiguous leads from the same electrode, using a 50 V, 120 mA
current, known to increase the local temperature up to 7882C within a few seconds. This
leads to a spherical brain tissue lesion of about 5 mm in diameter, centered around the
heated bipole, in 1030 seconds. The SEEG recording is performed immediately before
and after the procedure to check its impact on the interictal epileptiform discharges. The
choice of SEEG targets and their number depend on the delineation of the epileptogenic
zone. These targets are previously evaluated using bipolar electrical stimulation in order to
avoid performing RFTC at eloquent cortical areas.
The RFTC can be used for various purposes. In difficult-to-operate patients with small
FCD located in an eloquent area or in patients with periventricular heterotopic nodules,
RFTC may allow the thermocoagulation of most of the epileptogenic zone to fully control
seizures (69). In most patients, however, RFTC is used to further evaluate the extent of the
epileptogenic zone. Specifically, a significant and prolonged reduction in seizure
frequency is thought to reflect a rather limited epileptogenic zone around the
thermocoagulated leads. Nine MRI-negative patients who underwent RFTC were reported
by our group (70). Three (33%) had a reduction of seizure frequency greater than 50%,
including two in whom the rate was 95%. Two of these patients later underwent surgery
that consisted of a tailored resection of the amygdala and temporal pole not including the
hippocampus. Both became seizure-free (class I of Engel). Among the six other patients
where RFTC failed to decrease seizure frequency, four have been operated on, all of
whom were seizure-free postoperatively (70).
Illustrative case: This is an ambidextrous 10-year-old boy, born in 1999, without any
adverse past history and a normal cognitive development. Seizures started at the age of 7
and proved to be drug-resistant from the onset. Most seizures occurred at night and did not
leave any memory of it in the patient. Conversely, daytime seizures started with
paresthesia of the right side of the tongue, rapidly followed by a sensation of jaw locking
and speech arrest. During this short-duration aura, the patient could not warn his family.
Video recording of seizures showed that the patient rapidly developed an asymmetrical
motor behavior, characterized by posturing of the right hemibody with the arm bent
upward, while the trunk and left hemibody demonstrated hyperkinetic movements.
Seizures were brief, lasting about 30 seconds without postictal confusion. There was no
history of secondary generalization of the seizures. Overall, ictal phenomenology
suggested a left-sided onset (right-sided paresthesias and posturing), rapidly involving the
primary or secondary somatosensory cortex of the tongue and premotor/motor cortex of
the jaw, but without other perisylvian sign (no hypersalivation, hemifacial tonic or clonic
movement or paresis, mastication, laryngeal spasm, gustatory or olfactory symptom,
vertigo, or auditory hallucination).
Interictal EEG consistently demonstrated left midtemporal spikes, more frequent during
sleep (Figure 11.4); MEG demonstrated a spike cluster located in the inferior bank of the
left perisylvian region. Using SAM analysis (synthetic aperture magnetometry), dipole
modeling localized the source of the spikes within the left insula (Figure 11.5). Scalp EEG
ictal onset was left-sided but without clear focalization at onset. The FDG-PET showed a
clear-cut hypometabolism encompassing most of the left perisylvian region, with a
maximal abnormality delineated by SPM analysis (statistical parametric mapping) in the
left opercular region (Figure 11.6).
Figure 11.4 Interictal scalp EEG recording. Scalp EEG (referential montage)
demonstrates spikes and polyspikes predominating over T3.
Figure 11.5. Magnetoencephalography. Upper row illustrates SAM (synthetic apperture

magnetometry) analysis, with a spike cluster located in the inferior bank of the left
perisylvian region. Lower row illustrates dipole modeling, showing a source of spikes
centered within the left insula.
Figure 11.6 PET findings. The FDG-PET shows left perisylvian hypometabolism (white
arrow), with a corresponding significant SPM cluster coregistered on MRI (green spot).
The SEEG plan was designed according to all the above data, with the primary
hypothesis that the seizure onset zone was located within the midposterior and superior
aspect of the left perisylvian region (i.e., posterior superior insula or frontoparietal
operculum). However, we considered the alternative hypothesis of a temporal lobe onset
according to the scalp EEG and MEG SAM findings. As illustrated in Figure 11.7, each
main gyri of the suprasylvian opercular region were sampled with SEEG (P, Q, N, G),
with the view that Q and N were the most likely candidates, and that P and G would
provide appropriate anterior and posterior borders of the seizure onset zone. These four
electrodes also investigated the insula, as well as electrodes T, U, and H which sampled its
inferior aspect plus the temporal operculum. The less likely possibility of a temporolimbic
onset was assessed by sampling the temporal pole (J), the amygdala (A), and the
hippocampus (B, E). An orbitofrontal lead (F) was also inserted.
Figure 11.7 Strategy of SEEG implantation. Image on the left shows a sagittal MRI
slice, cutting through the left perisylvian region, upon which all relevant imaging findings
are superimposed: blue corresponds to visually detected hypometabolism covering the
superior and inferior banks of the Sylvian fissure; green corresponds to the cluster
provided by SPM analysis of FDG-PET data (contrasted with a database of 50 controls);
yellow delineates the MEG focus provided by SAM analysis; red illustrates the cortical
region activated during language fMRI. Black dots correspond to implanted electrodes
whose targets were the following: A: amygdala and anterior middle temporal gyrus, B:
anterior hippocampus and middle temporal gyrus, E: posterior hippocampus and middle
temporal gyrus, F: orbitofrontal gyrus, G: posterior cingulate and supramarginalis gyrus,
H: posterior inferior insula and superior temporal gyrus, N: posterior superior insula and
parietal operculum, P: anterior superior insula and inferior frontal gyrus, Q: mid-superior
insula and frontal operculum, T and U: anterior inferior insula and superior temporal
gyrus.
The SEEG recordings demonstrated very focal interictal paroxysms and ictal onset
within the posterior aspect of the frontal operculum (Q lateral), which propagated to the
parietal operculum (N) (Figure 11.8). Seizures could be triggered by stimulating Q lateral,
while the stimulation of F (Brocas area) resulted in speech arrest.
Figure 11.8 SEEG findings. A very restricted area of almost permanent high-amplitude
spikes is observed over the lateral leads of electrode Q 67, corresponding to the frontal
operculum, with some slight propagations to the adjacent electrode N 67 (parietal
operculum). Seizure onset was observed over the same leads. All leads are displayed with
the same gain.
The RFTC was performed selectively on Q6Q7 and Q7Q8, showing an immediate
disappearance of spikes, not only on all leads at electrode Q, but also on those at electrode
N, suggesting that the spikes at the latter were propagated from Q (Figure 11.9).
Thereafter, the patient was seizure-free for 3 months, before seizures relapsed. An awake
corticectomy was performed, with a view to resecting the two small opercular gyri
targeted by electrodes Q and N (Figure 11.10). Pathology demonstrated a type II FCD, and
the patient has been seizure-free for 4 years.
Figure 11.9 Impact of thermolesion. Thermolesions were performed over q67 and
q78 bipoles. High-amplitude spikes that were recorded over q and n leads immediately
before the thermolesion, disappeared immediately after.
Figure 11.10 Surgery. A selective resection of the frontal operculum was undertaken,
resulting in long-term seizure freedom (class IA of Engel) with no neurological deficit.
Conclusion and perspectives on SEEG

The SEEG technique has expanded very significantly over the last 5 years, in parallel with
the increase in the number of patients with MRI-negative refractory focal epilepsy referred
to surgery. Whether this association is coincidental or partly reflects the relevance of
SEEG for investigating MRI-negative patients, is uncertain. In any case, the overall rates
of informative investigation, surgical indication, and excellent seizure outcome support the
use of SEEG in selected cases, in as much as its rate of major complications with either
permanent deficit or death is reasonably low ( 0.6%). Finally, the development of
frameless MRI-based and robot-assisted SEEG is facilitating the access to SEEG in new
centers.
The comparative effectiveness of SEEG and subdural grids also remains a matter of
debate, given the lack of controlled study addressing this issue. The dramatic shift from
grids to SEEG in major epilepsy surgery centers with a huge experience in the former type
of investigation, such as the Cleveland Clinic, suggests that SEEG might offer additional
chances to accurately localize and remove the epileptogenic zone. In a series of 70 frontal
lobe surgeries performed between 1995 and 2003 at the Cleveland Clinic, including 19
patients with a normal MRI, only 16% were seizure-free (71). Among the subset of 12
patients with an MRI-occult cortical dysplasia, only two patients were seizure-free at 1
year (16%), and only one at 2 years (8%). This contrasts with the 57% seizure-free rate
reported by the same group in 28 MRI-negative patients investigated with SEEG (10), as
well as with the 78% to 88% class I of Engel outcome reported by the Marseilles and St
Annes groups in a total of 30 patients with MRI-occult focal cortical dysplasia (14, 35).
The SEEG suffers a number of limitations, however, some of which could be tackled in
the future. One important issue is the lack of guidelines for optimal indication, SEEG
design (i.e., number and location of electrodes), and methods of implantation, with
significant heterogeneity of practice between centers. Harmonization should be promoted,
in as much as technological advances in the field progress at an increasingly rapid pace.
Indications for SEEG may deserve a consensus statement. The great majority of
successfully operated MRI-negative patients prove to suffer FCD at pathology, and most
often FCD type II. The latter are usually associated with suggestive features, in terms of
history (age of onset of epilepsy and drug resistance, seizure frequency and stereotypy
over time), interictal FDG-PET and EEG/MEG findings. It may be debated whether
patients with extratemporal seizures but no features supporting the hypothesis of an MRIoccult FCD should undergo SEEG. This issue is different in cryptogenic TLE where
seizure freedom can be obtained despite normal pathology. However, whether performing
SEEG with a view to sparing a normal-volume hippocampus is associated with clinically
relevant benefit remains to be demonstrated. The same is true for the predictive value of
thermolesions. Overall, many issues deserve to be addressed in the field of SEEG in the
hope of increasing the yield of this investigation in MRI-negative refractory focal
epilepsy.
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Chapter 12 Ultraslow and high-frequency recordings in

MRI-negative refractory focal epilepsy
Vlastimil Sulc and Gregory A. Worrell
Acknowledgments: This research was supported by NIH R01-NS63039 (GW), European

Regional Development Fund Project FNUSA-ICRC (No. CZ.1.05/1.1.00/02.0123), and
by the European Social Fund within the project Young Talent Incubator II (reg. no.
CZ.1.07/2.3.00/20.0117).
Scalp EEG and intracranial EEG (icEEG) are critical technologies for localization of
epileptogenic brain and guiding epilepsy surgery in patients with drug-resistant focal
epilepsy and negative MRI. Scalp EEG is universally used to confirm the diagnosis of
epilepsy and for developing a hypothesis for the localization of epileptogenic brain tissue.
In order to localize the brain region(s) generating seizures, patients with negative MRI
often have intracranial electrodes implanted based on the localization hypothesis
developed using noninvasive studies (semiology, scalp EEG, and functional imaging). It
can be argued that icEEG is the gold standard for localizing the seizure onset zone (SOZ)
[1], but whether there is an electrophysiological biomarker for the epileptogenic zone (EZ)
remains unanswered [2,3].
The EEG signature of epilepsy is the pathological electrical activity occurring during
seizures (ictal), but it has long been recognized that there are also brief epileptiform
transients between seizures (interictal), i.e., interictal epileptiform spikes and sharp waves
(IES) [4]. The significance of IES in epileptogenesis and seizure generation has been
widely debated, but IES have always played a clear and important role in clinical practice
for localization of epileptogenic brain tissue. Despite the well-established clinical
importance of icEEG and advances in digital electronics and computing that have
revolutionized animal electrophysiology [5], clinical icEEG continues to primarily utilize
narrow bandwidth (1100 Hz) recordings from widely spaced (510 mm) macroelectrodes
(> 1 mm2). A fundamental and unanswered challenge for clinical icEEG is the optimal
spatial resolution and recording frequency bandwidth.
Table 12.1 The EEG spectrum of human brain electrical activity
Direct current shifts (DC shifts)

Ultraslow oscillations (0.010.1 Hz) Low-frequency oscillations
Slow oscillations (0.11.0 Hz)
Berger Bands: Delta (14 Hz), theta (48 Hz), alpha (814 hz), beta (1430
Hz)
Gamma (3080 Hz)

Ripple (80250 Hz) High-frequency oscillations
Fast ripple (> 250 Hz)
The spatial organization of the human brain extends from neurons, submillimeter
diameter cortical columns composed of thousands of neurons, to centimetre-scale lobar
networks. The electrical activity generated by these neural assemblies range from direct
current shifts to high-frequency oscillations (~01000 Hz). This remarkable range of
human brain electrophysiology can now be probed with wide bandwidth acquisition
systems and hybrid electrodes containing micro- and clinical macroelectrodes [68].
The nomenclature used to describe oscillations outside the standard clinical Berger
Bands (125 Hz) is not firmly established, but includes ultraslow, slow, and highfrequency activity that are outside the common clinical bandwidth. In epileptic brain there
are a range of pathological transients in addition to IES, including high-frequency
oscillations (HFOs) [3,9], microseizures [10], focal ultraslow activity [7,11,12], and
alterations in network synchrony and connectivity [13]. These interictal abnormalities are
all promising biomarkers for mapping the spatial extent of epileptic brain, but reliably
differentiating normal from pathological brain activity remains a fundamental challenge
[14,15]. This is particularly true for HFOs, which are associated with normal activity like
perceptual binding [14], memory encoding, and consolidation [16], sensory coding
[17,18]\ and motor movements [9,19], but are sometimes pathological oscillations
generated by epileptogenic brain tissue [3,20]. In the following sections, we discuss
HFOs, microseizures, focal slow activity, and synchrony and the evidence that they are
signatures, i.e. potential biomarkers of epileptogenic brain tissue.
Figure 12.1 Hybrid micro- and macro strip (A), depth (B), and grid electrodes (C).
Microwire electrodes are embedded into the silastic substrate. Typical dimensions are
40m diameter microelectrodes separated by 500 to 1000 m. The hybrid electrodes
increase the spatial coverage without increasing the number of clinical electrodes. When
the embedded microwires are cut flush with the silastic substrate they should not increase
the risk of irritating or injuring the underlying cortical tissue.
Interictal and ictal high-frequency oscillations (HFO): In addition to their role in
normal brain function, high-frequency oscillations in the gamma, ripple, and fast ripple
(FR: 2501000 Hz) frequency ranges, are also increased in epileptogenic brain [3,14,20].
Analogous to the epileptic rats, both ripple and FR oscillations were first identified in
humans from recordings in epileptogenic hippocampus [6]. Ripple and FR oscillations
were found to be increased in slow-wave sleep compared to the waking period. In these
early studies FR were identified in epileptogenic hippocampus and ripples were decreased
in the epileptogenic hippocampus. These early animal studies were performed with
microwire electrodes in chemotoxin-induced epileptic rats [21], and the human studies
were primarily from patients with mesial temporal sclerosis [6]. This may explain why
subsequent studies have found that ripple HFOs are also increased, similar to fast ripples
in the SOZ [22,23]. Discrepancies could also originate from the fact that many more
recent human studies have employed macroelectrode recordings rather than the
microelectrodes used in the rat and early human studies. Multiple studies have
subsequently clearly demonstrated that ripples and FR are reliably recorded using clinical
macroelectrodes [23]. The fact that ripple HFOs are increased in the SOZ, rather than
decreased, is consistent with reports from animals describing an increase in ripples prior to
seizures [24], and supports the hypothesis that ripple-frequency HFOs are involved in the
generation of seizures [25] and may serve as an accurate biomarker of epileptogenic brain
tissue.
High-frequency oscillations at the onset of human seizures were initially described in
icEEG recordings of patients undergoing evaluation for epilepsy surgery [26,27]. These
early observations showed that focal seizures often begin with low-amplitude, highfrequency oscillations. The range of frequencies that have been reported vary, but are in
the gamma, ripple, and fast ripple frequency range: 30500 Hz [28], 40120 Hz [27], 60
100 Hz [29], 7090 Hz [30], 80110 Hz [26], and 100500 Hz [31]. Focal low-voltage
fast oscillations (> 20 Hz100 Hz) at seizure onset have been demonstrated to be
associated with good epilepsy surgery outcome if the SOZ was completely resected
[32,33]. Thus, there is now significant evidence that high-frequency oscillations are a
functional signature of the epileptogenic brain tissue [3], and that they play a role in
seizure generation [25]. Whether there are clinical advantages to recording icEEG at
submillimeter spatial scale with microelectrodes in order to more efficiently sample HFO
is not known.
Figure 12.2 KurskalWallis applied to HFO (ripple/fast ripple), electrode type

(micro/wiremacro), and brain regions of seizure onset zone (SOZ) and nonseizure onset
zone (NSOZ). Box-plots and the results from posthoc analysis (***p < 0.002, **p < 0.01,
*p < 0.05). The number of microwire ripple (Rm) and fast ripple (FRm) HFO are increased
in the SOZ compared to NSOZ. The number of macroelectrode ripple (RM) and fast ripple
(FRM) HFO were increased in the SOZ compared to NSOZ, but less significantly for fast
ripple. (Adapted from Worrell et al. 2008 [23].)
Association of HFO with surgery outcomes: In a recent study investigating the spatial
relation between HFOs and interictal epileptiform spiking in a group of lesional temporal
and extratemporal patients, HFOs had a tighter correlation with the SOZ [34] and ripples
and fast ripples HFOs were closely linked to the areas involved in seizure generation [35].
This study also showed that in focal cortical dysplasia, HFOs occurred in lesional areas
that were not part of the SOZ, which might indicate that the potential epileptogenicity of
these lesions is more widespread than the lesion visible on MRI.
In a subsequent study, Jacobs et al. correlated the resection of HFO-generating tissue
with epilepsy surgery outcome and demonstrated that resection of tissue-generating ripple
and FR HFOs was associated with a favorable outcome [22]. In a recent study by
Haegelen et al. [36], removing HFO-generating tissue led to an improved surgical
outcome in TLE group but not in a group of patients with ETLE. Further, Wu et al. [37]
used intraoperative recordings to identify fast-ripple HFO (> 250 Hz) and found that all
patients who had tissue with the HFO resected were seizure-free. In contrast, none of the
patients (5/5) who did not have all fast ripple HFO tissue resected became seizure-free,
including the one patient with negative MRI.
Scalp EEG recording of high-frequency oscillations

Studies using combined scalp and icEEG have previously reported that an epileptiform
sharp wave can be detected on surface EEG if at least approximately 7 cm2 of cortex is
involved. Given that HFOs are often spatially limited, this suggests a significant challenge
for the use of scalp EEG to detect HFOs. However, HFOs can be more widely distributed
than initially thought [38,39]. A recent study using wide bandwidth EEG recordings from
ten children with continuous spikes and waves during slow-wave sleep described HFOs on
scalp EEG concurrent with interictal spikes, with peak HFO power that ranged from 97.7
to 140.6 Hz [40]. These data showed brief HFO events visible in the raw scalp EEG data
associated with the EEG large-amplitude spike [40]. Similarly, in patients with focal
epilepsy, gamma- and ripple-band activity has been described on scalp EEG, most often
around the time of interictal spikes, but better than interictal in correlation with the SOZ
[41].
It is important to note that noncerebral activity (artifact) can be especially difficult to
separate from cerebral generators when analyzing band pass filtered data, as is often done
when analyzing HFOs. For example, induced gamma-band activity on scalp EEG during
presentation of a visual stimulus was shown to be artifact associated with microsaccade
eye movements [42]. Saccades are accompanied by a spike potential of muscle origin,
which have a broad high-frequency spectrum that could be misinterpreted as having a
cerebral origin. Thus, some of the induced gamma-band power recorded from scalp EEG
that was thought to be of cerebral origin is likely of muscular origin (eye movement
related) [42].
Interictal and ictal DC shifts and slow-frequency oscillations: Although recognized in
early animal cortical recordings [43], DC fluctuations and ultraslow frequency oscillations
have received relatively little attention in human brain recordings [7,11]. The sustained
DC and very slowly changing potentials (< 0.1 Hz) that characterize these activities likely
have a cortical origin given that they can be recorded from small regions of neocortex that
are devoid of inputs (i.e., neocortical slabs). Both neuronal and nonneuronal mechanisms
are likely involved in generating these activities [44,45]. Ultraslow and slow oscillations
synchronize higher-frequency oscillations and modulate cortical excitability, which may

explain the increase in epileptiform discharges seen in slow-wave sleep [11]. Recent
studies have demonstrated that ultraslow oscillations occurring during sleep can be focal
[46].
Figure 12.3 Wide bandwidth recording from 6x6 subdural grid. Right icEEG recording
from seizure onset region. At seizure onset there is a prominient slow wave with increased
amplitude of activity in the high-frequency range (bottom). (Courtesy of Matt Stead, MD,
PhD.)
The majority of human studies used AC coupled amplifiers with sufficiently long time
constants that record filtered DC shifts as slow-wave potentials. Focal ictal slow-wave
potentials were identified in 85% of 89 seizure onset in six patients with neocortical
epilepsy [12]. Bragin and colleagues reported 89% of hippocampal seizures with a highfrequency onset were associated with a coincident slow-wave potential [47]. There is
evidence for the localizing value of interictal and ictal DC shifts, but the ultimate clinical
utility remains to be determined [7].
Interictal microseizures: The ability to investigate in vivo human epileptogenic brain
across a wide range of spatial and temporal scales yields remarkably rich data. One of the
most dramatic findings is microdomain seizure-like events, apparent on microwires but
not detected on adjacent clinical macroelectrodes [10,48]. These seizure-like events, or
microseizures, are clinically silent electrographic events, detectable on microwires only.
Microseizures have spectral features, morphology, and durations similar to electrographic

seizures detected on macroelectrodes. Typical durations vary between 1060 seconds
(median of ~30 seconds), but can be over 100 seconds. Microseizures are subclinical, selflimiting, electrographical events that mostly remain isolated to a single microwire, but in
some cases evolve directly into macroelectrode seizures.
Conclusions: In summary, the search for interictal biomarkers of epileptogenic brain
remains an active area of research [2,3]. The existence of an interictal biomarker of the EZ
would be a transformative technology for epilepsy surgery, since it would eliminate the
reliance on chronic icEEG recording, and it would also help to delineate EZ in patients
with negative MRI. To date there is substantial evidence to support the clinical usefulness
of pathological interictal HFOs for localization of the EZ, and HFOs appear to be the best
interictal biomarker of the EZ. The results are very encouraging; however, to date they are
primarily from small retrospective studies in lesional or MRI-negative epilepsy, and few
have directly compared IES, HFO, and other potential interictal biomarkers to localization
provided by spontaneous seizures. In the future a prospective trial seeking class I evidence
for the clinical utility of wide bandwidth interictal electrophysiology in lesional or MRInegative focal epilepsy surgery should be possible.
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Chapter 13 Cortical mapping in MRI-negative epilepsy

surgery
Gonzalo Alarcn and Antonio Valentn
Introduction
Deciding the extension of a resection for the treatment of epilepsy should include two
objectives: a. Resection of the regions originating seizures, and b. Avoidance of functional
deficits resulting from the resection of functionally eloquent cortical areas. Obtaining
adequate seizure control often involves extending the resection beyond the limits of the
lesion or of the seizure onset zone. Since the regions originating seizures may be close to
or merged with functional cortex, measures must be taken to minimize the risk of function
loss. This is particularly relevant in patients with MRI-negative epilepsy, where most
removed cortex may be structurally normal and may possibly be functional. Limited
removal of association cortex does not usually induce severe neurological or cognitive
deficits. However, removal of language, primary motor or sensory areas can be associated
with corresponding transient or permanent deficits which should be avoided whenever
possible. Unilateral temporal resections can induce memory deficits in the small
proportion of patients where memory is lateralized to the resected hemisphere.
Identification of functional cortex (functional mapping) is therefore of paramount
importance to avoid its removal and, consequently, prevent deficits associated with
resection. The first approach to localization of motor, sensory and language areas can be
anatomical. However, given the individual variability in the location of these areas (Figure
13.1, see also Ojemann et al. (1) and Nii et al. (2)), their detailed localization in individual
patients may be required before resection to avoid their removal. For instance, although
the usual anatomical landmark to avoid receptive language area is 44.5 cm from the
temporal pole (sparing superior temporal gyrus), functional mapping has occasionally
identified language areas within 3 cm of the temporal tip (3, 4).
Figure 13.1. Distribution of functional areas in epileptic patients who underwent

functional mapping at Kings College Hospital, London, over the last 3 years. Patients
with normal MRI are shown in red, and patients with abnormal MRI are shown in blue.
The distribution of motor areas from 15 patients corresponding to the hand, wrist, and
fingers are shown over the precentral cortex. The distribution of Wernickes area from
eight patients is shown over the lateral temporal cortex. Note that there is a very
significant overlap between patients with normal and abnormal MRI. However, there are
some outliers among patients with normal MRI. Each circle corresponds to a subdural
implanted electrode. (Figure elaborated in collaboration with Drs Susana Sainz de la Maza
Cantero and Robert Morris.)
The methods used to identify functional cortex are the same for patients with MRInegative epilepsy, for those with MRI lesions, as well as for patients undergoing resections
in the absence of epilepsy (tumours, arteriovenous malformations). Electrical stimulation
through intracranial electrode mats has traditionally been used for this purpose (5). In
patients without epilepsy, intraoperative mapping is the preferred option, as there is no
need in these patients for chronic recordings to demonstrate ictal onset. There is some
evidence for reorganization of functional areas around and within macroscopic lesions (6
10), suggesting that individual variability might be larger in patients with detectable
lesions than in those with normal imaging. However, the patients studied in our centre
over the last 3 years showed a significant overlap in the distribution of functional maps
between patients with normal and abnormal MRI studies (Figure 13.1).
Functional mapping with electrical stimulation

History: The localization of human cerebral function has long been linked to
investigations in epilepsy. For over 20 centuries, epilepsy was not necessarily thought to
arise from the brain and was classified as idiopathic (coming from the brain) and
sympathetic or symptomatic (affecting the brain secondarily, after starting in other organs
as suggested by auras which could start anywhere in the body). Hughlings Jackson was
the first to provide a clear understanding of the significance of focal seizures as starting in
the brain. The study of focal seizures then became the starting point to understand the
localization of cortical function. Experimental demonstration for localization of cortical

function was first provided by Fritsch and Hitzig (11), Ferrier (12) and Luciani (13). Focal
movements were elicited by localized electrical stimulation of the motor cortex in animals,
with focal motor seizures and generalized seizures being induced by progressively
increasing stimulation intensities. Between 1901 and 1917, Sherrington reported
movements of the contralateral limbs induced by stimulation of the precentral gyrus in
apes, as well as conjugate eye movements induced by more anterior lateral frontal areas
and occipital cortex near the calcarine fissure. Vogt and Vogt (14) confirmed the finding of
contralateral eye movements elicited by stimulation of area 6 (anterior to area 4) of
Brodmann, and found that motor responses elicited by area 6 required higher intensity and
could be abolished by severing the fibers between areas 6 and 4. Consequently, they
described area 4 as primary motor field, subdivided area 6 into secondary and tertiary
motor fields and coined the term adversive for contralateral eye, ears and head turning
as if the animal was looking and listening to something on the contralateral side to
stimulation. Foerster (15) found that higher intensities applied to area 6, to area 5
(parietal) and to area 22 (temporal) induced bilateral movements and mass turning, and
called these areas extrapyramidal, considering them as secondary motor areas, to
distinguish them from the primary motor area (area 4) which gives rise to the pyramidal
tract. Penfield and Jasper (5) systematically applied electrical stimulation to map human
cortical function during presurgical assessment of epilepsy. They confirmed area 4
(precentral) as the primary motor cortex and areas 13 (postcentral) as the primary
somatosensory cortex in man (Figure 13.2A). They designed their famous homunculus
(Figure 13.2B) and described arrest of voluntary movements by stimulation of the
supplementary motor cortex and of the second sensory area (Figure 13.2C). They
emphasized the presence of connections between pre- and postcentral areas, describing
both areas as a sensorimotor unit, a view that has been confirmed by more recent studies
(16, 17).
Figure 13.2 Penfield and Jaspers diagrams showing the topographical organization of
motor and somatosensory areas. A. Sensory sequence in the postrolandic cortex shown on
a cross-section of the cerebral hemisphere. Lengths of the black lines in the cortex indicate
the approximate extent of the representation of sensation for each part of the body. B.
Sensory and motor homunculus. This was prepared as a visualization of the order and
comparative size of the parts of the body as they appear from medial and above down
upon the perirolandic cortex. C. Map of the somatic motor and sensory areas. The frontal
and parietal regions are spread up to form a map from the corpus calosum to the insula.
Thus, the medial surface of the hemisphere lies above, the bank of the fissure of Sylvius
below, and the lateral surface between the two. The supplementary motor and sensory
areas, and the second somatic sensory areas are stippled. The perirolandic sensorimotor
strip is indicated by parallel lines. The frontal eye field, whose stimulation induces
aversive eye and head rotation, is labeled as gaze. Reproduced with permission from
Penfield and Jasper (5).
General procedure: Electrical stimulation allows functional mapping by identification
and demarcation of the areas involved in a particular function. Functional mapping can be
obtained during chronic intracranial recordings in the telemetry ward (extraoperative) or
during surgery under local anaesthesia in the operating theatre (intraoperative). Functional
mapping is best performed with the patient awake and relaxed, though motor responses
can be induced under general anaesthesia, usually requiring higher intensities and
inducing cruder responses, thus providing less fine spatial resolution than those seen with
the awake patient. For mapping of sensory or speech areas with electrical stimulation, the
patient must be awake. Patients must be informed on the expected clinical responses that
may occur, as these may be distressing if unexpected (e.g., forced movements, speech
arrest), and on the risk of provoking seizures. Functional mapping is best performed
through mats of electrodes in order to guarantee adequate spatial sampling. Stimulation of
mesial temporal structures through the deepest contacts of subtemporal strips can be
painful, presumably due to stimulation of nearby cranial nerves. Electrical current can be
passed between pairs of adjacent electrodes at progressively increasing current intensities
and durations (typically biphasic 0.3 to 1 ms pulses of 0.5 to 15 mA at 50 Hz, lasting for
up to 10 seconds), while simultaneous electroencephalographic recordings are obtained

with the electrodes not used for stimulation. Stimulation is carried out with progressively
increasing strength, starting at low intensities (0.5 mA) and short durations (1 second),
then gradually increasing duration up to 610 s, then increasing intensity with short
duration, then increasing duration and so forth (e.g., 0.5 mA for 1 second, then 0.5 mA for
3 seconds, then 0.5 mA for 6 seconds, then 1 mA for 1 second, then 1 mA for 3 seconds,
etc.). The duration and intensity of stimulation are thus progressively increased until at
least one of the following circumstances occurs:
a. Positive clinical signs or symptoms (responses) are observed associated to
stimulation: Stimulation of motor cortex induces contralateral limb movements,
brief dystonic postures, or muscle contractions. When somatosensory cortex is
stimulated, patients may report contralateral paraesthesia (tingling, numbness,
burning or sensation of electricity). When visual cortex is stimulated, patient
may describe contralateral visual symptoms (flashing lights, lines, colours,
moving forms).
b. Negative clinical responses are observed associated with stimulation: These
responses consist of interruption of normal ongoing function. To identify such
responses, the patient must be engaged in activity. Speech arrest occurs when
motor speech area is stimulated, and inability to understand words occurs when
receptive speech areas are stimulated. Arrest of motor activity can occur while
stimulating premotor and supplementary motor cortices, which may manifest as
negative myoclonus and hand or limb drop.
c. After-discharges are observed on the EEG recording immediately following
stimulation: Brief runs of epileptiform discharges or ictal EEG patterns can be
induced by electrical stimulation (Figure 13.3). They are usually short and
asymptomatic. However, stimulation with higher intensities should be avoided
whenever possible, as it can induce longer after-discharges evolving to overt
seizures. This circumstance may have to be reconsidered in children (see below
under Electrical stimulation in children).
d. The upper limit of stimulation intensity and duration are reached, usually around
7.515 mA for 610 sec.
Figure 13.3 Two examples of after-discharges in the same patient. Functional mapping
was performed via a lateral frontal subdural mat and Sylvian and central 4-contact
subdural strips. A. Stimulation through electrodes 21 and 22 of the mat (circled on the Xray inset) for 3 seconds induced sustained after-discharges for several seconds at nearby
electrodes (arrow). B. Stimulation of electrodes 34 of the Sylvian strip (circled on the Xray inset) for 1.5 seconds induced a 2-second burst of after-discharges (arrow) at the
remaining electrodes of the strip. Note the large stimulation artefact obscuring EEG
recordings.
Functional mapping can also be carried out through depth electrodes. These are less
appropriate than mats in terms of spatial sampling, but allow testing the same functions
with lower intensities (up to 3 mA usually). Also, one Hz stimulation can be used to test
the motor cortex and underlying pyramidal tract with depth electrodes.
While stimulation is being carried out, clinical personnel should observe the patient and
the EEG for the occurrence of clinical responses or after-discharges. Should these occur,
stimulation must be repeated for reliability after at least 30 sec. The effects of stimulation
are reproducible and short lived, usually lasting for the duration of stimulation or a few
more seconds, unless an epileptic seizure is induced. The onset of positive or negative
signs or symptoms without after-discharges is the best indicator for localization of motor,
sensory or speech areas in the cortex underlying the stimulating electrodes. Similar signs
or symptoms, when associated with after-discharges, have more limited value, as they may
be due to cortical activation by after-discharges, which in 8% of cases propagate to
regions relatively distant from the stimulated cortex (18), possibly leading to
mislocalization of function. The threshold for functional responses and for afterdischarges is generally different at each stimulated site, may differ according to the
intertrial period and may show day-to-day fluctuations, making it important to optimize
the stimulation intensities for each tested site, progressively increasing stimulation
according to the procedure described above. Should after-discharges occur, stimulation at
the same site can be carried out again at slightly lower intensity, which sometimes avoids
the occurrence of further after-discharges, and then stimulation can be gradually increased
to test for functional threshold. In patients with large numbers of after-discharges, low
doses of lorazepam or diazepam can be administered prior to stimulation.
Positive clinical responses are sometimes induced by stimulation of secondary motor
and sensory areas. Stimulation of association cortex, other than speech areas, does not
usually induce clinical responses.
Changes in electrical charge density induced by this procedure and responsible for the
responses are very localized, attenuating rapidly over short distances, as shown by a finite
element model (19) and by the fact that clinical responses are very localized, i.e., change
or disappear dramatically when moving the stimulating electrodes only a few millimetres
apart (20, 21).
Safety issues: The charge used for stimulation is the product of current intensity and
pulse duration and can be expressed as per phase or as charge density (charge per unit of
electrode area). Smaller electrodes will induce higher charge densities, which may need to
be compensated with lower intensities. Chronic stimulation with charge density at
55C/cm2/phase was not associated with pathological changes (22), suggesting that
stimulation with charge density below this figure should be safe. In young children, where
myelinization is not complete, high current densities may be necessary (22). In practice,
the main side effect of electrical stimulation is the induction of a seizure, which in itself
may carry useful information (see below). Over a 20-year period, the author has seen only
one case of secondarily generalized convulsive status epilepticus induced by electrical
stimulation during functional mapping in a child with epilepsia partialis continua.
It has been suggested that stimulation with high frequencies (500 Hz) applied to motor
cortex can induce contralateral muscle potentials with possibly less risk of inducing
seizures (23). No kindling has been reported in humans. Stimulation thresholds do not
seem to decrease significantly with successive stimulation trials in man, and kindling of
the neocortex has not been observed in higher primates. Apart from the specific safety
issues with regard to electrical stimulation, surgical procedures carry the general risks of
untoward effects associated with neurosurgery and chronic implantation of intracranial
electrodes (infection, hemorrhage, subdural hematoma).
Mapping somatic sensorimotor cortex: Stimulation of the motor cortex induces
contralateral muscle tonic or clonic contractions and movements of the corresponding
limbs and muscle groups. Similarly, stimulation of the somatosensory cortex induces
contralateral paraesthesia in the corresponding limbs, most frequently tingling, numbness,
burning or tightening, and less frequently painful sensations or a sense of movement. Such
positive clinical responses are usually rather localized, most frequently involving one hand
or one side of the face as these are the areas with the largest cortical representation.
Indeed, this was the methodology used by Penfield to design his homunculus (5). More
rarely, stimulation can induce both motor and sensory responses, either because both
motor and sensory areas intermingle or due to stimulation of nearby secondary cortex or
association fibers. Indeed, sensory responses can be elicited precentrally and vice versa in
approximately 25% of subjects (5). Cessation of ongoing motor activity and dystonia has
been reported during stimulation of premotor cortex (24). Such arrest of motor activity
affects particularly fine distal movements and can be associated with contralateral or
ipsilateral decreased or increased motor tone. Motor arrest can be tested by asking the
patient to read during stimulation and, if reading arrest occurs, stimulation is repeated
while carrying out contralateral alternate movements to distinguish a negative motor
response from the speech arrest elicited when stimulating speech areas. Stimulation of the
primary motor cortex between upper face and finger areas, and stimulation of the
premotor cortex anterior to this region, can elicit head and eye turning in the direction
contralateral to stimulation (adverse rotation) (5, 25). These regions have also been called
frontal eye field. Stimulation of the motor cortex around the lip/mouth area can elicit
vocalization, a long drawn-out vowel sound made by symmetrical contraction of mouth,
pharynx, larynx and respiratory muscles. Respiratory arrest has been described with
stimulation of the lateral lower end of the sensorimotor strip (5). Unilateral stimulation of
mouth, tongue or throat areas can induce bilateral movements or contralateral unilateral
responses. Neck movements (aside from turning) can be induced by stimulation of two
regions, below and above the face area.
In humans, the supplementary motor cortex is the region anterior to the leg area in the
interhemispheric fissure and dorsal aspect of the superior frontal gyrus. Stimulation of this
region can induce aversive movements (i.e., this region is also called the supplementary
eye field) in addition to a variety of movements and dystonic postures (often bilateral,
involving aversive head rotation, and posturing of shoulders and elbows), arrest or
slowing of voluntary movements and speech, vocalization, sensations (general body
sensation, sensation of flush, cephalic, epigastric or indescribable sensations, contralateral
or bilateral leg sensations), autonomic changes (pupillary dilation and changes in heart
rate) and aphasia (5). The supplementary motor cortex shows a somatotopic organization
(26).
Motor (largely precentral) and sensory (largely postcentral) homunculi are rather
similar and tend to run in parallel, except that there is no motor representation for scalp or
genitalia. Sensory responses to stimulation are contralateral except those induced by

stimulation of face and tongue areas which can be bilateral, and those induced by
stimulation of the throat area which are usually bilateral. Stimulation of the tongue and
mouth areas can induce numbness or tingling, but not taste. There is a second sensory area
over suprasylvian cortex, covering pre- and postcentral regions (5). Stimulation of the
second sensory area induces similar responses to those described for the primary sensory
area, often associated with a desire to move or losing strength, or temporary paralysis in
the corresponding contralateral (and sometimes ipsilateral) region. Interestingly, cortical
stimulation can elicit somatosensory sensations in phantom limbs (27).
Single electrical pulses can induce very localized motor responses, often restricted to
one finger or muscle (28).
Mapping visual cortex: Stimulation of the occipital visual cortex induces phosphenes
(flickering lights, dancing lights, stars, colors, shades, gray spots) or elementary visual
shapes (lines, whirling circles) seen in the contralateral visual field. In man, areas 18 and
19 are most easily accessible with subdural electrodes. Area 17 at and around the calcarine
fissure (primary visual cortex) is rarely accessible, except the macula, which is
represented at the occipital pole. Stimulation of the parieto-occipital region can induce
adversive eye movements. In addition to visual cortex, resections should also spare visual
pathways, such as optic radiations and other connections that can be identified by
electrical stimulation (29).
Olfactory and gustatory sensations: Disagreeable smells can be elicited by stimulation
of the uncus and nearby olfactory bulb and amygdala. Tastes, usually bad, can be induced
by stimulating the insula (5).
Mapping auditory cortex: Stimulation of the posterior half of the superior temporal
gyrus can induce the perception of ringing, humming, buzzing and other sounds, as well as
deafness and distortion of incoming sounds. Sounds are referred to the opposite ear or to
both ears. Stimulation of the superior temporal gyrus can also be associated with
suppression of hearing (30).
Stimulating the insula (see also section below on autonomic function): It appears that
the insular cortex is connected to two different cortical networks, a visceral network
extending to the temporomesial structures and a somesthetic network reaching the
opercular cortex, which induce visceral or somatosensory sensations with stimulation of
the anterior or the posterior insula, respectively (31).
Mapping language: The specific areas of the brain responsible for language function
were some of the first functional areas to be identified, on the basis of patients who
developed aphasia after brain lesions. The initial findings showed that injuries located in
the inferior frontal gyrus were associated with disruption of executing speech and writing
(32). Patients with more posterior lesions, in a region located mainly over the posterior
and superior aspect of the lateral temporal lobe, developed problems in the analysis and
interpretation of language (33). Essentially, the region described by Broca was associated
with speech production (and is often called Brocas area or motor speech area), whereas
the area described by Wernicke was engaged in speech understanding (and is commonly
referred to as Wernickes area or receptive speech area). The distributions and connections
between language areas are shown in Figure 13.4. In addition, mapping with electrical
stimulation has shown that the basal temporal language area is located in the area of the
fusiform gyrus, 19 cm posterior to the temporal tip (34). Bilateral representation of the
basal temporal language function has been suggested by event-related potentials (35) and
functional neuroimaging (36).
Figure 13.4 Lateral view of the human left cerebral hemisphere, highlighting the main
areas involved in movement control and language. The arcuate fasciculus connects
Wernickes and Brocas areas. (Reproduced with permission from Principles of Neural
Science, 2nd edn, edited by ER Kandel and JH Schwartz, Elsevier: New York, 1985,
Figure 15, p. 8.)
Lateralization of language has been traditionally achieved with the amytal test (also
called, amylobarbital or Wada test). Alternative methods for lateralization are presently
emerging (see Chapter 8).
For localization of speech areas, rather than their lateralization, functional mapping
with electrical stimulation may be required. Speech responses to electrical stimulation are
usually negative. Arrest of ongoing speech can be induced by stimulation of Brocas area
and disturbance in speech understanding can be observed when stimulating Wernickes
area. Consequently, in order to assess language function the patient must be undertaking a
language task during stimulation. Different tasks can be tested which can be localized to
different cortical areas (Table 13.1). Stimulation is started at the beginning of the task and
patients are assessed during stimulation. If speech disturbance occurs, stimulation should
be repeated for reliability.
Table 13.1 Location of sites involved in various language tasks
FUNCTION
TESTED
LOCATION OF SITES IDENTIFIED
Orofacial
motor
sequencing
Perisylvian region of frontal, temporal and parietal cortex
Automatic
speech (speech
arrest)

Posterior inferior frontal cortex
Basal temporal cortex
Posterior inferior frontal cortex Posterior STG
Posterior STG, inferior parietal lobule and superior aspect
of posterior middle temporal gyrus (Wernickes area)
Repetition
Posterior STG
Posterior STG
Phoneme
identification

Mid to posterior STG
Visual naming
Posterior temporal cortex

Basal temporal languge cortex
Posterior STG
Mid to posterior temporal cortex
Auditory
naming
Lateral temporal cortex

Anterior temporal lobe
Auditory
verbal
comprehension
Mid to posterior STG

Posterior STG, posterior inferior frontal cortex
STG, middle portion MTG, lateral frontal and posterior
inferior frontal cortex
Short-term
verbal memory
Temporoparietal lateral cortex (acquisition) lateral frontal

cortex (retrieval)
Reading
(sentence
completion)
Middle temporal gyrus and inferior parietal lobule
Reading
(syntax)
Inferior and lateral frontal, parietal and temporal cortex

(anterior to visual naming sites, broader area than naming
sites)
Verb
generation
Frontal lobe (1 cm from visual naming sites) and

temporoparietal cortex (unrelated to visual naming sites)
Writing
Posterior inferior frontal cortex

Modified with permission from Hamberger 2007(39); STG = superior temporal

gyrus; MTG = midtemporal gyrus.
For localization of Brocas area, the traditional task consists of asking the patient to
read, count or recite a known lullaby or song, while checking for pauses in speech
associated with stimulation. For identification of the Wernickes area, three different
methods with minor modifications are the most commonly used (Figure 13.5); see also
Ojemann, 1981 (37):
a. Auditory responsive naming: During stimulation, the patient listens to a brief
description (Tell me what is a barking pet.) and should name the described
item.
b. Picture selection: During electrical stimulation, the name of an item is said aloud
by the examiner, and after stimulation the patient has to point at the named item
among four drawings of common objects.
c. Visual confrontation naming: During stimulation, the examiner says What is
this? while a drawing of a common object is presented to the patient who has to
name it.
Figure 13.5 Commonly used paradigms to identify receptive (Wernickes) language

areas showing the time course of language task and stimulation. The down arrows indicate
the onset of electrical stimulation. Reproduced with permission from Malow et al. (38).
Both auditory and visual tasks should be used in each patient, as the distribution of the
auditory naming site (auditory responsive naming) appears to be more anterior in the
temporal lobe than the visual naming site (picture selection and visual confrontation
naming) (38, 39).
More recently other tasks have been suggested for assessment of Brocas and
Wernickes areas, including spontaneous speech, word repetition, object description,
reading, comprehension, and verb generation (39). Results from these tasks can point to
close, but different, brain regions to those identified with more traditional tasks. However,
the number of different tasks to be performed in a patient is necessarily limited. A
selection of the most clinically relevant tasks is required for each individual case.
Electrical stimulation of the basal temporal language area elicits a range of responses
from complete expressive, receptive and repetition deficits at higher stimulus intensities to
anomia and other aphasic symptoms at lower intensities (40, 41).
In essence, electrical stimulation behaves as a temporary and reversible lesion,
replicating the deficits associated with resection, and is presently considered as the gold
standard for the identification of the specific areas responsible for language (37, 39). The
difficulties in mapping language in children have been reviewed elsewhere (42).
New noninvasive functional methods (PET, MEG, fMRI) have implicated larger areas
of the brain in some aspects of speech. For instance, although the superior temporal gyrus
appears to be related to the analysis of the speech sound, other temporoparietal regions can
be necessary for language comprehension. These regions include the midtemporal gyrus,
the inferior temporal gyrus, the fusiform and the angular gyrus (Brodmann areas; 20, 21,
27, 36, 39). In the case of language syntactic production and processing, different regions
located in the inferior frontal gyrus appear to be responsible (Brodmann areas; 44, 45, 47).
Electrical stimulation and diffusion tensor imaging can identify the arcuate fasciculus
(connecting Brocas and Wernickes areas), and both techniques colocalize well with
anterior language areas, but less so with posterior language areas, suggesting that the latter
may be more dispersed (43).
Autonomic function: Stimulation of areas just above the Sylvian fissure and in the
insula can elicit autonomic changes such as salivation, taste and abdominal sensations
(nausea, epigastric sensations). Stimulation of the supplementary motor cortex can induce
pupillary and heart rate changes.
Mapping memory: Recent memory is processed independently by both hemispheres,
particularly by medial temporal structures in either hemisphere (44, 45) although lateral
temporal neocortex may also be involved (4648), especially for verbal memory in the
dominant hemisphere (49, 50). Occasionally, memory processing is lateralized to the side
of the proposed resection and localization of the areas involved in memory may be
desirable. This requires timing of stimulation to a memory task in order to establish if
lower memory performance is associated with electrical stimulation. Such tests are time
consuming (51) and are not standardized at present. Memory mapping has been restricted
to those patients who failed the Wada test (see below) or those whose livelihood depends
on having good memory (52). In such patients, resection could be tailored to spare the
lateral temporal memory sites and the anterior portion of the hippocampus (48, 49)
Stimulation of the temporal lobe (not necessarily medial) can induce memory
recollections and disturbances such as dj vu (5). Feindel and Penfield found arrest of
memory encoding when stimulating near the human hippocampus (53). However,
disruption of memory performance with unilateral electrical stimulation of human medial
temporal structures only occurred in a minority of patients and required the induction of
after-discharges by the stimulus (54, 55). Nevertheless, temporary amnesia could be
induced more readily when stimulating medial temporal structures bilaterally with trains
of electrical pulses lasting 3 to 50 seconds (568). Thus, these early studies suggested that
in order to demonstrate an effect on episodic memory, stimulation had to be either
unilateral with after-discharges or bilateral. Later studies provided evidence that electrical
stimulation of medial temporal structures at a level below that required for eliciting afterdischarges can induce material-specific deficits in recognition memory tests, either by
stimulating unilaterally at a single site (51, 59, 60) or bilaterally (61). More recently,
Lacruz and colleagues (45) have shown that even a single electrical pulse applied to the
hippocampus can produce memory deficits if applied bilaterally but not unilaterally.
Stimulation of the lateral temporal neocortex of the dominant hemisphere can also induce
errors in verbal memory (62). Memory is clearly a complex function which involves a
variety of sites and tasks. For this reason, memory mapping with electrical stimulation is
nonstandard, and reviews of strategies can be found elsewhere (63, 64).
Indications of electrical stimulation for mapping: The main indication for functional
mapping is planning of resections close to primary motor, sensory or language areas. For
language testing, it is preferable that the dominant hemisphere is identified prior to
stimulation (see Chapter 8). The need for mapping in the assessment of standard temporal
lobectomies is controversial, as standard temporal lobectomies are made smaller in the
dominant hemisphere to minimize language deficits. In our experience, speech mapping of
Wernickes area is often useful in patients with lateral temporal epilepsies, particularly if
seizure onset is posterior.
Intraoperative vs. extraoperative functional mapping: Intraoperative mapping under
local anaesthesia requires patient cooperation under difficult circumstances and time is
usually limited to around 1 hour. Intraoperative mapping may not be possible in children
or in patients with learning difficulties. In such patients and in those requiring chronic
intracranial EEG recordings for seizure localization, mapping may be more accurately
performed during chronic recordings, in one or several sessions over several hours,
allowing for test and retesting of responses for reliability. Intraoperative mapping requires
simultaneous acute electrocorticography to record after-discharges, since induction of
seizures in the operating theatre in a patient with an open skull is highly undesirable.
Stimulation at or above after-discharge threshold must be reduced to a minimum, as the
risk of inducing seizures increases under these circumstances. The methodology for
functional mapping during intraoperative recordings is essentially similar to that used
during extraoperative recordings. However, the methods used to perform operations with
intraoperative mapping vary among centers. Opening the skull with the patient awake is
often disagreeable for patient and surgeon. In our centre, we tend to carry out the
procedure in two consecutive days. On the first day, the craniotomy is performed and
closed under general anaesthesia. On the second day under local anaesthesia, the skin and
craniotomy are reopened, the electrodes are applied to the cortex, functional mapping with
electrical stimulation is performed and a tailored resection is carried out. This allows for
final functional evaluation during the resection. Other centers prefer to carry out the
complete procedure in one session, including periods of general and local anaesthesia.
Under this approach, it may be difficult to maintain an airway access while the patient is
awake. Lateral decubitus and propofol anaesthesia may be helpful (65). A combination of
propofol and dexmedetomidine sedation appears to be successful in transitioning patients
from asleep to awake (66). There is evidence that intra- and extraoperative mapping are
mutually complementary (67).
Electrical stimulation in children

Experimental and clinical evidence suggest that neuronal plasticity in the immature brain
can allow reorganization of function after brain injury (6870). Language can shift to the
opposite hemisphere and full recovery can follow resections in the dominant hemisphere
before the age of 67 (69, 71). However, resection of primary motor cortex tends to
generate permanent motor deficits, particularly affecting fine hand movements.
Myelinization in children is incomplete and functional mapping in children should be
carried out with caution because they tend to require higher current intensities or pulse
durations than adults. In children below the age of 10, the threshold for after-discharges is
often lower than the threshold for functional responses. Functional mapping is then carried
out by identification of the areas that consistently show the lowest functional threshold.
Identification of sensory or language areas, which requires active patient cooperation, is
not possible in infants, toddlers and young children below the age of 4. Somatosensory
evoked potentials may prove more helpful in this age group. The challenges of functional
mapping in children have been extensively reviewed (7274).
Functional mapping without electrical stimulation

A number of alternatives to electrical stimulation have been used or are being evaluated
for functional mapping. Recording of evoked responses on the surface of the cortex has
been used to map somatosensory cortex (7579), auditory areas (80) and motor cortex
(81). Muscle responses evoked by cortical stimulation can be used to identify motor cortex
(79, 82, 83). Fast rhythms associated with functional activities are increasingly being used
to identify the areas involved in motor, sensory, language and cognitive functions, but
their utility is still under evaluation (8489). Some encouraging reports suggest that
transcranial magnetic stimulation could be used for noninvasive functional mapping (90).
Maps of magnetoencephalographic (MEG) responses can be used to localize sensorimotor
cortex (91) and language areas (92, 93). The use of neuroimaging and the amytal test for
functional mapping are reviewed in Chapter 8. It is becoming increasingly apparent that
most techniques are complementary rather than exclusive.
Electrical stimulation for the identification of epileptogenic

cortex
Electrical stimulation with the parameters used for functional mapping often induces runs
of epileptiform discharges or other ictal patterns in the EEG. A number of terms have been
used to designate such responses: after-discharges, electrically induced seizures,
electrographic seizures and subclinical seizures. The latter two terms are inaccurate
because electrographic/subclinical seizures can occur spontaneously and because such
discharges are not necessarily asymptomatic. After-discharges usually last for a few
seconds and tend to remain localized to the areas around the stimulated cortex. Under
these circumstances they are usually not associated with clinical signs if they remain
restricted to noneloquent cortex. However, if after-discharges propagate to eloquent areas,
their presence may affect the interpretation of functional mapping, because clinical signs
may be due to the disruption of functional areas by after-discharges rather than to the
direct local effects of electrical stimulation. Occasionally after-discharges last longer and
propagate to more widespread regions, sometimes evolving into a clinically overt seizure
with cognitive impairment, sensory or motor manifestations, or other ictal signs. The use
of after-discharges to detect epileptogenic areas has long been debated (9496). Afterdischarges can be induced in areas other than the seizure onset zone and their presence is
not a very clear marker for epileptogenic cortex. In early studies, it was suggested that the
region whose stimulation produced the longest after-discharges or the only afterdischarges was the origin of spontaneous seizures in 75% of cases (5). A study of 133
patients with temporal lobe epilepsy found a 77% concordance between spontaneous
seizures and after-discharges (97). Another large study of 126 patients, which included 38
patients having a single seizure focus, found concordance between the topographies of
focus and after-discharges in 88% of temporal lobe seizures, 92% of frontal seizures and
100% of posterior seizures (96). The areas whose stimulation induces the patients
habitual aura or habitual seizures may be a more reliable marker for epileptogenicity. A
study of 72 patients reported a high correlation between onset zone for spontaneous
seizures and the sites stimulated to induce the patients habitual auras or seizures,
particularly for medial temporal lobe epilepsy (98).
The area showing lowest current intensity required to induce after-discharges (lowest
after-discharge threshold) does not seem to be a reliable predictor of spontaneous seizure
onset (98). After-discharge threshold is usually decreased at the site of seizure onset but
can be elevated in about 25% of patients (96), presumably due to the neuronal loss
inherent to some pathologies. Furthermore, once after-discharges have been elicited, their
threshold may change (94).
Interestingly, briefer stimulation with a 1-millisecond single electrical pulse can induce
EEG responses which are useful to identify epileptogenic cortex (99).
What can we do if seizures arise from functionally eloquent

areas?
Removal of the precentral motor cortex induces paresis of the corresponding contralateral
muscle groups. In the case of the upper limb, gross movements of shoulder, arm and hand
may return after a few months, but fine finger movements seldom, if ever, recover.
Ablation of the lower limb areas induces partial paralysis. Excision of the face area can
induce hemiparesis of the lower face, but does not usually affect the forehead or eye
closure, in contrast to lesions of the cranial nerves or their nuclei. No clear paresis is
observed after removal of neck or trunk areas. Removal of motor cortex in children can
induce similar deficits to those seen in adults, in addition to affecting growth of the
corresponding areas. Transient occulomotor paralysis has been reported, associated with
lesions of the frontal eye fields (100, 101). Removal of the hand somatosensory area is
associated with astereognosis, which is often more disabling than initially thought.
Resection of the second sensory area does not usually induce deficits. Ablation of the
supplementary motor area does not seem to induce significant permanent deficits.
Transient dysphasia (in resections in the dominant hemisphere), contralateral hemiparesis
or neglect, or slowing of contralateral movements and contralateral forced (reflex)

grasping (difficulty in releasing objects after grasping) have been described after removal
of the supplementary motor area (5, 102). Speech deficits after resections before the age of
67 can be followed by complete recovery (see above). Unilateral resection of the
auditory areas does not usually induce deficits, as hearing is processed bilaterally.
Consequently, lesions near auditory cortex may be resectable without auditory mapping
(103), particularly in the nondominant hemisphere. Resection of the primary visual cortex
around the calcarine fissure (area 17) is associated with contralateral visual field defects.
Deficits after resections of other visual areas are less predictable as they may receive
bilateral representation. The contralateral visual field deficits occasionally induced by
temporal lobectomies are due to severing the optic radiations.
It is usually accepted that, once essential cortex is identified, resection must leave at
least 0.51 cm margin around eloquent areas. The usefulness of functional mapping in
standard anterior temporal lobectomies is controversial as lobectomies are smaller on the
dominant hemisphere (limited to the anterior 4 cm from the temporal tip) in order to spare
language areas. However, language areas have been found in the cortex to be resected in a
small proportion of patients (104) and transitory aphasias have been described after such
standardized resections (105). It has been suggested that intraoperative functional mapping
could help prevent speech deficits after right-sided resections in right-handed patients with
ictal speech and right-sided activation on fMRI speech mapping (106).
In patients where seizures arise from functional cortex in the hemispheric convexity,
multiple subpial transection has been proposed (107), a procedure that can preserve
function while relieving epilepsy in 3380% of patients (108111).
Evaluation
Electroencephalographic recording combined with functional mapping using subdural
electrode grids is a well-established technique that allows a tailored, maximal resection of
epileptogenic tissue with minimal injury to critical cortex (111). It is nevertheless difficult
to formally evaluate the efficacy of a procedure regularly used to prevent deficits because
the deficits that would have occurred had the procedure not been performed are unknown,
and controlled studies are usually unethical. After detailed functional mapping, resections
involving the primary motor cortex can abolish seizures and avoid motor deficits (113), or
induce mild deficits in a minority of patients (10).
In temporal lobectomies performed without functional mapping, either no language
deficits are observed (4), or small deficits in naming can be seen in patients undergoing
temporal lobectomy in the dominant hemisphere, particularly in those with later-onset
epilepsy (114). Rarely, right-sided temporal lobectomies performed on the dominant right
side can induce aphasia (115).
Clinical case
Patient with unremarkable previous medical or family history presents with late-onset
epilepsy at age 29. During the first alleged episode, he woke up at night with a strange
dizzy feeling and being generally unwell. Approximately a year later, he had a convulsive
seizure in sleep and suffered several complex partial seizures over the following 2 years.
He was diagnosed with epilepsy. He was then seizure-free for 3 years until he had another
convulsive tonicclonic seizure and started to suffer daytime seizures. The convulsive
seizures went away but he continued to suffer complex partial seizures, which are
described as follows: his mind feels jumbled up, he tries to get out of such a situation and
moves outside, he has an aura of dj vu and loses awareness of his surroundings,
according to his wife he licks his lips and rubs his fingers. The MRI examination was
normal. The FDG-PET scan showed a degree of hypometabolism over the left temporal
lobe.
The interictal EEG showed left temporal slowing of the background activity with
intermittent sharp waves in the same region. One complex partial seizure occurred during
EEG recording which was associated with nonforced turning of the head to the left and
difficulty with his speech at the end of the seizure. There was prominent slowing over the
left temporal area at seizure onset, although this is in the delta range and more posterior
than expected in hippocampal sclerosis, possibly suggesting a lateral temporal onset.
The patient was admitted for intracranial EEGvideo telemetry with subdural electrodes
(Figure 13.6). A lateral mat was included, given the above suggestion of lateral temporal
onset and postictal dysphasia. This approach would provide sufficient spatial sampling for
speech mapping and to detect a lateral temporal seizure onset. Two complex partial
seizures with a secondary generalization occurred with a clear ictal onset over the mesial
contacts of the left anterior subtemporal strip electrode. Single pulse electrical stimulation
showed delayed responses over the medial contacts of the anterior subtemporal electrode.
The results of speech mapping following an auditory responsive naming paradigm are
shown in Figure 13.6. Since Wernicks area was far from the seizure onset zone and from
the delayed responses to stimulation, it was decided to offer a left temporal lobectomy.
Figure 13.6 Intracranial EEGvideo telemetry with subdural electrodes. A 32-contact

lateral temporal and suprasylvian mat was implanted through a left lateral craniotomy, in
addition to four 8-contact subdural strips: frontal, anterior temporal, posterior temporal,
and occipital. Speech mapping following an auditory responsive naming paradigm was
carried out through adjacent pairs of electrodes. Stimulation at 2.5 mA through the
contacts shown in blue was associated with naming deficits and, consequently, these
contacts were considered to be overlying Wernickes area. Stimulation through contacts 7
8 of the mat (superior and posterior corner) was also associated with naming deficits but
only with high intensity of stimulation (7.5 mA), and consequently these contacts were
thought to be close but not overlying speech areas. The mat contacts are labelled 1 to 32,
with 1 being the contact at the anterior and superior corner of the mat, and contact 8 being
the contact at the posterior and superior corner of the mat.
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Chapter 14 Localization and surgery for MRI-negative

temporal lobe and temporal-plus epilepsies
Sang Kun Lee and Hye-Jin Moon
Introduction
Patients with refractory epilepsy have benefited from surgical treatment. However, most
surgical treatments involve medial temporal lobe epilepsy (medial TLE). Neocortical
epilepsy has comprised only a minor portion of surgeries in epilepsy surgical series until
now [1]. Epilepsy does not have homogenous clinical manifestations, and widely different
seizure semiologies can be found depending on the location of epileptogenic foci. A clear
understanding of epileptogenic networks has not been achieved. Scalp EEG often misleads
or falsely localizes the ictal onset zone because of the zones inaccessible location or
widespread ictal onset.
A focal structural lesion on MRI is usually a reliable indicator of the seizure onset [2,
3]. Concordant results of electrophysiological studies and MRI findings have high
predictive value for a good surgical outcome [4, 5]. However, MRI is negative in many
focal epilepsy patients, even in patients with cortical dysplasia. Multimodal evaluations
are mandatory for successful epilepsy surgery, and intracranial recording has an
indispensable role in these patients. Surgical outcome is usually less satisfactory for
patients with MRI-negative focal epilepsy [1, 6, 7]. In the context of these issues,
determining the prognostic factors for a good surgical outcome and suggesting guidelines
for successful epilepsy surgery are important for this special group of patients.
In a patient with presumed temporal lobe epilepsy (TLE) and negative MRI results, four
different situations are possible: medial TLE with normal MRI, neocortical TLE,
temporal-plus epilepsy (TPE), and extratemporal lobe epilepsy mimicking TLE. The term
TPE has been recently introduced to describe an epilepsy syndrome in which the patient
exhibits specific forms of seizures of multilobar origin that form a complex epileptogenic
network including the temporal lobe and the adjacent structures such as the orbitofrontal
area, insula, frontal and parietal operculum, and temporo-parieto-occipital junction [8].
The presence of extratemporal lobe epilepsy mimicking TLE and TPE can partly explain
the relatively less successful surgical outcome in MRI-negative TLE. Temporal lobectomy
by itself cannot achieve a seizure-free outcome for these patients. For example, the
surgical outcomes of 33 patients with TPE revealed that only 8% who underwent standard
anterior temporal lobectomy became seizure-free [8].
The MRI technique can successfully detect hippocampal sclerosis. Coronal slices
perpendicular to the long axis of the hippocampus can show reduced hippocampal volume,
increased signal intensity on T2-weighted imaging, and disrupted internal architecture.
However, subtle changes or a specific subtype of hippocampal sclerosis may escape
detection by MRI. A pathology study of a series of patients with negative MRI findings
showed that 9% had hippocampal sclerosis [9]. Our surgical series of pathologically
proven medial TLE also demonstrated that 16 of 121 (13%) patients had normal MRI [10].
As a result, even though the MRI may be normal, we cannot exclude the possibility of
medial TLE with hippocampal sclerosis. Clear identification of these four specific
situations can lead to successful epilepsy surgery for TLE patients with negative MRI
findings. In this chapter, we describe the semiological and electrophysiological
characteristics, including extracranial and intracranial studies, for differentiating the four
situations. We also examine the importance of functional neuroimaging for the success of
epilepsy surgery in these patients.
Semiology
The symptoms and signs generated by ictal discharge in a specific cortical area or a brain
structure can sometimes lead to the identification of the epileptogenic zone. This
symptomatogenic zone is generally believed to be in close proximity to the epileptogenic
zone [11]. However, because more cortical areas are silent to ictal electrical stimulation,
the clinical signs and symptoms can emerge only when the ictal discharge spreads to a
cortical area which retains a particular function [12]. Therefore, clinical signs and
symptoms can falsely suggest the epileptogenic zone. Aura as the first ictal semiology can
provide a valuable clue to the localization of an epileptogenic zone [12]. Certain auras are
useful for differentiating lateral from medial TLEs [13]). Auras are classified as simple
auditory (primary auditory cortex), complex auditory (auditory association cortex),
vertiginous (temporo-occipital or temporoparietal junction) [14], and complex visual
(temporo-occipital junction and basal temporal cortex). Abdominal and olfactory auras
occur predominantly in medial TLE, although olfactory aura can also be found in seizures
originating from the orbitofrontal cortex and insula. Autonomic symptoms and signs of an
aura can also be produced by activation of the insula, anterior cingulum, supplementary
sensory motor area, and medial structures including the amygdala [15]. Fear aura is
common in seizures originating from medial temporal structures including the amygdala.
Psychic auras such as fear and dj vu or jamais vu can be observed in neocortical TLE
and medial TLE. Stimulation of the parietal operculum and mesiobasal temporal regions
generates gustatory hallucinations [16]. Euphoria is suggested as an aura originating from
mesiobasal temporal structures [17].
Automotor seizures are characterized by repetitive, stereotypic, semipurposeful motor
behaviors involving primarily the distal limbs, mouth, and tongue. These comprise the
most prominent symptomatology of TLE, whereas frontal lobe complex partial seizures
have hyperkinetic proximal limb automatism [18]. Two studies have reported clinical
differences between medial TLE and lateral TLE [19, 20]. However, except for auras,
certain types of symptomatology are not specific to medial or lateral TLE. The most
common initial symptoms are oroalimentary and hand automatisms in medial TLE and
anterior neocortical TLE [21]. Staring without automatism is more common in posterior
neocortical TLE, although dialeptic seizure itself provides no useful localizing
information. Secondarily generalized tonicclonic seizures (2GTCS) occur significantly
earlier in posterior neocortical TLE. Longer interhemispheric propagation times have been
reported in patients with hippocampal sclerosis compared with those without hippocampal
sclerosis [22]. However, the most common symptomatology of TLE (automotor seizure)
can originate in other areas. For example, the most common semiology of frontal lobe
epilepsy (FLE) verified by invasive studies and surgery was complex partial seizure of the
TLE type with or without 2GTCS (25.3%) [23]. Early ictal propagation to the temporal
lobe in FLE could generate automotor seizures typical of TLE.
Compared with TPE patients, typical TLE patients more frequently have an ability to
present with warnings of seizure onset such as abdominal aura and gestural automatism,
and with postictal amnesia [24]. The presence of early ictal signs and symptoms
suggesting the initial involvement of the perisylvian region, the orbitofrontal cortex, or the
temporo-parieto-occipital junction should also be considered to indicate possible TPE [8].
Patients with TPE more frequently have gustatory hallucinations and vestibular illusions at
seizure onset. They also tend to have versive manifestations and dysphoric mood in the
postictal phase [24].
Interictal and ictal EEG

Temporal interictal epileptiform discharges are the most common abnormality in TLE.
This abnormality is found more often in surgical series than in nonsurgical series (more
than 90% vs. 2275%) [25, 26, 27]. However, this difference may be due to sampling bias
because EEG recordings may have been more frequently performed in surgical series than
in nonsurgical series patients.
Bilateral independent epileptiform discharges are also common in TLE, although they
do not necessarily indicate bilateral independent ictal onset. A single two-hour recording
of interictal EEG in a surgical series of medial TLE showed temporal lobe epileptiform
discharges in 79.9% of patients [28]. The correct lateralization of the epileptogenic side
was possible in 90.9% of patients of medial TLE with unilateral interictal epileptiform
discharges; 50%70% of interictal spikes occurred in one temporal lobe in 13.8% of
patients and more than 70% in 19.3% of patients. However, the surgical outcomes did not
differ significantly between the unilateral-only and bilateral-independent groups.
Temporal interictal epileptiform discharges can also be observed in extratemporal lobe
epilepsy such as FLE or occipital lobe epilepsy.
Starting with a surgical series of refractory epilepsy patients (unpublished data), we
analyzed 62 cases of neocortical TLE with negative MRI in which 27 patients had
interictal epileptiform discharges in the corresponding temporal lobe. Twenty-one of the
43 patients with a seizure-free outcome exhibited concordant focal interictal epileptiform
discharges. The presence of interictal spikes is associated with good surgical outcome [29,
30]. Poor outcome can be predicted by the presence of spikes distant from the resected
lobe, multiple spikes, or generalized spikes and waves [31].
The TPE patients more frequently show precentral interictal spikes that differ
topographically from those of patients with medial TLE [24]. The TPE patients also
exhibit more frequent bilateral interictal abnormalities, suggesting poor outcome after
surgery [24, 32].
Ictal EEGs correctly localized the epileptogenic zone in 50.2% of extratemporal
epilepsy patients and 74.5% of neocortical TLE patients [33]. The most common ictal
rhythm was rhythmic temporal theta activity. In this study, rhythmic temporal theta
activity was seen predominantly in seizures of temporal lobe origin compared with other
epilepsies. Rhythmic temporal theta activity was also the most common ictal rhythm in
neocortical TLE (43% of seizures and 50% of patients). In our series based on 39 cases of
neocortical TLE confirmed by invasive studies, 74% of patients had at least one
localizable ictal onset rhythm in the temporal lobe, and 52% of ictal EEGs showed
localizable temporal ictal onset [34]. The most common frequency of ictal rhythms in
neocortical TLE was theta followed by beta, alpha, and delta (36%, 23%, 16%, and 14%
respectively).
In a surgical series of neocortical TLE with negative MRI, ictal scalp EEG usually
showed high localizing value [29]. However, there may have been a selection bias
underlying this high diagnostic sensitivity because more patients with localized ictal EEG
might have been recruited to the surgery, especially in the absence of a lesion on MRI.
Initial ictal scalp EEG was of limited value in differentiating anterior neocortical TLE
from posterior neocortical TLE [21] because many seizures had diffuse regional ictal onset
in the temporal lobe. Confident differentiation of medial TLE from neocortical TLE is
difficult [19, 35]. One report suggested that an initial 25 Hz polymorphic rhythm is
specific to neocortical TLE [36]. However, other studies have argued that the initial fast
activity was more specific for neocortical epilepsies and a reflection of the proximity of
the intracranial ictal onset zone to the scalp-recording electrodes.
There is also the possibility of false localization of ictal onset in the scalp EEG. We
studied 33 consecutive patients with neocortical epilepsy with negative MRI who had a
scalp ictal onset zone localized in the temporal lobe and good surgical outcome after focal
neocortical resection [29]. The ictal onset zones confirmed by intracranial study were the
neocortical temporal (22 patients), parietal [5], frontal [3], temporoparietal [2], and
occipital [1] areas. As a result, if based solely on scalp ictal EEG, an extratemporal ictal
onset zone could not have been identified in patients with presumed neocortical TLE with
negative MRI.
The location of the first ictal rhythm outside the borders of the temporal lobe was
significantly associated with the presence of TPE [24]. However, neither temporal lobe
interictal spikes nor temporal ictal onset allows one to rule out the possibility of TPE.
Other studies have suggested that initial ictal onset rhythm outside the temporal lobe or in
the posterior temporal area is predictive of surgical failure after temporal lobectomy [38,
39].
Outcome and prognostic factors for the success of epilepsy

surgery in MRI-negative TLE
Positive prognostic factors for the surgical resolution of neocortical epilepsy are the
presence of a tumor, an abnormal MRI, EEGMRI concordance, and extensive surgical
resection. The resection of an epileptogenic lesion with an ictal onset zone is the most
important factor for a good surgical outcome [40, 41, 42]. Most surgical series suggest that
identification of a specific lesion usually leads to a favorable outcome (Table 14.1) [2, 3,
43, 44]. Cortical dysplasia has been identified as a negative prognostic factor and,
compared with other types of CNS lesions, the presence of a tumor has a higher chance of
seizure remission [45, 46]. In cases involving a tumor, epileptogenic lesions are more
easily detected and represent a more circumscribed pathology, whereas cortical dysplasia
has a tendency to be more widespread than revealed by MRI [47, 48].
Table 14.1 Surgical outcomes according to MRI findings
Negative
MRI
Lesion on
MRI
Spencer [98]
Guldvog et al.
[94]
Yun et al. [44]
43% (n=43)
45% (n=33)
40% (n=82)
70% (n=183)
57% (n=47)
62% (n=111)
Temporal
Guldvog et al.
[94]
Berkovic et al.
[42]
50% (n=26)
33% (n=21)
59% (n=27)
65% (n=86)
Extratemporal area
Guldvog et al.
[94]
Zentner et al. [1]
29% (n=7)
20% (n=10)
55% (n=20)
61% (n=46)
Extramesial
temporal
Smith et al. [96]
37% (n=65)
70% (n=86)
Frontal
Smith et al. [97]
29% (n=17)
70% (n=32)
Sites
Authors
All lobes
n: number of patients
There is inherent difficulty in identifying the epileptogenic zone in MRI-negative
neocortical epilepsy, and this difficulty may lead to incomplete resection. However, even
in MRI-negative epilepsy, surgical outcome is better for TLE than for extratemporal lobe
epilepsy. The rates of seizure-free outcomes are 3170% for MRI-negative temporal lobe
epilepsy and 1757% for extratemporal MRI-negative epilepsy (Table 14.2) [29, 30, 31,
49, 50, 51]. Two large series by Lee et al. [29] and Jayakar et al. [30] reported rates of
seizure-free outcomes as 47% and 55% for MRI-negative TLE and 41% and 43% for
MRI-negative extratemporal lobe epilepsy patients, respectively. However, compared with
epilepsy with focal MRI abnormality, a relatively poor outcome of MRI-negatve cases is
noticeable [5, 41, 52].
Table 14.2 Surgical outcomes for MRI-negative epilepsy patients
Number of
Authors
Foci
patients
II
Siegel et al. [49]
TLE
10
70%
20%
10%
ExTLE
14
57%
21%
21%
TLE
43
42%
19%
14%
26%
ExTLE
27
30%
4%
7%
59%
TLE
13
31%
54%
15%
ExTLE
11
45%
20%
35%
TLE
13
62%
31%
8%
0%
ExTLE
17%
17%
33%
33%
TLE
47
47%
15%
17%
21%
ExTLE
54
41%
15%
17%
28%
TLE
31
55%
10%
16%
19%
ExTLE
58
43%
5%
31%
21%
Blume et al. [31]
Chapman et al.
[50]
Alarcn et al.
[51]
Jayakar et al.
[30]
Lee et al. [29]
III
IV
I, II, III, IV: Surgical outcome, Engel classification; TLE: temporal lobe epilepsy;
ex-TLE: extratemporal lobe epilepsy
Localization by FDG-PET and interictal EEG and complete resection of the abnormal
foci are associated with seizure-free outcomes [29, 30]. Concordance between two or
more presurgical evaluations among interictal EEG, ictal EEG, FDG-PET, and ictal
SPECT is significantly related to a seizure-free outcome [29]. Seven years after our first
report, we wanted to know if the surgical outcomes had changed after the introduction of a
new strategy. We compared the surgical outcomes of epilepsy patients with negative MRI
before and after a change in selection strategy (unpublished data). The new strategy was to
select candidate patients with a high concordance rate in presurgical evaluations (interictal
EEG, ictal EEG, FDG-PET, and ictal SPECT). The concordance score was significantly
higher in the new group than in the old group. Concordance with two or more modalities
was 54% in the old group and 83% in the new group. The surgical outcome was
significantly improved. In the old group, 73 patients (82%) had a good surgical outcome
(Engel class 13) and 42 patients (47.2%) were seizure-free. In the new group, 50 patients
(94.3%) had a good surgical outcome, and 35 patients (66%) were seizure-free. The
improvement in surgical outcome was statistically significant. There was a significant
decrease in the use of frontoparietal lobe surgery and an increase in the use of neocortical
temporal lobe surgery after application of the new strategy. Compared with a 58.1%
seizure-free rate in the old group, 25 of 31 patients (80.6%) with neocortical TLE with
negative MRI achieved a seizure-free outcome. This result suggested that adequate
selection of patients with refractory TLE with negative MRI based on the concordant
presurgical evaluations could lead to a much better surgical outcome.
Role of functional neuroimaging

The FDG-PET and ictal SPECT techniques (Figures 14.1 and 14.2) may be critical for
localizing the seizure focus, especially in MRI-negative patients. The FDG-PET and
subtraction SPECT techniques are valuable in the diagnosis of MRI-negative neocortical
epilepsy [53, 54, 55, 56]. However, in patients with intracranial ictal onset zones outside
the temporal lobe, their value is limited. Localized PET abnormalities have been found in
only 2945% of MRI-negative frontal lobe epilepsy patients [29, 57, 58]. Compared with
FLE, FDG-PET scanning is more useful in MRI-negative TLE patients. One study
demonstrated that 26 of 30 patients with TLE without hippocampal sclerosis had
concordant FDG-PET lateralization [59]. In our series, FDG-PET correctly localized the
focus in 14 of 16 patients with MRI-negative TLE [29]. In our recent analysis, FDG-PET
scans correctly localized the focus in 38 of 42 patients (90.5%) with MRI-negative
neocortical TLE who had a seizure-free outcome after surgery (unpublished data). This
high diagnostic sensitivity may also reflect a selection bias; that is, patients with high
concordant presurgical evaluations (positive results in the evaluations) tended to be
recruited for surgery.
Figure 14.1. FDG-PET in a patient with MRI-negative epilepsy. Note the temporal lobe
hypometabolism extending to the right posterior area (arrow).
Figure 14.2 Ictal and interictal SPECT in a patient with MRI-negative epilepsy. Note the
increased focal hyperperfusion in the left posterior temporal area (arrow).
The application of the SPM technique in the interpretation of FDG-PET scans may
yield better results than visual analysis [60]. It would be useful if FDG-PET scans could
differentiate medial TLE from neocortical TLE, especially in MRI-negative patients. An
SPM analysis of FDG-PET in TLE patients may be helpful in discriminating medial TLE
from neocortical TLE [61]. In the neocortical TLE group, glucose metabolism was
preserved in the medial temporal structures. Another study also compared the metabolic
patterns of FDG-PET between patients with hippocampal sclerosis and those with
negative MRI [62]. Patients with hippocampal sclerosis had greater hypometabolism in
the mesial temporal/hippocampal region. Conversely, those with negative MRI had greater
inferolateral hypometabolism. However, because there is overlap of metabolic patterns
between medial TLE and neocortical TLE patients, hypometabolism can extend beyond
the epileptogenic zone. Therefore, it may not be easy to differentiate medial TLE from
neocortical TLE based solely on FDG-PET results.
Subtraction ictal SPECT is valuable for localizing neocortical epilepsy [63, 64].
Subtraction peri-ictal SPECT showed localized hyperperfusion in 66.786% of neocortical
epilepsy patients, even in the absence of lesions on MRI [64, 65]. The localization by
subtraction SPECT is predictive of surgical outcome [66], although the results depend on
the location of the epileptogenic zone and interpretation criteria. The seizure onset can be
localized in only 3343% of patients with FLE [29, 67, 68].
Ictal SPECT is especially valuable in the diagnosis of MRI-negative TLE. Our group
performed ictal SPECT in 26 of 43 patients with MRI-negative neocortical TLE who had a
seizure-free outcome after surgery. In this series, the diagnostic sensitivity of ictal and
interictal subtraction SPECT was as high as in that of the FDG-PET results; 22 patients
(84.6%) had the correct localizing results (unpublished data). Advanced ictal SPECT
analysis with SPM has been reported to distinguish between mesial temporal and lateral
temporal neocortical seizure foci (see Chapter 5).
It would have been useful for ictal SPECT or PET to be able to distinguish between
MRI-negative TLE and TPE. However, there is no solid evidence for this. In some cases,
ictal SPECT has demonstrated focal hyperperfusion in the posterior temporal area
suggesting neocortical TLE (Figure 14.2). However, the focus of abnormal perfusion is
not always precisely at the seizure onset zone. This phenomenon could be explained by
spreading ictal rhythms. As a result, the ictal hyperperfused patterns are heavily dependent
on the timing of the SPECT radiotracer injection. For example, abnormal SPECT may
primarily involve the lateral temporal cortex even in the patients with medial TLE [69].
Therefore, there is still the possibility of false localization or false lateralization despite
the use of functional imaging tests in MRI-negative epilepsy. An epileptogenic zone
outside the temporal lobe can occur in patients diagnosed with MRI-negative lateral TLE
based on long-term scalp video-EEG monitoring and the results of additional functional
neuroimaging [36]. To avoid this pitfall, intracranial electrodes need to be placed carefully
on the temporal lobe and adjacent areas.
Deciding on the extent of surgery based on the interpretation

of intracranial EEG findings
Accurate localization of the ictal onset zone using intracranial electrodes is one of the
most sensitive and important methods for successful epilepsy surgery [70, 71, 72, 73]. In
the presurgical evaluation of a patient with MRI-negative neocortical epilepsy, intracranial
monitoring is indispensable, but it has the limitation of insufficient sampling. To obtain
appropriate information from intracranial monitoring, many intracranial electrodes are
needed. Nevertheless, because these electrodes cover only a limited portion of the brain,
the true ictal onset zone can sometimes be missed [74] and repositioning or additional
electrodes may be needed.

The placement of intracranial electrodes should be based on the results of the
noninvasive presurgical evaluation. Because MRI-negative epilepsy may have medial
temporal lobe seizure onset, the medial temporal structures should also be implanted with
electrodes. Depth electrodes are used preferentially to record at the medial temporal
structures. These electrodes can be inserted orthogonally, parasagittally, or through the
occipital lobe to traverse the extent of the hippocampus. Subdural strip electrodes can also
be used successfully to cover the medial inferior temporal area. However, subclinical
seizure activities could appear only at depth electrodes and not be seen at nearby medial
temporal subdural strip electrodes [75]. Coverage of the medial temporal, lateral temporal,
and nearby structures could be accomplished with a combination of grids, strips, and depth
electrodes. However, even extensive coverage sometimes cannot differentiate lateral TLE
from medial TLE. There are a number of temporal lobe seizures manifested by a lowvoltage fast discharges starting almost simultaneously at the medial and lateral temporal
lobe structures [76, 77]. It is unclear whether these simultaneous onsets may reflect true
onset at the same time, or insufficient coverage by the intracranial electrodes. For the
dominant hemisphere, coverage of the posterior aspects of the superior and middle
temporal gyri is useful to detect language areas leading to the safe surgery. Electrical
stimulation of these areas can interrupt reading, naming, comprehension, and other
language-related functions. Critical language area is usually located more than 4 cm from
the temporal tip with some exceptions. To deal with ictal onset zone at the temporoparieto-occipital junctions of TPE, signs of Gerstman syndrome should also be tested by
electrical stimulation. Language function may also be observed at the temporal base [78].
However, resection of this basal temporal language area does not necessarily lead to
significant or permanent language deficit.
The objectives of intracranial EEG are to identify interictal abnormalities and the ictal
onset zone, and to map the cortical function. Based on these results, the physician can
determine the extent of the surgical resection. The intracranial ictal onset pattern itself
may also be important. A variety of electrographic intracranial seizure onset patterns are
also known [79, 80, 81, 82]. However, the first electrographic change does not always
indicate a true ictal onset zone, and some patterns represent a propagated phenomenon
[81, 82]. The surgical outcome depends strongly on the identification and complete
resection of a well-defined true epileptogenic zone [30, 83]. Therefore, the extent of the
resection may contribute to the surgical outcome. A meta-analysis of the predictors of
surgical outcomes [84] found that various studies have confirmed a better surgical
outcome after extensive resection than after limited resection. Another study of subdural
electrode analysis of cortical dysplasia demonstrated that ictal onset at the edge of the
subdural electrode coverage and incomplete resection of ictal epileptiform abnormalities
predict an increased risk of seizure recurrence [85].
It is generally accepted that patients with medial TLE have a high epileptogenicity in
the hippocampus, and the epileptogenic network of medial TLE has been investigated
thoroughly. By contrast, analysis of the epileptogenic zone in neocortical epilepsy is more
complicated because of the heterogeneity of the area involved and the underlying
pathology of neocortical epilepsy. Neocortical epilepsy seems to have a very diverse
epileptogenic network and spreading pathways, even with similar epileptogenic zone
locations. Better understanding of the epileptogenic network of neocortical epilepsy will

contribute to better surgical outcomes.
At present, the identification of TPE relies on intracranial EEG findings, based on a
high suspicion of TPE and adequate placement of intracranial electrodes on adjacent
structures including the insula [25]. In TPE patients, surgery is usually performed as a
tailored resection including at least the temporal pole and mesial temporal structures. The
posterior limits of the temporal lobe vary, and surgery should be guided by the results
from intracranial electrodes. In some TPE patients, resection has been extended outside
the temporal lobe to include the orbitofrontal cortex, frontal pole, prefrontal cortex,
parietal operculum, inferior parietal cortex, or temporo-occipital junction. Incomplete
resection is common in the dominant hemisphere [24].
To identify the intracranial EEG factors that predict a good surgical outcome, we
analyzed intracranial EEGs in 177 consecutive patients who had undergone resective
epileptic surgery [86]. The results of invasive evaluations indicated that slow propagation
and focal or regional ictal onset were associated with a seizure-free outcome. A seizurefree outcome was significantly associated with a resection that included the area showing
ictal spreading rhythm during the first 3 seconds or that included the areas covered by all
of the electrodes showing pathological delta waves or frequent interictal spikes of more
than 0.2 Hz. In other words, resection that includes more electrodes showing ictal rhythm
or interictal abnormalities predicts a good surgical outcome. We could not find any
specific relationship between ictal onset intracranial EEG morphologies and surgical
outcome, although ictal onset in the beta or gamma range tends to be associated with a
good surgical outcome. Electrodes that record high-frequency ictal discharges at seizure
onset are believed to be closer to the seizure onset zone [87, 88]. Some researchers have
argued that low-voltage-localized beta activity is a marker of the site of seizure onset [74,
89], but others have disputed this hypothesis [81, 82]. Whether a specific ictal onset
morphology or frequency can predict a better surgical outcome remains unclear.
A two-stage approach or replacement of intracranial electrodes may be necessary in
some cases, especially in TPE or extratemporal lobe epilepsy mimicking TLE. Our group
recruited 18 patients who underwent a second invasive study comprising repositioning or
additional implantation of intracranial electrodes performed 1 week after the initial
invasive study [90]. Repositioning of intracranial electrodes identified a new ictal onset
zone in 13 patients. In another four patients, we changed the proposed resection margin
based on the second evaluation. Seven of 11 patients who were ultimately identified in the
second evaluation to have a focal ictal onset zone became seizure-free after the operation.
The spatial limit of the ictal rhythm is an important predictor for good surgical outcome.
These findings support consideration of a one-week repositioning interval for intracranial
electrodes in selected patients.
The recent effort to identify correctly the ictal onset zone has motivated studies of
transient high-frequency oscillations [91, 92, 93]. These studies reported that an increase
in high-frequency oscillations in the neocortex is found consistently in the ictal onset
zone. A better understanding of the meaning of these high-frequency oscillations may
contribute to better surgical outcomes in MRI-negative refractory epilepsy.
Conclusion
There is an inherent difficulty in identifying the epileptogenic zone in patients with MRInegative neocortical epilepsy, which often results in incomplete resection. However, with
careful interpretation of other studies, including functional neuroimaging and concordant
results, surgical treatment can benefit patients with MRI-negative neocortical epilepsy,
especially those with MRI-negative TLE. The FDG-PET technique and subtraction ictal
SPECT are very useful for detecting MRI-negative TLE. The rate of seizure-free outcome
was around 50% for MRI-negative TLE in the previous reports and can increase to 80%
when the surgery is performed based on concordant results of presurgical evaluations.
Careful selection of patients with a high rate of concordance of presurgical evaluations
will contribute to better surgical outcomes. However, the possibility of false localization
of ictal EEG or functional neuroimaging in MRI-negative TLE should be considered. The
possibility of TPE and extratemporal lobe epilepsy mimicking TLE should also be
considered. Careful interpretation of semiology and electrophysiological studies is
mandatory. Adequate placement of intracranial electrodes on adjacent areas is crucial
when evaluating these patients. Intracranial EEG is one of the most important procedures
for planning surgery and achieving a good surgical outcome in resective epilepsy surgery.
Slow propagation and focal or regional ictal onset are associated with a seizure-free
outcome. Resection that includes more electrodes with an ictal rhythm or interictal
abnormalities predicts a good surgical outcome. The repositioning of intracranial
electrodes might identify a new ictal onset zone. A 1-week interval for repositioning of
intracranial electrodes may be helpful in selected patients, especially in those with TPE or
extratemporal lobe epilepsy mimicking TLE.
Illustrated case
A 21-year-old man had experienced seizure since the age of 14 years. His seizures were
characterized by visual illusions (objects were moving and slanted) followed by brief loss
of consciousness with staring, which occasionally progressed to secondarily generalized
tonicclonic seizures (GTCS). Ictal coughing or whistling sometimes occurred. The
average frequency of seizures was four times a month for complex partial seizures and
once a month for secondarily GTCS. Treatment with a combination of four different
antiepileptic drugs was not effective in decreasing the seizure frequency.
Video-EEG monitoring recorded a brief dialeptic seizure followed by version to the left
side and secondarily GTCS. The patient reported experiencing a visual aura just before
loss of consciousness. Frequent interictal sharp waves were found in the right posterior
temporo-occipital area. Ictal EEG showed a right temporal dominant rhythmic delta
activity at seizure onset, which was followed by high-amplitude rhythmic delta activity.
The results of an epilepsy-protocol MRI (3 Tesla) were normal. An FDG-PET scan
showed right temporal hypometabolism that extended to the posterior area (Figure 14.1);
MEG demonstrated interictal spikes at the right posterior temporal area (Figure 14.3C).
Figure 14.3 Illustrated case. (A) Interictal EEG shows the right posterior temporooccipital sharp waves (arrow). (B) Ictal EEG shows the right temporal dominant rhythmic
delta activity at seizure onset, which was followed by high-amplitude rhythmic delta
activity. (C) Interictal epileptiform discharges were found on the right posterior temporal
area by MEG. (D) High-frequency oscillations were observed in the multiple channels
(arrows). (E) Intracranial ictal onset zone was channel 25 and 26, which showed highfrequency fast activity (arrow). (F) The results of brain mapping and resection.
Considering the aura as a visual illusion and the results of the FDG-PET scans and
interictal EEG, we placed intracranial electrodes to cover both the right posterior temporoparieto-occipital area and the right temporal lobe. We resected the right posterior temporooccipital junction area based on the high-frequency oscillations on interictal intracranial
EEG and intracranial ictal onset area (Figure 14.3). The patient has been seizure-free after
surgery for 2 years.
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Chapter 15 Localization and surgery in MRI-negative

frontal lobe epilepsies
Chaturbhuj Rathore and Kurupath Radhakrishnan
Introduction
Frontal lobe epilepsies (FLE) account for 20% to 25% of all patients with antiepileptic
drug (AED)-resistant focal epilepsies undergoing resective epilepsy surgery, second only
to temporal lobe epilepsies (TLE).1,2 The presence of an MRI-defined focal lesion is the
single most important predictor of favorable seizure outcome following surgeries
involving frontal lobes.24 Therefore, selection of patients with AED-resistant epilepsies
suspected to be originating from the frontal lobe for resective surgery, whose MRI fail to
show a lesion, poses one of the most challenging problems in the field of epilepsy surgery.
Many epilepsy surgery centers even exclude MRI-negative FLE patients from presurgical
evaluation. However, recent advances in the understanding of the various FLE subsyndromes through meticulous study of successfully operated patients, as well as advances
in noninvasive source localization and intracranial EEG studies, have made it worthwhile
to pursue presurgical evaluation in MRI-negative patients with a reasonable chance of
favorable postoperative seizure outcome.24 In this chapter, we intend to review the
diagnosis, presurgical evaluation, and surgical treatment of MRI-negative and AEDresistant FLE, and also highlight the various challenges encountered en route.
Prevalence of AED-resistant MRI-negative FLE

Antiepileptic drug-resistant epilepsy is diagnosed when there is inadequate control of
seizures despite use of potentially effective AEDs at tolerable levels for 1 to 2 years.
Among patients with AED-resistant epilepsies, it is difficult to compute the true
prevalence of MRI-negative FLE. The majority of the surgical series do not report on the
patients who are not selected for surgery, and at many centers, patients with normal MRI
do not undergo presurgical evaluation. On the other hand, in nonsurgical series, in the
absence of an MRI lesion, reliable localization of the epileptogenic zone may often not be
possible. In a study (which included both temporal and extratemporal epilepsies) from the
Department of Epileptology, University of Bonn, Bonn, Germany (hereafter referred to as
the Bonn series), out of 1192 patients who underwent presurgical evaluation during a 7year period, 191 MRI-negative patients were identified (16% of all presurgical patients).3
While 73% of patients with a demonstrable lesion in the MRI underwent surgery, only
15% of MRI-negative patients were operated on.3 At the authors epilepsy center, out of
285 consecutive patients with extratemporal lobe epilepsy who underwent presurgical
evaluation, 122 (42.8%) had normal MRI; nearly half of them had FLE.5 Only 25% of
these patients could be selected for surgery; the most common reason for exclusion from
surgery was a normal MRI.5 Despite advances in MRI techniques, MRI-negative cases
account for 18% to 43% of all presurgically studied patients.6,7 In the studies that had
specifically reported the surgical outcome of FLE patients, the proportion of patients with
normal MRI has varied from 25% to 45%.2,4 Many a time, the quality of the MRI
performed may not be satisfactory enough to detect the lesion or the neuroradiologist
reading the MRI may not be experienced enough to identify occult lesions. In the Bonn
series, among nine MRI-negative patients who underwent surgery and had distinct
histopathological lesions in the resected specimens, repeat review of their presurgical MRI
detected lesions in eight.3
Challenges in the diagnosis of MRI-negative FLE

Frontal lobe is the largest of all lobes in brain, accounting for one-third of the total
hemispheric volume. Large areas of frontal lobes, especially the mesial and basal frontal
regions, are inaccessible to standard 1020 system of EEG electrode placement. The
extensive connections between the frontal lobes and other lobes through corpus callosum,
cortical and subcortical pathways, allow rapid spread of interictal and ictal activity
contributing to the low sensitivity and specificity of the scalp EEG. Due to the same
reasons, there is a considerable overlap in the semiological characteristics and the EEG
patterns of the seizures originating from different frontal regions, making it difficult to
distinguish between them. The sensitivity and specificity of various functional imaging
techniques like positron emission tomography (PET) and single photon emission
computed tomography (SPECT) are lower in FLE than in TLE. The larger areas of frontal
lobes often require extensive coverage during invasive EEG studies, which escalates the
cost, complications and sampling error. Lastly, the extent of surgical resection is often
compromised by the close proximity of the epileptogenic zone to eloquent cortical
regions. Because of these reasons, in the absence of a clearly identifiable MRI lesion,
reliable localization of the epileptogenic zone in FLE becomes a daunting task that
necessitates the need for a multimodal and comprehensive diagnostic evaluation, which
often ends up as an expensive and unrewarding undertaking.
Diffrential diagnosis of FLE-like seizures in MRI-negative

patients
Unilateral clonic seizures, tonic asymmetric seizures with preserved consciousness,
hypermotor seizures and more frequent occurrence during sleep are generally considered
to be typical of FLE.8 In patients presenting with FLE-like seizures and normal MRI, a
heterogeneous variety of nonepileptic and epileptic paroxysmal events needs to be
considered in the differential diagnosis before proceeding with the presurgical evaluation
(Table 15.1). Although careful clinical histories can distinguish most of the disorders
listed in Table 15.1 from FLE, video-EEG monitoring and/or polysomnography may be
required to establish the diagnosis in difficult cases. Psychogenic nonepileptic spells
(PNES) is the most frequent condition misdiagnosed as frontal lobe seizures. A very
gradual onset and termination, discontinuous, irregular or asynchronous motor activity,
side-to-side head shaking, opisthotonic posturing, pseudosleep, stuttering and weeping are
characteristics that are strongly associated with PNES.9 Contrary to the usual perception,
nocturnal frontal lobe epilepsy (NFLE) is neither a benign nor a homogenous disorder.
Familial and sporadic forms of NFLE exist, and both can present with different seizure
types, including paroxysmal arousal, nocturnal paroxysmal dystonia and episodic
nocturnal wanderings.10 About 30% of patients with NFLE can be resistant to AEDs.10
More than one-third of patients with NFLE present with personal or family history of
parasomnias, thereby complicating the differential diagnosis between these two
disorders.11 Researchers in Australia demonstrated that clinical history alone can
accurately discriminate between NFLE and parasomnias.12 In the test battery they
developed, called FLEP scale, while later age at onset, longer duration (> 2 minutes) of
events and occurrence during later part of sleep favored parasomnia, stereotypy, clustering
and ability to recall were more frequently associated with NFLE.12 A recent study that
compared the diagnostic value of FLEP scale against nocturnal polysomnography showed
that FLEP scale failed to give a diagnosis of NFLE in only four out of 71 (5.6%)
patients.13 The FLE-like seizures might originate in the temporal or parietal lobes or in the
insula.10,14 Hypothalamic hamartoma is known to present as pseudotemporal and
pseudofrontal epilepsy syndromes.15 Even an experienced neuroradiologist might fail to
identify a small sessile hypothalamic hamartoma in the MRI. Ring chromosome 20 should
be suspected in patients with recurrent frontal lobe nonconvulsive status epilepticus and
normal MRI.16 Individuals with Ring chromosome 20 syndrome may have normal
cognition despite poorly controlled seizures and no dysmorphic features, making the
diagnosis difficult unless there is a high index of suspicion.17
Table 15.1 Differential diagnosis of MRI-negative AED-resistant frontal lobe
epilepsies
Psychogenic nonepileptic spells
Parasomnias
Noctural frontal lobe epilepsies
Familial
Sporadic
Pseudofrontal epilepsies originating from temporal lobe, insula, parietal lobe
or hypothalamic hamartoma
Ring chromosome 20 syndrome
Localization of seizure onset
In patients with FLE-like seizures and normal MRI, an earnest effort should be made to
obtain as much clinical and EEG clues as possible that can help to localize the ictal onset
to areas within the frontal lobe as depicted in Figure 15.1. Thus, broadly dorsolateral
frontal, mesial frontal and basal frontal epilepsies, and several sublobar syndromes within
them are recognized (Table 15.2); however, as discussed below, many of them may not be
discernible clinically or electrographically.
Figure 15.1 Anatomy diagram showing the localization of important functional areas on
the dominant frontal lobe. Clockwise from top: lateral view; inferior (basal) view: and
medial view.
Table 15.2 Surgically relevant frontal sublobar epilepsy syndromes
Dorsolateral frontal lobe epilepsy
Central lobar epilepsy
Premotor cortex epilepsy
Prefrontal cortex epilepsy
Mesial frontal lobe epilepsy
Mesial primary motor cortex epilepsy
Supplementary sensorimotor area (SSMA) epilepsy
Anterior cingulate cortex epilepsy

Mesial prefrontal cortex epilepsy
Basal frontal lobe epilepsy
Orbitofrontal cortex epilepsy
Anterobasal prefrontal (frontopolar) cortex
epilepsy
Seizure semiology
The video-EEG recorded semiology has severe limitations in localizing origin of seizures
to different frontal regions because of rapid spread within the frontal lobe and extrafrontal
regions.18 However, seizures originating from a particular area of the frontal lobe more
often follow a pattern of propagation and careful analysis of the sequence in which
different semiological features occur (cluster analysis) can help in localization of the
epileptogenic zone. Based upon such analysis in patients who are rendered seizure-free
following restricted resections as well as in patients with well-defined focal MRI lesions,
certain seizure semiologies have been correlated with distinct frontal regions, which can
be a useful guide while evaluating MRI-negative FLE patients.
General semiological characteristics of frontal lobe seizures

Compared to temporal lobe seizures, frontal lobe seizures are briefer, more frequent,
abrupt in onset and offset with minimal postictal confusion, and have a tendency to occur
during sleep.8,19,20 Similarly, the presence of motor features in the early part of semiology
like tonic posturing, clonic jerks and version, generalized tonic or clonic movements with
preserved consciousness, motor agitations and bicycling pedal automatisms strongly
suggest frontal lobe seizures.19,20 Even though abdominal auras can rarely occur in FLE,
abdominal aura progressing on to hypomotor seizures with oroalimentary automatisms is
typical of TLE, which allows its discrimination from FLE.21 On the other hand, certain
combinations of features suggest against frontal lobe seizures. These include fear behavior
associated with olfactory and gustatory auras, absence seizures without focal features and
presence of visual auras.8,19,20
Frontal lobe seizure types and their localization significance

Frontal seizures can be divided into six main types: clonic seizures, asymmetrical tonic
seizures, complex motor seizures, absence-like seizures, versive seizures and
operculoinsular seizures. Clonic motor seizures indicate seizure origin in the contralateral
perirolandic area. Due to the close proximity of the sensory area, one-third of patients may
have associated somatosensory aura. Depending upon the initial site of activation in the
central area, clonic jerks can start in the face, distal upper limb or foot, and then spread to
other regions. Asymmetrical tonic seizures in its classical form is associated with
abduction at the shoulder along with flexion of elbow and head deviation giving rise to a
fencing posture or as if one is looking at ones own hand.22 Ajmone-Marsan and Ralston23
named this semiology as M2e sign corresponding to the secondary motor area in
French. The asymmetrical tonic seizures indicate activation of SSMA which may also
occur due to spread from mesial parietal, dorsolateral frontal or anterior cingulate cortex.
Hypermotor seizures (HMS) are brief, tend to occur during sleep and do not usually
generalize. Rheims and colleagues,24 based on seizure semiology and intracranial EEG,
distinguished two types of hypermotor seizures: HMS1 characterized by marked agitation
that included body rocking, kicking, boxing and associated facial expression of intense
fear; and HMS2 characterized by mild agitation that included horizontal body movements
or trunk rotation while lying in bed usually associated with tonic/dystonic posturing.
While HMS1 had more often a ventromedial frontal cortex epileptogenic zone, HMS2 was
more frequently associated with a mesial premotor cortex epileptogenic zone. Frontal
absence seizures are the least common type of frontal seizures. They are usually brief, but
may be quite prolonged in some patients. The frontal absence seizures have been typically
associated with anterior cingulate cortex but may arise from the frontal basal region.25
These areas have rich callosal connections or connections to the thalamus which result in
rapid bilateral spread with loss of awareness. Versive seizures are characterized by the
forced, either tonic or clonic, eye and head version to the contralateral side, which may be
followed by asymmetrical tonic limb posturing and secondarily generalization. Versive
phenomena occurring at the onset usually indicate seizure origin from premotor or
dorsolateral prefrontal cortex at or near to frontal eye field. The manifestations of
operculoinsular seizures include contralateral facial jerks, hypersalivation, mastication,
perioral paresthesia and choking sensations along with autonomic features. These seizures
subsequently spread to involve other frontal or temporal lobe regions.25
Pure aphasic seizures without any other ictal manifestations occur with the
involvement of Brocas area on the dominant side. Seizures from frontal basal and
cingulate cortex can rapidly propagate to temporal lobes and may manifest as
pseudotemporal epilepsy.25 Akinetic seizures or motor inhibitory seizures, characterized by
the sudden inability to initiate or maintain (negative myoclonus) movements, are rare
manifestations of frontal lobe seizures. These are thought to be caused by the activation of
negative motor areas which are situated just in front of the motor face area in the inferior
frontal gyrus and just in front of the SSMA.26 Gelastic seizures can arise from anterior
cingulate cortex, while autonomic seizures with visceral or peripheral autonomic
manifestations along with olfactory aura can arise from frontal basal regions.
Scalp EEG in frontal lobe epilepsy

The pitfalls in the interpretation of the scalp EEG in FLE are listed in Table 15.3. Placing
additional electrodes within frontal regions as per the 105 system may improve
localization. In a study of 53 patients from the Mayo Clinic, Rocheter, MN, USA, who
were seizure-free after localized frontal resections, Vadlamudi and colleagues27 found that
ten (18.9%) patients had no detectable IEDs, five (9.4%) had only extrafrontal or
generalized IEDs, while two (3.8%) had only contralateral IEDs. The IEDs restricted to
the region of the seizure focus were seen in only 19 (35.8%) patients; whereas an
additional 14 (26.4%) had concordant IEDs, but also with generalized or extrafrontal
IEDs. Localized IEDs are more common in dorsolateral FLE as compared to mesial or
frontal basal epilepsies due to the greater proximity to scalp electrodes (Figure 15.2). In
the study by Vadlamudi and colleagues,27 concordant IEDs were seen in 72% of patients
with dorsolateral FLE and 33% of those with mesial FLE. Similarly, the localized and fast
ictal discharges are also more likely to occur in dorsolateral FLE as compared to other
sites (Figure 15.2). Presence of localized interictal or ictal beta activity is one of the most
reliable localizing features, and predictor of good seizure outcome, as it indicates
proximity to the underlying source.28 On the other hand, mesial FLE either shows
bifrontal, generalized or no IEDs (Figure 15.3).29 Patients with epileptogenic zones
involving the SSMA have IEDs restricted to the central regions. These patients can also
have intermittent rhythmic theta activity over the central region during wakefulness which
can provide useful localizing information. Ictal rhythms in mesial FLE usually consist of a
diffuse burst attenuation pattern followed by diffuse beta activity which may be more
prominent or occur earlier over the central regions. Patients with frontal basal or anterior
cingulate epilepsies commonly have unilateral or bilateral temporal IEDs and temporal
ictal discharges (Figure 15.4). Finally, ictal rhythms are usually obscured by the myogenic
and movement artifacts in patients with hypermotor seizures (Figure 15.3).
Figure 15.2 The imaging and EEG findings in an 18-year-old male with AED-resistant
seizures from 5 years of age. The semiology consisted of head version to left side
followed by bilateral tonic posturing. (A) MRI axial fluid attenuated inversion recovery
(FLAIR) sequence and (B) saggital 3D-FLAIR sequence show left middle frontal gyrus
focal cortical dysplasia (FCD) at the bottom of the sulcus; (C) interictal EEG in common
average montage shows left fronto-centro-parietal interictal discharges and occasional
right centroparietal discharges spreading to right frontal region; (D) ictal EEG shows left
frontal focal beta activity at the onset.
Figure 15.3 The imaging and EEG findings in a 27-year-old female with AED-resistant
hypermotor seizures from 5 years of age. The semiology consisted of extreme fear
followed by vocalization and restlessness lasting for 15 seconds, occurring 34 times in a
day. (A) MRI coronal fluid attenuated inversion recovery (FLAIR) sequence and (B)
sagittal T2W sequence shows right anterior cingulate focal cortical dysplasia (FCD); (C)
interictal EEG in common average montage shows generalized spike-wave discharge; (D)
ictal EEG shows movement and myogenic artifacts at ictal onset. There was no discernible
ictal rhythm during the seizure. Patient underwent lesionectomy and is seizure- and AEDfree for the last 4 years. Histopathology revealed type IIB FCD.
Figure 15.4 The imaging and EEG findings in a 26-year-old female from an area
endemic for neurocysticercosis having AED-resistant hypomotor seizures from 13 years
of age. Semiology was characterized by the behavioral arrest along with bimanual and oral
automatisms not preceded by any aura. (A) MRI axial 3D-fluid attenuated inversion
recovery (3D-FLAIR) sequence and (B) sagittal proton density sequence shows right
frontalbasal calcified lesion with surrounding gliosis; (C) interictal EEG with sphenoidal
electrodes shows bilateral anterior temporal spikes; (D) ictal EEG at onset shows 3.5 Hz
rhythmic spikes over the right temporal region, which subsequently evolved into 6 Hz
rhythmic theta activity over the same region.
Table 15.3 Pitfalls in the interpretation of scalp EEG in FLE
Interictal epileptiform discharges
None
Contralateral to the epileptogenic
focus
Midline
Multifocal
Generalized
Ictal EEG activity
None
Obscured by artifacts
Nonlocalizing
Nonlateralizing
Advanced structural imaging in MRI-negative FLE

A careful analysis of the available MRI sequences is one of the most important aspects of
the evaluation in patients with apparent MRI-negative FLE, as detection of even subtle
abnormality can serve as a substrate for intracranial EEG and improve postoperative
outcome. Most of the patients with MRI-negative FLE have focal cortical dysplasia (FCD)
as underlying pathology, which is usually located at the bottom of the sulcus, especially in
the regions of the F1/F2 sulcus and the F2/F3 sulcus, and a careful image analysis focused
at these regions can yield valuable results.30 Other methods to improve the spatial
resolution, such as the use of phased-array surface coils combined with higher MRI fields,
and the newer sequences like 3D-FLAIR imaging can help in detection and better
delineation of subtle abnormalities (Figure 15.5).31 Certain post-processing MRI methods
like 3D and curvilinear reformatting, texture analysis and quantification of gray and white
matter by voxel-based morphometry can help in identifying the subtle areas of cortical
thickness and focal cortical dysplasias. Decrease in N-acetyl aspartate/phosphocreatine
creatine ratio on proton magnetic resonance spectroscopy has been found to correlate with
the epileptogenic zone in patients with FLE and can be useful for lateralization purposes.32
Figure 15.5 MRI findings in a patient with AED-resistant right-sided focal motor clonic
seizures. (A1) 1.5 T fluid attenuated inversion recovery (FLAIR) axial sequence showing
ill-defined hyperintensity over left motor area. This was initially interpreted as normal.
The 1.5 T 3D-FLAIR axial sequences (A2 and A3) clearly show focal cortical dysplasia
involving left motor area.
PET in MRI-negative FLE

The FDG-PET is probably the most important investigation in patients with MRI-negative
FLE as it can provide a substrate for placement of intracranial electrodes. However, there
is a relative dearth of data about the sensitivity and specificity of FDG-PET in MRInegative FLE patients. In a series of 29 patients with FLE who were seizure-free following
surgery, 14 had normal MRI. Of these 14 patients, localized PET hypometabolism was
found in five (36%) patients, while it provided lateralizing information in another three
(21%).33 In another study, FDG-PET provided correct localization in four of 14 (28%)
patients with cryptogenic FLE who were seizure-free following surgery.34 In a series of 24
patients with extratemporal lobe epilepsy and either normal MRI or discordant
noninvasive data, FDG-PET was negative in nine (37%) patients, provided localizing
information in four (17%) patients and showed nonlocalizing (ambiguous, lateralizing or
multifocal) hypometabolism in another 11 (46%) patients.35 In spite of the small numbers
reported in the literature, it appears that FDG-PET can provide localizing information in
one-third of patients with MRI-negative FLE (Figure 15.6). Use of the newer techniques
like statistical parametric mapping (SPM) and 3D-stereotactic surface projection (3D-SSP)
images can improve the localizing value of FDG-PET, especially in patients with more
extensive areas of hypometabolism. Similarly the coregistration of PET scans with MRI
can allow the detection of subtle areas of hypometabolism which usually corresponds to
type II FCD. In patients with Taylor-type FCD (type IIA-B), which are usually located at
the bottom of the sulcus, a recent study has shown that FDG-PET coregistered with MRI
could detect hypometabolism in 18 of 23 (78%) patients, which was subsequently found to
correlate with the epileptogenic zone.36
Figure 15.6 MRI and FDG-PET findings in a patient with AED-resistant hypermotor
seizures. (A1) Normal 1.5 T fluid attenuated inversion recovery (FLAIR) coronal
sequence; FDG-PET axial (A2) and coronal (A3) sequences showing hypometabolism
involving left basifrontal region extending to dorsolateral region. (The images with the
courtesy and permission of Prof. John S. Duncan, Department of Clinical and
Experimental Epilepsy, National Hospital for Neurology and Neurosurgery, Queen Square,
London, United Kingdom.)
Use of other radioligands and receptor-based PET imaging such as 11C-flumazenil
(FMZ) PET, alpha-11C-methyl-L-tryptophan (AMT) PET and opioid-based ligands has
been studied in a small number of patients. In a study which compared the utility of FDGPET and FMZ PET in patients with refractory focal epilepsy, FDG-PET was abnormal in
five of 11 patients with MRI-negative FLE while FMZ PET was abnormal in six
patients.37 However, most of the PET scans utilizing radioligands other than FDG have
not been standardized and are available only in a research setting.
SPECT in MRI-negative FLE

Only limited data is available about the utility of ictal SPECT specifically in MRInegative FLE. Objective evaluation methods like subtraction ictal SPECT coregistered
with MRI (SISCOM) and statistical parametric mapping (SPM) are superior to visual
interpretation (see Chapter 5 for more information on SPECT). Overall, SISCOM and ictal
SPECT evaluated with SPM provide correct localization in 5060% of patients with
extratemporal lobe epilepsy and lateralization in another 20%, although few studies have
suggested correct localization rates as high as 90% in patients with FLE.38,39 Correct
localization with SPECT and inclusion of the areas of hyperperfusion detected on
SISCOM in the surgical resection have been found to be associated with improved seizure
outcomes.38 Importantly, SPECT can provide false localization and lateralization in 10%
to 15% of patients with FLE, usually to the ipsilateral temporal lobe, or more commonly
with multiple areas of hyperperfusion, the significance of which needs to be determined
with regard to other presurgical data.40
Magnetic source imaging

Magnetoencephalography (MEG) combined with source modeling and coregistered to
MRI, called magnetic source imaging (MSI), can provide the source localization of the
interictal spikes irrespective of the lesion status. The MEG technique is less sensitive in
detection of deeper sources and hence its sensitivity is higher in dorsolateral FLE than in
mesial or basal FLE. In one of the prospective studies which evaluated the localizing value
of MSI, PET and SPECT in relation to the intracranial EEG localization of the
epileptogenic zone in 60 patients with nonlocalizing or discordant information on
noninvasive studies, MSI had a sensitivity of 64% and specificity of 79%, which were
better than those of PET and SPECT.35 All three modalities, however, provided
complementary information in different patients. Other studies have also shown that
postoperative seizure outcome is better if MSI-identified dipole clusters are included in
the resection.41
Electric source imaging

The electric source imaging (ESI) is a source modeling technique which utilizes realistic
head models and inverse source estimation methods to detect the source of EEG spikes
(see Chapter 7 for more information on ESI). It is a relatively newer method in presurgical
evaluation and hence its validity and utility in routine presurgical evaluation is still being
investigated. In a large clinical series of 152 operated patients, ESI had a sensitivity of
84% and a specificity of 88% in correctly localizing the epileptogenic zone if the EEG
was recorded with a large number of electrodes (128256 channels) and the individual
MRI was used as head model.42
EEG-functional MRI
Spike-related blood oxygen level dependent (BOLD) activation can be used for source
localization in difficult cases by simultaneous continuous fMRI with scalp EEG recording
(EEG-fMRI). A few small clinical studies have demonstrated its utility in source
localization when other conventional tools fail to provide the localizing information.
Inclusion of areas of BOLD activation detected by EEG-fMRI within surgical resection
has been shown to improve the surgical outcome.43 Newer techniques like analysis of
topographic spike maps when there are no spikes during fMRI session and use of ictal
EEG-fMRI are being explored to improve its utility (see Chapter 8 for more information).
Functional MRI
Almost all patients with MRI-negative FLE will require intracranial EEG and functional
mapping if the mapped epileptogenic zone is at proximity to the eloquent regions.
Preoperative language fMRI is important for deciding the hemispheric dominance as many
patients with left hemispheric epilepsy may have atypical language lateralization.44
Functional MRI for language and motor functions can be used as an additional tool to
minimize the deficits while planning resection.
Multimodlity integration in a single space

The information provided by the different methods of source localization is diverse. The
spatial relationship between the localization provided by these different modalities can be
better assessed by integrating these modalities in a single 3D space. Thus the areas of PET
hypometabolism, SISCOM hyperperfusion, MSI and ESI dipoles, and EEG-fMRIdetected BOLD signals can be coregistered with 3D volumetric MRI images. These can be
further supplemented by the inclusion of language and motor activation areas on MRI.
Finally, the CT scan showing the position of intracranial electrodes can be coregistered
within the same space, which can depict the spatial relationship between the ictal onset
zone, irritative zone, important functional areas and localization provided by the different
modalities over the anatomical space. The final image can even be included in the
neuronavigation system during surgery so as to provide the real-time view of different
regions during surgery.
Intracranial EEG
Intracranial EEG remains the gold standard for defining the epileptogenic zone and
guiding the final resection in patients with MRI-negative FLE. The strategy of placement
and area of coverage is defined by the primary hypothesis regarding the likely
epileptogenic zone, which is generated by the careful analysis of all the noninvasive data.
Success of any epilepsy surgery depends upon the accurate localization and complete
removal of the epileptogenic zone without compromising the important functional areas.
All the possible noninvasive resources should be exhausted even at the expense of
redundancy before planning the invasive evaluation so as to avoid the sampling error
during intracranial EEG. However, the number of tests undertaken and the strategy of
intracranial EEG are also determined by the availability of various resources and expertise
at the individual center.
The strategy of intracranial coverage should be optimized to detect the ictal onset zone,
sites of early propagation and the irritative zones for the localization. The nearby eloquent
regions also should be covered for the electrical stimulation and mapping. In the absence
of an anatomical landmark in MRI-negative patients, this is usually guided by the results
of various functional imaging and other source localization methods. Various studies have
shown that the inclusion of the areas defined by the FDG-PET, SISCOM, MSI and EEGfMRI within the surgical resection tends to improve the outcome.36,38,41.43 This often
results in the extensive coverage over large areas of the frontal lobes. In patients with
uncertain lateralization, sometimes bilateral coverage is required which is associated with
lowest rates of success and highest rates of complications, which again underscore the
need for the careful analysis of each modality starting from the seizure semiology to detect
subtle clues about the laterality. In spite of the extensive coverage, one should be prepared
to modify or supplement the coverage during the same setting, if the need arises. Many
patients may require multistage intracranial monitoring.
The types of electrodes used vary in different centers according to the philosophy and
the available expertise. Using large grids and multiple strips improves the spatial coverage
and facilitates functional mapping. However, these may fail to detect or falsely localize the
ictal onsets from deeper sources, which are more readily detected by depth electrodes.
Hence, the policy of combining depth and subdural electrodes is most likely to give the
best possible results. Some centers which routinely perform stereo EEG (SEEG) have
reported the best results in nonlesional FLE even with nonlateralized noninvasive data.7
However, the technique of SEEG is complex and expertise is available only in few
epilepsy centers in the world.
Management of patients with MRI-negative FLE

A management algorithm for patients with MRI-negative FLE is illustrated in Figure 15.7.
Complete seizure control is virtually unachievable even after resective surgery in more
than half of patients with MRI-negative FLE, necessitating a very careful discussion
through a patient management conference about the pros and cons of surgery. Useful
palliation can sometimes be achieved by modification of AED treatment, ketogenic diet
and vagus nerve stimulation in those who are not favorable surgical candidates. In this
chapter, we shall restrict our discussion to resective surgery.
Figure 15.7 A management algorithm for AED-resistant MRI-negative frontal lobe

epilepsy.
Resective surgery
The resection following the intracranial EEG in nonlesional epilepsy is often designed to
include the ictal onset zone, early propagation sites and areas showing frequent interictal
discharges. The irritative zone is often widespread on intracranial EEG and the removal of
all the areas showing spikes is neither warranted nor feasible. However, inclusion of areas
showing frequent rhythmic spikes (1/sec) or bursts of fast activity within the surgical
resection has shown to improve the postoperative outcome.45 Few studies have also shown
that removal of the areas showing persistent slow (delta) waves also improves the
outcome.46 An ictal onset confined to three to four electrodes in the form of fast beta
activity (3040 Hz) is the best indicator of a localized onset. However, ictal onset may
take the form of rhythmic spike-wave discharges or slower rhythms. Recently, the
detection of high-frequency oscillations (HFO) on intracranial EEG in extratemporal
epilepsies has been considered as an important advancement in localizing the
epileptogenic zone. The areas showing HFO often colocalized with the epileptogenic zone
and its removal has been shown to improve the surgical outcome.47 The elicitation of
electrographic seizures and after-discharges on cortical stimulation can also provide
further localization information. The areas showing after-discharges on single pulse
stimulation has been shown to help in detection of ictal onset zone in FLE.48 Due
importance should also be given to the localization provided by the noninvasive source
localization methods while planning the resection. As far as possible all areas showing
abnormalities on different modalities should also be included within the resection without
involving eloquent cortex.
Patients might have widespread epileptogenic zones in MRI-negative FLE which can
involve large parts of a frontal lobe. Fortunately, large areas of frontal lobe in front of the
precentral gyrus can be resected, if required, without producing any major permanent
deficits. Originally, four different types of frontal resections were proposed:49 (1) Total
frontal lobectomy, which involves resection of the three frontal gyri on the lateral side
along with the resection of anterior cingulate gyrus; (2) Paramedian frontal resection,
which involves resection from the frontal pole to precentral gyrusi extending laterally to
the middle frontal gyrus and medially to include anterior cingulate cortex and SSMAThis
may be planned for the seizure originating from medial frontal region including anterior
cingulate cortex and SSMA; (3) Frontopolar resection, which includes removal of frontal
pole and adjacent basal and lateral frontal cortexThis is usually undertaken for
frontobasal and frontopolar epilepsiesi. (4) Central resections, which consist of removal of
the lower central areas up to 3 cm above the Sylvian fissure. These anatomically defined
resection strategies can help in defining the final resection areas after intracranial EEG.
Surgical strategies which make use of the electroclinical characteristics of frontal sublobar
syndromes are summarized in Table 15.4.
Table 15.4 Electroclinical characteristics and surgical treatment of frontal
sublobar syndromes
Anatomical
area
Predominant
seizure
type/s
Interictal
EEG
Ictal EEG
Surgical strategy
Precentral
region
Contralateral
clonic
seizures
Unilateral
or bilateral
central
spikes (Cz,
C3, C4)
spikes
Central beta
activity
Lower central
region can be
resected without
any major deficits;
Brocas area must
be spared
Premotor and
dorsolateral
frontal region
Versive;
asymmetrical
tonic seizures
Lateralized
frontal
spikes; fast
activity
Lateralized
frontal beta
activity
Restricted
resections as
defined by
invasive EEG;
likely to have best
outcome
Supplementary
sensorimotor
area
Asymmetrical
tonic seizures
No spikes;
unilateral
or bilateral
Burst
attenuation
patterns
Paramedian
resection
restricted/extended
central
spikes and
central
theta
activity
followed by
centrally
dominant
generalized
fast activity
as per invasive
EEG without
permanent deficits
Anterior
cingulate cortex
Hypermotor
seizures;
frontal
absences;
fearful aura
No spikes;
bilateral
and
generalized
spikes;
temporal
spikes
No discernible
activity or
diffuse
generalized
rhythms
Paramedian
resection
restricted/extended
as per invasive
EEG without
permanent deficits
Basifrontal and
frontopolar
regions
Hypermotor
seizures;
olfactory or
gustatory aura
No spikes;
bilateral
and
generalized
spikes;
temporal
spikes
No discernible
activity or
diffuse
generalized
rhythms;
temporal ictal
rhythms
Frontopolar
resection
restricted/extended
as per invasive
EEG
Operculoinsular
region
Facial clonic
jerks; perioral
and
autonomic
symptoms
Unilateral
or bilateral
frontal
spikes;
temporal
spikes
Diffuse fast
activity
followed by
frontotemporal
ictal rhythms
Restricted
resections as
defined by
invasive EEG
Postoperative outcome of MRI-negative FLE

There are no studies which have entirely focused on the surgical outcome of MRI-negative
FLE. Most of the reports describing the surgical outcome of extratemporal epilepsies and
MRI-negative epilepsies in general have also included patients with MRI-negative FLE. It
is worth remembering that a majority of patients with MRI-negative FLE do not undergo
surgery. Hence, the patients in various surgical series usually represent the selected group
of patients where localization could be achieved and surgical resection was considered
feasible. Moreover, the results from different studies are difficult to compare due to the
heterogeneity in patient selection, type of presurgical investigations, underlying
pathological substrates and nature of surgical resection. In the Bonn series,3 the seizurefree outcome following surgery was 66% in the MRI-positive group, 38% in the MRInegative group, and 10% in those denied surgery. Thus, the rates of seizure outcome of
MRI-negative patients are generally lower when compared to MRI-positive patients, but
are better than those without surgery.
Two recent meta-analyses compared the successful seizure outcome between MRI-
negative and MRI-positive FLE patients, defined as Engel class I outcome after at least 1
year of postoperative follow-up. In the first meta-analyses, which included all
extratemporal cases, the Engel class I outcome was noted in 35% (95% confidence
intervals [CI] 2742%) of 124 nonlesional cases compared to 60% (5466%) of 225
lesional cases (odds ratio, 2.6 [1.35.4]; p < 0.001).50 In another meta-analysis focusing
entirely on FLE, 39% of 245 patients with MRI-negative FLE had Engel class I outcome
after 4 years of follow-up as compared to 61% of 382 patients with MRI-positive FLE (p
< 0.001).4 Thus overall, one-third of patients have long-term seizure freedom following
surgery for MRI-negative FLE and an additional 20% have significant reduction in
seizures.
Predictors of outcome following resective surgery

Higher concordance between different modalities is the most important predictor of the
favorable outcome following MRI-negative surgery.34 The completeness of resection of
the epileptogenic zone in MRI-negative cases is difficult to determine. The total frontal
resection was found to be associated with a better outcome as compared to more restricted
resections.4 For lesions adjoining eloquent cortical areas, partial resection plus multiple
subpial transection may be a worthwhile option. Other factors found to be inconsistently
predictive of favorable long-term postoperative outcome in FLE are the absence of febrile
seizures, beta ictal onset on scalp EEG, absence of extrafrontal MRI and EEG
abnormalities, slow propagation of seizures on intracranial EEG, normal postoperative
EEG and absence of seizures during the first postoperative year.2,4
An illustrative case
A 38-year-old male presented with drug-resistant seizures from the age of 5 years. The
semiology consisted of aura of palpitations followed by asymmetrical tonic posturing and
sudden falls, each lasting for 20 seconds and occurring at a frequency of one to two per
day. A 3 T MRI showed left mesial temporal sclerosis. Interictal EEG showed right-central
and centroparietal interictal epileptiform discharges. The video-EEG recorded semiology
suggested predominant tonic posturing of the left upper limb associated with ictal rhythm
over the central region. Interictal PET was normal while ictal SPECT showed two clusters
of hyperperfusion at the central midline and right insular regions. Magnetic source
imaging showed MEG clusters over the central region (Figure 15.8A). There was no spike
during the EEG-fMRI session. The EEG-fMRI analysis with topographic maps of spikes
recorded during vEEG monitoring showed BOLD signals over the right parietal region
(Figure 15.8B).
Figure 15.8 Illustrative case.

Overall data were considered to suggest a probable epileptogenic zone over the right
mesial frontal region, and left mesial temporal sclerosis was considered as an incidental
lesion. Intracranial EEG was undertaken with seven depth electrodes targeting the anterior
and posterior insula, anterior and posterior supplementary sensorimotor area (SSMA), and
anterior, middle and posterior cingulum (Figure 15.8C,D,E). The ictal onset zone was
delineated at the anterior SSMA with rapid propagation to the posterior SSMA (Figure
15.8F,G). Based upon this, the patient underwent resection of the right SSMA with
minimal extension to the premotor area (Figure 15.8H). The patient is seizure-free for the
last 2 years. (All images in radiological convention; AC=Anterior cingulum).
This case highlights how the careful analysis at each step helps in establishing a
plausible hypothesis to guide intracranial EEG and the inherent limitations of each
modality.
(Case and figures with the courtesy and permission of Prof. John S. Duncan,
Department of Clinical and Experimental Epilepsy, National Hospital for Neurology and
Neurosurgery, Queen Square, London, United Kingdom, where CR underwent a
fellowship.)
Acknowledgments
The authors wish to thank their colleagues at the R. Madhavan Nayar Center for
Comprehensive Epilepsy Care, Trivandrum for their valuable assistance during the
preparation of the manuscript; Dr. C. Kesavadas for the MRI images; and Mr. G.
Lijikumar and Ms. S. Vasanthi for processing the illustrations. We also thank Prof. John S.
Duncan for providing permission to publish some of the figures and the illustrative case
from the Department of Clinical and Experimental Epilepsy, National Hospital for
Neurology and Neurosurgery, Queen Square, London, United Kingdom, where CR
underwent a fellowship.
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Chapter 16 Localization and surgery in MRI-negative

posterior cortex epilepsies
Christoph Baumgartner and Susanne Pirker
Introduction
Posterior cortex epilepsies comprise epilepsies with seizures originating from the occipital
lobe, the parietal lobe, the occipital border of the temporal lobe or from any combination
of these regions.1,2 No clear anatomic and neurophysiologic distinctions can be drawn
between these cortical areas, and the epileptogenic zones are frequently not restricted to a
single lobe.3 Therefore several authors believe that it makes sense to group these patients
in a single group of so-called posterior cortex epilepsies,2 while others propose to
distinguish between patients with well-defined and circumscribed seizure onset zones
within subcompartments of the posterior cortex.4,5
Posterior cortical resections comprise less than 10% of all epilepsy surgeries.4 Reports
on seizure-free outcome largely vary between 25% and 90%.2,420 Several important large
series on posterior cortex epilepsy surgery cover time periods before the introduction of
high-resolution MRI and therefore bear limitations for conclusions on surgical treatment
of MRI-negative epilepsies.1,68,2123 Most recent studies on epilepsy surgery in the
posterior cortex using high- resolution MRI as part of their presurgical evaluation protocol
reported exclusively,2,5,911,24,25 or predominately, on lesional cases.4,1216,26,27 Therefore
the data on epilepsy surgery in MRI-negative posterior cortex epilepsies are rather
limited4,1220,26,27 and/or include MRI-negative patients with seizure onset zones in
different neocortical regions.2831
Clinical seizure semiology

Clinical seizure semiology is the initial decisive step for the diagnosis of MRI-negative
posterior cortex epilepsies. In general, one can distinguish the early seizure manifestations
reflecting epileptic activity in the seizure onset zone within the posterior cortex from
subsequent seizure manifestations resulting from seizure spread to the temporal or frontal
lobes.6,7,22,23,32,33
Occipital lobe seizures

Early seizure manifestations indicating an occipital seizure onset include elementary
visual hallucinations, ictal amaurosis, blinking, eye movement sensations and head/eye
deviation.32 Elementary visual hallucinations represent the most frequent initial symptom
indicating an occipital seizure onset, and occur in 5070% of patients.5,6,16,18,23
Elementary visual hallucinations usually consist of multicolored and circular patterns,

located unilaterally contralateral to the epileptic focus. These patterns usually multiply and
become larger, but without any particular movement other than changing positions and
luminance within their visual territory.34 The presence of a visual aura does not correlate
with a specific location within the occipital lobes.16 Furthermore, visual auras including
elementary hallucinations, illusions and visual loss do not exclusively occur in occipital
lobe epilepsy, but also in patients with occipitotemporal and anteromedial temporal
seizure onset. On the contrary, complex hallucinations and concentric changes of visual
field (tunnel vision) never occur in occipital lobe seizures, but only with occipitotemporal
and anteromedial temporal seizure onsets.35
Blinking was observed in 1556% of patients,6,18,23 has a forced quality, may consist of
eyelid flutter and occurs after the visual hallucination phase when consciousness is
impaired.34
Eye movement sensation without detectable movement and/or nystagmoid eye
movements as an initial symptom are thought to reflect seizure activity in the
extracalcarine occipital cortex.32 These symptoms were reported in 716% of patients.6,23
Versive eye/head movements occur in 1050% of occipital lobe epilepsy patients and
are always contralateral to the seizure focus.6,27 In about one-third of patients, versive
eye/head movements are not associated with visual auras. Versive eye/head movements
are accompanied by focal somatomotor manifestations in less than half of the patients.
Therefore they are thought to be generated either by propagation to the frontal eye field
and from there to the paramedian pontine reticular formation (PPRF) or by direct
propagation to the superior colliculus and subsequent PPRF activation without frontal
involvement.27
Based on clinical seizure semiology, it is not possible to distinguish mesial versus
lateral occipital lobe seizures.36
Subsequent seizure manifestations resulting from medial inferior spread via
occipitotemporal projections produce symptoms typical of medial temporal lobe epilepsy,
including visceral sensations, experiential phenomena, loss of consciousness, motionless
stare and automatisms, and occur in 3471% of patients.5,6,9,16,23,32 Spread to the temporal
neocortex results in complex visual and auditory hallucinations. Medial suprasylvian
spread produces asymmetric tonic seizures, whereas lateral suparsylvian spread produces
unilateral clonic activity. These spread patterns to the frontal lobe were observed in 12
38% of patients.5,6,9,16,23 Spread to the contralateral occipital lobe can cause ictal
blindness, occurring in 1540% of patients.6,18,23,32 In 2956% of patients different
seizure patterns occur due to different spread patterns.6,9,23,32
When lesions were localized below an imaginary line drawn at the level of the Sylvian
fissure, patients had fewer motor phenomena. Seizures originating from this inferior
region seemed to have better chances to propagate to the temporal lobe, whereas seizures
emanating from other posterior cortical areas probably have more complex and diffuse
propagation patterns, with greater involvement of motor areas.2
Parietal lobe seizures

Early seizure manifestations indicating a parietal seizure onset consist of contralateral
somatosensory auras, most commonly described as numbness or tingling sensations, and
less frequently as pain, thermal sensations, disturbances of body image including a
sensation of movement or spatial displacement of one extremity, twisting or turning
sensations, inability to move or feeling of weakness of one extremity.33 However, only
less than 2563% of patients experience somatosensory auras because, except for the
primary somatosensory area, the parietal lobe appears to be clinically silent in terms of
seizure symptomatology.7,17,22,32
Other auras include aphasia, vertiginous sensations, cephalic sensations and complex
visual or auditory hallucinations which are not generated in the seizure onset zone but
result from seizure spread.7,17,22,33
Subsequent seizure manifestations are caused by posterior spread to the occipital lobe
(ictal amaurosis), by anterior spread to the lateral convexity including sensorimotor cortex
(focal clonic activity) and premotor eyefield (version), by anterior medial spread to the
supplementary motor area (asymmetric tonic seizures) and to the temporolimbic region
(automotor and dialeptic seizures).7,17,22,24,33 In one study, 61% of patients with tonic
posturing had seizure onset zones that had included the superior parietal lobule, suggesting
spread to the supplementary motor area; 79% of patients with automatisms had seizure
onset zones that had included the inferior parietal lobule, suggesting seizure spread to the
temporal lobe.7 Up to 50% of patients experience more than one seizure type, thus
indicating different propagation pathways.17
Bartolomei and coworkers37 studied neural networks underlying parietal lobe seizures
using stereotaxic EEG. They correlated the degree of epileptogenicity in various
subcompartments of the parietal lobe with clinical seizure manifestations. They proposed
to classify parietal seizures into four main subgroups with maximal epileptogenicity in the
anterior superior parietal lobule corresponding to Brodmann area 5 forming the
somatosensory association cortex, in the posterior superior parietal lobule corresponding
to Brodmann area 7, in the inferior parietal lobule comprising the angular and
supramarginal gyri corresponding roughly to Brodmann areas 39 and 40 and finally the
parietal operculum involved in sensory processing. Eighty-eight percent of patients
reported at least one aura, with somatosensory auras (35%), vertiginous auras (23.5%),
fear (17%) and complex visual hallucinations (17%) being the most frequent subjective
seizures symptoms. Somatosensory auras were reported in all four groups, particularly
frequent in the operculum group. Vertiginous auras were most frequent in seizures from
the superior parietal lobule and fear unexpectedly arose from the posterior superior
parietal lobule. Ipsilateral version was the most frequent objective seizure manifestation
(64%) and occurred most often in seizures involving the posterior superior parietal lobule.
Hyperkinetic behavior (motor agitation), which occurred in 23%, was observed in seizures
from inferior parietal regions. Fluchere and coworkers38 reported three patients with
seizure onsets in the inferior parietal lobule or the parietal operculum with ipsilateral ictal
hemiballic-like movements with contralateral dystonia as a localizing symptom pointing
towards a posterior seizure origin. Consciousness was impaired in most cases, which
probably can be explained by an excess of EEG signal synchrony within parietal

associative cortices.39
Problems with clinical seizure semiology in posterior cortex

epilepsies
One of the major problems in MRI-negative posterior cortex epilepsies is that 50% of
patients do not demonstrate early seizure manifestations pointing towards a posterior
seizure onset, with misleading auras or initial seizure manifestations arising from seizure
spread to the temporal or frontal lobes.5,16
Scalp EEG
Interictal scalp EEG in occipital lobe epilepsy
Although interictal scalp EEG is frequently abnormal in occipital epilepsy, its localizing
value is limited. Especially, epileptiform discharges on the mesial and basal occipital
surface may remain unrecognized on the scalp. Whereas spikes confined to the occipital
lobes are infrequent and occur in less than 20% of patients, the most common findings
include spikes over the temporo-occipital or posterior temporal regions that are often in a
wide and bilateral independent field distribution. Furthermore, secondary bilateral
synchrony with a frontal maximum can be seen. Nonspecific abnormalities include focal
slowing, decreased alpha, absent or asymmetric photic responses and asymmetric
posterior occipital sharp transients of sleep (POSTs).1,3,6,9,12,16,23,34,40,41 No interictal scalp
EEG feature is useful to distinguish between mesial and lateral occipital epilepsy.36
Interictal scalp EEG in parietal lobe epilepsy

Interictal spikes restricted to the parietal lobe as the sole interictal epileptiform
abnormality represent an exceptional finding. Interictal spikes usually can be recorded
from fronto-centro-parietal, parieto-posterior-temporal, fronto-centro-temporal, frontotemporo-parietal, and posterior head regions or from the entire hemisphere. Spikes can be
recorded bilaterally or contralaterally to the seizure focus in up to one-third of patients.
Secondary bilateral synchrony with a frontal maximum occurs in up to 30% of
patients.1,3,7,13,22,24,33
Ictal scalp EEG in occipital lobe epilepsy

Ictal EEG activity restricted to the occipital lobe can be seen only in 1730% of
patients.6,9 Ictal EEG patterns over the posterior quadrant occur in 4143%.16,42 Temporal
and temporo-occipital EEG seizure patterns can be recorded in up to 50% of patients.6 In
some series, ictal EEG was nonlocalized, mis-localized to another lobe or mis-lateralized
to the contralateral hemisphere in 4370% of cases.9,12,42 Ictal scalp EEG may be useful to
distinguish between mesial versus lateral occipital lobe epilepsy. Regional occipital
seizure patterns were seen in four (36%) out of 11 patients with laterally originating
occipital seizures, but in none of 20 patients with seizures originated mesially.36
Ictal scalp EEG in parietal lobe epilepsy

Whereas regional patterns restricted to the parietal or centroparietal regions can be
recorded in a minority of patients, ictal EEG changes more frequently are merely
lateralized to the hemisphere ipsilateral to the side of seizure onset without further
localizing evidence, or remain nonlocalized. Frequently, ictal EEG patterns become visible
only after propagation to the temporal or frontal lobes, suggesting a wrong localization, or
after propagation to the contralateral hemisphere, suggesting even a wrong lateralization
of the seizure onset zone.7,13,17,22,24,42
In conclusion both interictal and ictal scalp EEG are of limited localizing value in
posterior cortex epilepsies.
Other noninvasive tests

Because clinical seizure semiology and scalp EEG especially in MRI-negative patients
can be misleading for the localization of posterior cortex epilepsies, other noninvasive
methods are needed for optimal planning of invasive evaluation and surgery. Ictal SPECT
proved useful in MRI-negative patients with occipital lobe epilepsy to correctly lateralize
and localize the seizure onset zone.26 However, it should be kept in mind that ictal SPECT
can also be nonlocalizing, or mis-localizing, by showing temporal hyperperfusion due to
rapid seizure spread to the temporal lobe.16 Other potentially valuable noninvasive
methods include high-resolution interictal EEG source imaging (ESI),43 FDG-PET
coregistered with MRI44 and magnetoencephalography (MEG).45,46 However, both highresolution interictal ESI and MEG rely on localization of the irritative zone, which is often
widespread and can provide false localizing information in posterior cortex epilepsies.
High-resolution ictal ESI might prove more reliable (see Chapter 7).
Invasive evaluation
All patients with MRI-negative posterior cortex epilepsies definitely need an invasive
evaluation before resective surgery, in order to delineate the seizure onset zone and map
eloquent cortex. Planning of the invasive evaluation needs to take into account all
information provided from noninvasive investigations, including clinical semiology, scalp
EEG and ictal SPECT. Whether other techniques like PET, high-resolution ESI, MEG or
spike-triggered fMRI are useful in this regard needs to be clarified. One important
question to address is whether the temporal lobe and insular cortex need to be covered by
invasive electrodes. Markers of significant early temporal involvement include temporal
type auras such as epigastric rising sensations and dj vu sensations,15 as well as
temporal spikes on scalp EEG.4 Most invasive studies of the posterior cortex have used
subdural strip and grid electrodes.4,5,1114,16,28,36 However, excellent localization could
also be achieved by stereoelectroencephalography.8,47,48 Jobst and colleagues16 showed
that patients in whom all three surfaces of the occipital lobe were covered by subdural
electrodes had a better outcome than those with only limited coverage. A more
comprehensive intracranial study will increase the chances to better delineate the
epileptogenic zone, and will also facilitate the precise delineation and preservation of
eloquent cortex.5,16 In this respect, a sublobar categorization of the occipital lobe into
medial, lateral and basal zones, based on anatomical landmarks, seems to be useful.5
Occipitotemporal epilepsy
Patients with posterior cortex epilepsies frequently show signs of temporal involvement as
evidenced from clinical semiology, electrophysiological abnormalities, or both. Olivier
and colleagues49 reported a patient with clinical and scalp EEG features indicating both
occipital and temporal involvement. On stereotaxically implanted depth electrodes, most
seizures started in the occipital lobes, but clinical symptoms only occurred after spread of
ictal discharges to the temporal lobe. The patient was rendered seizure-free after temporal
lobe resection. Palmini and colleagues48 selected eight patients out of a group of more
than 40 with presumed occipital lobe epilepsy when they fulfilled the following discrepant
criteria: on the one hand (a) an aura considered to be of occipital origin, (b) an occipital
interictal spike focus, (c) an occipital lesion or (d) a combination of all of these; on the
other hand all patients showed scalp EEG changes and clinical seizure semiology
suggesting temporal involvement. The seizure onset zone could not be localized by scalp
EEG. Depth electrodes showed that the seizure onset could be ordered along an
occipitotemporal gradient. A consistent occipital lobe seizure onset was seen in patients
who had only elementary visual auras. Those patients who had inconsistent or no aura
suggesting an occipital lobe onset most often had temporal lobe seizures. However,
temporal lobectomy was of limited benefit in the majority of these patients. Aykut-Bingol
and Spencer50 described the syndrome of nontumoral occipitotemporal epilepsy in 16
patients who had at least two characteristics indicating occipital lobe involvement (clinical
symptoms, interictal spike focus, ictal onset or a lesion on MRI) and one pointing towards
temporal lobe involvement (interictal spikes or seizure onset); 69% of patients had
neuronal migration disorders. Clinical seizure semiology indicated an occipital lobe
seizure onset in 81% of patients. Scalp EEG showed temporal spikes in nine patients and
occipital spikes in one patient. On intracranial EEG, the seizure onset zone could be
localized to the temporo-occipital junction in 77% of patients. Postoperative seizure
control was best with occipital and temporal resections, but a good outcome could be
achieved in some patients after occipital resections alone, even with ipsilateral temporal
EEG findings. On the contrary, temporal resections uniformly failed to control seizures.
Several recent studies on posterior cortex epilepsies showed that temporal type auras
like epigastric rising sensations10,18,20 and dj vu5 were predictors of an unfavorable
surgical outcome. Jehi and colleagues4 showed that patients with preoperative ipsilateral
temporal spiking were twice as likely to fail surgery compared to patients with no
extraposterior (outside of parieto-occipital) spikes. The authors attributed surgical failure
in this group to an incomplete resection of a rather large epileptogenic region extending
anteriorly to the insula or to the anterior temporal lobe. Indeed, five of 11 patients re-
evaluated after seizure recurrence had seizures arising from the temporoparietal junction.
Potential pathophysiologic bases underlying these occiptotemporal epilepsies include
vascular mechanisms, intrahemispheric occipitotemporal secondary epileptogenesis or an
underlying developmental disorder.4,48,50
In conclusion posterior cortex epilepsies showing clinical or electrophysiological signs
of temporal involvement should undergo comprehensive invasive exploration of the
temporal lobe and insula.
Outcome
Seizure-free outcome after posterior cortex epilepsy surgery varied between 25% and 90%
in different series.2,420 Jehi and colleagues4 presented a longitudinal study of surgical
outcome following posterior cortex epilepsy surgery in 57 patients with a mean follow-up
of 3.3 years. However, only two MRI-negative patients were included in this study. The
estimated chance of seizure freedom was 68.5% at 1 year, 65.8% between 2 and 5 years
and 54.8% at 6 years and beyond. The outcome after occipital (seizure freedom at 5 years:
89%) and parieto-occipital resections (seizure freedom at 5 years: 93%) was better than
after parietal resections (seizure freedom at 5 years: 52%), which could be explained by
more conservative resections in the parietal lobe. Thus outcome after posterior cortex
epilepsy surgery seems to be more favorable than after frontal lobe surgeries.51
Predictors for postoperative seizure control

Several studies tried to identify possible prognostic variables for postoperative seizure
control in posterior cortex epilepsies. It should be noted that in all series, only small
numbers or single cases of MRI-negative patients were included. Therefore it remains a
matter of debate whether the proposed prognostic factors remain valid for MRI-negative
patients.
Factors that have been reported to be predictive for favorable postoperative seizure
control included early age at epilepsy onset,12 shorter epilepsy duration,2,12 normal
neurological examination prior to surgery,2 lateralizing aura and clinical seizure
semiology,10 absence of a temporal-type aura including epigastric rising sensations, dj
vu sensation and abdominal auras,15 no versive head turning unaccompanied by visual
aura,15 absence of a history of generalized tonicclonic seizure,11 absence of ipsilateral
temporal spikes on scalp EEG,4 a focal ictal scalp EEG onset,8 complete coverage of all
three occipital surfaces on invasive EEG,16 focal interictal intracranial activity,8 complete
resection of the irritative spiking zone delineated on invasive EEG,52 complete resection
of the ictal onset zone defined by invasive EEG,8 absence of spikes on postresection
electrocorticography,6,7 lobectomy or multilobar resection as opposed to lesionectomy,4
presence of a histopathological lesion,53 low-grade tumor or cortical dysplasia on
histological examination,4,15 and absence of spikes on postoperative EEG.4,11 However,
most of these parameters except presence of a histopathological lesion could not be
reproduced in other studies.
Neurological complications
One of the major concerns of epilepsy surgery is the avoidance of new neurological
deficits caused by the surgical procedure. In posterior cortex epilepsy, potential
neurological deficits induced by surgery include visual field deficits, hemisensory
syndromes, hemiparesis, Gerstmann syndrome and language deficits.
Occipital resections bear a high risk of creating or worsening a visual field defect. Preand postoperative visual field testing is therefore mandatory. In a large series from Binder
and colleagues,12 visual field defects were present preoperatively in 36% of patients,
whereas 42% suffered new or aggravated visual field defects after the operation. These
findings are similar to other reports in the literature.1,2,4,5,10,11,15,16,18,36 Visual function
can be compromised by lesioning either the primary visual cortex or the optic radiation.5
Resections of the left ventral occipitotemporal (vOT) area in the vicinity of the
occipitotemporal sulcus, which lies between the lateral fusiform gyrus and the medial
surface of the posterior inferior temporal gyrus, can result in reading deficits while speech
production and comprehension remain intact.54,55 The fMRI technique and diffusion
tensor imaging tractography should be useful to preserve visual function in occipital lobe
resections.56,57 In any case, the high probability of this postoperative neurological deficit
and its functional implications need to be discussed frankly with the patient before the
surgery.12
In parietal resections, in addition to visual field deficits, hemisensory syndromes,
hemiparesis, Gerstmann syndrome and aphasia constitute the main surgical
complications.4,11,13,15,17 Gerstmann syndrome consists of agraphia, acalculia, finger
agnosia and rightleft disorientation, and results from damage of the dominant angular
gyrus, and also of the supramarginal gyrus and the intraparietal sulcus.13,58 In a series of
40 patients, transient postoperative deficits were observed in 30%, whereas permanent
deficits were seen in only 7.5% of patients.13 When the epileptogenic zone overlaps with
eloquent cortex, additional multiple subpial transections may be an option.13 The safety of
parietal lobe surgery can be improved by preoperative fMRI mapping and intraoperative
stimulation studies.
Neuropsychology
Studies on systematic neuropsychological testing before and after posterior cortex
epilepsy surgeries are scarce. Luerding and colleagues59 performed systematic
neuropsychological testing in 28 patients prior to and 6 months after posterior cortical
resections. Whereas postoperative verbal intelligence consistently increased, performance
intelligence decreased regardless of lesion side, postoperative seizure control or visual
field deficits after surgery. In another study, complete occipital lobectomy increased the
risk of postoperative decline of the Wechsler intelligence score.15 There is a definite need
for specially designed neuropsychological tests corresponding to the specific functions of
the cortical areas being considered for resection.59
Reports on MRI-negative posterior cortex epilepsies

Series that included well-documented cases of epilepsy
surgeries in MRI-negative posterior cortex epilepsies
Some well-documented illustrative cases of epilepsy surgeries in MRI-negative posterior
cortex epilepsies are summarized in the following.
Barba and colleagues8 presented 14 patients with posterior cortex epilepsies including
one MRI-negative patient. This patient showed multifocal interictal spikes and a focal
seizure onset on scalp EEG. After acute electrocorticography, a right occipital
corticectomy rendered the patient seizure-free. Histology showed irregular distribution of
neurons and glial cells. The patient suffered from a postsurgical homonymous left
hemianopia.
Bien and colleagues53 presented 190 MRI-negative patients who underwent presurgical
evaluation, 29 (15%) of them were eventually operated; 11 patients (38%) became
seizure-free (45% if including those with auras only). They distinguished between patients
with (nine patients) and without (20 patients) a distinct histopathological lesion. Seven of
nine histopathologically lesional patients (78%) became seizure-free compared with only
four of 20 patients (20%) without histopathological lesions. Three-fifths of the
histopathologically nonlesional patients had multifocal or extensive epileptogenic areas.
One MRI-negative patient with posterior cortex epilepsy was included in this study.
Clinical seizure semiology indicated an occipital or frontomedial seizure onset zone,
interictal scalp EEG showed left and right frontocentral spikes, ictal scalp EEG was
localized to the right and left frontal lobe, but was almost generalized. Ictal SPECT
including SISCOM showed a left occipital hyperperfusion. Depth electrodes showed right
and left fronto-parieto-occipital ictal EEG changes. After a left parieto-occipital resection,
seizures remained unchanged. A diffuse epileptogenic area was hypothesized
postoperatively.
Caicoya and colleagues14 presented 11 patients with occipital lobe epilepsy, seven of
whom underwent epilepsy surgery, including one MRI-negative patient. In this patient,
seizures started with amaurosis and were then characterized by a temporal semiology,
including nonreactivity, stereotypic language, and deviation of the left corner of the
mouth. Preoperative visual field perimetry was normal. Interictal scalp EEG showed left
occipital spikes and generalized slowing with a left posterior maximum. Ictal scalp EEG
was localized to the left occipital region. Intracranial subdural EEG showed a diffuse ictal
onset. Histological examination showed displaced neurons in the white matter. The patient
became completely seizure-free after a resection guided by electrophysiological findings,
and only suffered from a right inferior homonymous quadrantanopia.
Cukiert and colleagues28 studied 16 patients, with medically refractory extratemporal
epilepsy and normal or nonlocalizing MRI in ten and six patients, respectively. All
patients were evaluated with extensive coverage by subdural electrodes. Invasive ictal
EEG showed a focal seizure onset in all patients. Resections were maximized to include
both the ictal onset zone and the predominant interictal irritative zone; 13 patients (81.2%)
became seizure-free after surgery, the other three patients (18.8%) experienced a more
than 90% reduction of seizure frequency. Histology showed gliosis in ten specimens,
cortical dysplasia in five and no abnormalities in one case. Their series included six
patients with posterior cortex epilepsies (two parietal, one temporo-occipital and three
posterior quadrant resections with removal of occipital, parietal and posterior temporal
cortex). Three of these six patients had normal MRI scans including one patient with a
temporo-occipital resection and two patients with parietal resections. All three patients
became seizure-free. Histology showed dysplasia in two and gliosis in one patient.
Jehi and colleagues4 presented 57 patients with posterior cortex epilepsy surgery
including three MRI-negative patients (two patients with MRI-negative MCD and one
patient with normal histology). Only one patient with MRI-negative MCD became
seizure-free. No further details regarding these patients could be derived from the paper.
Jobst and colleagues16 presented 14 patients with occipital lobe epilepsy including three
MRI-negative patients; 12 patients including two MRI-negative patients underwent
surgery. The first patient experienced an aura with blurry vision and simple visual
hallucinations (bright object followed by dark object); subsequently, random but not
lateralized body movements, screaming, head deviation to the left, automatisms and
altered consciousness were observed. Interictal scalp EEG showed bilateral independent
midanterior temporal sharp waves with equal frequency between sides. Ictal scalp EEG
showed either right midanterior or posterior temporal rhythmic theta activity, which then
became diffuse. Ictal SPECT scans were performed twice, one showed a left medial
temporal hyperperfusion, the other a left lateral temporal hyperperfusion. After invasive
evaluation with subdural grid electrodes, a small right-sided inferior occipital resection
was performed. Histology showed neuronal loss. Seizures were unchanged after the
operation (Engel class IV). The other MRI-negative patient experienced an aura with
bilateral hand paresthesias, then right hand automatisms, oral automatisms, and head
turning to the right accompanied by altered awareness. Interictal scalp EEG showed rare
right posterior temporal spikes. On ictal scalp EEG, a right posterior temporal build-up
could be observed. Two ictal SPECT scans showed a right posterior temporal
hyperperfusion. After invasive evaluation, a right-sided inferior occipital resection plus a
hippocampectomy rendered the patient seizure-free. Histology was normal for the
occipital specimen, but showed mesial temporal sclerosis. The operation caused a partial
visual field defect.
Sturm and colleagues26 presented ictal SPECT and interictal PET data in six patients
with occipital lobe epilepsy including two patients with normal MRI. The first patient had
bitemporal seizure onsets on scalp EEG. Whereas interictal PET showed bitemporal
hypometabolism, conventional ictal SPECT without subtraction showed a unilateral left
occipital hyperperfusion. Invasive EEG (subdural strips and bilateral hippocampal depth
electrodes) confirmed an occipital seizure onset congruent to hyperperfusion on ictal
SPECT. Pathology showed cortical dysplasia. Outcome after a follow-up of 28 months
was Engel class III. The second patient also had bitemporal seizure onsets on scalp EEG.
On interictal PET, a left temporal hypometabolism could be observed; on ictal SPECT, a

left occipital and bitemporal hyperperfusion. Invasive EEG showed a left occipital seizure
onset. Pathology again showed cortical dysplasia. Outcome after a follow-up of 32 months
was Engel class II.
Series of posterior cortex epilepsy surgeries including MRInegative patients but without detailed data
Binder and colleagues12 presented two MRI-negative patients in a series of 52 patients
with occipital lobe epilepsy. A topectomy was performed in both patients. On histology,
one patient showed a scar and the other patient a cortical dysplasia.
Binder and colleagues13 also included two MRI-negative patients in their series of 40
patients with parietal lobe epilepsy. A topectomy guided by intracranial EEG recordings
was performed in both patients.
Davis and colleagues15 presented 43 patients who had undergone posterior quadrant
epilepsy surgery. Surgical resections were occipital in 18 patients (42%), occipitoparietal
in 14 patients (33%), occipitotemporal in six patients (14%) and occipito-temporal-parietal
in five patients (12%). The primary sites of resections were occipital in 28 patients (65%),
parietal in ten patients (23%) and temporal in five patients (12%). At 1 year follow-up, 22
patients (51.2%) were Engel class I, ten patients (23.3%) Engel class II, five patients
(11.7%) Engel class III and six patients (14.0%) Engel class IV. Eight patients (19%) were
MRI-negative.
Hong and colleagues29 presented presurgical evaluation and surgical outcome in 41
MRI-negative patients with neocortical epilepsy including seven patients with occipital
lobe epilepsy and four with parietal lobe epilepsy. For the whole group, ictal scalp EEG
had the highest diagnostic sensitivity for localization of the epileptogenic lobe in patients
with a good surgical outcome (69.7% vs. 42.9% for FDG-PET and 33.3% for conventional
ictal SPECT). Engel class I outcome could be achieved in 4/7 patients with occipital lobe
epilepsy and in 2/4 patients with parietal lobe epilepsy.
Kim and colleagues,17 from the same group as the above, presented a series of 40
patients with parietal lobe epilepsy: 27 patients underwent epilepsy surgery (26 with a
follow-up for more than 1 year) including 14 patients with normal MRI; 14 patients (54%)
became seizure-free (9/12 [75%] with MRI lesions and 5/14 [35.7%] with normal MRI),
while 12 patients had persistent seizures (3/12 [25%] with MRI lesions and 9/14 [64.3%]
with normal MRI). The presence of an MRI lesion was a marginally significant predictor
for postoperative seizure control.
Lee and colleagues,18 from the same group as the above, presented 26 surgically treated
patients with occipital lobe epilepsy including 16 patients with normal or multiple lesions
on MRI: 16 patients (61.5%) were rendered seizure-free after the operation (7/10 [70%]
with localized MRI lesions; seven with normal MRI and two with multiple lesions on
MRI); ten patients had persistent seizures (3/10 [30%] with MRI lesions and 7/16 [43.8%]
with normal or multiple lesions on MRI). No significant association could be found
between a localized lesion on MRI and postoperative seizure control.
Lee and colleagues30 also presented 89 patients with MRI-negative neocortical epilepsy
(35 patients with frontal lobe epilepsy, 31 with neocortical temporal lobe epilepsy, 11 with
occipital lobe epilepsy, 11 with parietal lobe epilepsy and one with multifocal epilepsy). A
seizure-free outcome was achieved in 42 patients (47.2%) of the whole cohort, in 7/11
patients (63.6%) with occipital lobe epilepsy and in 3/11 patients (27.3%) with parietal
lobe epilepsy. Diagnostic sensitivities (defined as localization concordant with the resected
lobe) of interictal EEG, ictal scalp EEG, FDG-PET and subtraction ictal SPECT were
37.1%, 70.8%, 44.3% and 41.1%, respectively. Localizing values of individual modalities
for seizure-free patients were as follows: interictal EEG whole cohort 20/42, occipital
lobe epilepsy 4/7, parietal lobe epilepsy 0/3; ictal scalp EEG whole cohort 33/42,
occipital lobe epilepsy 7/7, parietal lobe epilepsy 1/3; FDG-PET whole cohort 23/40,
occipital lobe epilepsy 4/7, parietal lobe epilepsy 0/3. Localizations by FDG-PET and
interictal EEG were significantly associated with a seizure-free outcome, whereas
localization by ictal EEG and subtraction ictal SPECT were not. Surgical outcome was not
influenced by whether invasive ictal EEG onsets were focal or regional or by the
frequency of invasive ictal EEG patterns. Concordance between two or more presurgical
evaluation modalities was significantly related to a seizure-free outcome. Pathology
specimens were available for 80 patients showing cortical dysplasia including
microdysgenesis in 58 cases, migration abnormalities in ten, focal neuronal loss with
gliosis in nine, ischemic change in two and cortical dysplasia associated with
dysembryoplastic neuroepithelial tumor in one patient. Pathology results were not related
to surgical outcome.
McGonigal and colleagues47 presented a series of 100 patients who had undergone
SEEG evaluation including 43 patients with normal MRI and 57 with lesions on MRI.
Their series also included five MRI-negative patients with posterior cortex epilepsies
(three with occipital lobe epilepsy, one with parietal lobe epilepsy and one with temporoparieto-occipital junction epilepsy). All three patients with occipital lobe epilepsy
underwent corticectomy. Histology showed dysplasia in one patient rendered seizure-free
and gliosis in two patients with persistent seizures. Gamma knife surgery was performed
in the patient with parietal epilepsy with no outcome available yet. Surgery was offered,
but declined by the patient with temporo-parieto-occipital junction epilepsy.
Urbach and colleagues19 reported 42 patients who had undergone epilepsy surgery in
the parietal and occipital lobe. Two MRI-negative patients were operated on
electrophysiological basis. Histopathology was unrevealing, and both patients continued to
have seizures.
Yu and colleagues20 presented 43 patients with posterior cortex epilepsies including 11
patients with parietal lobe epilepsies, 13 with occipital lobe epilepsies and 19 with
seizures originating from the parieto-occipito-posterior-temporal cortex. A favorable
outcome could be achieved in 31 patients (72.1%) (Engel class I in 26 cases [60.5%] and
Engel class II in 5 cases [11.6%]); MRI showed focal epileptogenic lesions in 24 patients,
MRI was nonlocalizing in 19 patients including 13 MRI-negative patients, two patients
showed bilateral posterior cortical lesions, and four patients showed lesions in the
contralateral hemisphere or in the frontal or temporal lobe which were considered as
incidental and unrelated to seizures. A favorable outcome (Engel class I or II) could be
achieved in 14/19 cases (73.7%), which was comparable to patients with MRI-visible
lesions in the resected posterior cortex (17/24 patients [70.8%] with favorable outcome).
Case example
This right-handed female (Figure 16.1) patient was the product of unremarkable
pregnancy and delivery. The patient started to experience seizures at 3 years of age.
Seizures consisted of staring, nystagmoid eye movements, tonic eye deviation to the right,
slight head deviation to the right and tonic contraction of both upper extremities. The
patient remained partially responsive during seizures. Seizures occurred five to ten times a
day on average. During intensive video-EEG monitoring, interictal EEG showed repetitive
right occipital spikes (Figure 16.1A). Ictal EEG was nonlocalized. Ictal SPECT showed a
right occipital hyperperfusion (Figure 16.1B). Visual field testing was normal. The patient
was implanted with subdural grid electrodes covering the right lateral and mesial surface
of the occipital lobe (Figure 16.1C). Invasive EEG showed a lateral occipital seizure
onset. The patient was 23 years at the time of the operation. A lateral occipital resection
was performed guided by invasive EEG results in order to completely remove the seizure
onset zone. Histology showed focal cortical dysplasia type IIb. Postoperative visual field
testing was normal. The patient has remained seizure-free since the operation for 16 years.
Figure 16.1A. Interical EEG showing right occipital spikes, maximum over electrode
O2.
Figure 16.1B. Interictal (top) and ictal (bottom) SPECT. Ictal SPECT shows right
occipital hyperperfusion.
Figure 16.1C. Invasive evaluation with subdural grid electrodes covering the right
lateral and mesial surface of the occipital lobe.
Algorithm for evaluation of MRI-negative posterior cortex

epilepsies (Figure 16.2)
Conclusions
MRI-negative posterior cortex epilepsies pose a major challenge during presurgical
evaluation. Both clinical seizure semiology and scalp EEG data may be misleading by
indicating a temporal or frontal lobe seizure onset. Therefore a thorough analysis of
history and clinical seizure semiology are critical to identify symptoms of early posterior
cortical involvement. Scalp EEG should be evaluated for posterior cortical epileptiform
discharges, even when temporal, frontal or multifocal spikes or secondary bilateral
synchrony is present. Ictal SPECT may be helpful for confirming the diagnosis of
posterior cortex epilepsy and for planning invasive evaluations. Because outcome is
critically dependent on the presence of a lesion on histology (most often focal cortical
dysplasia) a re-evaluation of MRI should be done with all available information from
noninvasive tests before moving on to invasive evaluation. It has to be stressed that MRInegative and histology-negative patients will have only a small chance of becoming
seizure-free; fMRI and diffusion tensor imaging tractography should be done
preoperatively to map out eloquent cortex. An extensive coverage of the posterior cortex
including its lateral, mesial and basal surface is desirable to allow a comprehensive
delineation of the epileptogenic zone and of the eloquent cortex. If clinical seizure
semiology or scalp EEG point towards early temporal lobe involvement, the temporal lobe
and insular cortex should be covered by invasive electrodes as well. Surgical outcome is
favorable when a lesion can be identified on histology. The implications of visual field
deficits, hemisensory syndromes, hemiparesis, Gerstmann syndrome and language deficits
have to be frankly discussed with the patient before proceeding to invasive evaluation and
surgery.
Figure 16.2. Algorithm for evaluation of MRI-negative posterior cortex epilepsies. Blue
boxes: mandatory examinations. Yellow boxes: optional examinations. Red boxes: MRI
should be re-evaluated on the basis of all results available from noninvasive tests for the
presence of a possible epileptogenic lesion. Green boxes: invasive EEG evaluation is
necessary in every patient with MRI-negative posterior cortex epilepsy.
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Chapter 17 MRI-negative refractory focal epilepsy in

childhood
Prasanna Jayakar and Michael Duchowny
Introduction
The referral of children with refractory epilepsy for surgical intervention is now
axiomatic. Recurrent seizures that begin early in life are associated with later cognitive
decline and a reduced quality of life, and thus mandate earlier rather than later referral.
Long-term seizure freedom rather than improvement is the primary surgical goal. In
response, most pediatric epilepsy surgery centers now accept infants and very young
children as potential candidates, and have protocols in place to localize seizure origin,
maximize postoperative success and reduce potential surgical complications.
The importance of MR imaging in the preoperative evaluation for epilepsy surgery
cannot be overestimated. In a recent review of current practice worldwide by the ILAE
taskforce [1], MR imaging was performed in 99.5% of pediatric epilepsy surgical
candidates. Utilizing high-resolution epilepsy protocols and expert interpretation, MR
imaging can detect focal abnormalities in as many as 85% of patients with previously
negative studies [2]. The demonstration of a focal lesion helps define the epileptogenic
region (ER) and assists the surgical strategy either in preparation for single stage
procedures, or in guiding placement of intracranial electrodes to gather further
electrophysiological data.
In contrast, the inability to detect a focal lesion on MRI presents significant challenges
to the successful localization of the epileptogenic zone. Histopathological analysis of
tissue removed in MRI-negative cases often reveals microscopic abnormalities. The
incidence of MRI-negative cases in the ILAE taskforce series was 17% [1], although
meta-analysis of patients of all ages reveals a considerably higher incidence of MR
negativity in the pediatric population, 31% in children versus 21% in adults [3]. Referral
bias is undoubtedly important as some centers report an incidence of MRI-negative cases
as high as 53% [4].
This chapter focuses on select aspects of epilepsy surgery in the MRI-negative cohort
that are unique to childhood. We review specific challenges to the definition of the cohort,
candidacy and special syndromes, evaluation and outcomes.
Definition of the cohort

As in adults, the MRI-negative cohort in children includes not only patients with normal
MRI scans but also with nonspecific findings such as cortical atrophy or ventriculomegaly
and incidental focal abnormalities [5]. A word of caution is in order with regard to the
MRI investigation of focal malformations of cortical development (FCD) in early
childhood. The MR appearance of FCD often changes during brain maturation. Although
FCD may be detected in infancy, being hypointense on T1-weighted images and
hyperintense on T2-weighted images, these findings may become more apparent or
occasionally completely disappear on later scans [6]. This problem is particularly
significant in Taylor-type FCD. Unfortunately, there is considerable variability across
centers on specifics of MRI sequences and the ILAE is proposing age-specific
recommendations for children under age 2 years [7].
Utilizing 3 T MRI or advanced computerized postprocessing to define statistical
variations in cortical thickness, signal intensities or graywhite blurring may increase the
diagnostic yield but are not an absolute requirement for clinical definition of the MRInegative cohort. Furthermore, the argument can be made that identification of the lesion
does not necessarily simplify the evaluation process or influence outcome in cases of
FCD; thus children revealing subtle FCD lesions may be considered within the broader
definition of an MRI-negative cohort.
Special MRI-negative refractory focal epilepsy populations

in childhood
Focal cortical dysplasia
Focal cortical dysplasia (FCD) accounts for the majority of MRI-negative epilepsy
surgical cases. Indeed the MRI evaluation is negative in approximately one-quarter of
children with FCD [8]. It comprises a significant proportion of cryptogenic childhood
cases and likely contributes to the over-representation of MRI-negative cases in childhood.
In the largest reported MRI-negative pediatric epilepsy surgical series [5], FCD was
observed in 77 of 102 (75%) surgical specimens; 71 of the 77 specimens contained lowergrade features (92%). In a smaller pediatric series, all 14 patients harbored FCD [9], and it
is not unusual to observe different subtypes of FCD in different lobes of multilobar
resections [9, 10].
Medically resistant cases of pediatric focal epilepsy due to FCD typically begin in the
first few years of life [8]. Affected patients evidence significant rates of neurological
disability, daily seizures and status epilepticus [8]. Pre- and perinatal lesions occur in
12.5% of patients with FCD, particularly low-grade dysplastic subtypes [11], whereas
postnatal comorbid disorder such as head injury and infection are unusual [8]. This
population is thus extremely high risk for morbidity and resource-intensive for their
medical care.
Given the high incidence of FCD in the MRI-negative pediatric epilepsy surgical
cohort, expertise with the underlying neurological issues is imperative. Electrophysiologic
investigations reveal a high incidence of focal intermittent slowing and slow background
activity on EEG [8]; a normal EEG is observed in only a small minority of children.
Regional ictal patterns occur in over half of children with FCD [8]. Because of widespread
dysplastic involvement in the very young, large resections including multilobar procedures
and hemispherectomy are common, and a high proportion of children require invasive
EEG recording.
West syndrome
Infantile spasms were viewed historically as a form of primary generalized epilepsy until
surgical resection of discrete cortical lesions in symptomatic patients resulted in dramatic
cessation of the spasms [13]. This cortical hypothesis for epileptogenesis in West
syndrome was supported by PET studies revealing localized regions of hypometabolism in
the epileptogenic zone [14] which reformulated the spasms as a rapid secondary
generalized epilepsy. In medically refractory cases, focal or regional excisional procedures
can achieve cessation of spasms, long-term seizure freedom and improved cognitive status
[14, 15].
MRI-negative cryptogenic cases of West syndrome with hypsarrhythmic EEGs that are
medication-resistant are an important sub group for surgical consideration. The EEG
evaluation may yield important information supporting potential surgical candidacy. In a
study of hypsarrhythmic EEG patterns, Gaily et al. [16] showed that hypsarrhythmic
EEGs were asymmetric in 25% and asynchronous in 7% of cases. These lateralized
features correlated with ictal EEG discharges contralateral to the clinically involved side,
and demonstrated that coexistent partial motor seizures are particularly frequent.
Localized EEG features including paroxysmal fast frequencies, rhythmic discharges and
subclinical seizures are now recognized frequently in MRI-negative surgically treated
cases of infantile spasms [17].
Use of PET scans plays an important role in the evaluation of medically refractory
infantile spasms [18]. If concordance can be demonstrated between the zone of
hypometabolism and focal EEG findings, seizure freedom is distinctly possible.
Unfortunately, only about 20% of infants demonstrate a focal hypometabolic zone, the
remainder showing either multiple hypometabolic foci (65%) or diffuse and symmetric
hypometabolic changes (5%) [18]. Bi-temporal metabolism occurs in 10% of cases and is
associated with a high rate of autism [19].
Preoperative investigations
MRI-negative children should undergo an intense evaluation for exclusionary criteria:
genetic/idiopathic (e.g., SCN1A, atypical BECTS), neurodegenerative or metabolic
syndromes that may present as refractory partial seizures (Table 17.1). They also require
serial assessments to document temporal consistency of clinical semiology and diagnostic
localization. The time frame over which consistency is conferred depends on the degree of
acuity of presentation, including catastrophic seizures and neurocognitive or behavioral
deterioration.
Table 17.1 Candidacy screen: conditions that need to be excluded
Genetic/idiopathic (especially SCN1A, autosomal dominant frontal lobe
epilepsy, atypical benign focal epilepsy of childhood)
Neurodegenerative syndromes
Inborn errors of metabolism

Zellweger syndrome
Pyruvate dehydrogenase deficiency
Fumarase deficiency
CPT 2 deficiency
Glutaric acidemia type 1
Consistent focal findings on the scalp EEG (Figure 17.1) and clearly delineated ictal
semiology are the cornerstones of the evaluation of children with MRI-negative focal
epilepsy. Both are influenced by maturational factors, and the potential for significant
changes over time must always be considered. This is especially evident in infants whose
symptomatic focal epilepsy is more likely to propagate to motor pathways leading to
apparent electroclinically generalized epileptic seizures [20].
Figure 17.1 Scalp EEG showing semi-periodic discharges consistently over the right
centrotemporal region.
All children with refractory MRI-negative focal epilepsy should initially undergo
video-EEG recording with ictal capture. The demonstration of a focal region of
epileptogenesis should prompt reinvestigation of the MRI for evidence of subtle
abnormalities. Ideally, the epileptogenic region should be convergent with the
semiologically suspect anatomic region of seizure onset. Particular attention must be given
to the identification of electrographic features at seizure onset that suggest lateralized or
regional seizure origin.
The role of functional imaging in pediatric cases is well established. Ictal SPECT and
PET are both sensitive and specific tools to delineate temporal and extratemporal seizure
onset zones [2124]. Functional imaging is generally required in all MRI-negative patients
and is obligatory if there is clinical and electrophysiological divergence. Although ictal
SPECT is considered superior for localizing extratemporal foci and PET superior for
temporal foci, a comparison of both modalities in pediatric temporal lobe epilepsy reveals
diagnostic accuracy in the range of 8090% for both [25].
More recently, magnetoencephalography (MEG) has been employed successfully in
MRI-negative cases. In a cohort of 22 children with subtle or nonfocal MRI findings,
Ramachandran Nair and colleagues [26] identified 17 (77%) with good surgical outcome
and eight (36%) who became seizure-free. Postoperative seizure freedom correlated with
the presence of MEG clusters within the resection margin whereas bilateral MEG dipole
clusters or scattered dipoles correlated with seizure persistence. Seizure freedom was
greater when there was complete concordance between MEG and EEG localization.
Multiple seizure types predicted poor postoperative outcome.
The use of multiple modalities to define the epileptogenic zone in MRI-negative
pediatric refractory focal seizures is widely regarded as state-of-the-art [5, 9, 27, 28].
Which modalities are utilized depends to a large extent on local institutional protocols and
resources, and there is only limited data to support the superiority of a single approach. In
a study of 14 children undergoing comprehensive multimodal investigations for refractory
MRI-negative focal epilepsy, SISCOM and MEG showed better concordance with
intracranial EEG data than PET [9]. However, PET and SPECT data do not guarantee a
seizure-free outcome [28]. As the number of patients in these studies was limited, it is
difficult to draw any definitive conclusions.
In the largest cohort of MRI-negative children with refractory focal epilepsy reported to
date, 102 patients underwent multimodal investigation that integrated PET and SPECT
with video-EEG, extra operative subdural recording and electrocorticography [5]. This
comprehensive pre- and perioperative approach facilitated excisional procedures in 102
children, including 66 unilobar and 36 multilobar resections. Of note, preoperative
evaluations were individualized according to individual profiles rather than being rigidly
tracked through a preset protocol. This multimodal flexible approach did not aim to
employ all possible diagnostic modalities yet achieved successful surgical planning and a
reasonably good rate of postoperative seizure-freedom (44% at 2 years).
Functional considerations
Patients with MRI-negative refractory focal epilepsy are more likely to exhibit atypical
language representation. In a study of 102 patients with left hemisphere epileptogenic
zones evaluated with fMRI language tasks [29], atypical language was more prevalent if
the MRI was normal (36%) compared to 21% with hippocampal sclerosis (HS) and 14%
with other focal cortical lesions (dysplasia, tumor, vascular malformation). Of particular
relevance for pediatric epilepsy surgery, atypical language was over-represented in

patients with early seizure onset and atypical handedness. Atypical language
representation was associated with lower verbal abilities and a trend towards lower
nonverbal abilities.
Receptive language competence appears particularly vulnerable to reorganization. In a
study of the relationship of age of onset of temporal lobe epilepsy to subsequent
intellectual ability, Cormack et al. [30] found that seizure onset in the first year of life was
associated with a particularly high (82.4%) incidence of later intellectual impairment.
Epilepsy originating from either temporal lobe in early life was sufficient to produce
intellectual dysfunction. In contrast, seizure frequency and the duration of the epilepsy
were not significant variables.
The selective vulnerability of the temporal lobe to early-life seizures and lack of any
relationship to underlying pathological substrate was further confirmed in two recent
investigations [31, 32]. Both studies, one in an adult cohort, and one in a pediatric cohort,
revealed an increased incidence of atypical language representation on functional MRI and
a higher incidence of left-handedness. The children in the Kresk et al. [32] study
additionally evidenced linguistic deficits and relatively greater vulnerability for receptive
versus expressive language networks.
The collective evidence from several lines of investigation therefore suggests that MRInegative patients, particularly if the temporal lobe is the epileptogenic source, must
undergo a careful evaluation of language representation. Assumptions of cortical sites for
language cannot be taken for granted, and the sites are most likely to be atypical in MRInegative temporal lobe patients. By contrast, data on motor representation in MRInegative children are limited, although anecdotal cases have demonstrated atypical
functional organization that may have relevance to surgical planning.
Invasive investigations
Invasive EEG recording is considered the gold standard in MRI-negative cases, but data
on its utility in children are limited [33]. Utilization occurs mainly where there is
inconclusive or divergent noninvasive data. Also, utility may be greater in extratemporal
or multilobar foci as compared to temporal foci that are often amenable to standard
lobectomies. Rates of explantation without resection vary considerably across centers, and
given the additional risk and costs, added caution is recommended in patient selection [34]
or utilizing invasive EEG as an exploratory procedure without an a priori hypothesis of the
epileptogenic region to guide electrode placement.
Invasive EEG can be recorded via subdural, depth or a combination of electrodes. The
electrodes may be placed through an open craniotomy or stereotactic depth placement; the
latter is generally feasible only above age 3 years. As in adults, the ictal onset zone is
considered the most localizing marker but other markers such as significant background
abnormalities, repetitive or rhythmic interictal discharges, or intraictal activations deserve
added consideration in the absence of a structural lesion. More recently, interictal highfrequency oscillations have attracted attention but their role in localizing seizure onset in
children is uncertain.
Electrocorticography (ECoG) is influenced by anesthesia and generally provides only

interictal data, which limits its usefulness [35, 36]. In a subset of patients with FCD
however, the ECoG may reveal continuous focal ictalinterictal discharges. These
discharges often correlate with the ictal onset zone (Figure 17.2). They thus serve as a
reliable marker of the epileptogenic region and may alleviate the need for ictal capture
through extraoperative invasive EEG recording.
Figure 17.2 Subdural EEG recording showing interictal semi-periodic discharges. Ictal
onset (arrow) is characterized by alteration in the rate of the discharges followed by their
disappearance and focal attenuation.
Decision algorithm
Each center generally adopts its own specific protocol to define the epileptogenic region in
this cohort. Nonetheless, given the escalating number of diagnostic tests and the costs and
risks incurred without necessarily documented benefit, the ILAE is proposing
recommendations to achieve a certain degree of standardization [7]. As mentioned earlier,
MRI-negative children should have a greater emphasis on exclusionary criteria:
genetic/idiopathic (e.g., SCN1A, atypical BECTS), neurodegenerative and metabolic
syndromes as compared to lesional cases, and they should undergo serial assessment to
document temporal consistency of localization.
Centers dealing with MRI-negative cases are expected to have capabilities for ancillary
investigations that include most of the following: 3D EEG source, MEG, FDG-PET or
SPECT to allow a hypothesis for location of the epileptogenic region that can then be
confirmed by either ECoG or extraoperative invasive recordings; FDG-PET and SPECT
are the most widely used ancillary tests. Between the two functional imaging modalities,
FDG-PET is easier to perform and has been proposed as the initial test in MRI-negative
cases, particularly if FCD is the predominant substrate; SPECT is better suited than FDGPET in patients with prior resections, but is technically more challenging and requires
seizures to be of sufficient frequency and duration to permit adequate ictal capture. Both
PET and ictal SPECT are susceptible to the effects of seizure propagation and are thus
useful mainly for defining overall ER location but not necessarily its extent. Subtraction of
ictal and interictal SPECT potentially overcomes this limitation but imposes the need for
an additional SPECT test and computational expertise. Additional electrophysiologic
corroboration is therefore strongly recommended.
The MEG technique is advocated at some centers while 3D EEG source imaging is
generally underutilized. Given the complementary nature of 3D EEG and MEG, usage of
both tests optimally as simultaneous recordings, is encouraged. However, in consideration
of the significant cost-differential between the two tests, it is suggested that 3D EEG be
used first, and MEG used when the former is inconclusive or divergent. The MEG method
may be particularly justified in MRI-negative cases where the dipole source is suspected
to be tangential such as rolandic, sylvian or interhemispheric foci, or in postoperative
failures where the EEG fields are likely to be distorted.
Outcome of surgical intervention

There is a paucity of information about postoperative seizure outcome in MRI-negative
pediatric epilepsy patients. In an early report of 75 children with refractory focal epilepsy
undergoing excisional procedures, 59% were seizure-free at 2-year follow-up. Seizure
outcome for the 40 MRI-positive cases was not statistically different from the 35 MRInegative cases [4]. When Engel class I and II outcomes were combined, the MRI-positive
group maintained a slight overall advantage (80% versus 74%). This cohort was a pure
pediatric population as the mean age at seizure onset was 2.8 years and mean age at
surgery was 7.7 years. A much higher proportion of MRI-negative cases were
extratemporal, and 73% of patients underwent extraoperative intracranial EEG evaluation.
Completeness of resection of the epileptogenic zone was the only significant predictor of
surgical success, thus confirming that neither the pathological substrate nor the presence
of a focal MRI lesion are critical variables for postoperative seizure freedom.
In a cohort of purely MRI-negative children, the rate of seizure freedom at 2 years was
44% [5]. Although the rate of seizure freedom was lower than the Paolicchi and
colleagues [4] study, the 44% 2-year seizure-free rate remained stable at 5 years and
decreased only slightly to 38% at 10 years. Thus, long-term seizure freedom is possible in
MRI-negative children with pharmacoresistant focal epilepsy. Completeness of resection
was again found to be the most important variable affecting surgical success; the presence
of convergent interictal spike discharges on scalp EEG also correlated with seizure
freedom.
Comparable rates of seizure freedom were reported in three other pediatric cohorts [9,
26, 28]. The incidence of postoperative seizure freedom ranged between 3650% at time
of follow-up, and the best predictor of seizure freedom was completeness of resection.
Neuropsychological testing obtained pre- and postoperatively revealed no significant
deterioration in overall cognitive status [28]. Scalp-recorded MEG clusters correlated with
a favorable outcome, a finding consistent with the predictive power of interictal
epileptiform discharges [5]. Of some significance, the performance of multiple subpial
transections (MST) either as the sole procedure or in conjunction with excisional
procedures was significantly associated with poorer seizure outcome. This finding likely
reflects the known suboptimal outcome if eloquent cortical regions are found in proximity
to the epileptogenic zone [4].
While the numbers of children with normal or nonspecific MRI scans who undergo
surgical therapy is small, the existing evidence indicates that by using a multimodal
approach, favorable outcomes are indeed possible and that rates of seizure freedom are
comparable to adults. While focal cortical dysplasia is the underlying pathology in the
majority of candidates, outcome is pathology-independent and only depends on the
completeness of resecting the epileptogenic region. Incomplete resections generally lead
to less favorable outcomes, yet, some children may achieve seizure freedom or substantial
reduction of seizure burden and should not be excluded from surgical consideration.
The number of children with refractory focal epilepsy representing the MRI-negative
cohort is unknown but it is important to increase awareness of the promising outcomes of
resective surgery to promote early referrals and optimize the benefit of surgical
interventions.
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Chapter 18 Surgical approaches and techniques in MRInegative focal epilepsy

Sumeet Vadera and William Bingaman
Introduction
There are approximately 50 million people in the world affected by epilepsy. Chronic
epilepsy is associated with devastating socioeconomic and psychosocial consequences as
well as increased risk of injury and sudden death for the patient1. In patients with clear
lesions on magnetic resonance imaging (MRI), several surgical series have shown that
complete resection of the abnormality and damaged surrounding cortex is one of the most
important prognostic factors associated with seizure freedom postoperatively and may
lead to a better long-term outcome14. Patients with MRI-negative epilepsy pose a much
greater challenge to the neurosurgeon, and the work-up and surgical treatment require a
greater reliance on invasive epilepsy mapping techniques. It is also important to note that
seizure-free outcomes in patients with MRI-negative epilepsy may not be as good as for
lesional epilepsy56.
Patients with MRI-negative epilepsy often undergo an extensive work-up, which may
include invasive intracranial electrode monitoring, to better localize the epileptogenic zone
(EZ). Because the preoperative work-up is so important in evaluating patients with MRInegative epilepsy, we will discuss each of the methods that may be used by the epilepsy
team to aid with the localization of the EZ. We will then describe the most relevant
surgical techniques and approaches used to treat these challenging patients, and finally, the
most common histopathologies will be discussed.
Preoperative work-up
During the preoperative work-up, all epilepsy patients considered to be surgical candidates
should undergo thorough history and physical exam, a video-electroencephalography
(vEEG) study, neuropsychological testing, and high-resolution epilepsy protocol 3-Tesla
MRI (Table 18.1). Other tests that may be performed include 18-fluorodeoxyglucose
positron emission tomography (18-FDG-PET), magnetoencephalography (MEG),
difference in single photon emission computed tomography studies (subtraction SPECT),
functional MRI, or sodium amytal intracarotid testing (WADA). Whether these tests are
performed or not depend on the patients semiology, imaging, and EEG findings.
Table 18.1 Sequences obtained during epilepsy-protocol MRI
Axial
Coronal
Sagittal
T2-weighted
T1/T2-weighted
Fluid attenuated inversion

recovery (FLAIR)
Magnetization prepared rapid

gradient echo (MPRAGE)
Gradient echo (GRE)
FLAIR
T1weighted
Additionally, patients should be discussed in a multidisciplinary epilepsy management

conference, which includes neurosurgeons, epileptologists, neuroradiologists,
psychiatrists, and neuropsychologists to incorporate a variety of different management
opinions and options.
With regards to surgical management options in the setting of MRI-negative epilepsy, if
all available studies do not clearly localize to a specific region, or if the lesion is close to
eloquent cortex, patients are then further evaluated with intracranial subdural grid and
depth electrodes (SGD) or stereoelectroencephalography (SEEG). Placement of electrodes
is individualized based on the patients clinical, electrophysiologic, and neuropsychologic
data. These electrodes are able to localize the hypothetical EZ, as well as map eloquent
cortex in the comfort of an extraoperative setting. After implantation, patients remain in
the epilepsy monitoring unit with the electrodes in place until they generate enough
seizures to localize the ictal onset zone. This usually lasts between 7 to 10 days, but
patients should be counseled that it might take much longer.
Preoperative evaluation
The epileptogenic zone is simply defined as the region of the brain that generates seizures.
The complete removal of this area is required for seizure freedom after epilepsy surgery7.
To date, there is no single test or imaging study that can adequately identify the EZ. The
preoperative evaluation includes video-electroencephalography (vEEG), interpretation of
seizure semiology, and imaging studies, and this information is used to create a hypothesis
of the EZ. When the noninvasive data is concordant, a surgical plan can be generated.
When the data are not concordant, or an MRI lesion is absent, invasive intracranial
recordings are often necessary to gain ictal onset and functional information to further
guide a possible surgical intervention.
MRI
Despite several advancements in the quality and sequences available with MRI, there are
still many patients that are found to have MRI-negative epilepsy7. Studies have shown that
an estimated 20% of patients with medically refractory MRI-negative focal epilepsy will
be found to have lesions on higher-field (3-Tesla and above) MRI scans1,7,8. For this
reason, the authors believe that it is appropriate to reimage patients with MRI-negative
epilepsy on higher-field MRI scanners when possible. Most centers have specific
sequences which are performed on all epilepsy patients (epilepsy protocol) which
usually include sagittal T1, axial T2, axial and coronal fluid attenuated inversion recovery
(FLAIR), and coronal magnetization prepared rapid gradient echo (MPRAGE) sequences
(see Table 18.1 for complete list). Contrast is not routinely administered unless neoplastic
disease is suspected.
It is also very important that an experienced neuroradiologist examine the MRI scans
because subtle lesions (cortical dysplasia) are common and can be easily missed by the
untrained eye. The most common histopathologic abnormality identified in patients with
MRI-negative epilepsy is focal cortical dysplasia (FCD) and is reported to be invisible on
standard imaging studies in approximately 30% of cases79.
Positron emission tomography

Positron emission tomography (PET) studies utilize the radioactive tracer 18fluorodeoxyglucose (18-FDG) to quantify cerebral metabolism, usually during the
interictal state. The interaction between negatively charged particles in the brain and the
positively charged 18-FDG particles is detected by the PET scanner. The epileptic focus is
often incorporated within areas of hypometabolism on PET scans, and therefore this study
can be very helpful in surgical planning in MRI-negative epilepsy cases (Figure 18.1).
One drawback to PET scans is that the areas of hypometabolism often overestimate the
location of the EZ9. Nevertheless, in the 1990s (preMRI), Dr. Chugani showed that in
patients with infantile spasms, PET was able to effectively identify areas of FCD and
guide surgical treatment when the MRI showed no lesion10,11.
Figure 18.1 A PET study showing mild reduction in FDG activity in left lateral frontal
lobe compared with the right side, in a patient with MRI-negative epilepsy.
Single photon emission computed tomography

Single photon emission computed tomography (SPECT) studies utilize intravenous
injection of radiolabeled tracers at the onset of the seizure to evaluate cerebral blood flow.
Increased perfusion (compared to the interictal state) suggest ictal onset, while
surrounding areas are often noted to have postictal suppression of perfusion (Figure 18.2).
Difficulties in obtaining radioactive tracer, the logistics of injecting the patient at seizure
onset, and costs associated with the test make SPECT an unrealistic part of the routine
preoperative evaluation.
Figure 18.2 Ictal hyperperfusion in right posterior orbitofrontal region on subtraction

SPECT study.
Magnetoencephalography
Magnetoencephalography (MEG) studies evaluate magnetic dipoles generated by cerebral
activity in normal and abnormally functioning brain tissue. The MEG method has some
benefits over standard scalp EEG in that it is able to evaluate dipoles that arise in deeper
structures and dipoles that are not orthogonal to the skull. The dipole maps that are
generated can be useful in defining the irritative zone. This is most useful when the
dipoles are found to be close to one another, which is labeled a cluster. A cluster is defined
as at least five dipoles with less than 1 cm between adjacent sources12. The limited
availability of MEG has made this option more useful for research purposes and less
popular within the clinical realm. In patients with MRI-negative epilepsy, this can be a
useful supplemental test, especially when a cluster is noted that is concordant with other
functional imaging studies.
Several studies have shown that in MRI-negative epilepsy, resection of clusters, or
clusterectomy, improves postoperative seizure-free outcomes13. In our institution, we
recently evaluated the outcomes in patients undergoing resective surgery for epilepsy; we
found a statistically significant correlation between seizure freedom and the complete
removal of MEG clusters in patients undergoing extratemporal lobe resections. This was
independent of underlying etiology and presence or absence of a lesion.
Subdural grid and depth (SGD) electrode implantation

The main implantation strategy is designed to prove the hypothesis formed during the
epilepsy management conference and is based upon semiology, vEEG, and any other
additional tests required (PET, SPECT, MEG). Therefore, the area covered by subdural
grids and depth electrodes is usually decided prior to the commencement of surgery based
upon the preoperative work-up. A volumetric MRI scan is performed the day prior to
surgery with fiducials placed along the scalp to allow for coregistration of the MRI to the
patients anatomy intraoperatively.
A craniotomy is performed around the area of interest and the dura is opened to allow
for placement of the grids and depths. Stereotactic guidance is used to assist with the
placement of the depth electrodes in the region of interest within the deeper structures of
the brain (i.e., hippocampus, amygdala, cingulate gyrus) and the grids are then laid across
the cortex to cover the areas of interest as well as eloquent cortical areas. All leads are
sutured down to the dural edges to prevent them from being dislodged while the patient is
being monitored.
Postoperatively, patients undergo thin-cut CT scans and AP and lateral skull X-rays to
better visualize the location of the electrodes with respect to anatomical landmarks. These
steps are all performed to assist the epileptologists with interpreting the EEG data and
mapping areas of eloquent cortex. It also helps the surgeons decide where to safely plan
the resection at a later time.When the patient has been monitored for a sufficient amount
of time for the ictal onset zone to be mapped, the patient will then undergo cortical
stimulation, at which point the electrodes are individually stimulated and electrodes with
underlying cortical functions are noted. A map is created that incorporates both the
functional and ictal onset zones. The options available for resection are then discussed
with the patient prior to the second surgery, at which point electrodes are removed and a
tailored resection is performed. In performing the resection, it is important to include ictal
onset electrodes, early-spread electrodes, and electrodes with frequent interictal spiking
when safe to do so. The surgeon must also utilize tactile feedback intraoperatively and
respect the functional cortex limitations (i.e., Take what you can theory).
Although medically refractory epilepsy patients with MRI-negative focal epilepsy are a
challenging group to treat, a recent study from our institution looking at MRI-negative
extratemporal epilepsy undergoing invasive electrodes showed a 42% seizure-free rate at 2
years19. This rate is comparable to what is reported in the literature. For this reason, it is
still important to consider surgery in this difficult-to-treat group of patients.
Stereoelectroencephalography (SEEG)
This method allows for individualized implantation of intracerebral electrodes designed
according to the individual patients electrophysiology, anatomy, and semiology. Among
the areas that can be explored with SEEG electrodes are the anatomic lesion (if present),
the structure(s) of ictal onset, and the possible pathway(s) of propagation of the seizures
(functional networks). The desired targets are accessed using commercially available
depth electrodes, and implantation is performed using conventional stereotactic technique
through 2.5 mm drill holes. Implanted electrodes have a variable number of contacts (four
to 16), depending on the location and the desirable recording space (distance from target
to dura). The SEEG electrodes are usually placed with a straight lateral trajectory but also
can be implanted using oblique orientations. This flexibility allows for intracranial
recording from lateral, intermediate, or deep cortical and subcortical structures in a threedimensional arrangement. After placement, the patient may be transported directly to the
epilepsy monitoring unit and treatment progresses in a similar manner as for the subdural
electrode patient. A recent study from our center showed that in patients undergoing SEEG
with a negative preoperative MRI, 57% were seizure-free at 1 year, and so this is certainly
another viable option when utilized in the correct patient population20.
Temporal lobe surgery

Temporal lobe epilepsy is the most common cause of complex partial seizures in adults,
and mesial temporal sclerosis (MTS) is the most common pathology14. Postoperative
seizure-free outcomes have been quoted in the literature as ranging from 7090% seizurefree after temporal lobectomy in this group1415. As discussed previously in this chapter,
patients with clear lesions on MRI have better postoperative seizure-free outcomes than
those without a lesion. It is also important to note that the presence of hippocampal
atrophy lessens the risk of postoperative memory deficits, whereas normal hippocampal
volume is associated with higher risk for postoperative deficits, especially in dominant
lobe resection.
When determining a surgical strategy in patients with MRI-negative epilepsy that
localizes to the temporal lobe, there are several factors that should be considered.
One of the most important factors to consider is where language and verbal memory
reside. If the patient is right-handed, there is a high likelihood that verbal memory and
language areas lateralize to the left hemisphere. If this patient also has epilepsy that
appears to lateralize to the left temporal lobe, the risk of neuropsychological decline
following surgery must be estimated. Generally, formal neuropsychological testing, fMRI,
and/or WADA testing may be performed to evaluate language lateralization and
verbal/visual memory status. If these studies show that the patient is left hemisphere
dominant, then invasive electrode implantation may be used to better localize the ictal
onset zone and predict the impact on the patients language and memory. On the other
hand, if the patient has temporal lobe epilepsy that localizes to the right hemisphere, then
an aggressive resection of the complete lateral temporal lobe and mesial structures may be
performed with minimal risk to language and memory.
Extratemporal surgery
In adults, extratemporal lobe epilepsy is not as common as temporal lobe epilepsy. As
previously discussed, the underlying pathology is often cortical dysplasia and this often
results in a diffuse epileptic focus, which can be difficult to visualize and resect entirely.
Seizure-free outcomes in extratemporal lobe epilepsy are also not as favorable as for
temporal lobe epilepsy3,6. Surgical planning in these challenging cases almost always
mandates implantation of invasive electrodes to define the ictal onset region. When the EZ
is suspected to involve eloquent cortex, subdural electrode application allows for cortical
stimulation and functional mapping.
The following clinical case helps to illustrate the work-up and treatment options related
to patients with MRI-negative epilepsy. The patient was a 20-year-old right-handed male
with a history of epilepsy that began at the age of 11. He had no past major medical
disorder, nor risk factors for seizure development. His developmental milestones were
normal, and he had a normal neurological exam. The patient described a somatosensory
aura that involved his left arm and face, which then progressed to an akinetic seizure. The
patient had seven to eight seizures per day, and had failed eight different antiepileptic
drugs. Most seizures were focal and involve only the left arm and face but they
occasionally evolved into generalized tonicclonic seizures.
The patient was monitored in the epilepsy-monitoring unit with video-EEG and was
found to have clinical seizures with the inability to move the left arm, followed by a
change in facial expression where he would appear stunned while attempting to reposition
the left arm using the right. His larger seizures involved face pulling towards the left with
head and eye deviation to the left followed by initial flexion, then extension of the left
arm, and then flexion of the right arm and leg. Scalp EEG seizures involved the right
frontocentral region (F4/C4) with subsequent spread to also involve the right
centroparietal leads.
A 3-Tesla MRI brain scan study was normal; PET showed mild symmetric
hypometabolism involving both temporal poles, and SPECT showed right posterior frontal
hyperperfusion; MEG showed no interictal spikes but patient did have one clinical seizure
while in the MEG machine and a spike cluster was noted in the right frontocentral region.
At this point the patients seizure semiology was in agreement with a regional localization
to the right frontocentral region of the brain. Whereas the MRI was nonlesional, the ictal
SPECT, MEG, and scalp EEG were in agreement with the proposed hypothesis of
localization of the seizure onset zone at the right frontocentral region. Surgical decision
making at this point involved localizing the region of ictal onset and defining its
relationship to functional cortex. Subdural grid and depth electrodes were recommended
to accomplish these goals and after informed consent and discussion about the not
insignificant risks of resection of the perirolandic cortex, the electrodes were implanted to
target the right dorsolateral and mesial perirolandic, premotor and parietal cortex, and
depth electrodes were placed in the precentral and posterior frontal regions to evaluate the
areas of interest (Figure 18.3a).
Figure 18.3 (a) Intraoperative photograph demonstrating subdural grid placement on the
cortex. (b) Functional map showing functional cortex and ictal and interictal regions. (Red
rectangle ictal onset zone; yellow rectangle location of nonclinical seizures; orange
ovals interictal spikes; CS clinical seizure induced; green quadrant circles related
to function in a limb, left upper extremity in this case; meaning of full green dots not
determinable from patients records.)
After implantation, the patient underwent routine head CT scan and AP/lateral skull Xrays and was admitted to the neuro-stepdown unit for close observation overnight. The
patient was then transferred to the epilepsy monitoring unit the next morning for seizure
monitoring. The patient was observed for 7 days during which he had 7 clinical seizures
localizing to the right posterior middle and inferior frontal gyri with rapid spread to the
perirolandic cortex (Figure 18.3b). The patient also underwent cortical mapping during
this period.
After discussion of risks and benefits of the procedure, the patient underwent cortical
resection of the posterior aspect of the middle and inferior frontal gyri without
complication. The patient was discharged home in a stable condition 2 days later. On the
6-month follow-up visit, the patient was noted to be seizure-free. Pathology was notable
for mild focal architectural disorganization consistent with malformation of cortical
development.
Histopathology
Interestingly, 3050% of specimens obtained in MRI-negative epilepsy surgeries are
found to harbor lesions on histopathological examination3,8. The most common
histopathological abnormality identified is focal cortical dysplasia (FCD)16. Although
these lesions are difficult to discern from normal tissue by appearance, they often have a
very firm or rubbery texture that can be appreciated intraoperatively by the surgeon
performing the resection. This characteristic can be very helpful to help the surgeon gauge
the extent of resection. Oftentimes, abnormalities in the area of the resection can be noted
upon re-review of the preoperative imaging. As discussed earlier, neuroradiologists and
neurosurgeons skilled at interpreting epilepsy-protocol MRI studies may help to spot these
subtle findings and potentially simplify the surgical planning. Because FCD is the most
common histopathological abnormality noted in patients with MRI-negative epilepsy, it is
important to understand these lesions and their classification. The diagnosis is broad and
includes multiple variations that can range from extremely subtle to obvious on MRI.
These lesions are epileptogenic and always involve disorganization and architectural
abnormalities of the cortex. The transmantle sign has been described as a hyperintense
funnel-shaped extension of the lesion down towards the ventricle, which is thought to be
caused by the migration of these aberrant cells along radial glial processes (Figure 18.4).
MRI-negative epilepsy typically involves type I or IIa and is challenging to treat because
of the potential for other regions of the cortex outside of the current EZ to be dysplastic,
and therefore potentially epileptic in the future. This may explain some of the late
recurrences of epilepsy in patients initially seizure-free for years following treatment of
the original EZ17,18.
Figure 18.4 Transmantle sign (white arrow) extending towards the left lateral ventricle.
The International League Against Epilepsy (ILAE) proposed an updated classification
scheme of FCD in 2011, which is the most widely accepted16 (Table 18.2).
Table 18.2 Updated International League Against Epilepsy (ILAE) classification
of focal cortical dysplasia16
FCD type I (isolated)
Ia
Focal cortical dysplasia with abnormal radial cortical lamination
Ib
Focal cortical dysplasia with abnormal tangential cortical lamination
Ic
Focal cortical dysplasia with abnormal radial and tangential cortical

lamination
Type II (isolated)
IIa
Focal cortical dysplasia with dysmorphic neurons
IIb
Focal cortical dysplasia with dysmorphic neurons and balloon cells
IIc
Cortical lamination abnormalities adjacent to vascular malformation
IId
Cortical lamination abnormalities adjacent to any other lesion acquired

during early life, e.g., trauma, ischemic injury, encephalitis
Type III (not otherwise specified)

III
If clinically/radiologically suspected principal lesion is not available for

microscopic inspection
Conclusion
The surgical treatment of MRI-negative epilepsy is challenging and requires the epilepsy
team to utilize a variety of techniques to better localize the EZ prior to resection. Patients
with MRI-negative epilepsy should be evaluated by an experienced neurosurgeon and
epilepsy team in a center that is well versed in the treatment of MRI-negative epilepsy. It
is also very important to have a frank discussion with the patient regarding what to expect
after surgery, as postoperative outcomes have been shown to be less favorable than in
patients with lesional epilepsy.
References
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patients with MRI-negative temporal lobe epilepsy. Epilepsia. 2010 Nov;51(11):2260
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3. Rgis J, Tamura M, Park MC, et al. Subclinical abnormal gyration pattern, a potential
anatomic marker of epileptogenic zone in patients with magnetic resonance imaging
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4. Englot DJ, Han SJ, Berger MS, et al. Extent of surgical resection predicts seizure
freedom in low-grade temporal lobe brain tumors. Neurosurgery. 2012 Apr;70(4):921

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focal positron emission tomographic abnormalities in children with intractable epilepsy.
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using magnetoencephalography-guided neuronavigation in epilepsy surgery in pediatric
patients. J Neurosurg (Pediatrics 2). 2005;102:18796.
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nonlesional epilepsy. Epilepsia. 2011 Jul;52(Suppl 4):1014.
14. Vale FL, Effio E, Arredondo N, et al. Efficacy of temporal lobe surgery for epilepsy
in patients with negative MRI for mesial temporal lobe sclerosis. J Clin Neurosci. 2012
Jan;19(1):1016.
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Feb;53(2):3428.
16. Blmcke I, Thom M, Aronica E, et al. The clinicopathologic spectrum of focal
cortical dysplasias: a consensus classification proposed by an ad hoc Task Force of the
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17. Jehi L, Sarkis R, Bingaman W, et al. When is a postoperative seizure equivalent to
epilepsy recurrence after epilepsy surgery? Epilepsia. 2010 Jun;51(6):9941003.
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determinants following posterior cortex epilepsy surgery. Epilepsia. 2009
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Chapter 19 Histopathology findings in MRI-negative focal

epilepsy
Ingmar Blmcke and Roland Coras
Most surgically resected epileptogenic brain lesions are detectable by high-resolution MRI
at 1.5 or 3 T, such as long-term epilepsy-associated tumors and hippocampal sclerosis of
malformations of cortical development (MCD), and MRI visibility is a favorable predictor
of postsurgical seizure control. However, recent studies suggest that comparable seizure
control can be achieved after epilepsy surgery in patients with MRI-negative TLE, with
55% of patients remaining free of disabling seizures after a mean follow-up of 2 years [1]
to 5.8 years [2]. In this chapter, we will discuss the spectrum of histopathological changes
that can be observed in tissue specimens obtained from patients with MRI-negative focal
epilepsy, with particular emphasis on the cellular architecture that hides such lesions from
detection with currently available MRI protocols. However, neither the European Epilepsy
Brain Bank nor the German Neuropathology Reference Center for Epilepsy Surgery allow
us yet to reliably retrieve clinical information of how many operated patients were
reported MRI negative. The increasing interest in this matter will help us to close this
knowledge gap in the near future.
MRI-negative FCDs
The most prominent example for a structural brain abnormality identifiable in MRInegative focal epilepsies may be focal cortical dysplasia (FCD) type IIa (Figure 19.1);
FCDs represent a composite group of cortical malformations [3], which are increasingly
recognized as a frequent morphological substrate for severe therapy-refractory epilepsy in
children and young adults. However, not all FCD variants can be reliably detected by
high-resolution MRI [4; 5]. The term FCD was originally coined by Taylor and colleagues
in 1971 describing ten patients with microscopic evidence for dysmorphic neurons [6]. In
half of these patients, the authors also described balloon cells. The current ILAE
classification separate both variants into FCD type IIa (dysmorphic neurons, no balloon
cells) and IIb (dysmorphic neurons and balloon cells) [3]. Yet, there is no distinguishing
evidence for the clinical course, etiology and molecular-genetic or biological
pathomechanisms of type IIa and IIb FCDs [5]. Furthermore, dysmorphic neurons are very
similar between both variants and cannot be distinguished by morphometric analysis [7]. It
is solely the presence of balloon cells, accompanied by lack of myelin and
oligodendrocytes that makes the difference between the two subtypes of type II FCDs.
Figure 19.1 MRI findings in histopathologically verified FCD type IIa. Presurgical MRI
findings (T2) at 1.5 T (A) and 3 T (B) and postsurgical 3 T (C) in a patient with
histopathologically classified FCD type IIa. D: NeuN staining revealed an abnormal
layering with intermingled dysmorphic neurons. E: Dysmorphic neurons always present
with an abnormal accumulation of neurofilament proteins (SMI32 staining). Red dotted
line in C indicates the extent of resection in the left temporal lobe. Roman numbers in D:
cortical layers. Insets in D and E: higher magnification showing a typical dysmorphic
neuron. Scale bar in E = 500 m; applies also to D. Scale bars in insets in D and E = 50
m.
We recently studied a cohort of 52 FCD patients using the 2011 classification of the
International League Against Epilepsy (ILAE) and systematically analyzed those
histopathological characteristics which could also be assessed on MRI, i.e., cortical
thickness, graywhite matter boundary, myelination and cellular composition of FCD
subtypes [7]. In contrast to existing data, cortical thickness was significantly increased in
both FCD type II variants, with a distinct loss of myelin content specifying the
transmantle sign of FCD type IIb [7]. Presence of the transmantle sign has been
suggested to allow complete resection of FCD type IIb and achieve seizure control in up to
80% of patients [5]. In contrast, FCD type IIa is less frequently encountered and more
likely to escape visually guided MRI reading, even in highly experienced centres [5].
Abnormally increased cortical thickness in FCD type IIa lesions, as well as abnormal
graywhite matter boundary due to increased neuronal heterotopia, could be detectable by
systematic use of modern morphometric post-processing MRI protocols [8]. However,
cortical thickness is always difficult to assess on MRI unless very thin sections are
acquired as a volumetric data set. Prospective imaginghistopathology correlations will
be, therefore, essential to further improve our knowledge of disease-specific cellular
components and their corresponding MRI signaling abnormality.
Another challenge in presurgical MRI diagnosis concerns FCD ILAE type I. Systematic
histopathological analysis identified a smaller cortical ribbon with higher neuron densities
and persisting neuronal microcolumns in FCD type Ia [7, 9, 10]. The 2011 ILAE
classification introduced this new FCD type Ia because it likely represents a specific
clinicopathologic entity [3]. Patients with such FCD are characterized by early seizure
onset, severe psychomotor retardation and mild hemispheric hypoplasia without MR
visibility of any other lesion. Drug resistance is frequent and surgical resection-achieved
seizure control in only 21% of children in an initial series addressing this isolated FCD
subtype [11]. With increasing diagnostic and neurosurgical experience, however, the
prospect for this peculiar group of young patients to become seizure-free has improved to
almost 50% of cases [12]. Indeed, the vast majority of FCD type I patients from our
European Epilepsy Brain Bank (EEBB) series belong to this clinicopathologic entity.
Neuropathological hallmarks include abnormal cortical layering affecting both radial
migration and maturation of neurons. This aberrant pattern resembles those
neurodevelopmental minicolumns described by the radial unit lineage model [13]. A
minicolumnar organization of the neocortex, especially in somatosensory regions
representing visual and auditory fields and the magnopyramidal region of the temporal
lobe, has been described in normal and diseased brain [14; 15; 16; 17]. However, to date,
there are no molecularbiological nor genetic data available to clarify or even suggest the
underlying pathomechanism in this difficult-to-treat-epileptic disorder. In contrast to FCD
type Ia, FCD ILAE type Ib presents with abnormal cortical architecture compromising its
horizontal layering. Neither specific imaging findings, clinical courses nor histopathology
patterns have been systematically described for this rare disorder [7], and it is most likely
that current MRI protocols will not reliably detect this FCD.
MRI-negative hippocampal sclerosis

Five to 10% of histopathologically confirmed TLE patients with hippocampal sclerosis
(HS) do not present with classical MRI abnormalities, which include hippocampal atrophy
and increased intensity on T2-weighted or FLAIR images (Figure 19.2). This results from
the heterogeneous presentation of clinicopathological HS subtypes, i.e., including a rare
and atypical variant with predominant neuronal cell loss in CA4 only, also known as HS
ILAE type 3 [18, 19].
Figure 19.2 MRI findings in histopathologically verified type 3 of TLE-HS. A:

Presurgical T2 MRI finding (3 T) in a TLE patient with histopathologically classified
hippocampal sclerosis on the right side (white arrow). Here, volumetric loss was virtually
not detectable. B: NeuN staining confirmed the diagnosis of HS ILAE type 3 showing a
neuronal cell loss predominantly affecting sector CA4 [19]. CA1CA4: Sectors on the
cornu ammonis. DGe: External limb of the dentate gyrus. DGi: Internal limb of the
dentate gyrus. Scale bar in B = 1000 m.
Hippocampal sclerosis is the most frequent structural brain lesion encountered in adult
patients with drug-resistant epilepsy, and surgical resection is an established treatment
modality [20] offering postoperative seizure freedom within the first 2 years in
approximately 6080% [21; 22; 23; 24; 25; 26]. Clinical studies define mesial temporal
lobe epilepsy, however, as a heterogenous entity with different etiologies and clinical
histories [27; 28; 29; 30]. Neuropathological investigations have also described different
patterns of neuronal cell loss within hippocampal subfields [31; 32; 33; 34; 35; 36; 37; 38;
39; 40]. The earliest neuropathology study in epilepsy patients dates back to 1825, in
which Bouchet and Cazauvielh described a hardened and shrunken hippocampus in
autopsy brains from patients with clinical history of epilepsy [41]. In 1899, Bratz made
available a detailed description of unilaterally atrophic hippocampus, illustrating severe
loss of pyramidal neurons and gliosis in CA1, less severe neuronal loss in the hilus of the
dentate gyrus and adjacent sector CA3, and preservation of neurons in the CA2, subiculum
and the granule cell layer of the dentate gyrus [41]. In 1966, Margerison and Corsellis
defined two types of hippocampal damage [18]. One was similar to that from Bratz [42]
with severe neuronal loss in CA1 and CA4, and sparing of CA2. The other pattern was
characterized by neuronal loss confined to the CA4 region or end-folium, termed endfolium sclerosis. Since then, atypical HS variants have been histopathologically
confirmed and can be detected in up to 16% of all surgical TLE cases [33, 39, 39, 40].
With the continuous progress of imaging techniques in terms of field strength and postprocessing, it can be expected that histological knowledge of HS subtypes will translate
into clinical protocols helping to recognize such atypical HS variants already during the
presurgical clinical monitoring. Indeed, the degree of atrophy has been shown to correlate
with the severity of neuronal loss within hippocampal subfields as determined by various
pathological gradings, including Wylers classification [43, 84]. However, the limited
resolution of current clinical protocols still precludes a direct visualization of hippocampal
subfields on MRI.
Another intriguing issue remains the association between HS and FCD, classified as
FCD ILAE type IIIa [3]. Despite the many published results, neither a distinct etiology nor
a clinicopathological phenotype for the association between HS and FCD IIIa has been
identified, which elicits continuous debates about the issue [44]. Notwithstanding, HS is
frequently associated with other pathologies [45], and electroclinical as well as imaging
abnormalities in TLEHS patients often extend beyond the hippocampus, suggesting a
more widespread substrate for the generation or persistence of seizures [46; 47; 48; 49;
50]. Ipsilateral temporal atrophy with temporo-polar gray/white matter blurring can be
visible on MRI in up to 70% of TLEHS patients [51; 52; 53]. It was often regarded as a
sensitive radiological FCD marker, but a recent study directly correlating 7T MRI with
histopathology including electron microscopy revealed severe and patchy myelin loss in
temporal white matter as underlying substrate of the abnormal MRI signal, rather than any
kind of cortical/subcortical dysplasia [54]. In fact, histopathologically proven cortical
abnormalities in TLE-HS patients are rare and cannot be reliably detected by current MRI
protocols. In only 10% of surgical specimens from temporal lobe of HS patients, an
abnormal band of small neurons can be observed in the outer part of neocortical layer II
[55]. This pattern presents with severe neuronal cell loss in layers II and III and laminar
astrogliosis. There is no correlation between this FCD IIIa variant and MRI findings [56,
57]. Small lentiform nodular heterotopia can be identified as another structural
abnormality in the temporal lobe of patients with TLEHS, which also remain undetected
by MRI [58]. However, we do not have evidence for the dysplastic nature of these MRI
invisible HS-associated lesions nor for their pathophysiologic impact to trigger seizures.
Several aspects argue rather for a common etiology between HS and FCD type IIIa.
Patients from both groups have a similar age at onset and a similar history of febrile
seizures as an initial precipitating injury [59]. No other clinical differences have yet been
identified between HS and HS/FCD type IIIa cases [54]. Accordingly, postsurgical
outcome is similar in patients with HS only compared to HS with FCD type IIIa [60].
MRI-negative abnormalities in white matter

Increased numbers of heterotopic white matter neurons can be frequently encountered in
epileptic brain tissue (Figure 19.3), and was described in children and adults with
hippocampal sclerosis, FCDs as well as in patients with primary generalized epilepsy [61,
62, 63, 64, 7]. However, this cellular abnormality is usually not visible at the MRI level
(Figure 19.3A) and does not account for a blurred white-gray matter boundary visible in
almost 70% of patients with TLEHS [54]. Heterotopic neurons in the white matter even
represent a physiological feature of the temporal lobe [65, 66, 67]. Their significant
increase and abundance in epileptic tissue suggest, however, an association with chronic
epileptic activity, i.e., seizure-induced neurogenesis [68] or may point to early
disturbances in the architectural development of the cortex and white matter [65].
According to the current ILAE classification of FCDs, increased numbers of heterotopic
neurons in white matter location should be neuropathologically diagnosed as a mild form
of cortical malformation (mMCD type II) using Palminis classification system [68], if
occurring as isolated finding without HS, tumors or other principal lesions [3].
Figure 19.3 MRI findings in histopathologically verified mild malformation of cortical

development (mMCD type II). Presurgical (A) and postsurgical (B) MRI findings (T2) at
3 T in a patient with histopathologically classified mMCD type II. NeuN (C) and Map2
(D) stainings reveal a normal thickness of the cortical ribbon without gross architectural
disturbances. Note the blurred gray-white matter boundaries (white arrows in C and D)
and the increased numbers of heterotopic neurons. within the subcortical white matter
(WM). Red dottet line in B indicates the extent of resection in the right temporal lobe.
Roman numbers in C: cortical layers. Scale bar in D = 500 m applies also to C.
On the other hand, MRI abnormalities are frequently encountered in white matter of
epilepsy patients, but usually lack any histopathological counterpart. It rather suggests a
relationship between seizures and transient functional white matter changes. MRI scans
performed early after status epilepticus identify temporary occurrence of brain edema [70,
71], which could also be experimentally induced following kainate injection [72]. In
agreement with these findings, seizure activity induces local vasodilatation and enhanced
cerebral blood flow. Other pathophysiological consequences of seizure activity include
enhanced metabolic activity followed by consumptive hypoxia [73] as well as a transient
rise of intracerebral pressure, which is rapidly normalized via blood autoregulation
mechanisms. The latter can be impaired by hypercapnia which also results in focal
breakdown of the bloodbrain barrier (BBB) and extravasation of protein and liquid into
the brain [74]. Thus, abundance of substances from blood plasma within perivascular
spaces supports severe white matter BBB dysfunction and may directly induce an
epileptogenic focus [75]. Indeed, angiopathic white matter changes with a significantly
enlarged VirchowRobin space have been histopathologically described in human
epilepsy brain tissue [76].
MRI-negative and microscopically nonlesional

In our large European Epilepsy Brain Bank series, about 8% of all specimens were
microscopically reported negative or nonlesional. Microscopy negative cases may result
from off-target neurosurgery or insufficient tissue sampling. However, we will have to
also consider subtle microscopic lesions beyond currently available detection levels.
Another issue of debate remains the presence of reactive astrogliosis, which is a consistent
finding in any epileptogenic brain tissue. To date, astrogliosis is not classified as specific
neuropathologic disease entity. Astrogliosis can be microscopically detected by
immunostaining for glial fibrillary acidic protein (GFAP), and presents with a broad
spectrum of changes ranging from reversible cell hypertrophy with preservation of cellular
domains to long-lasting scar formation with rearrangement of tissue structure [77]. Since
astrogliosis is also common in any other neurological disorders without seizure, we
assume astrogliosis is a consequence of chronic epileptic activity rather than a specific
epileptogenic trigger. This view has been challenged by the many discoveries on
pathophysiological mechanisms elicited by astroglia [78]. As a prominent example, the
molecular phenotype of astrocytes significantly influences neuronal microenvironment
and contributes to increased neuronal excitability [79]. The contribution of astrocytes to
proepileptogenic inflammatory signaling cascades is also well recognized [80]. In
addition, astrocytes are the brains resource for adenosine-kinase, a degrading enzyme for
adenosine [81]. Experimental data showed evidence that any focus of astrogliosis will
create adenosine deficiency, and, thereby, promote a proictogenic microenvironment [82,
83]. Describing and clarifying these diverse cellular reactivity patterns in epileptic tissue
at a clinical diagnostic level, as well as deciphering their epileptogenic cellular and
network properties, represent an intriguing field of translational research in the future.
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Chapter 20 Neuropsychological issues in MRI-negative focal

epilepsy surgery: evaluation and outcomes
Rosana Esteller, Daniel L. Drane, Kimford J. Meador and David W. Loring
History of neuropsychological evaluation in epilepsy surgery

The first epilepsy surgery began in the 1880s at Queen Square and was based solely upon
clinical findings and semiology. Horsleys first case presented with an old depressed skull
fracture, with seizures beginning in the contralateral limbs. Horsleys second case
presented with seizures starting in the left thumb and forefinger. Jackson noted that the
motor activity was identical to the motor response of electrical stimulation of the motor
hand area in primates. At surgery, a tuberculoma was found and removed from the exact
location predicted by Jackson [1].
In the 1930s, Berger first recorded electroencephalograms (EEGs) from humans, and
Foerster employed EEG to guide epilepsy surgery. Soon after, Jasper and Penfield at the
Montreal Neurological Institute (MNI) and Bailey and Gibbs at the University of Chicago
used EEG to identify focal epileptic discharges, which led to the concept that
psychomotor seizures commonly arose from the anterior temporal lobe (TL) and that
resection of this region could control seizures. In 1950, Penfield and Flanigin published
the first case series of anterior temporal lobectomies for the treatment of poorly controlled
epilepsy [2].
In this era, Penfield and Jaspers use of cortical mapping advanced our knowledge of
cortical functions, and allowed tailoring of surgical resections to avoid or reduce
postoperative deficits [3]. Juhn Wada developed the intracarotid amobarbital procedure to
lateralize language function and was invited to the MNI to apply the technique, now
commonly referred to as the Wada test, to epilepsy surgery [4]. Shortly thereafter, patient
HM underwent bilateral TL resections for epilepsy and developed a severe amnestic
syndrome. This case and others, including some with unilateral resections and presumed
damage to the contralateral mesial TL, demonstrated the importance of these structures to
memory. Milner performed detailed neuropsychological testing on HM and other patients,
leading to the routine use of neuropsychology to predict cognitive outcome [5]. Milner
also modified the Wada test to predict postoperative memory outcome [6].
The preoperative epilepsy surgery evaluation involves not only localization of the
seizure onset zone but also of the regions of function and dysfunction [7]. The localization
of function/dysfunction assumes greater importance when no structural abnormality can
be identified. When a structural abnormality is present and consistent with the seizure
onset region, there is not only a higher probability that the seizure focus is in this area, but
also that this region is less likely to be functionally relevant. The assessment of
function/dysfunction has changed over time and continues to evolve, with approaches to
functional assessment including the neurological exam, Wada test, neuropsychological
evaluation, PET, SPECT, MEG, fMRI, evoked potentials, and cortical mapping.
Neuropsychological issues in MRI-negative epilepsy

Magnetic resonance imaging is the most commonly employed neuroimaging modality in
the epilepsy surgery evaluation [8]. It allows the identification of the epileptogenic lesion
when present, and can be used in parallel with other diagnostic modalities to aid in
localizing the epileptogenic zone. MRI-negative, normal MRI, and nonlesional epilepsy
are equivalent ways to characterize patients without observable lesions on high-resolution
MRI. These patients generally include those denoted as cryptogenic or idiopathic TL
patients with no mesial temporal sclerosis (MTS) [9].
Anatomical versus functional integrity

Patients with medically refractory epilepsy are at risk for gradual neuropsychological
deterioration, poor academic performance, decreased occupational success, pain disorders,
neurobehavioral conditions, and reduced quality of life [1013]. Temporal lobe epilepsy
(TLE) is the most common epilepsy form amenable for surgical resection [14]. Patients
undergoing anterior temporal lobectomy (ATL) have a 1-year postsurgical seizure freedom
rate in the order of 65% to 77% [15, 16]. Seizure freedom rates at 10-year postsurgical
follow-up have been reported to be 27% and 66% for frontal and TLE, respectively [15
17]. Wide variations in seizure freedom rate have been reported for nonlesional MRI
patients, ranging from 18% to 63% [18, 19]. A positive MRI is a consistent predictor of
favorable seizure outcome after ATL.
High-resolution MRI is used presurgically to identify structural brain abnormalities.
MRI lesions are often in the area of seizure onset, and generally correlate with the
dysfunctional region. However, around one-third of patients undergoing ATL have
negative MRI findings [20, 21]. As clinical lesions are known to alter normal brain
functions, negative MRI findings suggest greater functional brain integrity, and are
associated with a poorer prognosis after resective surgery [18]. The presurgical functional
integrity of the tissue to be resected is also a strong predictor of postsurgical memory
deficits following ATL [22]. Besides MRI-negative results, other indicators of presurgical
functional integrity of the temporal region to be resected include greater activation on
fMRI during memory tasks, a lack of significant asymmetry in TL activation on FDG-PET
[23], and intact memory on presurgical neuropsychological assessment or Wada test [24].
Memory decline is the most frequently reported deficit in TLE patients after resective
surgery. Patients with a language-dominant TL seizure focus are at risk for auditory/verbal
memory deficits, whereas those with a nondominant TL seizure focus may display visual
memory deficits [25, 26]. Deficits in naming ability (word-finding, naming to description,
confrontational naming) and semantic fluency are also frequent in patients with dominant
TL seizures [27, 28]. Recent research suggests these deficits are much more pronounced
when sampling a broader range of object type (e.g., names of persons and landmarks are
more impacted than man-made objects) [29, 30]. Patients with average or higher memory
and language scores present higher risk of postsurgical memory/language declines
compared to those with lower scores in these domains [31], although functionally
appreciable declines can continue to occur even in patients with impaired performance on
standardized cognitive measures.
Functional reserve and functional adequacy

There are important contributions from both ipsilateral and contralateral hippocampal
function that are related to postsurgical memory changes. Functional reserve refers to the
capacity of the contralateral hippocampus to support memory after resection of the
ipsilateral mesial temporal lobe associated with the seizure focus, whereas functional
adequacy refers to the functional capacity of the ipsilateral hippocampus that is being
resected [32]. Whereas both factors play a role in determining memory decline following
TL resective surgery, functional reserve of the contralateral side better characterizes the
risk for global memory decline, whereas the functional adequacy of the tissue to be
included in resection better characterizes risk of material-specific memory decline.
Because functional adequacy of the MRI-negative temporal lobe is high, a significant
memory change following resection of the temporal lobe is predictable.
Neuropsychological deficit patterns as an aid to confirm

seizure localization
Due to the lack of abnormality, MRI-negative patients tend to be more challenging for
seizure localization than lesional patients. In such cases, neuropsychological evaluation
can sometimes be useful for confirming the seizure onset zone. The vast majority of
neuropsychological studies have focused on TLE; some have studied frontal lobe
epilepsies (FLE) and very few parietal (PLE) or occipital epilepsies (OLE). Nevertheless,
some characteristic neuropsychological deficit profiles have emerged over time, and can
be used to confirm lateralization or localization of seizure onset in many epilepsy patients.
Tables 20.1A and B summarize some of these findings, and include specific
neuropsychological tests that can be used to determine the presence of cognitive deficits
associated with each brain region (tables adapted from [33, 34]).
Table 20.1A Neuropsychological profiles of presurgical deficits in temporal lobe
epilepsy
Group
Presurgical
deficit
TLE
Language:
naming
(auditory/visual)
Laterality
L. Naming
deficits are
common
(proper nouns
often worse
than common
nouns).
Areas to emphasize
during assessment
of neurocognitive
domain
Naming (e.g.,
visual,
auditory/naming
to description,
categoryrelated)
Common and
Possible tests to
consider
Boston
Naming Test,
Columbia
Auditory
Naming Test,
categoryrelated
Memory and
learning:
Materialspecific
memory deficits
L & R.
Semantic
fluency.
proper noun
semantic
fluency
categories
naming tests
Various
semantic
fluency
paradigms
L. Common
auditory/verbal
memory
deficits.
Auditory/verbal
learning,
memory
retention, and
recognition:
List
learning
tasks
Contextual
memory
Associative
learning
(with both
easy and
hard wordpairs)
Rey Auditory
Verbal
Learning
Test,
California
Verbal
Learning
Test, Verbal
Selective
Reminding
Test
Logical
Memory
Subtest
(Wechsler
Scales),
Reitan Story
Memory
Verbal Paired
Associates
(VPA) subtes
(Wechsler
Scales;
WMS-III
VPA appears
less helpful
than other
versions, as it
eliminated the
easier word
pairs)
R. Sometimes
visual memory
deficits.
Visual learning,
memory
retention, and
recognition:
Simple
geometric
designs
Face recall
Visual
reproduction
(Wechsler
Memory
Scales: older
versions
appear to be
more useful
Complex
visual
designs
Route
learning
Object
recognition:
Categoryrelated object
recognition
deficits
Executive control
processes:
Complex
problem solving
Response
inhibition
for
lateralization
than the 3rd
edition)
Face
recall/hospita
facial
recognition
task
Rey Complex
Figure Test,
MCG
complex
figures
R. Recognition
deficits often
present for
famous
persons/faces,
landmarks, &
animals with
anterior TL
dysfunction.
Object
recognition
Famous faces
test, category
related object
recognition
tests
L & R.
Frequent in
one or more of
these areas
(likely caused
by the
disruption of
temporofrontal
networks
secondary to
onset activity).
Complex
problem solving
Wisconsin
Card Sorting
Test, Brixton
Spatial
Anticipation
Task, Iowa
Gambling
Task
Response
inhibition
Color-word
interference
(Stroop) Test,
Haylings
Test, go/nogo tasks
Generative
fluency tasks
Various
verbal and
design
fluency tasks
L: Left, R: Right.
Table 20.1B Neuropsychological profiles of presurgical deficits in extratemporal
epilepsies
Group
Presurgical
deficit
FLE
Motor:
Motor
functioning
Executive control
processes:
Response
inhibition
Laterality
Areas to emphasize
during assessment
of neurocognitive
domain
Possible tests to
consider
L & R.
Frequent
motor deficits
contralateral to
side of seizure
focus (e.g.,
gross motor
speed, fine
motor speed,
and dexterity)
Handedness
Gross motor
speed
Fine motor
speed
Grip strength
Psychomotor
speed
Edinburgh
Handedness
Scale
Finger
tapping test
Grooved
pegboard test
Hand
dynamometer
WAIS
subtests (e.g.,
symbol
search, digit
symbol)
L & R.
Frequent
deficits
Response
inhibition
Color-word
interference
(Stroop) Test,
Haylings test,
go/no-go
tasks
Complex
problem solving
Wisconsin
card sorting
Test, Brixton
Spatial
Anticipation
Task, Iowa
Gambling
Task
Generative
fluency tasks
visual and
verbal
Controlled
oral word
association
(letter
fluency),
Complex
problem solving
semantic
fluency
paradigms
(cued and
uncued)
Action (verb)
fluency, 5point design
fluency
PCE
(OLE
&
PLE)
Sequencing
tasks
Trail making
test Part B
Attention
L & R.
Frequent
deficits in
primary and
complex
attention
Primary
attention
(auditory &
visual)
Complex
attention
Digit span
forward
(WAIS),
Picture
completion
(WAIS)
Digit span
backwards &
letter
number
sequencing
(WAIS),
trail-making
tests, spatial
span
Constructional
praxis
Frequently
have deficits
on
constructional
tasks due to
poor
organization &
planning
Graphomotor
copying tasks
Assembly tasks
Copying
simple
shapes (e.g.,
Greek cross,
Necker
cube), Rey
Complex
Figure Test
(Copy)
Language
L PLE.
Possible
deficits in
naming,
repetition,
comprehension
R PLE & R &
Naming
Boston
Naming Test
Sentence
repetition test
(multilingual
aphasia
exam)
L OLE.
Unlikely
language
deficits
Visual
processing:
Visuoperception,
acuity, visual
fields
Visualspatial
processing
Sensory
functioning
Token test
(various
versions)
L & R OLE.
Possible
problems
w/visuoperception
L & R OLE.
Sometimes
visual-field
cuts
(particularly
w/mesial
dysfunction
L & R OLE.
Possible
deficits in
color
processing &
object
localization
R PLE. Often
issues
w/visual
spatial
processing
Visuoperception
Visual acuity
and visual field
Visualspatial
Visual Object
Space
Perception
Battery
(VOSP),
facial
recognition
Snellen Eye
chart, visual
field
examination
Judgment of
line
orientation,
VOSP
Categoryrelated object
recognition
tests
L & R PLE.
May exhibit
issues
w/sensory
discrimination
or other
sensoryperceptual
issues
Visual,
auditory, and
tactile acuities
Snellen Eye
Chart
Extinction to
double
simultaneous
stimulation
Tactile form
recognition
reitanklove
Sensory
Examination
L: Left, R: Right, PCE: Posterior cortical epilepsies, OLE: Occipital lobe epilepsies,
PLE: Parietal lobe epilepsies
The natural spread of epileptiform activity through neuronal networks can cloud these
patterns, with neurocognitive deficit patterns often suggesting more widespread

dysfunction than the focal seizure onset zone. Confounding patterns are more likely to be
observed if patients are tested following secondarily generalized seizure spread, and these
deficits can persist beyond the postictal period if they occur with regular frequency and
intensity. In fact, widespread structural and functional changes have been observed in such
patients using PET scans [35], diffusion tensor imaging (DTI) [36], and volumetric studies
[37], with some of these abnormalities improving or resolving if seizure control is
achieved. In such cases, the neurocognitive results will sometimes implicate widespread
regions of dysfunction, yet there are still frequently patterns across tests that can be useful
for sorting out the main area of abnormality. For example, while memory deficits are
common in patients experiencing either TLE or FLE, the pattern of performance across
subcomponents of memory measures can suggest greater involvement of specific brain
regions. Patients with FLE often exhibit more difficulty with organizational aspects of
learning, which can lead to problems with both encoding and retrieval information, while
recognition recall may remain intact [38, 39]. In contrast, TLE patients often do not
improve with recognition cueing. The FLE patients have also been shown to exhibit
problems with release from proactive interference [40], recalling the temporal order of
events [41], and recalling the context of learning [42], errors which can contribute to
heightened false positive identifications and confusion of information across tests.
While both TLE and FLE patients frequently exhibit verbal fluency problems [28], FLE
patients have been shown to exhibit greater improvement when provided with structured
cueing on such tasks [43]. Traditionally, this pattern was thought to demonstrate that their
deficits resulted from organizational aspects of searching memory (access problems)
rather than a primary loss of information (degradation). More recent work is suggesting
that the TLE patients may also have access problems, which results from structural
decoupling of network regions rather than access problems resulting from executive
dysfunction seen in FLE [44]. The TLE patients often exhibit improvement in verbal
fluency tasks that are more dependent on frontal lobe regions if they become seizure-free
(e.g., letter and action verb fluencies), while functions more dependent on TL networks
tend to persist or worsen with surgery (e.g., semantic/category fluency) [45].
Some deficit patterns are more associated with specific regions, such as the tendency
for left TLE patients to exhibit auditory/verbal memory problems and naming deficits and
for right TLE patients to sometimes exhibit visual memory deficits [25, 26]. However, as
noted, many epilepsy patients will experience broader structural and functional deficits,
and will not produce these focal neurocognitive profiles [12]. Left TLE patients with more
mesial dysfunction will frequently exhibit deficits in associational learning [46] and
binding materials that cut across sensory, motor, and cognitive domains (e.g., relating a
name or broader linguistic information with a face or voice). Some evidence suggests that
contextual learning, such as story recall, may be more dependent on lateral TL regions
[47]. Naming has also been more associated with lateral and temporal polar regions [48,
49], although indirect evidence has led some to conclude hippocampal involvement in
naming [50]. Recent studies have found that right TLE patients frequently exhibit
recognition deficits that appear more akin to a limited prosopagnosic condition (e.g., not
recognizing familiar or famous faces, animals, or landmarks) [44, 51]. In addition to the
memory and verbal fluency patterns noted above, FLE patients will also exhibit deficits in
attention, motor processing [52], behavioral problems [53], and broader executive skills
(e.g., metacognition, sequencing, set shifting, response inhibition) [5456].

At present, we lack definitive profiles for preoperative functioning in the posterior
cortical epilepsies and have no prospective postsurgical outcome studies available for this
patient group [33]. Data from other neurological groups with parietal lobe damage suggest
that this group might exhibit deficits involving visuoperception, sensory processing,
visualspatial processing, constructional praxis, and attention at baseline. There are a few
isolated research reports suggesting presurgical deficits in some of these areas (e.g.,
visualspatial processing, sensory functioning) [57]. Presurgical visual field defects
appear to occur more often in OLE patients with mesial rather than lateral OL seizure
onset zones [58]. One very small, retrospective study examining the neurocognitive status
of children with occipital lobe (OL) seizure onset suggests that such patients experience an
elevated rate of scholastic difficulty, psychiatric disorders (i.e., primarily depression), and
cognitive dysfunction involving problems with face processing and making spatial
judgments [59].
Neuropsychological outcomes in MRI-negative patients

Neuropsychological outcomes, in MRI-negative patients have recently gained increasing
attention, although only a few studies have directly addressed this issue. Many older
outcome studies focused exclusively on patients with MTS and excluded more complex
cases (e.g., post-traumatic or postencephalitic epilepsies) in an effort to produce the
cleanest characterization patterns. More recently, the number of MTS cases at most
epilepsy surgical programs has seemed to decrease with a proportional rise in the number
of MRI-negative cases and those with widespread brain changes (e.g., frontal lobe
encephalomalacia in a post-traumatic epilepsy patient with TL seizure onset). From the
limited number of available studies, it appears that MRI-negative TL patients are more
susceptible to cognitive decline following resective surgery than lesional TL patients [19,
31, 60, 61], although some studies have failed to find a significant difference between
these patient groups [62]. These latter studies often involved small sample sizes, differed
in their selection criteria for offering resective surgery to nonlesional patients, and varied
in the neuropsychological measures used.
Based on available data, some general trends in well-localized, nonlesional cases
include: (a) greater declines in verbal memory following left ATL resection [19, 31, 60],
(b) greater declines in visual memory following right ATL procedures [60], and (c) greater
declines in visual confrontation naming performance and semantic fluency in left TL cases
[19].
Helmstaedter and colleagues [60] reported in a small series of individuals with TLE
that MRI-negative patients exhibited better memory functioning at baseline than MRIpositive patients, and declined more significantly following resective surgery. At followup, both groups were found to be comparable in performance level, and it was concluded
that the MRI-negative group had more to lose with surgery. Overall, findings were
strongest for verbal memory decline in left MRI-negative patients, but significant declines
were also observed in visual memory for right MRI-negative patients. In contrast, a
research group in Finland [62] reported that declines in memory were comparable for
lesional and nonlesional TLE patients, although seizure outcome was poorer in
nonlesional patients (40%). This study, however, employed a limited range of cognitive
measures, and it did not include tasks that have been proven to be especially sensitive to
hippocampal function (e.g., associative learning tasks). Using a more sensitive list
learning task, visual confrontation naming and semantic fluency, Bell and colleagues [19]
found greater declines in verbal memory in a small group (n = 40) of MRI-negative TLE
patients. They reported seizure improvement in 60% of their patients, although their study
was retrospective and the choice of candidates may have been more selective than other
studies. Using regression-based measures to identify individual patient declines,
Seidenberg and colleagues [31] found that following left ATL, MRI-negative TLE patients
declined on multiple verbal memory measures, memory for simple geometric designs,
confrontation naming, and verbal conceptualization; whereas declines in MRI-positive left
TLE patients were restricted to the ability to learn hard word-pair associations. Patients
undergoing right ATL without structural MRI abnormalities demonstrated decline in
memory for simple geometric designs, whereas right ATL patients with MRI abnormalities
demonstrated no significant postoperative change.
Knowledge of cognitive outcome following surgery in extratemporal lobe epilepsies is
primarily restricted to FLE. Moreover, nonlesional MRI status has not been systematically
studied as a predictor of outcome in any of the extratemporal epilepsies.
Although there is not a great deal of postsurgical data available for FLE, there is
evidence that both motor and neurocognitive functions decline with FL surgeries [38, 63,
64]. Outcome seems dependent on location of the surgical resection, and there are no
definitive studies clearly indicating whether this differs on the basis of MRI status. It
seems probable there will be some interaction between lesion location and MRI status, but
larger, prospective studies will be required to establish such patterns. Deficits observed in
FLE patients have included a variety of deficits in executive control processes (e.g.,
response inhibition, generative fluency, complex problem solving), aspects of memory
performance, and motor functions [38, 63, 64].
There are few studies examining postsurgical outcome for the posterior cortical
epilepsies, with most representing small, retrospective case series that blend a number of
heterogeneous patients. There has been no examination of MRI status in these studies,
although many of the posterior cortical epilepsies are lesional in nature. For OLE, a few
small case series studies have highlighted declines in performance-based intellectual
functioning, aspects of visuoperceptual processing, and a variety of visual abnormalities
(e.g., visual-field cuts, alterations in color vision) [6567]. A couple of studies have
indicated that larger OL resections result in greater declines in intellectual functioning.
Verbal intellectual functioning often improves in these patients with improved seizure
outcome. With parietal resections, there have been reports of sensory deficits with
inclusion of the postcentral gyrus, visuoperceptual, and constructional deficits following
right-sided resections, and language deficits after left parietal resections.
Neuropsychological testing as an aid to predict seizure

freedom
Blind assessment of neuropsychological data has not proven very useful for predicting
seizure freedom following surgery, likely due to many patients having structural and
functional deficits that greatly exceed the seizure onset zone. However, when combined
with other available data, neuropsychological test scores often add incremental value for
predicting seizure freedom. Studies in this area, which have generally been few in number,
have often examined more selective groups of epilepsy patients (e.g., TLE cases only,
excluding post-traumatic epilepsy); and have typically analyzed the multivariate
prediction of seizure freedom based on available neurological, disease-related, and
neuropsychological factors [31, 68, 69]. The presence of an MRI lesion tends to be one of
the stronger predictors of seizure freedom regardless of location of seizure onset [70].
Nevertheless, neuropsychological test scores and Wada memory lateralization scores both
contribute unique variance to the prediction of seizure freedom in both lesional and
nonlesional epilepsy. In TLE cases, for example, Wada memory asymmetries that strongly
favor the functioning of the contralateral (unresected) hemisphere, significantly predict a
better postoperative seizure outcome than cases where this asymmetry is lacking [71].
Hennessy et al. [72] reported that patients having neurocognitive profiles that lined up
with the side of surgery based on expected patterns of function tended to have better
seizure outcomes than those that did not, although this was not always the case, especially
for right ATL resection candidates. Potter et al. [68] observed that an index of language
function that included confrontation naming and nonverbal memory added unique
variance to predicting seizure freedom beyond that provided by demographic variables
(side of surgery, age of epilepsy onset) and MRI findings of MTS. There have also been
some studies demonstrating that patients with lower baseline general intellectual
functioning experience worse postoperative seizure control [7274]. This again seems
consistent with the idea that a focal resection in a patient with essentially global brain
dysfunction is less likely to be successful than in a patient with well-localized, focal
deficits consistent with the presumed seizure onset zone.
Finally, it is important for the neuropsychologist to provide input to the epilepsy
surgery program regarding potential neuropsychological risks with surgery. Although a
patient may have neurological findings supportive of having a good seizure-free outcome,
the possible risk of significant neuropsychological deficits could outweigh the potential
benefits of becoming seizure-free [75].
Known neuropsychological outcome predictors

The best candidates for epilepsy surgery are those with a single seizure focus that is
accurately localized to a well-defined area of the brain that can be resected without
producing additional unacceptable neuropsychological deficits. Epilepsy resection
surgeries are irreversible interventions; therefore, estimating preoperatively the risk of
potential neurocognitive losses is a key surgery decision factor, which is critical for MRInegative patients due to their increased risk of experiencing declines with surgery.
Neuropsychological assessment
One of the best predictors of postoperative neuropsychological decline is the cognitive test
performance obtained from presurgical neuropsychological baseline assessment, although
laterality of seizure focus is also an important factor. Neuropsychological scores are robust
predictors with a unique variance to predict memory outcome [34].

Patients with higher cognitive performance at baseline are at higher risk of postsurgical
decline [32, 69], whereas those with baseline deficits are at less risk of decline. As MRInegative patients tend to have higher cognitive scores at baseline, it is not surprising that
they would have an elevated risk of decline. One mediating variable appears to be age of
seizure onset, with an earlier age of onset associated with increased likelihood of
reorganization of brain functions and less risk of decline [76]. Patients whose
neuropsychological assessment deficits lateralize ipsilaterally to the side of their planned
surgical resection tend to have better outcomes than those whose results are less clearly
lateralizing. Nevertheless, patients with good presurgical lateralization to the hemisphere
to be resected can still experience a decline following surgery.
Wada test
The regions of the brain that control the functional capacity of language and memory vary
widely across individuals. Their lateralization has been historically done using the Wada
test to assess function of each cerebral hemisphere in independently supporting memory
and language prior to surgery [77].
Many comprehensive epilepsy centers have replaced the Wada test with fMRI or MEG,
or both, and there continues to be debate about the role of Wada because of the variability
of Wada protocols and their lack of standardization [77]. However, the Wada test remains
to be an important clinical tool for establishing language and memory hemispheric
dominance for predicting neuropsychological outcome of epilepsy surgery [78]. Research
suggests that Wada data are somehow independent from fMRI or MEG data [77]. More
specifically, while the Wada test assesses behavior with inactivation, fMRI and MEG
assess behavior with activation. Thus, the Wada test approximates the effects of surgery,
but it is being replaced in part by fMRI due to its invasive nature.
As indicated in Table 20.1, when memory is adequate with ipsilateral amobarbital
injection and poor with contralateral injection, then the Wada test results suggest a lesser
risk of memory deficits after resection. Conversely, when memory is poor with ipsilateral
injection and adequate with contralateral injection, then there is a higher risk of
postoperative memory loss.
Increasing evidence suggests that more selective surgical procedures as opposed to
extended standard resections can reduce the cognitive deficits associated with surgery [48,
60], providing support to the functional adequacy model.
Case examples
CASE 1: Left TLE; MRI-negative
The patient is a right-handed male in his early 40s presenting with an approximate 15-year
history of epilepsy. His first seizure was characterized by loss of memory followed by
secondary generalization of the seizure. He reported having two to three seizures per year,
described as spacing out or staring, but these events did not generalize when he was
compliant with his medications. He was previously a heavy alcohol drinker, and he
described multiple convulsive events in the context of alcohol withdrawal, but he had been
abstinent for over 10 years. His reported seizure frequency was likely underestimated
based upon the discrepancy of self-reported events vs. recorded seizures during videoEEG monitoring. Although interictal EEG was normal, there were five seizures with left
temporal EEG seizure onset recorded. He had one cousin with epilepsy. At the time of
evaluation, he was taking 500 mg of phenytoin and 400 mg of topiramate.
He obtained a high school diploma, and although he was never diagnosed with a
specific learning disability, he participated in special educational classes beginning in
middle school. As seen in Table 20.2, preoperative neuropsychological assessment
revealed average general functioning, with a slight advantage for nonverbal compared to
verbal tasks. His neuropsychological profile suggested mild cognitive difficulty consistent
with left TLE, including poor naming, decreased generative fluency to letter prompts, and
poorer verbal than visual memory reflected by an 11-point discrepancy on the Wechsler
Memory Scale-III. Verbal list learning and recall were in the impaired range. (Poor
generative letter fluency often occurs in patients with left TLE if there is disruption of
frontal lobe regions from seizure spread, but this deficit could also reflect cognitive side
effects of topiramate.)
Table 20.2 Known predictors of neuropsychological outcome in MRI-negative
surgical cases
Type of factor
Factors associated
with
neurocognitive
outcome
Favorable
outcome (lower
risk)
Unfavorable
outcome
(higher risk)
Time effect
Age of onset
Early
Late
Age at time of
surgery
Younger
Older
Duration with
epilepsy
Longer
Shorter
Neuropsychologicalassessment
Presurgical neuro
cognitive ability
(memory,
confrontation
naming)
Impaired
Intact
Lateralization and
evidence of
function/dysfunction
Side of planned
resection (language
dominance)
Nondominant
(typically right)
Dominant
(typically left)
Lesion
Presence of
Lack of lesion
establishment
lesion ipsilateral
to seizure focus
(MRI-negative
case) or lesion
contralateral to
seizure focus
Presurgical
lateralizing
neuropsychological
data (memory
impairment with
respect to side of
planned resection)
Memory
impairment
ipsilateral to
seizure focus
(i.e., left TL
onset and poor
verbal memory
but good visual
memory; or right
TL onset with
poor visual
memory but
good verbal
memory)
Memory
impairment
contralateral to
seizure focus
(i.e., left TL
onset and poor
visual memory
but good verbal
memory; or
right TL onset
with poor verbal
memory but
good visual
memory)
Presurgical EEG
abnormalities
observed
Ipsilateral
Bilateral
Presurgical Wada
memory
performance
Asymmetric
results: Memory
adequate with
ipsilateral
injection and
poor with
contralateral
injection
Opposite
asymmetry:
Memory poor
with ipsilateral
injection and
adequate with
contralateral
injection
PET
Hypometabolism
ipsilateral to
seizure focus
No
hypometabolism
ipsilateral to
seizure focus
fMRI
More activation
on side
contralateral to
planned
resection
More activation
on side
ipsilateral to
planned
resection
Cortical mapping
Eloquent
memory sites
Eloquent
memory sites
Surgical approach
Extent of resection
identified by
cortical mapping
contralateral to
seizure focus
identified by
cortical
mapping
ipsilateral to
seizure focus
Less extent of
resection
More extent of
resection
Wada memory results indicated no undue risk of decline following left ATL. Language
was lateralized to the left hemisphere and memory score asymmetries suggested that the
left TL (right hemisphere injection) was functioning at a lower level (Wada recognition =
5/10) than the right TL (left hemisphere injection, Wada recognition = 9/10). Risk factors
associated with cognitive decline include later age of seizure onset in his mid-20s and
normal MRI.
The patient experienced significant postoperative declines following left ATL in both
naming and verbal memory, with a smaller decline noted in his visual memory
performance (this decline was limited to a single test that required naming ability to
perform). Although list learning ability was in the impaired range preoperatively and
estimated to be at or below the 1st percentile, the 18-point raw score decline reflects
meaningful postsurgical change. In addition, although the patient could still recognize
familiar and famous persons, he experienced a severe naming impairment for these
individuals. Likewise, he was severely impaired at generating any proper nouns. For
example, he could not produce the names of stores, TV shows, famous persons or places
when prompted. He was reportedly seizure-free, but was still experiencing auras. In
contrast to the cognitive declines stated above, the patient experienced an improvement in
generative fluency to letter prompts. As he was still on the same AED regimen, this
improvement is thought to be due to an absence of seizure impact upon frontal lobe
regions [45].
CASE 2: Right TLE; MRI-negative

The patient is a right-handed male in his 40s and presents with an approximately 5-year
history of epilepsy. His seizures rapidly generalized but these were initially controlled
with medication. At the time of evaluation, he was experiencing two to three seizures per
year despite optimal medical management. During his video-EEG monitoring, there were
three events indicating right anterior temporal seizure onset. He was taking 700 mg of
carbamazepine.
The patient was a college graduate and had worked at a high-level job that required
seizure freedom for performance. At the time of surgery, he was working in a management
role for the same company but desired to return to his prior job. Preoperative
neuropsychological evaluation demonstrated normal naming, normal verbal learning and
memory, but a large 26-point discrepancy in favor of verbal memory on the Wechsler
Memory Scale delayed indices, and his visual memory performance was in the low end of
the average range.
Wada results indicated that the patient was left hemisphere dominant for language and
that memory functioning was normal for both temporal lobes (Wada recognition: left
injection=9/10; right injection = 10/10). The patient was considered to be at increased risk
for postoperative memory decline due to his intact baseline cognitive functioning, normal
Wada memory scores bilaterally, late age of seizure onset, and normal MRI. However,
because the surgery planned was a nondominant right ATL, verbal memory and language
were not at risk. The patient chose to go ahead with surgery, in the hopes that he could
return to his prior level of employment.
Following right anterior temporal lobectomy, he was seizure-free, but he experienced
large declines in his visual memory (32 points) with additional deficits involving object
recognition and attention. Although list learning did not change, the patient experienced
important declines in working memory and generative verbal fluencies. He also
experienced decreased ability to recognize familiar or famous individuals and landmarks,
and selective declines in his ability to recognize animals (i.e., he was much worse at
recognizing some categories of animals, such as birds). For example, when presented with
the picture of a pink flamingo standing on one leg, he responded, thats a turkeythe
bird we eat at Thanksgiving. He was also unable to perform a spatial memory task
postsurgically. He described an inability to recognize familiar persons, difficulty with
route learning, and increased difficulty to correctly associate names with faces. These
deficits compromised his ability to work in sales since surgery, and also contributed to
new problems with mood. He never returned to his previous level of employment, and his
wife divorced him after several years of marriage.
Neuropsychological domains of research

Future neuropsychological research should include prospective evaluation of MRInegative epilepsy patients, with the goals of systematically employing appropriate
cognitive measures, directly relating these measures to functional connectivity and
neuroimaging results, and exploring algorithms for outcome prediction following surgery.
Such research should also examine broader neurocognitive domains of function, as
emerging evidence suggests that important ability areas have not been adequately
investigated. Extratemporal lobe epilepsies have not been well studied with or without
regards to lesional status. Even in the better-studied TLE population, many important
functions have not been adequately evaluated, such as object recognition and categoryrelated naming and semantic fluencies, semantic memory, face-name learning, and aspects
of emotional and social/theory of mind processing. It will also be important to study the
differential impact upon cognition and function of the various treatment interventions
available for both nonlesional and lesional cases (e.g., ablations using radiofrequency or
ultrasound, selective laser amygdalohippocampotomy, gamma knife).
Summary
MRI-negative epilepsy patients are at increased risk for cognitive decline with resective
surgery to control their seizures. Improved methods of seizure onset identification, which
should be associated with better outcome prediction, continue to be developed. In addition
to the many promising techniques for improving seizure localization, new methods of
treatment intervention that will minimize the degree of functional tissue affected by that
intervention will contribute to improved cognitive outcomes.
Table 20.3 Pre- and postsurgical neuropsychological data for epilepsy patients
undergoing unilateral temporal lobe resection
Left TLE
Right TLE
Pre
Post
Pre
Post
WAIS-III FSIQ
96
75
116
106
Verbal Comprehension Index
89
82
118
114
Perceptual Reasoning Index
106
82
111
111
Working Memory Index
N/A
65
124
86
Processing Speed Index
N/A
86
N/A
88
Boston naming
50
40
59
56
BNT recognition
57
56
60
60
COWA
13
30
49
27
Animal fluency
13
11
22
14
Famous person fluency
10
WMS-III Verbal Delay
92
80
117
108
WMS-III Visual Delay
103
94
91
59
Rey AVLT Learning
32
18
55
57
Rey AVLT Delay
15
15
Neuropsychological measure
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Chapter 21 Conclusion
Philippe Ryvlin and Elson L. So
The 20 chapters in this book offer a comprehensive review of currently available

knowledge regarding epilepsy surgery in MRI-negative patients, and they suggest that we
have entered a novel era for treating these patients with the most challenging epilepsies.
Three primary messages in this book deserve to be emphasized.
The first message is that re-evaluation of MRI data, either through optimal acquisition
(more sensitive sequence, higher-field strength), post-processing tools, coregistration with
other modalities (especially FDG-PET), and expert reassessment, enhances the detection
of a large proportion of MRI-negative pathologies, such as focal cortical dysplasias (FCD)
(Chapter 3). Up to 89% of small FCD overlooked by experts could be detected by using
sophisticated post-processing methods of 3D-T1 MR images, coupled with neural
networks automatic detection (Chapter 3).
The second message relates to the conceptual framework of presurgical evaluation. In
patients with refractory focal epilepsy whose MRI discloses a well-defined epileptogenic
lesion, presurgical evaluation concentrates on refining the localization of the epileptogenic
zone (EZ) to be resected. In MRI-negative patients, presurgical evaluation also needs to
provide insights into the underlying pathology for several reasons: (i) the presence and
type of underlying pathology have a strong impact on the chance of postsurgical seizure
freedom, with optimal surgical outcome in focal cortical dysplasia (FCD) type II and endfolium sclerosis, and poorest outcome in patients with histologically normal resected
tissue; (ii) the extent of the EZ varies with the underlying pathology, being usually
circumscribed to a sulcus in MRI-negative FCD type II, and often much more extensive in
FCD type I (Chapter 11); and (iii) interpretation of presurgical data, such as the presence
or absence of a clear-cut interictal hypometabolism on FDG-PET, will differ as a function
of the suspected pathology. In other words, the what appears as important as the
where when contemplating surgical treatment of MRI-negative patients.
The third message relates to the classic but disputable notion that postsurgical outcome
is uniformly poorer in MRI-negative than in MRI-positive patients. Whereas the majority
of series of temporal and extra temporal lobe epilepsies lead to this conclusion, some
evidence suggests that this may not hold true if candidates are carefully selected for
surgery. For instance, patients with MRI-negative but FDG-PET-positive temporal lobe
epilepsy (TLE) have a similarly high rate of successful postsurgical outcome as those with
MRI evidence of hippocampal sclerosis (Chapters 4 and 14). Similar findings were
reported for MRI-occult FCD whereby the presence of concordant focal hypometabolism
was associated with rates of seizure freedom that are comparable to those observed in
MRI-detectable FCDs (i.e., about 90% class I Engel outcome) (Chapter 4). Altogether,
state-of-the-art presurgical evaluation of MRI-negative epilepsy suggests that the surgery
is worth undertaking, provided that there is an appropriate understanding of the issues at
stake.
The most frequent pathological findings observed in operated MRI-negative patients

are: (i) normal tissue in any lobe; (ii) FCD type IIA and type I in neocortical epilepsies;
and (iii) either subtle hippocampal sclerosis or end-folium sclerosis in mesial TLE
(Chapter 19). The exact proportion of each of these findings is unknown, and the
proportion largely depends on the recruitment bias at each epilepsy surgery center. In the
large European Epilepsy Brain Bank series, 8% of all resected specimen were
histologically normal (Chapter 19). Such negative pathology does not exclude good
surgical outcome following TLE surgery, but negative pathology makes excellent surgical
outcome very unlikely following extra temporal surgery (Chapter 15). Whether this
observation primarily reflects erroneous identification of the EZ, specific characteristics of
histologically normal EZ that would prevent effective surgical treatment, or both, is
unknown. Nonetheless, the observation militates for selecting patients with indirect
evidence of MRI-occult FCD for extratemporal lobe surgery.
The FDG-PET technique coregistered on MRI (PET-MRI) appears to be particularly
useful for suggesting the presence of FCD (Chapter 4). Not only does PET-MRI correctly
identify the location of MRI-occult FCD in about 80% of cases, it shows very focal and
severe hypometabolism with clear-cut borders, which is a metabolic pattern that is highly
suggestive of FCD in the majority of patients. When FDG-PET is normal in MRI-negative
TLE, PET investigation of 5-HT1A receptors seems to be clinically useful for confirming
the temporal origin of seizures, and for predicting favorable postsurgical outcome despite
the lack of detectable FDG hypometabolism (Chapter 4). However, only a limited number
of centers have access to PET tracers of the serotoninergic system.
Progress in the post-processing of ictal SPECT, and in particular the development of
SPM-based methods such as STATISCOM, helps to delineate the EZ at a subregional
rather than at a lobar level (Chapter 5). This gain in spatial resolution offers a substantial
advantage for investigating MRI-negative patients, minimizing the risk of unnecessarily
large placements of intracranial electrodes (Chapter 5).
Similarly, advances in the mapping of interictal epileptiform discharges using either
high-resolution EEG with electric source imaging (ESI), MEG and magnetic source
imaging, or EEG-fMRI, can more precisely identify the so-called irritative zone (Chapters
6, 7, and 8). Whereas we appreciate that the irritative zone does not always coincide with
the EZ, their usual overlap make all the above methods useful. Furthermore, when
investigating MRI-negative neocortical epilepsies with the hope of detecting an MRIoccult FCD, the presence of a well-delineated spike focus provides indirect arguments in
favor of FCD, whereas the lack of such focus makes FCD unlikely. However, the absence
of MEG-detected spikes would more strongly affirm the unlikelihood of deep-seated FCD
with undetectable scalp EEG spikes, because MEG is usually very sensitive in detecting
MEG spikes from deep-seated FCD. It also appears that the irritative zone better coincides
with the EZ in type II FCD than in other FCD types. In any event, recent studies
demonstrate that ESI, MSI, and EEG-fMRI abnormalities overlap with the EZ in 80% to
90% of MR-negative patients, and that the larger the resection of the spike focus
delineated by these techniques, the greater the chance of postsurgical seizure freedom
(Chapters 6, 7, and 8).
Whereas neuroimaging and electrophysiological investigations play a major role in the
presurgical evaluation of MRI-negative patients, one should not underestimate the value of
ictal phenomenology. In fact, advancing knowledge in electroclinical correlations
validated by intracranial EEG recordings is helping the identification of patterns of ictal
clinical sequence that are more reliable and distinct than in the past (Chapter 2).
The majority of MRI-negative patients will require intracranial EEG investigation prior
to surgical treatment. One exception might be nondominant mesial TLE where direct
surgery appears a reasonable option. Conversely, in dominant TLE, the possibility of
sparing a morphologically normal hippocampus if the EZ proves to selectively involve the
neocortex, the entorhinal cortex, the temporal pole, or the amygdala, justifies testing the
hypothesis with the appropriate intracranial EEG recording (Chapter 14). Indeed, verbal
memory loss proved to be significantly worse following anterior temporal lobectomy on
the side dominant for language in patients with normal MRI than in those with
hippocampal atrophy (Chapter 20). Invasive EEG investigation also appears to be
mandatory for extratemporal lobe epilepsy (Chapters 15 and 16). The respective
advantages and drawbacks of grids versus depth electrodes is still a matter of debate
(Chapters 10 and 11). However, there has been a recent trend in some major epilepsy
surgery centers in shifting from the former to the latter (Chapter 11). Reasons underlying
this recent boost in stereoelectroencephalograpy (stereo EEG or SEEG) include: (i) more
accessible technology, thanks to the development of robot-guided stereotaxy; (ii) evidence
of a lower rate of serious complications than previously thought, with 1% to 3% of
intracranial hematoma, rarely resulting in permanent deficit or death ( 0.6%); (iii)
greater sensitivity than grids in detecting deeply located MRI-occult FCD, which is often
located at the bottom of the sulcus; (iv) possibility of performing thermolesions of the
suspected epileptogenic zone at the end of the recording sessions, the impact of which on
seizures may help to refine the resective surgical strategy; and (v) high likelihood to result
in a firm conclusion whether or not resective epilepsy surgery should be performed
(Chapter 11).
Whatever the type of invasive investigation, the presence of high-frequency oscillations
(HFOs), either ripples or fast ripples, appears helpful for delineating the EZ (Chapter 12).
As for source imaging of interictal spikes, the extent of resection of HFO-generating tissue
positively correlates with surgical outcome (Chapter 12). The presence of a permanent or
subcontinuous focal spiking activity strongly suggests an underlying type II FCD.
Other specific diagnostic issues need to be considered for temporal and extratemporal
lobe epilepsy. In patients with negative MRI and suspected TLE, one needs to consider the
possibility of temporal-plus epilepsy (TPE) or extratemporal lobe epilepsy mimicking
TLE (Chapter 14). Temporal-plus epilepsy refers to an EZ that primarily involves the
temporal lobe but extends to the adjacent structures such as the orbitofrontal cortex, the
insula, the frontal or parietal operculum, or the temporo-parieto-occipital junction
(Chapter 14). In such patients, standard temporal lobectomy will usually fail to control
seizures, whereas a more extensive resection, guided by SEEG, leads to a class I Engel
outcome in two-thirds of patients (Chapter 14). Currently, invasive EEG remains the only
reliable way to distinguish TPE from TLE (Chapter 11). Extratemporal lobe epilepsy
mimicking TLE (usually originating in the extratemporal posterior cortex) can be
suspected on various grounds, including the lack of a classic FDG-PET pattern for TLE
(Chapters 4 and 14). There is however very little data available regarding MRI-negative
posterior cortex extratemporal epilepsy (Chapter 16).

MRI-negative FLE patients have been reported in several publications, typically
showing half the rate of postoperative seizure freedom as compared to lesional FLE
(Chapter 15). As previously emphasized, this unfavorable outcome is likely a result of the
combination of inappropriate selection of patients showing no evidence of an underlying
FCD, and a suboptimal placement of intracranial electrodes in patients whose MRInegative FCD will thus not be probed. Whereas FCD may affect any frontal sulcus,
specific attention should be paid to the depth of the superior frontal sulcus, which is often
overlooked on neuroimaging and not directly assessable with subdural grids. Efforts
should now be developed to define criteria for selecting appropriate candidates for
invasive EEG, based on the presence and/or congruence of noninvasive findings (videoEEG, FDG-PET, ictal SPECT, ESI, MEG, EEG-fMRI, etc.).
Index
abdominal (epigastric) aura 7, 12, 154, 188
after-discharges 138139, 145146
akinetic seizures 171
amaurosis, ictal 185
amnesia 144, 225
FLE 225
postictal 154
postsurgical 224
prosopagnosia 225
TLE 225226, 228
amygdala 154
anatomo-electro-clinical correlation theory 113
Animal fluency test 233
anterior temporal lobectomy (ATL) 224, 228229
neuropsychological outcome 233
aphasia 185, 189
Brocas 62
postictal 12
temporal lobectomy 147
artefacts 70
astereognosis 146
astrogliosis 19, 218
asymmetric ending 12
asymmetrical tonic seizures 171
attention 227
atypical benign partial epilepsy 5051
auditory aura 12, 154
auditory cortex 141
auditory response naming test 142143
auditory verbal comprehension 143
aura 137, 146147, 154, 185
auditory 12, 154

epigastric (abdominal) 7, 12, 154, 188
fear 154
olfactory 141, 154
psychic 154
vertiginous 154, 185
visual 154, 184, 187
see also specific symptoms
automatisms 7, 12
hand 154
oroalimentary 154
automotor seizures 7, 154
autonomic function 144
autosomal dominant nocturnal FLE 3
autosomal dominant partial epilepsy with auditory features 3
ballistocardiographic artefacts 70
balloon cells 214
basal FLE 172
benign Rolandic epilepsy (BRE) 5051
Berger Bands 129
99mTc-bicisate (tc-ECD) 38
biomarkers 3
blood flow PET 28
blood oxygenation level dependent signal see BOLD signal
bloodbrain barrier 218
BNT recognition 233
BOLD signal 68, 7072
interictal epileptiform discharge 71
Boston Naming Test 233
Brocas aphasia 62
Brocas area 142
cannabinoid type 1 (CB1) receptors 33
[11C]carbon 30
children see pediatric epilepsy
choline 23
cingulate gyrus 7
cingulate seizures 95
clonic motor seizures 171
clonic seizures 7
unilateral 12
complex partial seizures 8
constructional praxis 227
continuous spikes and waves during sleep (CSWS) 64
Controlled Oral Word Association (COWA) test 233
cortical dysplasia 3
focal see focal cortical dysplasia
as negative prognostic factor 155
cortical mapping see functional mapping
coughing, postictal 12
creatine 23
cryptogenic epilepsy 1
2D-temporal cluster analysis 75
DC shifts 129, 132133
deep epileptic discharges
ESI 6061
MEG 51
diffusion tensor imaging (DTI) 2223, 93, 225
diffusion-weighted MRI 80
dopamine 33
dorsolateral FLE 95, 170
DTI see diffusion tensor imaging
dynamic statistical parametric mapping (dSPM) 52, 57
dysphasia 146
dystonic hand posturing 12
echo planar imagine (EPI) 68

EEG 6, 8, 56, 68, 129, 238239
Berger Bands 129
DC shifts 129, 132133
EZ localization 6
fast ripple 129
gamma 129
history 223
ictal see ictal EEG
interictal see interictal EEG
intracranial see intracranial EEG
ripple 129
scalp see scalp EEG
slow oscillations 129
subdural see subdural EEG
ultraslow oscillations 129135
video-EEG 206
EEG source imaging 56
EEG-fMRI 7071, 238
background 70
FLE 176
focal epilepsy 71
novel techniques 75
presurgical evaluation 7172
statistical analysis 7071
electric source imaging (ESI) 5667, 238
case studies 6164
deep epileptic discharges 6061
electrode number/position 57
EZ localization 61
FLE 176
head models 5657
realistic 57
spherical 57
MRI-negative epilepsy 64
partial epilepsy 5860
posterior cortex epilepsies 187
source models 57
surgical outcome prediction 5960
electrocorticography 47
pediatric refractory focal epilepsy 202
electrodes
grid 90, 92, 208209
placement 94, 159
repositioning 160
strip 90
see also EEG
electroencephalography see EEG
electromagnetic topography
low-resolution 57
variable resolution 57
ellipsoidal volume analysis 53
encephalomalacia 2
end-folium sclerosis 216, 237
entorhinal cortex 20
epigastric (abdominal) aura 7, 12, 154, 188
epileptic encephalopathy 64
epileptiform spread 225
epileptogenic zone (EZ) localization 67, 41, 93, 153164, 238
advanced structural imaging 172
EEG 6, 171172, 177178
EEG-fMRI 176
electrical stimulation 145146
ESI 61, 176
FDG-PET 49, 156158

fMRI 177
MEG 50
MSI 176
multimodality image coregistration 177
neuropsychological deficit post-surgery 224228
PET 169, 172176
semiology 154
SPECT 169, 176
see also specific epilepsy syndromes
ESI see electric source imaging
euphoria 154
European Epilepsy Brain Bank (EEBB) 215, 218
event-related beamformer method 52
executive control 226227
extratemporal lobe epilepsy 104, 239
mimicking TLE 153, 239
presurgical deficits 227
surgery 209211
surgical outcome 156, 229
eye blinking 12, 184
eye movements
sensations of 184
versive 185
EZ see epileptogenic zone
Famous person fluency test 233
FCD see focal cortical dysplasia
[18F]FCWAY 32
FDG-PET 2830, 237
EZ localization 49, 156158
FLE 172176
fear aura 154

figure 4 sign 12
FLAIR 207
FLE see frontal lobe epilepsy
FLEP scale 169
fluid attenuated inversion recovery see FLAIR
[11C]flumazenil 3031, 174
[18F] fluorodeoxyglucose (FDG) 2830
fMRI see functional MRI
focal cortical dysplasia (FCD) 1, 3, 16, 28, 96, 198, 211
diagnostic techniques
FDG-PET 29
MRI 2122
SEEG 114115
histopathology 214216
pediatric 199
type I 215, 237
type II 237
type IIa 214, 237
type IIb 214
type IIIa 216217
focal epilepsy
diagnostic techniques
MEG 208
MRI 206207
PET 207
SEEG 209
SPECT 207
refractory 4
EEG-fMRI 71
pediatric 198204
ultraslow and high-frequency recordings 129135
subdural grid and depth electrode implantation 208209

surgical techniques 206213
extratemporal surgery 209211
preoperative evaluation 207
preoperative work-up 206207
temporal lobe surgery 209
focal malformations of cortical development see focal cortical dysplasia
Fourier transformation, short-time 52
frontal absence seizures 171
frontal eye field 140
frontal lobe epilepsy (FLE) 154, 168183, 239
amnesia 225
autosomal dominant nocturnal 3
basal 172
case history 180
diagnosis 169
differential diagnosis 169170
dorsolateral 95, 170
drug-resistant 168
advanced structural imaging 172
EEG-fMRI 176
ESI 176
fMRI 177
intracranial EEG 177178
MEG 50
MSI 176
PET 169, 172176
scalp EEG 171172
SPECT 169, 176
FLEP scale 169

ictal EEG 179
interictal EEG 179
management 178180
postoperative outcome 156, 179180
resective surgery 2, 178180
surgical outcome 180, 229
mesial 170
nocturnal 169
prevalence 168
seizure semiology 170171
seizure characteristics 171
seizure types 171
syndromes 170
frontal operculum 153
frontal pole seizures 95
functional adequacy 224
functional connectivity 75
functional mapping 136152
case history 147148
with electrical stimulation 137145
after-discharges post-stimulation 138
auditory cortex 141
autonomic function 144
EZ localization 145146
general procedure 137140
history 137
indications 144
insula 141
intraoperative vs. extraoperative 144145
language 141144
memory 144
negative signs with stimulation 138

olfactory and gustatory sensations 141
pediatric 145
positive signs with stimulation 138
safety issues 140
somatic sensorimotor cortex 140141
visual cortex 141
evaluation 147
history 223
seizures in functional eloquent areas 146147
without electrical stimulation 145
functional MRI 6880, 93
EEG-fMRI 7071
background 70
FLE 176
focal epilepsy 71
novel techniques 75
presurgical evaluation 7172
statistical analysis 7071
eloquent areas
mapping of 68
plasticity 70
FLE 177
language and memory mapping 69
pediatric 6970
principles 68
reliability 6869
with scalp EEG recording 176
Wada test see Wada test
functional neuroimaging 157158
functional reserve 224
GABAA receptors 3031
gelastic seizures 171

generalized autocalibrating partially parallel acquisitions (GRAPPA) 18
genetic mutations 64
Gerstmann syndrome 159, 189
glial fibrillary acidic protein (GFAP) 218
gliosis 3, 12, 20
astrogliosis 19
mesiotemporal 20
gradient magnetic-field topography (GMFT) 5253
grid electrodes 90, 92
focal epilepsy 208209
gustatory hallucinations 141, 154
gyral anomalies 21
hand
automatisms 154
dystonic posturing 12
head movements 185
head/eye deviation 12
hemiparesis 189
hemisensory syndromes 189
hemodynamic response function (HRF) 68, 70
99mTc-hexamethylpropylene amine oxime (Tc-HMPAO) 38
HFOs see high-frequency oscillations

high-frequency oscillations (HFOs) 129, 239
animal studies 130
human studies 130131
interictal/ictal 130131
scalp EEG 131132
and surgery outcome 131
high-frequency recordings 129135
high-resolution magnetization prepared rapid acquisitions with gradient echo (MPRAGE)
17
hippocampal sclerosis 16, 19, 23, 28, 214

end-folium type 216, 237
MRI detection 153
hippocampus
MRI
T2-relaximetry 20
volumetry 19
as site of TLE 159
FCD 214216
hippocampal sclerosis 216217
nonlesional specimens 218
white matter abnormalities 217218
5-HT see serotonin
hyperemia 38
hyperkinetic behavior 186
hypermotor seizures 171
hypometabolism 29, 61
hypothalamic hamartoma 169
ictal amaurosis 185
ictal DC shifts 132133
ictal EEG 8, 94, 154155
EZ localization 155
FLE 179
OLE 186
PLE 186
scalp 155
video recording 7
ictal SPECT 12, 3839, 4445, 158
ictal speech 12
ictalinterictal SPECT analyzed by SPM see ISAS
IED see interictal epileptiform discharge

image processing 1922
TLE 1921
image registration algorithms 8184
interpolation 8182
linear registration 8283
nonlinear spatial normalization (warping) 84
numerical minimization 81
infantile spasms see West syndrome
insula 141, 153
interictal DC shifts 132133
interictal EEG 6, 8, 12, 96, 154155
FLE 179
OLE 186
PLE 186
interictal epileptiform discharge (IED) 6, 68, 7071
bilateral 154
BOLD signal 71
temporal 154
see also symptomatogenic zone
interictal epileptiform spikes and sharp waves (IES) 129
interictal microseizures 133
International League Against Epilepsy (ILAE) 8, 211212, 214
interpolation 8182
intracarotid amobarbital test see Wada test
intracranial EEG 47, 68, 80, 90
coregistration 85
electrode placement 94, 159
electrode repositioning 160
extent of surgery 158160
FLE 177178
grid electrodes 90, 92
implantation 2, 6
indications 9293
interpretation 97
number/position 57
objectives 159
rationale 93
strip electrodes 90
ISAS 4142, 45
Jacksonian epilepsy 62
language
mapping 69, 141144
receptive language competence 201
lateralizing seizure phenomena 12
Leksell frame 116
feature and surface metrics 83
voxel intensity metrics 83
lobectomy
anterior temporal (ATL) 224, 228229
neuropsychological outcome 233
temporal 147, 153
local autoregressive average (LAURA) 57
low-resolution brain electromagnetic tomography (LORETA) 57
magnetic resonance encephalography (MREG) 68, 75
magnetic resonance imaging see MRI
magnetic resonance spectroscopy 23
magnetic source imaging (MSI) 4755, 238
FLE 176
magnetization prepared rapid gradient echo see MPRAGE
magnetoencephalography see MEG
malformations of cortical development (MCD) 214
malignant RolandicSylvian epilepsy (MRSE) 5051

MEG 3, 4755, 93
with FDG-PET 49
with SISCOM 49
FLE 176
focal epilepsy 208
pediatric refractory 201, 203
indications 5051
deep epileptic discharges 51
FLE 50
MRI-negative epilepsy 5152
MRSE 5051
novel analysis methods 5253
dynamic statistical parametric maps (dSPM) 52
ellipsoidal volume analysis 53
event-related beamformer method 52
gradient magnetic-field topography (GMFT) 5253
short-time Fourier transformation 52
synthetic aperture magnetometry (SAM) 52
volumetric imaging of epileptic spikes (VIES) 52
prediction of surgical outcome 4749
memory
deficit see amnesia
mapping 69, 144
short-term verbal 143
mesial FLE 170
mesial temporal lobe epilepsy (MTLE) 51
histopathology 216
SEEG 114
mesial temporal sclerosis (MTS) 224
mesiotemporal lobe
gliosis 20
MRI volumetry 1920
sclerosis 12, 16
[11C]methyl-L-tryptophan 174
microdysgenesis 1
microseizures 129, 133
minimum norm least-squares (MNLS) inverse 57
motor agitation 186
motor deficits 227
motor homunculus 141
motor inhibitory seizures 171
[18F]MPPF 32
MPRAGE 207
MRI 1627, 206
diffusion-weighted 80
DTI 2223
FCD 2122
focal epilepsy 206207
functional see functional MRI
high-resolution 224
hippocampal sclerosis 153
history 16
image processing 1922
optimization 1619
signal-to-noise ratio (SNR) 16
spatial resolution 17
specific absorption rate (SAR) 19
TLE 1921
mesiotemporal lobe 1920
neocortex 2021
volumetry 1920
voxel-based morphometry 2022

MRI-negative epilepsy
definition 1, 16
implications 13
issues 34
outcome 2
MRI-PET 238
MRSE see malignant RolandicSylvian epilepsy
MSI see magnetic source imaging
MTLE see mesial temporal lobe epilepsy
applications 8487
electrode coregistration and seizure mapping 85
MRI-PET 8485
MRI-SISCOM 85
neuroimaging tools 87
FLE 177
image registration algorithms 8184
interpolation 8182
preprocessing 8081
multiple subpial transections (MST) 204
N-acetylaspartate (NAA) 23
neocortical dysplasias 16
see also focal cortical dysplasia
neocortical epilepsies 114115
neuroimaging tools 87
see also specific methods
neurological complications 188189
neuropsychological evaluation 93, 223230

anatomical vs. functional integrity 224
history 223
outcome 228229
outcome predictors 230232
research 233
seizure freedom prediction 229230
seizure location and deficit pattern 224228
nocturnal epilepsy 3, 63, 100101
frontal lobe 169
nonlesional epilepsy 1, 8
literature studies 911
nonlesional specimens 218
higher-order complex deformations 84
lower-order scaling and skew terms 84
nose rubbing, postictal 12
object recognition 226
occipital lobe epilepsy (OLE) 96, 184185
EZ localization 225
scalp EEG
ictal 186
interictal 186
visual field defects 228
occipitotemporal epilepsy 187188
occulomotor paralysis 146
OLE see occipital lobe epilepsy
olfactory aura 141, 154
operculoinsular seizures 171
orbitofrontal epilepsy 95, 153
oroalimentary automatisms 154
orofacial motor sequencing 143

oscillations
high-frequency see high-frequency oscillations
slow-frequency 129, 132133
ultraslow frequency 129135
paramedian pontine reticular formation (PPRF) 185
paresis 146
parietal lobe epilepsy (PLE) 95, 185186
EZ localization 225
scalp EEG
ictal 186
interictal 186
parietal operculum 153
partial epilepsy 62
atypical benign 5051
autosomal dominant with auditory features 3
ESI 5860
SEEG 118119
pediatric epilepsy
electrical stimulation 145
fMRI 6970
refractory focal 198204
cohort definition 198199
decision algorithm 203
FCD 199
functional considerations 201202
invasive investigations 202203
preoperative investigations 199201
special populations 199
West syndrome 199
subdural EEG 96
Perceptual Reasoning Index 233

PET 3, 2837, 80, 93
blood flow 28
FDG-PET 2830, 237
FLE 172176
FLE 169, 172176
focal epilepsy 207
GABAA receptors 30
methodology 2829
MRI-PET 238
radioligands 30
[11C]alpha-methyl-tryptophan (AMT) 3132
[11C]carbon 30
[18F]FCWAY 32
[11C]flumazenil 3031, 174
[18F] fluorodeoxyglucose see FDG-PET
[11C]methyl-L-tryptophan 174
[18F]MPPF 32
in research 33
[carbonyl-11C]WAY 32
serotonin receptors 3233
serotoninergic neurons 3132
PET-MRI see MRI-PET
phoneme identification 143
picture selection test 142
plasticity 70
PLE see parietal lobe epilepsy
positron emission tomography see PET

posterior cortex epilepsy 184197
algorithms for evaluation 194195
case history 192194
invasive tests 187
neurological complications 188189
neuropsychology 189
noninvasive tests 186187
occipitotemporal epilepsy 187188
outcome 188
published reports 189192
with detailed data 189190
without detailed data 190192
scalp EEG 186
seizure semiology 184186
OLE 184185
PLE 185186
problems with 186
surgical outcome 229
posterior occipital sharp transients of sleep (POSTs) 186
postictal amnesia 154
presurgical evaluation see surgical outcome, predictors
Processing Speed Index 233
prosopagnosia 225
pseudotemporal/pseudofrontal epilepsy 169
psychic aura 154
psychogenic nonepileptic spells (PNES) 169
pulse artefacts 70
pure aphasic seizures 171
radial unit lineage model 215
radiofrequency thermocoagulation 119120
radioligands 30
[11C]alpha-methyl-tryptophan (AMT) 3132
[11C]carbon 30
[18F]FCWAY 32
[11C]flumazenil 3031
[18F] fluorodeoxyglucose (FDG-PET) 2830, 49
[18F]MPPF 32
in research 33
reading 143
receptive language competence 201
refractory focal epilepsy 4, 615
EEG-fMRI 71
pediatric 198204
candidacy screen 200
cohort definition 198199
decision algorithm 203
FCD 199
functional considerations 201202
invasive investigations 202203
preoperative investigations 199201
special populations 199
West syndrome 199
ultraslow and high-frequency recordings 129135
regional cerebral blood flow 38
repositioning of electrodes 160
Rey AVLT Delay Test 233
Rey AVLT Learning Test 233
Ring chromosome 20 syndrome 169
robot-assisted stereotaxy 116117
scalp EEG 96
FLE 171172
with fMRI 176
HFOs 131132
ictal 155
OLE
ictal 186
interictal 186
PLE
ictal 186
interictal 186
sclerosis
hippocampal 16, 19, 23, 28
mesiotemporal 12, 16
secondarily generalized tonicclonic seizures (2GTCS) 154
SEEG 112126, 207, 239
anatomo-electro-clinical correlation theory 113
case history 120123
complications 117118
current framework 113115
mesial temporal/temporolimbic epilepsies 114
neocortical epilepsies 114115
effectiveness 118119, 123
FLE 177
focal epilepsy 209
history 112113
limitations 124
orthogonal implantation 116
partial epilepsy 118119
radiofrequency thermocoagulation 119120
recording and stimulation 118
robot-assisted stereotaxy 116117
seizure propagation areas 113

surgical methods 115116
Talairach grid 116
seizure freedom, prediction of 229230
see also surgical outcome
seizure mapping 85
seizure onset zone (SOZ) 68, 72, 129
see also epileptogenic zone (EZ) localization
seizure propagation 97, 113
early/rapid 113
seizure types 7275
akinetic 171
asymmetrical tonic 171
automotor 7, 154
clonic 7
clonic motor 171
complex partial 8
frontal absence 171
gelastic 171
hypermotor 171
localization 2
motor inhibitory 171
operculoinsular 171
pure aphasic 171
semiology 78
case histories 812
simple partial 8
versive 171
seizure-like events 133
sensory functioning 227
sensory homunculus 141
serotonin receptors 3233
serotoninergic neurons 3132

short-term verbal memory 143
signal-to-noise ratio (SNR) 16
simple partial seizures 8
single photon emission computed tomography see SPECT
SISCOM 2, 29, 34, 39, 42, 45, 93, 101
with MEG 49
FLE 176
yield 4041
slow-frequency oscillations 129, 132133
somatic sensorimotor cortex 140141
spatial resolution 17
spatiotemporal dynamics 113
specific absorption rate (SAR) 19
SPECT 3, 3846, 80, 93, 101
case example 4344
FLE 169, 176
focal epilepsy 207
ictal 12, 3839, 4445, 158, 238
interictal 38
ISAS 4142, 45
optimization 42, 44
radiotracers 38
SISCOM 2, 29, 34, 39, 42, 45
yield 4041
SPM-based 3940
yield 4142
STATISCOM 42, 45
subtraction 3940, 158

speech areas 142143
speech deficits 146
spitting, ictal 12
SPM see statistical parametric mapping
staring 154
STATISCOM 42, 45, 85, 238
statistical ictal SPECT coregistered to MRI see STATISCOM
statistical parametric mapping (SPM) 49, 158
dynamic (dSPM) 52, 57
software 28
SPM-based SPECT 3940
yield 4142
status epilepticus 140
stereoelectroencephalography see SEEG
stereotaxy, robot-assisted 116117
stereotypies 62
see also automatisms
strip electrodes 90
subdural EEG 90111
case histories 98103
complications 105106
dorsolateral frontal lobe seizures 95
electrodes 9092
grid 90, 92
placement 9596
strip 90
frontal pole seizures 95
interpretation 9698
limitations 92
OLE 96
orbitofrontal epilepsy 95
pediatric 96
PLE 95
recording 92
strategies 9395
supplementary motor/cingulate seizures 95
TLE 96, 102103
subtraction ictal SPECT 3940, 158
coregistered to MRI see SISCOM
supplementary motor cortex 141
seizures originating from 95
surface-based registration 83
surgery 13, 153164
amnesia after 224
extent of 158160
extratemporal lobe epilepsy 209211
FLE 2, 178180
prognosis see surgical outcome
TLE 2, 224
surgical outcome 155157
case history 160161
extratemporal lobe epilepsy 156, 229
frontal epilepsy 179180
history of neuropsychological evaluation 223
neuropsychological evaluation 223230
pediatric refractory focal epilepsy 203204
posterior cortex epilepsy 188, 229
predictors 230232
TLE 156
see also specific methods
Sylvian fissure 51
symptomatogenic zone 7, 63, 154
synthetic aperture magnetometry (SAM) 52

T2-relaximetry 20
Talairach grid 116
temporal lobe epilepsy (TLE) 67, 153164, 168, 237, 239
amnesia 225226, 228
case histories 231233
epileptogenic focus 159
extratemporal lobe epilepsy mimicking 153, 239
FDG-PET 30
lateral 154
medial 154
with normal MRI 153
MRI 1921
mesiotemporal lobe 1920
neocortex 2021
MTLE 51
neocortical 153
subdural EEG 96, 102103
surgery 2, 156, 224
temporal lobe surgery 209
temporal lobectomy 147, 153
temporal-plus epilepsy (TPE) 153154, 239
bilateral IEDs 155
identification 159
temporolimbic epilepsy 114
temporo-parieto-occipital junction 153
TLE see temporal lobe epilepsy
tonic seizures, unilateral 12
tonicclonic seizures, secondarily generalized (2GTCS) 154
TPE see temporal-plus epilepsy

transient high-frequency oscillations 160
transmantle sign 211, 214
transporter hypothesis 33
ultraslow frequency oscillations 129135
urinary urge, peri-ictal 12
variable resolution electromagnetic topography (VARETA) 57
Verbal Comprehension Index 233
versive seizures 171
vertiginous aura 154, 185
vestibular illusions 154
video-EEG 206
ictal 7
visual aura 154, 184, 187
visual confrontation naming test 142143
visual cortex 141
visual field defects 188
PLE 228
visual processing 227
volumetric imaging of epileptic spikes (VIES) 52
volumetry 1920
vomiting, ictal 12
voxel intensity metrics 83
voxel-based morphometry 2022
Wada test 68, 223, 229231
language and memory mapping 69, 144
WAIS-III FSIQ 233
warping see nonlinear spatial normalization (warping)
Wernickes area 142, 148
West syndrome 199
white matter abnormalities 217218
WMS-III Verbal Delay 233

WMS-III Visual Delay 233
Working Memory Index 233
writing 143

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MRI-Negative

Evaluation and Surgical Management

University Printing House, Cambridge CB2 8BS, United Kingdom

13. Cortical mapping in MRI-negative epilepsy surgery

Department of Functional Neurosurgery, Neurological Hospital, Lyon, France

Mayo Systems Electrophysiology Laboratory, Mayo Clinic, Rochester, MN, USA;

Chapter 1 Scope and implications of MRI-negative

Definition of MRI-negative epilepsy

Implications of MRI-negative epilepsy

Despite the use of optimal conventional MR-imaging techniques, the proportion of

Scope of the issues

Visual reassessment of the MRI combined with morphometric analysis have

The rationale of epilepsy surgical intervention depends on the localization of the

Electroencephalography is the most specific method to define the epileptogenic cortex.

Ictal EEGvideo monitoring

(EEG monitoring, neuroradiology, etc.). In addition, seizure semiology can be used

n = number of subjects, m = male, f = female, bihem. = bihemispheric, histop. =

Lateralizing seizure phenomena

Head and eye deviation

Dystonic hand posturing

Automatisms with preserved

Peri-ictal urinary urge

Postictal nose rubbing

Unilateral clonic seizure

Unilateral tonic seizure

Unilateral eye blinking

Chapter 3 Clinical and advanced techniques for optimizing

Optimizing conventional structural MRI

Figure 3.1 High-resolution submillimetric MRI at 3 Tesla with 32-channel phased-array

Image processing of structural MRI

Temporal lobe epilepsy

Quantitative analysis of the mesiotemporal lobe

Quantitative analysis of the neocortex

Focal cortical dysplasia

Figure 3.4 Surface-based computational models of focal cortical dysplasia. In this

Diffusion tensor imaging

Magnetic resonance spectroscopy

volumes. Neurology. 2001; 56: 13359.

epilepsy. Neurology. 2009; 72: 174754.

Chapter 4 PET in MRI-negative refractory focal epilepsy

good prognosis of MRI-negative, PET-positive TLE patients (19, 20).

Other radioligands used clinically

5-HT1A (serotonin) receptors

A study using the 5-HT1A antagonist [carbonyl-11C]WAY 100635 analyzed with

Radioligands used in research

to SISCOM for determining seizure onset zones (45).

Case example (Figure 4.3)

Outlook and conclusions

coregistration improves detection of cortical dysplasia in patients with epilepsy.

parametric mapping of 5-HT1A receptor binding in temporal lobe epilepsy with

Chapter 5 Advanced SPECT image processing in MRInegative refractory focal epilepsy

Figure 5.1 Graphic representation of the SPECT-detected perfusion changes

99mTc-hexamethylpropylene amine oxime (Tc-HMPAO), and 99mTc-Bicisate

Subtraction SPECT techniques

SPM-based SPECT analysis

Yield of SISCOM in MRI-negative epilepsy

Yield of SPM-based subtraction SPECT in MRI-negative

detected, than when an abnormality is regional or undetectable, and that STATISCOM is

Techniques for optimizing yield of SPECT

A. Preparation for radiotracer injection

1. Process and review data for both hyperperfusion and

Role of ictal SPECT in delineating the surgical focus

21. Sulc V, Hanson D, Stykel S, et al. Statistical Parametric Mapping-based SPECT

MEG predicts outcome following surgery for MRI-negative