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Epilepsy
Evaluation and Surgical Management
MRI-Negative Epilepsy
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
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
made to disguise the identities of the individuals involved. Nevertheless, the authors,
editors and publishers can make no warranties that the information contained herein is
totally free from error, not least because clinical standards are constantly changing through
research and regulation. The authors, editors and publishers therefore disclaim all liability
for direct or consequential damages resulting from the use of material contained in this
book. Readers are strongly advised to pay careful attention to information provided by the
manufacturer of any drugs or equipment that they plan to use.
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
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
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
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
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.
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.
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.
21. Pillay, N., et al., Parahippocampal epilepsy with subtle dysplasia: A cause of image
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
MRI-Negative Epilepsy, ed. Elson L. So and Philippe Ryvlin. Published by Cambridge University Press.
Cambridge University Press 2015.
Interictal EEG
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
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)
Hemisphere of seizure
onset
Authors
Contralateral
[6264]
Contralateral
[63, 65]
Figure 4 sign
Contralateral to extended
arm
[66]
Nondominant
[67, 68]
Ictal speech
Nondominant
[69]
Postictal aphasia
Dominant
[69]
Ictal vomiting
Nondominant
[70]
Ictal spitting
Nondominant
[71]
Nondominant
[72]
Ipsilateral
[73]
Postictal coughing
Nondominant
[74]
Contralateral
[75]
Contralateral
[76]
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.
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.
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.
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].
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).
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].
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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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
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.
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.)
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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57. Rub S, Setoain X, Donaire A, Bargall N, Sanmart F, Carreo M, et al. Validation of
FDG-PET/MRI coregistration in nonlesional refractory childhood epilepsy. Epilepsia.
2011 Dec;52(12):221624.
58. Hammers A. LIRM-TEP hybride. Quelles applications en neurologie? [Hybrid MRIPET. Which applications in Neurology?] Neurologies. 2013 16(161):2449.
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
(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.
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.
Figure 5.3 Diagram of steps in attaining statistical ictal SPECT coregistered to MRI
(STATISCOM) images.
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
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
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%).
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
C. Interpretation of results
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.
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.
References
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SPECT coregistered to MRI (SISCOM) in presurgical evaluation of epilepsy. Epilepsia
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12. OBrien T, So E, Mullan B, et al. Subtraction SPECT co-registered to MRI improves
postictal SPECT localization of seizure foci. Neurology 1999;52:137146.
13. OBrien T, So E, Mullan B, et al. Subtraction ictal SPECT co-registered to MRI
improves clinical usefulness of SPECT in localizing the surgical seizure focus.
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14. Bell M, Rao S, So E, et al. Epilepsy surgery outcomes in temporal lobe epilepsy with
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15. OBrien T, So E, Mullan B, et al. Subtraction peri-ictal SPECT is predictive of
extratemporal epilepsy surgery outcome. Neurology 2000;55:16681677.
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
MRI-Negative Epilepsy, ed. Elson L. So and Philippe Ryvlin. Published by Cambridge University Press.
Cambridge University Press 2015.
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.
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.
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.
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.
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
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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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.
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
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.)
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.
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.
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.
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.
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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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.
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
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).
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).
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).
(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).
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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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.
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.
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.
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).
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.
Figure 9.3 Subtraction ictal SPECT (top) and statistical mapping (bottom) of the SPECT
activations in a patient with left temporal lobe epilepsy.
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
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
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.
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
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).
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.
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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.
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).
limitations.
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 11.2 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).
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).
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%).
No.
operated
%
class
I
% FCD type
II at
pathology
211
77
42
38%
Unknown
100
43
29
55%
34%
Chassoux et al.
Epilepsia 2012
62
25
25
88%
100%
(inclusion
criteria)
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.
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 11.6 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.
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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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.
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.
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.
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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 13.2 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
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
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
Orofacial
motor
sequencing
Automatic
speech (speech
arrest)
Repetition
Posterior STG
Posterior STG
Phoneme
identification
Visual naming
Auditory
naming
Auditory
verbal
comprehension
Short-term
verbal memory
Reading
(sentence
completion)
Reading
(syntax)
Verb
generation
Writing
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).
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).
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.
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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].
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].
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
37% (n=65)
70% (n=86)
Frontal
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
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%
Chapman et al.
[50]
Alarcn et al.
[51]
Jayakar et al.
[30]
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.
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.
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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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.
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
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
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
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.
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.
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
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.
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.
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.
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.
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
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.
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).
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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
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
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
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
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
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.
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.
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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refractory extratemporal epilepsy with normal or nonlocalizing magnetic resonance
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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.
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.
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
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
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.
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.
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.
References
1. Harvey AS, Cross JH, Shinnar S, Mathern GW: ILAE pediatric epilepsy surgery
survey taskforce. Defining the spectrum of international practice in pediatric epilepsy
surgery patients. Epilepsia 2008; 49:146155.
2. Van Oertzen J, Urbach H, Jungbluth S, Kurthen M, Reuber M, Fernandez G, et al.
Standard magnetic imaging is inadequate for patients with refractory focal epilepsy. J
Neurol Neurosurg Psychiatry 2002; 73:643647.
3. Tellez-Zenteno JF, Hernandez Ronquillo L, Moien-Afshari F, Wiebe S. Surgical
outcomes in lesional and non-lesional epilepsy: a systematic review and meta-analysis.
Epilepsy Res 2012; 89:310318.
4. Paolicchi JM, Jayakar P, Dean P, Yaylali I, Morrison G, Prats A, Resnick T, Alvarez L,
Duchowny M. Predictors of outcome in pediatric epilepsy surgery. Neurology 2000;
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M. Epilepsy surgery in patients with normal or nonfocal MRI scans: integrative
strategies offer long-term seizure relief. Epilepsia 2008; 49:758764.
6. Eltze CM, Chong WK, Bhate S, Harding B, Neville BGR, Cross JH. Taylor-type focal
cortical dysplasia in infants: some MRI lesions almost disappear with maturation of
myelination. Epilepsia 2005; 46:19881992.
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Utilization in Evaluation for Resective Epilepsy Surgery in Children. Recommendations
on behalf of the Task Force for Paediatric Epilepsy Surgery and the Diagnostic
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
FLAIR
T1weighted
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.
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.
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.
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.
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.
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
Ib
Ic
Type II (isolated)
IIa
IIb
IIc
IId
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
1. Duncan JS. Imaging in the surgical treatment of epilepsy. Nat Rev Neurol. 2010
Oct;6(10):53750.
2. Immonen A, Jutila L, Muraja-Murro A, et al. Long-term epilepsy surgery outcomes in
patients with MRI-negative temporal lobe epilepsy. Epilepsia. 2010 Nov;51(11):2260
9.
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
negative frontal lobe epilepsy. Neurosurgery. 2011 Jul;69(1):8093; discussion 934.
4. Englot DJ, Han SJ, Berger MS, et al. Extent of surgical resection predicts seizure
19. See SJ, Jehi LE, Vadera S, Bulacio J, Najm I, Bingaman W. Surgical outcomes in
patients with extratemporal epilepsy and subtle or normal MRI findings. Neurosurgery.
2013 May 14. [Epub ahead of print]
20. Gonzalez-Martinez J, Bulacio J, Alexopoulos A, Jehi L, Bingaman W, Najm I.
Stereoelectroencephalography in the difficult to localize refractory focal epilepsy:
early experience from a North American epilepsy center. Epilepsia. 2013
Feb;54(2):32330.
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.
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].
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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evaluation, PET, SPECT, MEG, fMRI, evoked potentials, and cortical mapping.
appreciable declines can continue to occur even in patients with impaired performance on
standardized cognitive measures.
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
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.
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].
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
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].
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.
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
89
82
118
114
106
82
111
111
N/A
65
124
86
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
10
92
80
117
108
103
94
91
59
32
18
55
57
15
15
Neuropsychological measure
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Chapter 21 Conclusion
Philippe Ryvlin and Elson L. So
MRI-Negative Epilepsy, ed. Elson L. So and Philippe Ryvlin. Published by Cambridge University Press.
Cambridge University Press 2015.
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
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
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
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
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
presurgical deficits 226227
receptive language competence 201
lateralizing seizure phenomena 12
Leksell frame 116
linear registration 8283
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
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
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
[carbonyl-11C]WAY 32
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
surgical outcome prediction 203204
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
posterior cortex epilepsies 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
pediatric 96
PLE 95
recording 92
strategies 9395
supplementary motor/cingulate seizures 95
surgical outcome prediction 103105
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